A Study Of Oral PF-02341066, A C-Met/Hepatocyte Growth Factor Tyrosine Kinase Inhibitor, In Patients With Advanced Cancer (PROFILE 1001)

• ClinicalTrials.gov Identifier: NCT00585195
• Recruitment Status: Completed
• First Posted: January 3, 2008
• Results First Posted: October 14, 2021
• Last Update Posted: February 8, 2023
• Sponsor: Pfizer
• Information provided by (Responsible Party): Pfizer

• Study Type: Interventional
• Study Design: Allocation: N/A; Intervention Model: Parallel Assignment; Masking: None (Open Label); Primary Purpose: Treatment
• Conditions: Non-Small Cell Lung Cancer ALK-positive; Non-Small Cell Lung Cancer c-Met Dependent; Non-Small Cell Lung Cancer ROS Marker Positive; Systemic Anaplastic Large-Cell Lymphoma; Advanced Malignancies Except Leukemia
• Interventions: Drug: PF-02341066; Drug: Rifampin; Drug: Itraconazole
• Enrollment: 596

Participant Flow

Recruitment Details
Pre-assignment Details	There was a lead-in period of 7 days in which single-dose pharmacokinetics of crizotinib or midazolam was characterized on Day-7, prior to initiation of continuous dosing in the first cycle (each cycle 28 days) of treatment in dose escalation cohorts and recommended phase 2 dose (RP2D) cohorts.

Arm/Group Title	Low Dose Escalation Cohort: Crizotinib 50 mg QD	Low Dose Escalation Cohort: Crizotinib 100 mg QD	Low Dose Escalation Cohort: Crizotinib 200 mg QD	Low Dose Escalation Cohort: Crizotinib 200 mg BID	Low Dose Escalation Cohort: Crizotinib 250 mg BID	Low Dose Escalation Cohort: Crizotinib 300 mg BID	High Dose Escalation Cohort: Crizotinib 300 mg QD	High Dose Escalation Cohort: Crizotinib 400 mg QD	High Dose Escalation Cohort: Crizotinib 500 mg QD	High Dose Escalation Cohort: Crizotinib 650 mg QD	High Dose Escalation Cohort: Crizotinib 800 mg QD	RP2D Cohort: ROS1-Positive NSCLC: Crizotinib 250 mg	RP2D Cohort: MET Exon 14 Alterations NSCLC: Crizotinib 250 mg	RP2D Cohort: MET Amplification NSCLC: Crizotinib 250 mg	RP2D Cohort: ALK-Negative Cohort 1, NSCLC: Crizotinib 250 mg	RP2D Cohort: ALK-Negative Cohort 2, NSCLC: Crizotinib 250 mg	RP2D Cohort: ALK-Positive Cohort, NSCLC: Crizotinib 250 mg	RP2D Cohort: Enriched Other: Crizotinib 250 mg	RP2D Cohort: Itraconazole Interaction: Crizotinib 250 mg +Itraconazole	RP2D Cohort: Rifampin Interaction: Crizotinib 250 mg +Rifampin	RP2D Cohort: Midazolam Interaction: Crizotinib 250 mg +Midazolam
Arm/Group Description	Participants received Crizotinib 50 milligram (mg) capsule or tablet orally once daily (QD) for up to 34 cycles (each cycle 28 days).	Participants received Crizotinib 100 mg capsule or tablet orally QD for up to 34 cycles (each cycle 28 days) and 2 mg oral dose of Midazolam along with Crizotinib 100 mg on Cycle 2 Day 1 only. Participants who did not receive Crizotinib on Day -7, received single 2 mg oral dose of Midazolam on Day -7.	Participants received Crizotinib 200 mg (2 capsules/tablet of 100 mg each) capsule/tablet orally QD for up to 34 cycles (each cycle 28 days).	Participants received Crizotinib 200 mg (2 capsules/tablet of 100 mg each) capsule/tablet orally twice daily (BID) for up to 34 cycles (each cycle 28 days).	Participants received Crizotinib 250 mg (2 capsules/tablet of 100 mg each + 1 capsule/tablet of 50 mg) capsule/tablet BID for up to 34 cycles (each cycle 28 days).	Participants received Crizotinib 300 mg (3 capsules/tablet of 100 mg each) capsule/tablet orally BID for up to 34 cycles (each cycle 28 days) and 2 mg oral dose of Midazolam along with Crizotinib 300 mg on Cycle 2 Day 1 only. Participants who did not receive Crizotinib on Day -7, received single 2 mg oral dose of Midazolam on Day -7.	Participants received Crizotinib 300 mg (3 capsules/tablet of 100 mg each) capsule/tablet QD for up to 7 cycles (each cycle 28 days).	Participants received Crizotinib 400 mg (4 capsules/tablet of 100 mg each) capsule/tablet QD for up to 7 cycles (each cycle 28 days).	Participants received Crizotinib 500 mg (5 capsules/tablet of 100 mg each) capsule/tablet QD for up to 7 cycles (each cycle 28 days).	Participants received Crizotinib 650 mg (6 capsules/tablet of 100 mg each + 1 capsule/tablet of 50 mg) capsule/tablet twice daily (BID) for up to 7 cycles (each cycle 28 days).	Participants received Crizotinib 800 mg (8 capsules/tablet of 100 mg each) capsule/tablet QD for up to 7 cycles (each cycle 28 days).	Participants received Crizotinib 250 mg (2 capsules/tablet of 100 mg each + 1 capsule/tablet of 50 mg) capsule/tablet orally twice daily (BID) with or without food for up to 105 cycles (each cycle 28 days).	Participants received Crizotinib 250 mg (2 capsules/tablet of 100 mg each + 1 capsule/tablet of 50 mg) capsule/tablet orally twice daily (BID) with or without food for up to 55 cycles (each cycle 28 days).	Participants received Crizotinib 250 mg (2 capsules/tablet of 100 mg each + 1 capsule/tablet of 50 mg) capsule/tablet orally twice daily (BID) with or without food for up to 101 cycles (each cycle 28 days).	Participants received Crizotinib 250 mg (2 capsules/tablet of 100 mg each + 1 capsule/tablet of 50 mg) capsule/tablet twice daily (BID) with or without food for up to 70 cycles (each cycle 21 days).	Participants received Crizotinib 250 mg (2 capsules/tablet of 100 mg each + 1 capsule/tablet of 50 mg) capsule/tablet orally BID with or without food for up to 70 cycles (each cycle 21 days).	Participants received Crizotinib 250 mg (2 capsules/tablet of 100 mg each + 1 capsule/tablet of 50 mg) capsule/tablet twice daily (BID) with or without food for up to 133 cycles (each cycle 28 days).	Participants received Crizotinib 250 mg (2 capsules/tablet of 100 mg each + 1 capsule/tablet of 50 mg) capsule/tablet orally twice daily (BID) with or without food for up to 54 cycles (each cycle 28 days).	Participants received with or without food Crizotinib 250 mg (2 capsules/tablet of 100 mg each + 1 capsule/tablet of 50 mg) capsule/tablet QD from Cycle 1Day1 to Cycle 2 Day1 thereafter 250 mg BID from Cycle 2 Day 2 up to 58 cycles (each cycle 28 days). Participants also received Itraconazole 200 mg QD from Cycle 1 Day 1 to Cycle 1 Day 16.	Participants received Crizotinib 250 mg (2 capsules/tablet of 100 mg each + 1 capsule/tablet of 50 mg) capsule/tablet twice daily (BID) with or without food from Cycle 1 Day 1 up to 13 cycles (each cycle 28 days). Participants also received commercially available Rifampin 650 mg QD from Cycle 1 Day 16 to Cycle 2 Day 1 (14 days) either one hour before or 2 hours after food.	Participants received Crizotinib 250 mg tablet/capsule (2 capsules/tablet of 100 mg each + 1 capsule/tablet of 50 mg) orally BID with or without food from Day 1 Cycle 1 up to 133 cycles (each cycle 28 days). Participants also received single 2 mg oral dose of Midazolam on Day -7 and another single 2-mg oral dose of Midazolam concurrently with Crizotinib on Cycle 2 Day 1
Period Title: Overall Study
Started	3	4	9	7	9	6	7	5	3	6	11	53	85	41	48	19	154	67	21	18	14
Treated	3	4	8	7	8	6	6	5	3	6	9	53	85	41	48	18	154	66	18	18	12
Completed	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0
Not Completed	3	4	9	7	9	6	7	5	3	6	11	53	85	41	48	19	154	67	21	18	14
Reason Not Completed
Adverse Event	0	0	0	0	2	1	0	1	0	0	3	0	8	6	4	1	14	9	2	3	1
Progressive Disease	2	2	5	4	6	4	6	3	0	5	2	25	29	26	21	12	94	42	4	9	8
Withdrawal by Subject	1	1	2	2	0	0	0	1	0	0	3	8	15	0	3	0	7	1	2	2	0
Other	0	1	1	1	0	1	0	0	2	1	0	19	24	7	11	3	28	12	10	4	2
Randomized not treated	0	0	1	0	1	0	1	0	0	0	2	0	0	0	0	1	0	1	3	0	2
Death	0	0	0	0	0	0	0	0	1	0	1	1	7	2	8	2	11	0	0	0	1
Lost to Follow-up	0	0	0	0	0	0	0	0	0	0	0	0	1	0	0	0	0	2	0	0	0
Site Terminated by Sponsor	0	0	0	0	0	0	0	0	0	0	0	0	1	0	0	0	0	0	0	0	0
Withdrawn Due to Pregnancy	0	0	0	0	0	0	0	0	0	0	0	0	0	0	1	0	0	0	0	0	0

Baseline Characteristics

Arm/Group Title		Low Dose Escalation Cohort: Crizotinib 50 mg QD	Low Dose Escalation Cohort: Crizotinib 100 mg QD	Low Dose Escalation Cohort: Crizotinib 200 mg QD	Low Dose Escalation Cohort: Crizotinib 200 mg BID	Low Dose Escalation Cohort: Crizotinib 250 mg BID	Low Dose Escalation Cohort: Crizotinib 300 mg BID	High Dose Escalation Cohort: Crizotinib 300 mg QD	High Dose Escalation Cohort: Crizotinib 400 mg QD	High Dose Escalation Cohort: Crizotinib 500 mg QD	High Dose Escalation Cohort: Crizotinib 650 mg QD	High Dose Escalation Cohort: Crizotinib 800 mg QD	RP2D Cohort: ROS1-Positive NSCLC: Crizotinib 250 mg	RP2D Cohort: MET Exon 14 Alterations NSCLC: Crizotinib 250 mg	RP2D Cohort: MET Amplification NSCLC: Crizotinib 250 mg	RP2D Cohort: ALK-Negative Cohort 1, NSCLC: Crizotinib 250 mg	RP2D Cohort: ALK-Negative Cohort 2, NSCLC: Crizotinib 250 mg	RP2D Cohort: ALK-Positive Cohort, NSCLC: Crizotinib 250 mg	RP2D Cohort: Enriched Other: Crizotinib 250 mg	RP2D Cohort: Itraconazole Interaction: Crizotinib 250 mg +Itraconazole	RP2D Cohort: Rifampin Interaction: Crizotinib 250 mg +Rifampin	RP2D Cohort: Midazolam Interaction: Crizotinib 250 mg +Midazolam	Total
Arm/Group Description		Participants received Crizotinib 50 milligram (mg) capsule or tablet orally once daily (QD) for up to 34 cycles (each cycle 28 days).	Participants received Crizotinib 100 mg capsule or tablet orally QD for up to 34 cycles (each cycle 28 days) and 2 mg oral dose of Midazolam along with Crizotinib 100 mg on Cycle 2 Day 1 only. Participants who did not receive Crizotinib on Day -7, received single 2 mg oral dose of Midazolam on Day -7.	Participants received Crizotinib 200 mg (2 capsules/tablet of 100 mg each) capsule/tablet orally QD for up to 34 cycles (each cycle 28 days).	Participants received Crizotinib 200 mg (2 capsules/tablet of 100 mg each) capsule/tablet orally twice daily (BID) for up to 34 cycles (each cycle 28 days).	Participants received Crizotinib 250 mg (2 capsules/tablet of 100 mg each + 1 capsule/tablet of 50 mg) capsule/tablet BID for up to 34 cycles (each cycle 28 days).	Participants received Crizotinib 300 mg (3 capsules/tablet of 100 mg each) capsule/tablet orally BID for up to 34 cycles (each cycle 28 days) and 2 mg oral dose of Midazolam along with Crizotinib 300 mg on Cycle 2 Day 1 only. Participants who did not receive Crizotinib on Day -7, received single 2 mg oral dose of Midazolam on Day -7.	Participants received Crizotinib 300 mg (3 capsules/tablet of 100 mg each) capsule/tablet QD for up to 7 cycles (each cycle 28 days).	Participants received Crizotinib 400 mg (4 capsules/tablet of 100 mg each) capsule/tablet QD for up to 7 cycles (each cycle 28 days).	Participants received Crizotinib 500 mg (5 capsules/tablet of 100 mg each) capsule/tablet QD for up to 7 cycles (each cycle 28 days).	Participants received Crizotinib 650 mg (6 capsules/tablet of 100 mg each + 1 capsule/tablet of 50 mg) capsule/tablet twice daily (BID) for up to 7 cycles (each cycle 28 days).	Participants received Crizotinib 800 mg (8 capsules/tablet of 100 mg each) capsule/tablet QD for up to 7 cycles (each cycle 28 days).	Participants received Crizotinib 250 mg (2 capsules/tablet of 100 mg each + 1 capsule/tablet of 50 mg) capsule/tablet orally twice daily (BID) with or without food for up to 105 cycles (each cycle 28 days).	Participants received Crizotinib 250 mg (2 capsules/tablet of 100 mg each + 1 capsule/tablet of 50 mg) capsule/tablet orally twice daily (BID) with or without food for up to 55 cycles (each cycle 28 days).	Participants received Crizotinib 250 mg (2 capsules/tablet of 100 mg each + 1 capsule/tablet of 50 mg) capsule/tablet orally twice daily (BID) with or without food for up to 101 cycles (each cycle 28 days).	Participants received Crizotinib 250 mg (2 capsules/tablet of 100 mg each + 1 capsule/tablet of 50 mg) capsule/tablet twice daily (BID) with or without food for up to 70 cycles (each cycle 21 days).	Participants received Crizotinib 250 mg (2 capsules/tablet of 100 mg each + 1 capsule/tablet of 50 mg) capsule/tablet orally BID with or without food for up to 70 cycles (each cycle 21 days).	Participants received Crizotinib 250 mg (2 capsules/tablet of 100 mg each + 1 capsule/tablet of 50 mg) capsule/tablet twice daily (BID) with or without food for up to 133 cycles (each cycle 28 days).	Participants received Crizotinib 250 mg (2 capsules/tablet of 100 mg each + 1 capsule/tablet of 50 mg) capsule/tablet orally twice daily (BID) with or without food for up to 54 cycles (each cycle 28 days).	Participants received with or without food Crizotinib 250 mg (2 capsules/tablet of 100 mg each + 1 capsule/tablet of 50 mg) capsule/tablet QD from Cycle 1Day1 to Cycle 2 Day1 thereafter 250 mg BID from Cycle 2 Day 2 up to 58 cycles (each cycle 28 days). Participants also received Itraconazole 200 mg QD from Cycle 1 Day 1 to Cycle 1 Day 16.	Participants received Crizotinib 250 mg (2 capsules/tablet of 100 mg each + 1 capsule/tablet of 50 mg) capsule/tablet twice daily (BID) with or without food from Cycle 1 Day 1 up to 13 cycles (each cycle 28 days). Participants also received commercially available Rifampin 650 mg QD from Cycle 1 Day 16 to Cycle 2 Day 1 (14 days) either one hour before or 2 hours after food.	Participants received Crizotinib 250 mg tablet/capsule (2 capsules/tablet of 100 mg each + 1 capsule/tablet of 50 mg) orally BID with or without food from Day 1 Cycle 1 up to 133 cycles (each cycle 28 days). Participants also received single 2 mg oral dose of Midazolam on Day -7 and another single 2-mg oral dose of Midazolam concurrently with Crizotinib on Cycle 2 Day 1	Total of all reporting groups
Overall Number of Baseline Participants		3	4	8	7	8	6	6	5	3	6	9	53	85	41	48	18	154	66	18	18	12	578
Baseline Analysis Population Description		Safety analysis (SA) set included all enrolled participants who received at least one dose of Crizotinib on Cycle 1 Day 1.
Age, Customized; Measure Type: Count of Participants; Unit of measure: Participants	Number Analyzed	3 participants	4 participants	8 participants	7 participants	8 participants	6 participants	6 participants	5 participants	3 participants	6 participants	9 participants	53 participants	85 participants	41 participants	48 participants	18 participants	154 participants	66 participants	18 participants	18 participants	12 participants	578 participants
less than 65 years		3 100.0%	4 100.0%	5 62.5%	5 71.4%	8 100.0%	6 100.0%	3 50.0%	5 100.0%	3 100.0%	6 100.0%	5 55.6%	23 43.4%	18 21.2%	20 48.8%	30 62.5%	12 66.7%	131 85.1%	51 77.3%	9 50.0%	12 66.7%	9 75.0%	368 63.7%
greater than or equals to 65 years		0 0.0%	0 0.0%	3 37.5%	2 28.6%	0 0.0%	0 0.0%	3 50.0%	0 0.0%	0 0.0%	0 0.0%	4 44.4%	30 56.6%	67 78.8%	21 51.2%	18 37.5%	6 33.3%	23 14.9%	15 22.7%	9 50.0%	6 33.3%	3 25.0%	210 36.3%
Sex: Female, Male; Measure Type: Count of Participants; Unit of measure: Participants
	Number Analyzed	3 participants	4 participants	8 participants	7 participants	8 participants	6 participants	6 participants	5 participants	3 participants	6 participants	9 participants	53 participants	85 participants	41 participants	48 participants	18 participants	154 participants	66 participants	18 participants	18 participants	12 participants	578 participants
	Female	3 100.0%	1 25.0%	2 25.0%	3 42.9%	4 50.0%	2 33.3%	3 50.0%	5 100.0%	0 0.0%	1 16.7%	3 33.3%	30 56.6%	48 56.5%	19 46.3%	24 50.0%	8 44.4%	80 51.9%	25 37.9%	11 61.1%	9 50.0%	8 66.7%	289 50.0%
	Male	0 0.0%	3 75.0%	6 75.0%	4 57.1%	4 50.0%	4 66.7%	3 50.0%	0 0.0%	3 100.0%	5 83.3%	6 66.7%	23 43.4%	37 43.5%	22 53.7%	24 50.0%	10 55.6%	74 48.1%	41 62.1%	7 38.9%	9 50.0%	4 33.3%	289 50.0%
Race/Ethnicity, Customized; Measure Type: Count of Participants; Unit of measure: Participants
	Number Analyzed	3 participants	4 participants	8 participants	7 participants	8 participants	6 participants	6 participants	5 participants	3 participants	6 participants	9 participants	53 participants	85 participants	41 participants	48 participants	18 participants	154 participants	66 participants	18 participants	18 participants	12 participants	578 participants
	White	2 66.7%	3 75.0%	7 87.5%	6 85.7%	8 100.0%	6 100.0%	6 100.0%	4 80.0%	2 66.7%	5 83.3%	8 88.9%	30 56.6%	60 70.6%	38 92.7%	35 72.9%	11 61.1%	98 63.6%	49 74.2%	13 72.2%	16 88.9%	11 91.7%	418 72.3%
	Black	1 33.3%	0 0.0%	0 0.0%	0 0.0%	0 0.0%	0 0.0%	0 0.0%	1 20.0%	1 33.3%	0 0.0%	0 0.0%	2 3.8%	2 2.4%	2 4.9%	1 2.1%	3 16.7%	5 3.2%	4 6.1%	3 16.7%	2 11.1%	0 0.0%	27 4.7%
	Asian	0 0.0%	0 0.0%	1 12.5%	0 0.0%	0 0.0%	0 0.0%	0 0.0%	0 0.0%	0 0.0%	0 0.0%	1 11.1%	21 39.6%	15 17.6%	1 2.4%	9 18.8%	2 11.1%	43 27.9%	9 13.6%	0 0.0%	0 0.0%	0 0.0%	102 17.6%
	Other	0 0.0%	1 25.0%	0 0.0%	1 14.3%	0 0.0%	0 0.0%	0 0.0%	0 0.0%	0 0.0%	1 16.7%	0 0.0%	0 0.0%	8 9.4%	0 0.0%	3 6.3%	2 11.1%	8 5.2%	4 6.1%	2 11.1%	0 0.0%	1 8.3%	31 5.4%

Outcome Measures

1. Primary Outcome

Title	Dose-Escalation Cohort: Maximum Tolerated Dose (MTD) of Crizotinib
Description	MTD: Dose level at which at most 1 of 6 participants experienced DLT within and including 28 days of treatment (during Cycle 1 [1 cycle=28 days]) with next higher dose having at least 2/3 or 2/6 participants experiencing a DLT. DLT was defined as any of following: Hematologic toxicities- 1) prolonged grade 4 neutropenia for >7 days. 2) Febrile neutropenia: grade 4 neutropenia with fever greater than (>) 38.5 degree Celsius, both sustained over a 24 hour period (3) neutropenic infection: greater than or equal to (>=) Grade 3 neutropenia with Grade >=3 infection. (4) Grade >=3 thrombocytopenia with bleeding/grade 4 lasting >=7 days. Other non-hematologic toxicity included: Grade 3/4 toxicities (except for alopecia, Grade 3/4 hypophosphatemia, grade 3 hypertension with controlled blood pressure [less than (<) 140/90 millimeter of mercury, and Grade 3/4 hyperuricemia without signs and symptoms of gout). Nausea, vomiting/diarrhea must persist at grade 3/4 despite maximal medical therapy.
Time Frame	Cycle 1 (28 days)

Outcome Measure Data

Analysis Population Description

Safety analysis (SA) set included all enrolled participants who received at least one dose of Crizotinib on Cycle 1 Day 1.

Arm/Group Title	Low Dose Escalation Cohort: Crizotinib 50 mg QD	Low Dose Escalation Cohort: Crizotinib 100 mg QD	Low Dose Escalation Cohort: Crizotinib 200 mg QD	Low Dose Escalation Cohort: Crizotinib 200 mg BID	Low Dose Escalation Cohort: Crizotinib 250 mg BID	Low Dose Escalation Cohort: Crizotinib 300 mg BID	High Dose Escalation Cohort: Crizotinib 300 mg QD	High Dose Escalation Cohort: Crizotinib 400 mg QD	High Dose Escalation Cohort: Crizotinib 500 mg QD	High Dose Escalation Cohort: Crizotinib 650 mg QD	High Dose Escalation Cohort: Crizotinib 800 mg QD
Arm/Group Description:	Participants received Crizotinib 50 milligram (mg) capsule or tablet orally once daily (QD) for up to 34 cycles (each cycle 28 days).	Participants received Crizotinib 100 mg capsule or tablet orally QD for up to 34 cycles (each cycle 28 days) and 2 mg oral dose of Midazolam along with Crizotinib 100 mg on Cycle 2 Day 1 only. Participants who did not receive Crizotinib on Day -7, received single 2 mg oral dose of Midazolam on Day -7.	Participants received Crizotinib 200 mg (2 capsules/tablet of 100 mg each) capsule/tablet orally QD for up to 34 cycles (each cycle 28 days).	Participants received Crizotinib 200 mg (2 capsules/tablet of 100 mg each) capsule/tablet orally twice daily (BID) for up to 34 cycles (each cycle 28 days).	Participants received Crizotinib 250 mg (2 capsules/tablet of 100 mg each + 1 capsule/tablet of 50 mg) capsule/tablet BID for up to 34 cycles (each cycle 28 days).	Participants received Crizotinib 300 mg (3 capsules/tablet of 100 mg each) capsule/tablet orally BID for up to 34 cycles (each cycle 28 days) and 2 mg oral dose of Midazolam along with Crizotinib 300 mg on Cycle 2 Day 1 only. Participants who did not receive Crizotinib on Day -7, received single 2 mg oral dose of Midazolam on Day -7.	Participants received Crizotinib 300 mg (3 capsules/tablet of 100 mg each) capsule/tablet QD for up to 7 cycles (each cycle 28 days).	Participants received Crizotinib 400 mg (4 capsules/tablet of 100 mg each) capsule/tablet QD for up to 7 cycles (each cycle 28 days).	Participants received Crizotinib 500 mg (5 capsules/tablet of 100 mg each) capsule/tablet QD for up to 7 cycles (each cycle 28 days).	Participants received Crizotinib 650 mg (6 capsules/tablet of 100 mg each + 1 capsule/tablet of 50 mg) capsule/tablet twice daily (BID) for up to 7 cycles (each cycle 28 days).	Participants received Crizotinib 800 mg (8 capsules/tablet of 100 mg each) capsule/tablet QD for up to 7 cycles (each cycle 28 days).
Overall Number of Participants Analyzed	3	4	8	7	8	6	6	5	3	6	9
Measure Type: Number; Unit of Measure: milligram
	250	250	250	250	250	250	250	250	250	250	250

2. Primary Outcome

Title	Dose-Escalation Cohort: Recommended Phase 2 Dose (RP2D) of Crizotinib
Description	RP2D was defined as a dose below or equal to MTD, at which crizotinib was unlikely to cause a significant inhibition of CYP3A4 activity.
Time Frame	Cycle 1 (28 days)

Outcome Measure Data

Analysis Population Description

Safety analysis (SA) set included all enrolled participants who received at least one dose of Crizotinib on Cycle 1 Day 1.

Arm/Group Title	Low Dose Escalation Cohort: Crizotinib 50 mg QD	Low Dose Escalation Cohort: Crizotinib 100 mg QD	Low Dose Escalation Cohort: Crizotinib 200 mg QD	Low Dose Escalation Cohort: Crizotinib 200 mg BID	Low Dose Escalation Cohort: Crizotinib 250 mg BID	Low Dose Escalation Cohort: Crizotinib 300 mg BID	High Dose Escalation Cohort: Crizotinib 300 mg QD	High Dose Escalation Cohort: Crizotinib 400 mg QD	High Dose Escalation Cohort: Crizotinib 500 mg QD	High Dose Escalation Cohort: Crizotinib 650 mg QD	High Dose Escalation Cohort: Crizotinib 800 mg QD
Arm/Group Description:	Participants received Crizotinib 50 milligram (mg) capsule or tablet orally once daily (QD) for up to 34 cycles (each cycle 28 days).	Participants received Crizotinib 100 mg capsule or tablet orally QD for up to 34 cycles (each cycle 28 days) and 2 mg oral dose of Midazolam along with Crizotinib 100 mg on Cycle 2 Day 1 only. Participants who did not receive Crizotinib on Day -7, received single 2 mg oral dose of Midazolam on Day -7.	Participants received Crizotinib 200 mg (2 capsules/tablet of 100 mg each) capsule/tablet orally QD for up to 34 cycles (each cycle 28 days).	Participants received Crizotinib 200 mg (2 capsules/tablet of 100 mg each) capsule/tablet orally twice daily (BID) for up to 34 cycles (each cycle 28 days).	Participants received Crizotinib 250 mg (2 capsules/tablet of 100 mg each + 1 capsule/tablet of 50 mg) capsule/tablet BID for up to 34 cycles (each cycle 28 days).	Participants received Crizotinib 300 mg (3 capsules/tablet of 100 mg each) capsule/tablet orally BID for up to 34 cycles (each cycle 28 days) and 2 mg oral dose of Midazolam along with Crizotinib 300 mg on Cycle 2 Day 1 only. Participants who did not receive Crizotinib on Day -7, received single 2 mg oral dose of Midazolam on Day -7.	Participants received Crizotinib 300 mg (3 capsules/tablet of 100 mg each) capsule/tablet QD for up to 7 cycles (each cycle 28 days).	Participants received Crizotinib 400 mg (4 capsules/tablet of 100 mg each) capsule/tablet QD for up to 7 cycles (each cycle 28 days).	Participants received Crizotinib 500 mg (5 capsules/tablet of 100 mg each) capsule/tablet QD for up to 7 cycles (each cycle 28 days).	Participants received Crizotinib 650 mg (6 capsules/tablet of 100 mg each + 1 capsule/tablet of 50 mg) capsule/tablet twice daily (BID) for up to 7 cycles (each cycle 28 days).	Participants received Crizotinib 800 mg (8 capsules/tablet of 100 mg each) capsule/tablet QD for up to 7 cycles (each cycle 28 days).
Overall Number of Participants Analyzed	3	4	8	7	8	6	6	5	3	6	9
Measure Type: Number; Unit of Measure: milligram
	250	250	250	250	250	250	250	250	250	250	250

3. Primary Outcome

Title	Dose-Escalation and Recommended Phase 2 Dose (RP2D) Cohort: Area Under the Curve From Time Zero to Extrapolated Infinite Time (AUCinf) of Crizotinib on Day -7
Description	AUCinf = Area under the plasma concentration versus time curve (AUC) from time zero (pre-dose) extrapolated to infinite time (0-inf).
Time Frame	Pre-dose, 1, 2, 4, 6, 8, 9, 24, 48 and any two time points (72, 96, 120 and 144 hours) post-dose on Day -7

Outcome Measure Data

Analysis Population Description

Pharmacokinetic (PK) parameter analysis population included all participants treated (including Day -7 dose) who had at least 1 of the PK parameters of interest for Crizotinib. "Overall number of participants analyzed (N)" signifies participants evaluable for this outcome measure (OM). Data for this OM was planned to be collected for individual arms of low and high dose escalation and combined RP2D Cohort excluding "Low Dose Escalation Cohort: Crizotinib 100 mg QD" arm.

Arm/Group Title	Low Dose Escalation Cohort: Crizotinib 50 mg QD	Low Dose Escalation Cohort: Crizotinib 200 mg QD	Low Dose Escalation Cohort: Crizotinib 200 mg BID	Low Dose Escalation Cohort: Crizotinib 250 mg BID	Low Dose Escalation Cohort: Crizotinib 300 mg BID	High Dose Escalation Cohort: Crizotinib 300 mg QD	High Dose Escalation Cohort: Crizotinib 400 mg QD	High Dose Escalation Cohort: Crizotinib 500 mg QD	High Dose Escalation Cohort: Crizotinib 650 mg QD	High Dose Escalation Cohort: Crizotinib 800 mg QD	RP2D Cohort: Crizotinib 250 mg
Arm/Group Description:	Participants received Crizotinib 50 milligram (mg) capsule or tablet orally once daily (QD) for up to 34 cycles (each cycle 28 days).	Participants received Crizotinib 200 mg (2 capsules/tablet of 100 mg each) capsule/tablet orally QD for up to 34 cycles (each cycle 28 days).	Participants received Crizotinib 200 mg (2 capsules/tablet of 100 mg each) capsule/tablet orally twice daily (BID) for up to 34 cycles (each cycle 28 days).	Participants received Crizotinib 250 mg (2 capsules/tablet of 100 mg each + 1 capsule/tablet of 50 mg) capsule/tablet BID for up to 34 cycles (each cycle 28 days).	Participants received Crizotinib 300 mg (3 capsules/tablet of 100 mg each) capsule/tablet orally BID for up to 34 cycles (each cycle 28 days) and 2 mg oral dose of Midazolam along with Crizotinib 300 mg on Cycle 2 Day 1 only. Participants who did not receive Crizotinib on Day -7, received single 2 mg oral dose of Midazolam on Day -7.	Participants received Crizotinib 300 mg (3 capsules/tablet of 100 mg each) capsule/tablet QD for up to 7 cycles (each cycle 28 days).	Participants received Crizotinib 400 mg (4 capsules/tablet of 100 mg each) capsule/tablet QD for up to 7 cycles (each cycle 28 days).	Participants received Crizotinib 500 mg (5 capsules/tablet of 100 mg each) capsule/tablet QD for up to 7 cycles (each cycle 28 days).	Participants received Crizotinib 650 mg (6 capsules/tablet of 100 mg each + 1 capsule/tablet of 50 mg) capsule/tablet twice daily (BID) for up to 7 cycles (each cycle 28 days).	Participants received Crizotinib 800 mg (8 capsules/tablet of 100 mg each) capsule/tablet QD for up to 7 cycles (each cycle 28 days).	Participants received Crizotinib 250 mg tablet/capsule (2 capsules/tablet of 100 mg each + 1 capsule/tablet of 50 mg) orally BID up to 124 months.
Overall Number of Participants Analyzed	3	7	2	8	1	5	5	2	6	8	29
Geometric Mean (Geometric Coefficient of Variation); Unit of Measure: nanogram*hour per milliliter
	274.43; (22%)	1378.05; (144%)	946.93; (38%)	1817.35; (34%)	2320.00	3457; (42%)	3078; (119%)	2107; (53%)	3979; (39%)	7547; (76%)	2489.39; (53%)

4. Primary Outcome

Title	Dose-Escalation and Recommended Phase 2 Dose (RP2D) Cohort: Area Under the Curve From Time Zero to End of Dosing Interval (AUCtau) of Crizotinib on Day -7
Description	Area under the plasma concentration versus time curve from time 0 to end of dosing interval (AUCtau), where dosing interval is 12 hours for BID dose and 24 hours for QD dose.
Time Frame	Pre-dose, 1, 2, 4, 6, 8, 9, 24, 48 and any two time points (72, 96, 120 and 144 hours) post-dose on Day -7

Outcome Measure Data

Analysis Population Description

PK parameter analysis population included all participants treated (including Day -7 dose) who had at least 1 of the PK parameters of interest for Crizotinib. Here, "N" signifies participants evaluable for this OM. Data for this OM was planned to be reported for individual arms of low and high dose escalation and combined RP2D Cohort excluding "Low Dose Escalation Cohort: Crizotinib 100 mg QD" arm.

Arm/Group Title	Low Dose Escalation Cohort: Crizotinib 50 mg QD	Low Dose Escalation Cohort: Crizotinib 200 mg QD	Low Dose Escalation Cohort: Crizotinib 200 mg BID	Low Dose Escalation Cohort: Crizotinib 250 mg BID	Low Dose Escalation Cohort: Crizotinib 300 mg BID	High Dose Escalation Cohort: Crizotinib 300 mg QD	High Dose Escalation Cohort: Crizotinib 400 mg QD	High Dose Escalation Cohort: Crizotinib 500 mg QD	High Dose Escalation Cohort: Crizotinib 650 mg QD	High Dose Escalation Cohort: Crizotinib 800 mg QD	RP2D Cohort: Crizotinib 250 mg
Arm/Group Description:	Participants received Crizotinib 50 milligram (mg) capsule or tablet orally once daily (QD) for up to 34 cycles (each cycle 28 days).	Participants received Crizotinib 200 mg (2 capsules/tablet of 100 mg each) capsule/tablet orally QD for up to 34 cycles (each cycle 28 days).	Participants received Crizotinib 200 mg (2 capsules/tablet of 100 mg each) capsule/tablet orally twice daily (BID) for up to 34 cycles (each cycle 28 days).	Participants received Crizotinib 250 mg (2 capsules/tablet of 100 mg each + 1 capsule/tablet of 50 mg) capsule/tablet BID for up to 34 cycles (each cycle 28 days).	Participants received Crizotinib 300 mg (3 capsules/tablet of 100 mg each) capsule/tablet orally BID for up to 34 cycles (each cycle 28 days) and 2 mg oral dose of Midazolam along with Crizotinib 300 mg on Cycle 2 Day 1 only. Participants who did not receive Crizotinib on Day -7, received single 2 mg oral dose of Midazolam on Day -7.	Participants received Crizotinib 300 mg (3 capsules/tablet of 100 mg each) capsule/tablet QD for up to 7 cycles (each cycle 28 days).	Participants received Crizotinib 400 mg (4 capsules/tablet of 100 mg each) capsule/tablet QD for up to 7 cycles (each cycle 28 days).	Participants received Crizotinib 500 mg (5 capsules/tablet of 100 mg each) capsule/tablet QD for up to 7 cycles (each cycle 28 days).	Participants received Crizotinib 650 mg (6 capsules/tablet of 100 mg each + 1 capsule/tablet of 50 mg) capsule/tablet twice daily (BID) for up to 7 cycles (each cycle 28 days).	Participants received Crizotinib 800 mg (8 capsules/tablet of 100 mg each) capsule/tablet QD for up to 7 cycles (each cycle 28 days).	Participants received Crizotinib 250 mg tablet/capsule (2 capsules/tablet of 100 mg each + 1 capsule/tablet of 50 mg) orally BID up to 124 months.
Overall Number of Participants Analyzed	3	8	5	9	1	6	5	3	6	8	46
Geometric Mean (Geometric Coefficient of Variation); Unit of Measure: nanogram*hour per milliliter
	137.40; (8%)	658.64; (136%)	338.39; (50%)	558.01; (33%)	863.00	1731; (51%)	1377; (114%)	1300; (61%)	1906; (39%)	3423; (57%)	741.50; (45%)

5. Primary Outcome

Title	Dose-Escalation and Recommended Phase 2 Dose (RP2D) Cohort: Area Under the Curve From Time Zero to End of Dosing Interval (AUCtau) of Crizotinib on Cycle 1 Day 1
Description	Area under the plasma concentration versus time curve from time 0 to end of dosing interval (AUCtau), where dosing interval is 12 hours for BID dose and 24 hours for QD dose.
Time Frame	Pre-dose, 2, 4 and 6 hours post dose on Cycle 1 Day 1

Outcome Measure Data

Analysis Population Description

PK parameter analysis population included all participants treated (including Day -7 dose) who had at least 1 of the PK parameters of interest for Crizotinib. Here, "N" signifies participants evaluable for this OM. Data for this OM was planned to be collected for low dose escalation cohort (excluding Crizotinib 50 mg QD, Crizotinib 200 mg QD and Crizotinib 250 mg BID arms) and combined RP2D cohort and was not planned to be collected for high dose escalation cohort.

Arm/Group Title	Low Dose Escalation Cohort: Crizotinib 100 mg QD	Low Dose Escalation Cohort: Crizotinib 200 mg BID	Low Dose Escalation Cohort: Crizotinib 300 mg BID	RP2D Cohort: Crizotinib 250 mg
Arm/Group Description:	Participants received Crizotinib 100 mg capsule or tablet orally QD for up to 34 cycles (each cycle 28 days) and 2 mg oral dose of Midazolam along with Crizotinib 100 mg on Cycle 2 Day 1 only. Participants who did not receive Crizotinib on Day -7, received single 2 mg oral dose of Midazolam on Day -7.	Participants received Crizotinib 200 mg (2 capsules/tablet of 100 mg each) capsule/tablet orally twice daily (BID) for up to 34 cycles (each cycle 28 days).	Participants received Crizotinib 300 mg (3 capsules/tablet of 100 mg each) capsule/tablet orally BID for up to 34 cycles (each cycle 28 days) and 2 mg oral dose of Midazolam along with Crizotinib 300 mg on Cycle 2 Day 1 only. Participants who did not receive Crizotinib on Day -7, received single 2 mg oral dose of Midazolam on Day -7.	Participants received Crizotinib 250 mg tablet/capsule (2 capsules/tablet of 100 mg each + 1 capsule/tablet of 50 mg) orally BID up to 124 months.
Overall Number of Participants Analyzed	4	2	5	88
Geometric Mean (Geometric Coefficient of Variation); Unit of Measure: nanogram*hour per milliliter
	457.55; (32%)	383.98; (10%)	763.71; (57%)	663.39; (56%)

6. Primary Outcome

Title	Dose-Escalation and Recommended Phase 2 Dose (RP2D) Cohort: Area Under the Curve From Time Zero to End of Dosing Interval (AUCtau) of Crizotinib on Cycle 1 Day 15
Description	Area under the plasma concentration versus time curve from time 0 to end of dosing interval (AUCtau), where dosing interval is 12 hours for BID dose and 24 hours for QD dose.
Time Frame	Pre-dose, 1, 2, 4, 6, 8, 9 and 24 hours post dose on Cycle 1 Day 15

Outcome Measure Data

Analysis Population Description

The PK parameter analysis population included all participants treated (including Day -7 dose) who have at least 1 of the PK parameters of interest for Crizotinib. Here, "Overall number of participants analyzed" signifies number of participants evaluable for this outcome measure. Data for this outcome measures was planned to be collected for individual arms of dose escalation cohorts and combined RP2D Cohort.

Arm/Group Title	Low Dose Escalation Cohort: Crizotinib 50 mg QD	Low Dose Escalation Cohort: Crizotinib 100 mg QD	Low Dose Escalation Cohort: Crizotinib 200 mg QD	Low Dose Escalation Cohort: Crizotinib 200 mg BID	Low Dose Escalation Cohort: Crizotinib 250 mg BID	Low Dose Escalation Cohort: Crizotinib 300 mg BID	High Dose Escalation Cohort: Crizotinib 300 mg QD	High Dose Escalation Cohort: Crizotinib 400 mg QD	High Dose Escalation Cohort: Crizotinib 500 mg QD	High Dose Escalation Cohort: Crizotinib 650 mg QD	High Dose Escalation Cohort: Crizotinib 800 mg QD	RP2D Cohort: Crizotinib 250 mg
Arm/Group Description:	Participants received Crizotinib 50 milligram (mg) capsule or tablet orally once daily (QD) for up to 34 cycles (each cycle 28 days).	Participants received Crizotinib 100 mg capsule or tablet orally QD for up to 34 cycles (each cycle 28 days) and 2 mg oral dose of Midazolam along with Crizotinib 100 mg on Cycle 2 Day 1 only. Participants who did not receive Crizotinib on Day -7, received single 2 mg oral dose of Midazolam on Day -7.	Participants received Crizotinib 200 mg (2 capsules/tablet of 100 mg each) capsule/tablet orally QD for up to 34 cycles (each cycle 28 days).	Participants received Crizotinib 200 mg (2 capsules/tablet of 100 mg each) capsule/tablet orally twice daily (BID) for up to 34 cycles (each cycle 28 days).	Participants received Crizotinib 250 mg (2 capsules/tablet of 100 mg each + 1 capsule/tablet of 50 mg) capsule/tablet BID for up to 34 cycles (each cycle 28 days).	Participants received Crizotinib 300 mg (3 capsules/tablet of 100 mg each) capsule/tablet orally BID for up to 34 cycles (each cycle 28 days) and 2 mg oral dose of Midazolam along with Crizotinib 300 mg on Cycle 2 Day 1 only. Participants who did not receive Crizotinib on Day -7, received single 2 mg oral dose of Midazolam on Day -7.	Participants received Crizotinib 300 mg (3 capsules/tablet of 100 mg each) capsule/tablet QD for up to 7 cycles (each cycle 28 days).	Participants received Crizotinib 400 mg (4 capsules/tablet of 100 mg each) capsule/tablet QD for up to 7 cycles (each cycle 28 days).	Participants received Crizotinib 500 mg (5 capsules/tablet of 100 mg each) capsule/tablet QD for up to 7 cycles (each cycle 28 days).	Participants received Crizotinib 650 mg (6 capsules/tablet of 100 mg each + 1 capsule/tablet of 50 mg) capsule/tablet twice daily (BID) for up to 7 cycles (each cycle 28 days).	Participants received Crizotinib 800 mg (8 capsules/tablet of 100 mg each) capsule/tablet QD for up to 7 cycles (each cycle 28 days).	Participants received Crizotinib 250 mg tablet/capsule (2 capsules/tablet of 100 mg each + 1 capsule/tablet of 50 mg) orally BID up to 124 months.
Overall Number of Participants Analyzed	3	4	8	4	5	4	6	2	3	5	3	19
Geometric Mean (Geometric Coefficient of Variation); Unit of Measure: nanogram*hour per milliliter
	206.13; (76%)	1086.99; (34%)	2047.13; (45%)	1780.21; (69%)	3083.93; (31%)	4066.67; (53%)	4375; (34%)	3385; (24%)	6655; (4%)	6362; (37%)	10480; (76%)	3879.56; (45%)

7. Primary Outcome

Title	Dose-Escalation and Recommended Phase 2 Dose (RP2D) Cohort: Area Under the Curve From Time Zero to End of Dosing Interval (AUCtau) of Crizotinib on Cycle 2 Day 1
Description	Area under the plasma concentration versus time curve from time 0 to end of dosing interval (AUCtau), where dosing interval is 12 hours for BID dose and 24 hours for QD dose.
Time Frame	Pre-dose, 1, 2, 4, 6, 8, 9 and 24 hours post dose on Cycle 2 Day 1

Outcome Measure Data

Analysis Population Description

The PK parameter analysis population included all participants treated (including Day -7 dose) who have at least 1 of the PK parameters of interest for Crizotinib. Here, "Overall number of participants analyzed" signifies number of participants evaluable for this outcome measure. Data for this outcome measures was planned to be collected for individual arms of dose escalation cohorts and combined RP2D Cohort.

Arm/Group Title	Low Dose Escalation Cohort: Crizotinib 50 mg QD	Low Dose Escalation Cohort: Crizotinib 100 mg QD	Low Dose Escalation Cohort: Crizotinib 200 mg QD	Low Dose Escalation Cohort: Crizotinib 200 mg BID	Low Dose Escalation Cohort: Crizotinib 250 mg BID	Low Dose Escalation Cohort: Crizotinib 300 mg BID	High Dose Escalation Cohort: Crizotinib 300 mg QD	High Dose Escalation Cohort: Crizotinib 400 mg QD	High Dose Escalation Cohort: Crizotinib 500 mg QD	High Dose Escalation Cohort: Crizotinib 650 mg QD	High Dose Escalation Cohort: Crizotinib 800 mg QD	RP2D Cohort: Crizotinib 250 mg
Arm/Group Description:	Participants received Crizotinib 50 milligram (mg) capsule or tablet orally once daily (QD) for up to 34 cycles (each cycle 28 days).	Participants received Crizotinib 100 mg capsule or tablet orally QD for up to 34 cycles (each cycle 28 days) and 2 mg oral dose of Midazolam along with Crizotinib 100 mg on Cycle 2 Day 1 only. Participants who did not receive Crizotinib on Day -7, received single 2 mg oral dose of Midazolam on Day -7.	Participants received Crizotinib 200 mg (2 capsules/tablet of 100 mg each) capsule/tablet orally QD for up to 34 cycles (each cycle 28 days).	Participants received Crizotinib 200 mg (2 capsules/tablet of 100 mg each) capsule/tablet orally twice daily (BID) for up to 34 cycles (each cycle 28 days).	Participants received Crizotinib 250 mg (2 capsules/tablet of 100 mg each + 1 capsule/tablet of 50 mg) capsule/tablet BID for up to 34 cycles (each cycle 28 days).	Participants received Crizotinib 300 mg (3 capsules/tablet of 100 mg each) capsule/tablet orally BID for up to 34 cycles (each cycle 28 days) and 2 mg oral dose of Midazolam along with Crizotinib 300 mg on Cycle 2 Day 1 only. Participants who did not receive Crizotinib on Day -7, received single 2 mg oral dose of Midazolam on Day -7.	Participants received Crizotinib 300 mg (3 capsules/tablet of 100 mg each) capsule/tablet QD for up to 7 cycles (each cycle 28 days).	Participants received Crizotinib 400 mg (4 capsules/tablet of 100 mg each) capsule/tablet QD for up to 7 cycles (each cycle 28 days).	Participants received Crizotinib 500 mg (5 capsules/tablet of 100 mg each) capsule/tablet QD for up to 7 cycles (each cycle 28 days).	Participants received Crizotinib 650 mg (6 capsules/tablet of 100 mg each + 1 capsule/tablet of 50 mg) capsule/tablet twice daily (BID) for up to 7 cycles (each cycle 28 days).	Participants received Crizotinib 800 mg (8 capsules/tablet of 100 mg each) capsule/tablet QD for up to 7 cycles (each cycle 28 days).	Participants received Crizotinib 250 mg tablet/capsule (2 capsules/tablet of 100 mg each + 1 capsule/tablet of 50 mg) orally BID up to 124 months.
Overall Number of Participants Analyzed	3	3	5	3	5	2	5	3	2	4	2	16
Geometric Mean (Geometric Coefficient of Variation); Unit of Measure: nanogram*hour per milliliter
	425.90; (49%)	1595.58; (30%)	1719.30; (68%)	2255.70; (14%)	3054.45; (29%)	3644.72; (17%)	4815; (23%)	3839; (65%)	6330; (64%)	7273; (48%)	8733; (63%)	4163.77; (40%)

8. Primary Outcome

Title	Dose-Escalation and Recommended Phase 2 Dose (RP2D) Cohort: Trough Concentration (Ctrough) of Crizotinib Cycle 1 Day 15
Description	Ctrough refers to plasma concentration of Crizotinib observed just before treatment administration.
Time Frame	Pre-dose on Cycle 1 Day 15

Outcome Measure Data

Analysis Population Description

PK parameter analysis population included all participants treated (including Day -7 dose) who had at least 1 of the PK parameters of interest for Crizotinib. Here, "N" signifies participants evaluable for this OM. Data for this OM was planned to be collected for individual arms of low dose escalation and combined RP2D Cohort and not planned to be collected for high dose escalation cohort".

Arm/Group Title	Low Dose Escalation Cohort: Crizotinib 50 mg QD	Low Dose Escalation Cohort: Crizotinib 100 mg QD	Low Dose Escalation Cohort: Crizotinib 200 mg QD	Low Dose Escalation Cohort: Crizotinib 200 mg BID	Low Dose Escalation Cohort: Crizotinib 250 mg BID	Low Dose Escalation Cohort: Crizotinib 300 mg BID	RP2D Cohort: Crizotinib 250 mg
Arm/Group Description:	Participants received Crizotinib 50 milligram (mg) capsule or tablet orally once daily (QD) for up to 34 cycles (each cycle 28 days).	Participants received Crizotinib 100 mg capsule or tablet orally QD for up to 34 cycles (each cycle 28 days) and 2 mg oral dose of Midazolam along with Crizotinib 100 mg on Cycle 2 Day 1 only. Participants who did not receive Crizotinib on Day -7, received single 2 mg oral dose of Midazolam on Day -7.	Participants received Crizotinib 200 mg (2 capsules/tablet of 100 mg each) capsule/tablet orally QD for up to 34 cycles (each cycle 28 days).	Participants received Crizotinib 200 mg (2 capsules/tablet of 100 mg each) capsule/tablet orally twice daily (BID) for up to 34 cycles (each cycle 28 days).	Participants received Crizotinib 250 mg (2 capsules/tablet of 100 mg each + 1 capsule/tablet of 50 mg) capsule/tablet BID for up to 34 cycles (each cycle 28 days).	Participants received Crizotinib 300 mg (3 capsules/tablet of 100 mg each) capsule/tablet orally BID for up to 34 cycles (each cycle 28 days) and 2 mg oral dose of Midazolam along with Crizotinib 300 mg on Cycle 2 Day 1 only. Participants who did not receive Crizotinib on Day -7, received single 2 mg oral dose of Midazolam on Day -7.	Participants received Crizotinib 250 mg tablet/capsule (2 capsules/tablet of 100 mg each + 1 capsule/tablet of 50 mg) orally BID up to 124 months.
Overall Number of Participants Analyzed	3	4	8	3	5	4	24
Geometric Mean (Geometric Coefficient of Variation); Unit of Measure: nanogram per milliliter
	7.29; (42%)	32.61; (36%)	48.18; (58%)	126.76; (97%)	232.59; (33%)	307.83; (59%)	280.43; (75%)

9. Primary Outcome

Title	Dose-Escalation and Recommended Phase 2 Dose (RP2D) Cohort: Trough Concentration (Ctrough) of Crizotinib on Cycle 2 Day 1
Description	Ctrough refers to plasma concentration of Crizotinib observed just before treatment administration.
Time Frame	Pre-dose on Cycle 2 Day 1

Outcome Measure Data

Analysis Population Description

PK parameter analysis population included all participants treated (including Day -7 dose) who had at least 1 of the PK parameters of interest for Crizotinib. Here, "N" signifies participants evaluable for this OM. Data for this OM was planned to be collected for individual arms of low dose escalation and combined RP2D Cohort and not planned to be collected for high dose escalation cohort".

Arm/Group Title	Low Dose Escalation Cohort: Crizotinib 50 mg QD	Low Dose Escalation Cohort: Crizotinib 100 mg QD	Low Dose Escalation Cohort: Crizotinib 200 mg QD	Low Dose Escalation Cohort: Crizotinib 200 mg BID	Low Dose Escalation Cohort: Crizotinib 250 mg BID	Low Dose Escalation Cohort: Crizotinib 300 mg BID	RP2D Cohort: Crizotinib 250 mg
Arm/Group Description:	Participants received Crizotinib 50 milligram (mg) capsule or tablet orally once daily (QD) for up to 34 cycles (each cycle 28 days).	Participants received Crizotinib 100 mg capsule or tablet orally QD for up to 34 cycles (each cycle 28 days) and 2 mg oral dose of Midazolam along with Crizotinib 100 mg on Cycle 2 Day 1 only. Participants who did not receive Crizotinib on Day -7, received single 2 mg oral dose of Midazolam on Day -7.	Participants received Crizotinib 200 mg (2 capsules/tablet of 100 mg each) capsule/tablet orally QD for up to 34 cycles (each cycle 28 days).	Participants received Crizotinib 200 mg (2 capsules/tablet of 100 mg each) capsule/tablet orally twice daily (BID) for up to 34 cycles (each cycle 28 days).	Participants received Crizotinib 250 mg (2 capsules/tablet of 100 mg each + 1 capsule/tablet of 50 mg) capsule/tablet BID for up to 34 cycles (each cycle 28 days).	Participants received Crizotinib 300 mg (3 capsules/tablet of 100 mg each) capsule/tablet orally BID for up to 34 cycles (each cycle 28 days) and 2 mg oral dose of Midazolam along with Crizotinib 300 mg on Cycle 2 Day 1 only. Participants who did not receive Crizotinib on Day -7, received single 2 mg oral dose of Midazolam on Day -7.	Participants received Crizotinib 250 mg tablet/capsule (2 capsules/tablet of 100 mg each + 1 capsule/tablet of 50 mg) orally BID up to 124 months.
Overall Number of Participants Analyzed	3	3	5	3	5	3	18
Geometric Mean (Geometric Coefficient of Variation); Unit of Measure: nanogram per milliliter
	12.68; (94%)	31.91; (34%)	54.04; (85%)	157.24; (17%)	232.45; (32%)	329.50; (40%)	312.99; (55%)

10. Primary Outcome

Title	Dose-Escalation and Recommended Phase 2 Dose (RP2D) Cohort: Maximum Observed Plasma Concentration (Cmax) of Crizotinib on Day -7
Description	Cmax is defined as the observed maximum plasma concentration post drug administration.
Time Frame	Pre-dose, 1, 2, 4, 6, 8, 9, 24, 48 and any two time points (72, 96, 120 and 144 hours) post-dose on Day -7

Outcome Measure Data

Analysis Population Description

PK parameter analysis population set. "N"=participants evaluable for this outcome measure. Data for this OM was planned to be collected for dose escalation cohorts (both low and high) and combined RP2D Cohort excluding "Low Dose Escalation Cohort: Crizotinib 100 mg QD" cohort arms.

Arm/Group Title	Low Dose Escalation Cohort: Crizotinib 50 mg QD	Low Dose Escalation Cohort: Crizotinib 200 mg QD	Low Dose Escalation Cohort: Crizotinib 200 mg BID	Low Dose Escalation Cohort: Crizotinib 250 mg BID	Low Dose Escalation Cohort: Crizotinib 300 mg BID	High Dose Escalation Cohort: Crizotinib 300 mg QD	High Dose Escalation Cohort: Crizotinib 400 mg QD	High Dose Escalation Cohort: Crizotinib 500 mg QD	High Dose Escalation Cohort: Crizotinib 650 mg QD	High Dose Escalation Cohort: Crizotinib 800 mg QD	RP2D Cohort: Crizotinib 250 mg
Arm/Group Description:	Participants received Crizotinib 50 milligram (mg) capsule or tablet orally once daily (QD) for up to 34 cycles (each cycle 28 days).	Participants received Crizotinib 200 mg (2 capsules/tablet of 100 mg each) capsule/tablet orally QD for up to 34 cycles (each cycle 28 days).	Participants received Crizotinib 200 mg (2 capsules/tablet of 100 mg each) capsule/tablet orally twice daily (BID) for up to 34 cycles (each cycle 28 days).	Participants received Crizotinib 250 mg (2 capsules/tablet of 100 mg each + 1 capsule/tablet of 50 mg) capsule/tablet BID for up to 34 cycles (each cycle 28 days).	Participants received Crizotinib 300 mg (3 capsules/tablet of 100 mg each) capsule/tablet orally BID for up to 34 cycles (each cycle 28 days) and 2 mg oral dose of Midazolam along with Crizotinib 300 mg on Cycle 2 Day 1 only. Participants who did not receive Crizotinib on Day -7, received single 2 mg oral dose of Midazolam on Day -7.	Participants received Crizotinib 300 mg (3 capsules/tablet of 100 mg each) capsule/tablet QD for up to 7 cycles (each cycle 28 days).	Participants received Crizotinib 400 mg (4 capsules/tablet of 100 mg each) capsule/tablet QD for up to 7 cycles (each cycle 28 days).	Participants received Crizotinib 500 mg (5 capsules/tablet of 100 mg each) capsule/tablet QD for up to 7 cycles (each cycle 28 days).	Participants received Crizotinib 650 mg (6 capsules/tablet of 100 mg each + 1 capsule/tablet of 50 mg) capsule/tablet twice daily (BID) for up to 7 cycles (each cycle 28 days).	Participants received Crizotinib 800 mg (8 capsules/tablet of 100 mg each) capsule/tablet QD for up to 7 cycles (each cycle 28 days).	Participants received Crizotinib 250 mg tablet/capsule (2 capsules/tablet of 100 mg each + 1 capsule/tablet of 50 mg) orally BID up to 124 months.
Overall Number of Participants Analyzed	3	8	5	9	1	6	5	3	6	8	46
Geometric Mean (Geometric Coefficient of Variation); Unit of Measure: nanogram per milliliter
	24.19; (36%)	67.64; (106%)	55.73; (45%)	87.02; (34%)	130.00	184.7; (65%)	115.9; (85%)	146.6; (31%)	154.3; (30%)	270.9; (47%)	108.40; (42%)

11. Primary Outcome

Title	Dose-Escalation and Recommended Phase 2 Dose (RP2D) Cohort: Maximum Observed Plasma Concentration (Cmax) of Crizotinib on Cycle 1 Day 1
Description	Cmax is defined as the observed maximum plasma concentration post drug administration.
Time Frame	Pre-dose, 2, 4 and 6 hours post dose on Cycle 1 Day 1

Outcome Measure Data

Analysis Population Description

PK parameter analysis population included all participants treated (including Day -7 dose) who had at least 1 of the PK parameters of interest for Crizotinib. Here, "N" signifies participants evaluable for this OM. Data for this OM was planned to be collected for low dose escalation cohort (excluding Crizotinib 50 mg QD, Crizotinib 200 mg QD and Crizotinib 250 mg BID arms) and combined RP2D cohort and was not planned to be collected for high dose escalation cohort.

Arm/Group Title	Low Dose Escalation Cohort: Crizotinib 100 mg QD	Low Dose Escalation Cohort: Crizotinib 200 mg BID	Low Dose Escalation Cohort: Crizotinib 300 mg BID	RP2D Cohort: Crizotinib 250 mg
Arm/Group Description:	Participants received Crizotinib 100 mg capsule or tablet orally QD for up to 34 cycles (each cycle 28 days) and 2 mg oral dose of Midazolam along with Crizotinib 100 mg on Cycle 2 Day 1 only. Participants who did not receive Crizotinib on Day -7, received single 2 mg oral dose of Midazolam on Day -7.	Participants received Crizotinib 200 mg (2 capsules/tablet of 100 mg each) capsule/tablet orally twice daily (BID) for up to 34 cycles (each cycle 28 days).	Participants received Crizotinib 300 mg (3 capsules/tablet of 100 mg each) capsule/tablet orally BID for up to 34 cycles (each cycle 28 days) and 2 mg oral dose of Midazolam along with Crizotinib 300 mg on Cycle 2 Day 1 only. Participants who did not receive Crizotinib on Day -7, received single 2 mg oral dose of Midazolam on Day -7.	Participants received Crizotinib 250 mg tablet/capsule (2 capsules/tablet of 100 mg each + 1 capsule/tablet of 50 mg) orally BID up to 124 months.
Overall Number of Participants Analyzed	4	2	5	98
Geometric Mean (Geometric Coefficient of Variation); Unit of Measure: nanogram per milliliter
	54.89; (53%)	64.14; (2%)	114.09; (48%)	98.86; (55%)

12. Primary Outcome

Title	Dose-Escalation and Recommended Phase 2 Dose (RP2D) Cohort: Maximum Observed Plasma Concentration (Cmax) of Crizotinib on Cycle 1 Day 15
Description	Cmax is defined as the observed maximum plasma concentration post drug administration.
Time Frame	Pre-dose, 1, 2, 4, 6, 8, 9 and 24 hours post dose on Cycle 1 Day 15

Outcome Measure Data

Analysis Population Description

The PK parameter analysis population included all participants treated (including Day -7 dose) who have at least 1 of the PK parameters of interest for Crizotinib. Here, "Overall number of participants analyzed" signifies number of participants evaluable for this outcome measure. Data for this outcome measures was planned to be collected for individual arms of dose escalation cohorts (both low and high) and combined RP2D Cohort.

Arm/Group Title	Low Dose Escalation Cohort: Crizotinib 50 mg QD	Low Dose Escalation Cohort: Crizotinib 100 mg QD	Low Dose Escalation Cohort: Crizotinib 200 mg QD	Low Dose Escalation Cohort: Crizotinib 200 mg BID	Low Dose Escalation Cohort: Crizotinib 250 mg BID	Low Dose Escalation Cohort: Crizotinib 300 mg BID	High Dose Escalation Cohort: Crizotinib 300 mg QD	High Dose Escalation Cohort: Crizotinib 400 mg QD	High Dose Escalation Cohort: Crizotinib 500 mg QD	High Dose Escalation Cohort: Crizotinib 650 mg QD	High Dose Escalation Cohort: Crizotinib 800 mg QD	RP2D Cohort: Crizotinib 250 mg
Arm/Group Description:	Participants received Crizotinib 50 milligram (mg) capsule or tablet orally once daily (QD) for up to 34 cycles (each cycle 28 days).	Participants received Crizotinib 100 mg capsule or tablet orally QD for up to 34 cycles (each cycle 28 days) and 2 mg oral dose of Midazolam along with Crizotinib 100 mg on Cycle 2 Day 1 only. Participants who did not receive Crizotinib on Day -7, received single 2 mg oral dose of Midazolam on Day -7.	Participants received Crizotinib 200 mg (2 capsules/tablet of 100 mg each) capsule/tablet orally QD for up to 34 cycles (each cycle 28 days).	Participants received Crizotinib 200 mg (2 capsules/tablet of 100 mg each) capsule/tablet orally twice daily (BID) for up to 34 cycles (each cycle 28 days).	Participants received Crizotinib 250 mg (2 capsules/tablet of 100 mg each + 1 capsule/tablet of 50 mg) capsule/tablet BID for up to 34 cycles (each cycle 28 days).	Participants received Crizotinib 300 mg (3 capsules/tablet of 100 mg each) capsule/tablet orally BID for up to 34 cycles (each cycle 28 days) and 2 mg oral dose of Midazolam along with Crizotinib 300 mg on Cycle 2 Day 1 only. Participants who did not receive Crizotinib on Day -7, received single 2 mg oral dose of Midazolam on Day -7.	Participants received Crizotinib 300 mg (3 capsules/tablet of 100 mg each) capsule/tablet QD for up to 7 cycles (each cycle 28 days).	Participants received Crizotinib 400 mg (4 capsules/tablet of 100 mg each) capsule/tablet QD for up to 7 cycles (each cycle 28 days).	Participants received Crizotinib 500 mg (5 capsules/tablet of 100 mg each) capsule/tablet QD for up to 7 cycles (each cycle 28 days).	Participants received Crizotinib 650 mg (6 capsules/tablet of 100 mg each + 1 capsule/tablet of 50 mg) capsule/tablet twice daily (BID) for up to 7 cycles (each cycle 28 days).	Participants received Crizotinib 800 mg (8 capsules/tablet of 100 mg each) capsule/tablet QD for up to 7 cycles (each cycle 28 days).	Participants received Crizotinib 250 mg tablet/capsule (2 capsules/tablet of 100 mg each + 1 capsule/tablet of 50 mg) orally BID up to 124 months.
Overall Number of Participants Analyzed	3	4	8	4	5	4	6	3	3	5	4	24
Geometric Mean (Geometric Coefficient of Variation); Unit of Measure: nanogram per milliliter
	24.44; (68%)	85.66; (66%)	149.06; (29%)	188.84; (56%)	326.51; (24%)	420.15; (46%)	315.2; (50%)	215.5; (26%)	395.3; (16%)	379.2; (28%)	671.3; (76%)	411.11; (51%)

13. Primary Outcome

Title	Dose-Escalation and Recommended Phase 2 Dose (RP2D) Cohort: Maximum Observed Plasma Concentration (Cmax) of Crizotinib on Cycle 2 Day 1
Description	Cmax is defined as the observed maximum plasma concentration post drug administration.
Time Frame	Pre-dose, 1, 2, 4, 6, 8, 9 and 24 hours post dose on Cycle 2 Day 1

Outcome Measure Data

Analysis Population Description

The PK parameter analysis population included all participants treated (including Day -7 dose) who have at least 1 of the PK parameters of interest for Crizotinib. Here, "Overall number of participants analyzed" signifies number of participants evaluable for this outcome measure. Data for this outcome measures was planned to be collected for individual arms of dose escalation cohorts (both low and high) and combined RP2D Cohort.

Arm/Group Title	Low Dose Escalation Cohort: Crizotinib 50 mg QD	Low Dose Escalation Cohort: Crizotinib 100 mg QD	Low Dose Escalation Cohort: Crizotinib 200 mg QD	Low Dose Escalation Cohort: Crizotinib 200 mg BID	Low Dose Escalation Cohort: Crizotinib 250 mg BID	Low Dose Escalation Cohort: Crizotinib 300 mg BID	High Dose Escalation Cohort: Crizotinib 300 mg QD	High Dose Escalation Cohort: Crizotinib 400 mg QD	High Dose Escalation Cohort: Crizotinib 500 mg QD	High Dose Escalation Cohort: Crizotinib 650 mg QD	High Dose Escalation Cohort: Crizotinib 800 mg QD	RP2D Cohort: Crizotinib 250 mg
Arm/Group Description:	Participants received Crizotinib 50 milligram (mg) capsule or tablet orally once daily (QD) for up to 34 cycles (each cycle 28 days).	Participants received Crizotinib 100 mg capsule or tablet orally QD for up to 34 cycles (each cycle 28 days) and 2 mg oral dose of Midazolam along with Crizotinib 100 mg on Cycle 2 Day 1 only. Participants who did not receive Crizotinib on Day -7, received single 2 mg oral dose of Midazolam on Day -7.	Participants received Crizotinib 200 mg (2 capsules/tablet of 100 mg each) capsule/tablet orally QD for up to 34 cycles (each cycle 28 days).	Participants received Crizotinib 200 mg (2 capsules/tablet of 100 mg each) capsule/tablet orally twice daily (BID) for up to 34 cycles (each cycle 28 days).	Participants received Crizotinib 250 mg (2 capsules/tablet of 100 mg each + 1 capsule/tablet of 50 mg) capsule/tablet BID for up to 34 cycles (each cycle 28 days).	Participants received Crizotinib 300 mg (3 capsules/tablet of 100 mg each) capsule/tablet orally BID for up to 34 cycles (each cycle 28 days) and 2 mg oral dose of Midazolam along with Crizotinib 300 mg on Cycle 2 Day 1 only. Participants who did not receive Crizotinib on Day -7, received single 2 mg oral dose of Midazolam on Day -7.	Participants received Crizotinib 300 mg (3 capsules/tablet of 100 mg each) capsule/tablet QD for up to 7 cycles (each cycle 28 days).	Participants received Crizotinib 400 mg (4 capsules/tablet of 100 mg each) capsule/tablet QD for up to 7 cycles (each cycle 28 days).	Participants received Crizotinib 500 mg (5 capsules/tablet of 100 mg each) capsule/tablet QD for up to 7 cycles (each cycle 28 days).	Participants received Crizotinib 650 mg (6 capsules/tablet of 100 mg each + 1 capsule/tablet of 50 mg) capsule/tablet twice daily (BID) for up to 7 cycles (each cycle 28 days).	Participants received Crizotinib 800 mg (8 capsules/tablet of 100 mg each) capsule/tablet QD for up to 7 cycles (each cycle 28 days).	Participants received Crizotinib 250 mg tablet/capsule (2 capsules/tablet of 100 mg each + 1 capsule/tablet of 50 mg) orally BID up to 124 months.
Overall Number of Participants Analyzed	3	4	5	3	5	3	6	3	2	4	2	18
Geometric Mean (Geometric Coefficient of Variation); Unit of Measure: nanogram per milliliter
	47.99; (23%)	133.69; (48%)	146.26; (38%)	238.84; (12%)	327.94; (25%)	474.68; (43%)	275.0; (28%)	248.2; (60%)	327.9; (47%)	419.8; (36%)	700.0; (37%)	477.85; (44%)

14. Primary Outcome

Title	Dose-Escalation and Recommended Phase 2 Dose (RP2D) Cohort: Time to Reach Maximum Observed Plasma Concentration (Tmax) of Crizotinib on Day -7
Description	Tmax was defined as the time to reach the observed maximum plasma concentration (Cmax).
Time Frame	Pre-dose, 1, 2, 4, 6, 8, 9, 24, 48 and any two time points (72, 96, 120 and 144 hours) post-dose on Day -7

Outcome Measure Data

Analysis Population Description

PK parameter analysis population included all participants treated (including Day -7 dose) who had at least 1 of the PK parameters of interest for Crizotinib. Here, "N" signifies participants evaluable for this OM. Data for this OM was planned to be collected for individual arms of low and high dose escalation cohorts (excluding 'Low Dose Escalation Cohort: Crizotinib 100 mg QD' arm) and combined RP2D.

Arm/Group Title	Low Dose Escalation Cohort: Crizotinib 50 mg QD	Low Dose Escalation Cohort: Crizotinib 200 mg QD	Low Dose Escalation Cohort: Crizotinib 200 mg BID	Low Dose Escalation Cohort: Crizotinib 250 mg BID	Low Dose Escalation Cohort: Crizotinib 300 mg BID	High Dose Escalation Cohort: Crizotinib 300 mg QD	High Dose Escalation Cohort: Crizotinib 400 mg QD	High Dose Escalation Cohort: Crizotinib 500 mg QD	High Dose Escalation Cohort: Crizotinib 650 mg QD	High Dose Escalation Cohort: Crizotinib 800 mg QD	RP2D Cohort: Crizotinib 250 mg
Arm/Group Description:	Participants received Crizotinib 50 milligram (mg) capsule or tablet orally once daily (QD) for up to 34 cycles (each cycle 28 days).	Participants received Crizotinib 200 mg (2 capsules/tablet of 100 mg each) capsule/tablet orally QD for up to 34 cycles (each cycle 28 days).	Participants received Crizotinib 200 mg (2 capsules/tablet of 100 mg each) capsule/tablet orally twice daily (BID) for up to 34 cycles (each cycle 28 days).	Participants received Crizotinib 250 mg (2 capsules/tablet of 100 mg each + 1 capsule/tablet of 50 mg) capsule/tablet BID for up to 34 cycles (each cycle 28 days).	Participants received Crizotinib 300 mg (3 capsules/tablet of 100 mg each) capsule/tablet orally BID for up to 34 cycles (each cycle 28 days) and 2 mg oral dose of Midazolam along with Crizotinib 300 mg on Cycle 2 Day 1 only. Participants who did not receive Crizotinib on Day -7, received single 2 mg oral dose of Midazolam on Day -7.	Participants received Crizotinib 300 mg (3 capsules/tablet of 100 mg each) capsule/tablet QD for up to 7 cycles (each cycle 28 days).	Participants received Crizotinib 400 mg (4 capsules/tablet of 100 mg each) capsule/tablet QD for up to 7 cycles (each cycle 28 days).	Participants received Crizotinib 500 mg (5 capsules/tablet of 100 mg each) capsule/tablet QD for up to 7 cycles (each cycle 28 days).	Participants received Crizotinib 650 mg (6 capsules/tablet of 100 mg each + 1 capsule/tablet of 50 mg) capsule/tablet twice daily (BID) for up to 7 cycles (each cycle 28 days).	Participants received Crizotinib 800 mg (8 capsules/tablet of 100 mg each) capsule/tablet QD for up to 7 cycles (each cycle 28 days).	Participants received Crizotinib 250 mg tablet/capsule (2 capsules/tablet of 100 mg each + 1 capsule/tablet of 50 mg) orally BID up to 124 months.
Overall Number of Participants Analyzed	3	8	5	9	1	6	5	3	6	8	46
Median (Full Range); Unit of Measure: hour
	2.00; (1.75 to 4.08)	4.09; (1.08 to 6.00)	4.00; (4.00 to 4.08)	4.00; (1.00 to 8.95)	2.02; (2.02 to 2.02)	4.00; (2.00 to 6.00)	2.15; (1.00 to 6.00)	4.00; (2.00 to 8.00)	4.00; (1.98 to 6.00)	4.99; (2.15 to 6.13)	4.00; (2.00 to 9.33)

15. Primary Outcome

Title	Dose-Escalation and Recommended Phase 2 Dose (RP2D) Cohort: Time to Reach Maximum Observed Plasma Concentration (Tmax) of Crizotinib on Cycle 1 Day 1
Description	Tmax was defined as the time to reach the observed maximum plasma concentration (Cmax).
Time Frame	Pre-dose, 2, 4 and 6 hours post dose on Cycle 1 Day 1

Outcome Measure Data

Analysis Population Description

PK parameter analysis population included all participants treated (including Day -7 dose) who had at least 1 of the PK parameters of interest for Crizotinib. Here, "N" signifies participants evaluable for this OM. Data for this OM was planned to be collected for low dose escalation cohorts (excluding Crizotinib 50 mg QD, Crizotinib 200 mg QD and Crizotinib 250 mg BID arms) and combined RP2D cohort and was not planned to be collected for high dose escalation cohort.

Arm/Group Title	Low Dose Escalation Cohort: Crizotinib 100 mg QD	Low Dose Escalation Cohort: Crizotinib 200 mg BID	Low Dose Escalation Cohort: Crizotinib 300 mg BID	RP2D Cohort: Crizotinib 250 mg
Arm/Group Description:	Participants received Crizotinib 100 mg capsule or tablet orally QD for up to 34 cycles (each cycle 28 days) and 2 mg oral dose of Midazolam along with Crizotinib 100 mg on Cycle 2 Day 1 only. Participants who did not receive Crizotinib on Day -7, received single 2 mg oral dose of Midazolam on Day -7.	Participants received Crizotinib 200 mg (2 capsules/tablet of 100 mg each) capsule/tablet orally twice daily (BID) for up to 34 cycles (each cycle 28 days).	Participants received Crizotinib 300 mg (3 capsules/tablet of 100 mg each) capsule/tablet orally BID for up to 34 cycles (each cycle 28 days) and 2 mg oral dose of Midazolam along with Crizotinib 300 mg on Cycle 2 Day 1 only. Participants who did not receive Crizotinib on Day -7, received single 2 mg oral dose of Midazolam on Day -7.	Participants received Crizotinib 250 mg tablet/capsule (2 capsules/tablet of 100 mg each + 1 capsule/tablet of 50 mg) orally BID up to 124 months.
Overall Number of Participants Analyzed	4	2	5	98
Median (Full Range); Unit of Measure: hour
	2.52; (1.00 to 4.02)	4.00; (4.00 to 4.00)	4.00; (2.05 to 8.02)	4.05; (1.00 to 9.08)

16. Primary Outcome

Title	Dose-Escalation and Recommended Phase 2 Dose (RP2D) Cohort: Time to Reach Maximum Observed Plasma Concentration (Tmax) of Crizotinib on Cycle 1 Day 15
Description	Tmax was defined as the time to reach the observed maximum plasma concentration (Cmax).
Time Frame	Pre-dose, 1, 2, 4, 6, 8, 9 and 24 hours post dose on Cycle 1 Day 15

Outcome Measure Data

Analysis Population Description

The PK parameter analysis population included all participants treated (including Day -7 dose) who have at least 1 of the PK parameters of interest for Crizotinib. Here, "Overall number of participants analyzed" signifies number of participants evaluable for this outcome measure. Data for this outcome measures was planned to be collected for individual arms of dose escalation cohorts (both low and high) and combined RP2D Cohort.

Arm/Group Title	Low Dose Escalation Cohort: Crizotinib 50 mg QD	Low Dose Escalation Cohort: Crizotinib 100 mg QD	Low Dose Escalation Cohort: Crizotinib 200 mg QD	Low Dose Escalation Cohort: Crizotinib 200 mg BID	Low Dose Escalation Cohort: Crizotinib 250 mg BID	Low Dose Escalation Cohort: Crizotinib 300 mg BID	High Dose Escalation Cohort: Crizotinib 300 mg QD	High Dose Escalation Cohort: Crizotinib 400 mg QD	High Dose Escalation Cohort: Crizotinib 500 mg QD	High Dose Escalation Cohort: Crizotinib 650 mg QD	High Dose Escalation Cohort: Crizotinib 800 mg QD	RP2D Cohort: Crizotinib 250 mg
Arm/Group Description:	Participants received Crizotinib 50 milligram (mg) capsule or tablet orally once daily (QD) for up to 34 cycles (each cycle 28 days).	Participants received Crizotinib 100 mg capsule or tablet orally QD for up to 34 cycles (each cycle 28 days) and 2 mg oral dose of Midazolam along with Crizotinib 100 mg on Cycle 2 Day 1 only. Participants who did not receive Crizotinib on Day -7, received single 2 mg oral dose of Midazolam on Day -7.	Participants received Crizotinib 200 mg (2 capsules/tablet of 100 mg each) capsule/tablet orally QD for up to 34 cycles (each cycle 28 days).	Participants received Crizotinib 200 mg (2 capsules/tablet of 100 mg each) capsule/tablet orally twice daily (BID) for up to 34 cycles (each cycle 28 days).	Participants received Crizotinib 250 mg (2 capsules/tablet of 100 mg each + 1 capsule/tablet of 50 mg) capsule/tablet BID for up to 34 cycles (each cycle 28 days).	Participants received Crizotinib 300 mg (3 capsules/tablet of 100 mg each) capsule/tablet orally BID for up to 34 cycles (each cycle 28 days) and 2 mg oral dose of Midazolam along with Crizotinib 300 mg on Cycle 2 Day 1 only. Participants who did not receive Crizotinib on Day -7, received single 2 mg oral dose of Midazolam on Day -7.	Participants received Crizotinib 300 mg (3 capsules/tablet of 100 mg each) capsule/tablet QD for up to 7 cycles (each cycle 28 days).	Participants received Crizotinib 400 mg (4 capsules/tablet of 100 mg each) capsule/tablet QD for up to 7 cycles (each cycle 28 days).	Participants received Crizotinib 500 mg (5 capsules/tablet of 100 mg each) capsule/tablet QD for up to 7 cycles (each cycle 28 days).	Participants received Crizotinib 650 mg (6 capsules/tablet of 100 mg each + 1 capsule/tablet of 50 mg) capsule/tablet twice daily (BID) for up to 7 cycles (each cycle 28 days).	Participants received Crizotinib 800 mg (8 capsules/tablet of 100 mg each) capsule/tablet QD for up to 7 cycles (each cycle 28 days).	Participants received Crizotinib 250 mg tablet/capsule (2 capsules/tablet of 100 mg each + 1 capsule/tablet of 50 mg) orally BID up to 124 months.
Overall Number of Participants Analyzed	3	4	8	4	5	4	6	3	3	5	4	24
Median (Full Range); Unit of Measure: hour
	2.00; (1.00 to 4.00)	2.51; (0.00 to 6.08)	4.07; (1.00 to 6.00)	5.01; (2.08 to 8.03)	4.00; (0.97 to 6.07)	4.99; (3.98 to 6.22)	5.13; (1.93 to 7.88)	5.17; (0.933 to 6.00)	4.00; (4.00 to 9.00)	5.98; (4.00 to 6.00)	5.03; (4.00 to 6.03)	4.00; (0.00 to 9.03)

17. Primary Outcome

Title	Dose-Escalation and Recommended Phase 2 Dose (RP2D) Cohort: Time to Reach Maximum Observed Plasma Concentration (Tmax) of Crizotinib Cycle 2 Day 1
Description	Tmax was defined as the time to reach the observed maximum plasma concentration (Cmax).
Time Frame	Pre-dose, 1, 2, 4, 6, 8, 9 and 24 hours post dose on Cycle 2 Day 1

Outcome Measure Data

Analysis Population Description

The PK parameter analysis population included all participants treated (including Day -7 dose) who have at least 1 of the PK parameters of interest for Crizotinib. Here, "Overall number of participants analyzed" signifies number of participants evaluable for this outcome measure. Data for this outcome measures was planned to be collected for individual arms of dose escalation cohorts (both low and high) and combined RP2D Cohort.

Arm/Group Title	Low Dose Escalation Cohort: Crizotinib 50 mg QD	Low Dose Escalation Cohort: Crizotinib 100 mg QD	Low Dose Escalation Cohort: Crizotinib 200 mg QD	Low Dose Escalation Cohort: Crizotinib 200 mg BID	Low Dose Escalation Cohort: Crizotinib 250 mg BID	Low Dose Escalation Cohort: Crizotinib 300 mg BID	High Dose Escalation Cohort: Crizotinib 300 mg QD	High Dose Escalation Cohort: Crizotinib 400 mg QD	High Dose Escalation Cohort: Crizotinib 500 mg QD	High Dose Escalation Cohort: Crizotinib 650 mg QD	High Dose Escalation Cohort: Crizotinib 800 mg QD	RP2D Cohort: Crizotinib 250 mg
Arm/Group Description:	Participants received Crizotinib 50 milligram (mg) capsule or tablet orally once daily (QD) for up to 34 cycles (each cycle 28 days).	Participants received Crizotinib 100 mg capsule or tablet orally QD for up to 34 cycles (each cycle 28 days) and 2 mg oral dose of Midazolam along with Crizotinib 100 mg on Cycle 2 Day 1 only. Participants who did not receive Crizotinib on Day -7, received single 2 mg oral dose of Midazolam on Day -7.	Participants received Crizotinib 200 mg (2 capsules/tablet of 100 mg each) capsule/tablet orally QD for up to 34 cycles (each cycle 28 days).	Participants received Crizotinib 200 mg (2 capsules/tablet of 100 mg each) capsule/tablet orally twice daily (BID) for up to 34 cycles (each cycle 28 days).	Participants received Crizotinib 250 mg (2 capsules/tablet of 100 mg each + 1 capsule/tablet of 50 mg) capsule/tablet BID for up to 34 cycles (each cycle 28 days).	Participants received Crizotinib 300 mg (3 capsules/tablet of 100 mg each) capsule/tablet orally BID for up to 34 cycles (each cycle 28 days) and 2 mg oral dose of Midazolam along with Crizotinib 300 mg on Cycle 2 Day 1 only. Participants who did not receive Crizotinib on Day -7, received single 2 mg oral dose of Midazolam on Day -7.	Participants received Crizotinib 300 mg (3 capsules/tablet of 100 mg each) capsule/tablet QD for up to 7 cycles (each cycle 28 days).	Participants received Crizotinib 400 mg (4 capsules/tablet of 100 mg each) capsule/tablet QD for up to 7 cycles (each cycle 28 days).	Participants received Crizotinib 500 mg (5 capsules/tablet of 100 mg each) capsule/tablet QD for up to 7 cycles (each cycle 28 days).	Participants received Crizotinib 650 mg (6 capsules/tablet of 100 mg each + 1 capsule/tablet of 50 mg) capsule/tablet twice daily (BID) for up to 7 cycles (each cycle 28 days).	Participants received Crizotinib 800 mg (8 capsules/tablet of 100 mg each) capsule/tablet QD for up to 7 cycles (each cycle 28 days).	Participants received Crizotinib 250 mg tablet/capsule (2 capsules/tablet of 100 mg each + 1 capsule/tablet of 50 mg) orally BID up to 124 months.
Overall Number of Participants Analyzed	3	3	5	3	5	3	6	3	2	4	2	18
Median (Full Range); Unit of Measure: hour
	1.02; (1.00 to 4.00)	3.98; (2.00 to 4.02)	4.00; (2.00 to 4.17)	4.00; (3.95 to 4.00)	4.00; (4.00 to 6.00)	4.05; (3.98 to 9.00)	3.00; (1.00 to 5.95)	4.00; (2.08 to 6.00)	7.59; (6.18 to 9.00)	4.30; (4.00 to 9.00)	5.00; (4.00 to 6.00)	4.00; (0.00 to 9.02)

18. Primary Outcome

Title	Dose-Escalation and Recommended Phase 2 Dose (RP2D) Cohort: Plasma Decay Half-Life (t1/2) of Crizotinib on Day -7
Description	Plasma decay half-life is the time measured for the plasma concentration of Crizotinib to decrease by one half.
Time Frame	Pre-dose, 1, 2, 4, 6, 8, 9, 24, 48 and any two time points (72, 96, 120 and 144 hours) post-dose on Day -7

Outcome Measure Data

Analysis Population Description

PK parameter analysis population included all participants treated (including Day -7 dose) who had at least 1 of the PK parameters of interest for Crizotinib. Here, "N" signifies participants evaluable for this OM. Data for this OM was planned to be collected for individual arms of low and high dose escalation cohort and combined RP2D cohort excluding "Low Dose Escalation Cohort: Crizotinib 100 mg QD" arm.

Arm/Group Title	Low Dose Escalation Cohort: Crizotinib 50 mg QD	Low Dose Escalation Cohort: Crizotinib 200 mg QD	Low Dose Escalation Cohort: Crizotinib 200 mg BID	Low Dose Escalation Cohort: Crizotinib 250 mg BID	Low Dose Escalation Cohort: Crizotinib 300 mg BID	High Dose Escalation Cohort: Crizotinib 300 mg QD	High Dose Escalation Cohort: Crizotinib 400 mg QD	High Dose Escalation Cohort: Crizotinib 500 mg QD	High Dose Escalation Cohort: Crizotinib 650 mg QD	High Dose Escalation Cohort: Crizotinib 800 mg QD	RP2D Cohort: Crizotinib 250 mg
Arm/Group Description:	Participants received Crizotinib 50 milligram (mg) capsule or tablet orally once daily (QD) for up to 34 cycles (each cycle 28 days).	Participants received Crizotinib 200 mg (2 capsules/tablet of 100 mg each) capsule/tablet orally QD for up to 34 cycles (each cycle 28 days).	Participants received Crizotinib 200 mg (2 capsules/tablet of 100 mg each) capsule/tablet orally twice daily (BID) for up to 34 cycles (each cycle 28 days).	Participants received Crizotinib 250 mg (2 capsules/tablet of 100 mg each + 1 capsule/tablet of 50 mg) capsule/tablet BID for up to 34 cycles (each cycle 28 days).	Participants received Crizotinib 300 mg (3 capsules/tablet of 100 mg each) capsule/tablet orally BID for up to 34 cycles (each cycle 28 days) and 2 mg oral dose of Midazolam along with Crizotinib 300 mg on Cycle 2 Day 1 only. Participants who did not receive Crizotinib on Day -7, received single 2 mg oral dose of Midazolam on Day -7.	Participants received Crizotinib 300 mg (3 capsules/tablet of 100 mg each) capsule/tablet QD for up to 7 cycles (each cycle 28 days).	Participants received Crizotinib 400 mg (4 capsules/tablet of 100 mg each) capsule/tablet QD for up to 7 cycles (each cycle 28 days).	Participants received Crizotinib 500 mg (5 capsules/tablet of 100 mg each) capsule/tablet QD for up to 7 cycles (each cycle 28 days).	Participants received Crizotinib 650 mg (6 capsules/tablet of 100 mg each + 1 capsule/tablet of 50 mg) capsule/tablet twice daily (BID) for up to 7 cycles (each cycle 28 days).	Participants received Crizotinib 800 mg (8 capsules/tablet of 100 mg each) capsule/tablet QD for up to 7 cycles (each cycle 28 days).	Participants received Crizotinib 250 mg tablet/capsule (2 capsules/tablet of 100 mg each + 1 capsule/tablet of 50 mg) orally BID up to 124 months.
Overall Number of Participants Analyzed	3	7	2	8	1	5	5	2	6	8	31
Median (Full Range); Unit of Measure: hour
	48.20; (45.50 to 56.80)	46.70; (30.40 to 67.20)	52.60; (51.70 to 53.50)	47.35; (36.80 to 57.70)	45.70; (45.70 to 45.70)	43.33; (35.4 to 52.3)	49.06; (33.2 to 79.3)	46.36; (43.0 to 49.8)	42.17; (28.3 to 53.8)	38.78; (30.9 to 55.3)	43.20; (27.10 to 63.40)

19. Primary Outcome

Title	Dose-Escalation and Recommended Phase 2 Dose (RP2D) Cohort: Number of Participants With Treatment Emergent Adverse Events (TEAES) and Serious Adverse Events (SAEs)
Description	An AE was any untoward medical occurrence in a participant who received investigational product without regard to possibility of causal relationship. SAE was an AE resulting in any of the following outcomes or deemed significant for any other reason: death; initial or prolonged inpatient hospitalization; life-threatening experience (immediate risk of dying); persistent or significant disability/incapacity; congenital anomaly; medically important events. AEs included both serious and all non-serious adverse events. TEAEs were those with initial onset or increasing in severity on or after the first dose of investigational product administration.
Time Frame	up to 189 Months

Outcome Measure Data

Analysis Population Description

SA set included all enrolled participants who received at least one dose of Crizotinib on Cycle 1 Day 1.

Arm/Group Title	Low Dose Escalation Cohort: Crizotinib 50 mg QD	Low Dose Escalation Cohort: Crizotinib 100 mg QD	Low Dose Escalation Cohort: Crizotinib 200 mg QD	Low Dose Escalation Cohort: Crizotinib 200 mg BID	Low Dose Escalation Cohort: Crizotinib 250 mg BID	Low Dose Escalation Cohort: Crizotinib 300 mg BID	High Dose Escalation Cohort: Crizotinib 300 mg QD	High Dose Escalation Cohort: Crizotinib 400 mg QD	High Dose Escalation Cohort: Crizotinib 500 mg QD	High Dose Escalation Cohort: Crizotinib 650 mg QD	High Dose Escalation Cohort: Crizotinib 800 mg QD	RP2D Cohort: ROS1-Positive NSCLC: Crizotinib 250	RP2D Cohort: MET Exon 14 Alterations NSCLC: Crizotinib 250 mg	RP2D Cohort: MET Amplification NSCLC: Crizotinib 250 mg	RP2D Cohort: ALK-Negative Cohort 1, NSCLC: Crizotinib 250 mg	RP2D Cohort: ALK-Negative Cohort 2, NSCLC: Crizotinib 250 mg	RP2D Cohort: ALK-Positive Cohort, NSCLC: Crizotinib 250 mg	RP2D Cohort: Enriched Other: Crizotinib 250 mg	RP2D Cohort: Itraconazole Interaction: Crizotinib 250 mg +Itraconazole	RP2D Cohort: Rifampin Interaction: Crizotinib 250 mg +Rifampin	RP2D Cohort: Midazolam Interaction: Crizotinib 250 mg +Midazolam
Arm/Group Description:	Participants received Crizotinib 50 milligram (mg) capsule or tablet orally once daily (QD) for up to 34 cycles (each cycle 28 days).	Participants received Crizotinib 100 mg capsule or tablet orally QD for up to 34 cycles (each cycle 28 days) and 2 mg oral dose of Midazolam along with Crizotinib 100 mg on Cycle 2 Day 1 only. Participants who did not receive Crizotinib on Day -7, received single 2 mg oral dose of Midazolam on Day -7.	Participants received Crizotinib 200 mg (2 capsules/tablet of 100 mg each) capsule/tablet orally QD for up to 34 cycles (each cycle 28 days).	Participants received Crizotinib 200 mg (2 capsules/tablet of 100 mg each) capsule/tablet orally twice daily (BID) for up to 34 cycles (each cycle 28 days).	Participants received Crizotinib 250 mg (2 capsules/tablet of 100 mg each + 1 capsule/tablet of 50 mg) capsule/tablet BID for up to 34 cycles (each cycle 28 days).	Participants received Crizotinib 300 mg (3 capsules/tablet of 100 mg each) capsule/tablet orally BID for up to 34 cycles (each cycle 28 days) and 2 mg oral dose of Midazolam along with Crizotinib 300 mg on Cycle 2 Day 1 only. Participants who did not receive Crizotinib on Day -7, received single 2 mg oral dose of Midazolam on Day -7.	Participants received Crizotinib 300 mg (3 capsules/tablet of 100 mg each) capsule/tablet QD for up to 7 cycles (each cycle 28 days).	Participants received Crizotinib 400 mg (4 capsules/tablet of 100 mg each) capsule/tablet QD for up to 7 cycles (each cycle 28 days).	Participants received Crizotinib 500 mg (5 capsules/tablet of 100 mg each) capsule/tablet QD for up to 7 cycles (each cycle 28 days).	Participants received Crizotinib 650 mg (6 capsules/tablet of 100 mg each + 1 capsule/tablet of 50 mg) capsule/tablet twice daily (BID) for up to 7 cycles (each cycle 28 days).	Participants received Crizotinib 800 mg (8 capsules/tablet of 100 mg each) capsule/tablet QD for up to 7 cycles (each cycle 28 days).	Participants received Crizotinib 250 mg (2 capsules/tablet of 100 mg each + 1 capsule/tablet of 50 mg) capsule/tablet orally twice daily (BID) with or without food for up to 105 cycles (each cycle 28 days)	Participants received Crizotinib 250 mg (2 capsules/tablet of 100 mg each + 1 capsule/tablet of 50 mg) capsule/tablet orally twice daily (BID) with or without food for up to 55 cycles (each cycle 28 days).	Participants received Crizotinib 250 mg (2 capsules/tablet of 100 mg each + 1 capsule/tablet of 50 mg) capsule/tablet orally twice daily (BID) with or without food for up to 101 cycles (each cycle 28 days).	Participants received Crizotinib 250 mg (2 capsules/tablet of 100 mg each + 1 capsule/tablet of 50 mg) capsule/tablet twice daily (BID) with or without food for up to 70 cycles (each cycle 21 days).	Participants received Crizotinib 250 mg (2 capsules/tablet of 100 mg each + 1 capsule/tablet of 50 mg) capsule/tablet orally BID with or without food for up to 70 cycles (each cycle 21 days).	Participants received Crizotinib 250 mg (2 capsules/tablet of 100 mg each + 1 capsule/tablet of 50 mg) capsule/tablet twice daily (BID) with or without food for up to 133 cycles (each cycle 28 days).	Participants received Crizotinib 250 mg (2 capsules/tablet of 100 mg each + 1 capsule/tablet of 50 mg) capsule/tablet orally twice daily (BID) with or without food for up to 54 cycles (each cycle 28 days).	Participants received with or without food Crizotinib 250 mg (2 capsules/tablet of 100 mg each + 1 capsule/tablet of 50 mg) capsule/tablet QD from Cycle 1Day1 to Cycle 2 Day1 thereafter 250 mg BID from Cycle 2 Day 2 up to 58 cycles (each cycle 28 days). Participants also received Itraconazole 200 mg QD from Cycle 1 Day 1 to Cycle 1 Day 16.	Participants received Crizotinib 250 mg (2 capsules/tablet of 100 mg each + 1 capsule/tablet of 50 mg) capsule/tablet twice daily (BID) with or without food from Cycle 1 Day 1 up to 13 cycles (each cycle 28 days). Participants also received commercially available Rifampin 650 mg QD from Cycle 1 Day 16 to Cycle 2 Day 1 (14 days) either one hour before or 2 hours after food.	Participants received Crizotinib 250 mg tablet/capsule (2 capsules/tablet of 100 mg each + 1 capsule/tablet of 50 mg) orally BID with or without food from Day 1 Cycle 1 up to 133 cycles (each cycle 28 days). Participants also received single 2 mg oral dose of Midazolam on Day -7 and another single 2-mg oral dose of Midazolam concurrently with Crizotinib on Cycle 2 Day 1
Overall Number of Participants Analyzed	3	4	8	7	8	6	6	5	3	6	9	53	85	41	48	18	154	66	18	18	12
Measure Type: Count of Participants; Unit of Measure: Participants
AEs	3 100.0%	4 100.0%	8 100.0%	7 100.0%	8 100.0%	6 100.0%	6 100.0%	4 80.0%	3 100.0%	6 100.0%	9 100.0%	53 100.0%	85 100.0%	41 100.0%	47 97.9%	18 100.0%	154 100.0%	66 100.0%	18 100.0%	18 100.0%	12 100.0%
SAEs	0 0.0%	0 0.0%	1 12.5%	2 28.6%	4 50.0%	2 33.3%	2 33.3%	2 40.0%	1 33.3%	2 33.3%	4 44.4%	24 45.3%	54 63.5%	25 61.0%	22 45.8%	9 50.0%	75 48.7%	29 43.9%	7 38.9%	6 33.3%	6 50.0%

20. Primary Outcome

Title	Dose-Escalation Cohort: Number of Participants With Dose-limiting Toxicities (DLT)
Description	Dose-limiting toxicity (DLT) was defined as any of the following: Hematologic- prolonged grade 4 neutropenia for >7 days. Febrile neutropenia, defined as grade 4 neutropenia with fever greater than (>)38.5 degree Celsius, both sustained over a 24 hour period, neutropenic infection: greater than or equal to (>=)Grade 3 neutropenia with Grade >=3 infection. Grade >=3 thrombocytopenia with bleeding or grade 4 lasting >=7 days Lymphopenia was not considered a DLT unless accompanied by infection. Other non-hematologic toxicity: Grade 3 or 4 toxicities (except for alopecia, Grade 3/4 hypophosphatemia, grade 3 hypertension with controlled blood pressure [less than (<) 140/90], and Grade 3/4 hyperuricemia without signs and symptoms of gout). Nausea, vomiting or diarrhea must persist at grade 3 or 4 despite maximal medical therapy.
Time Frame	Cycle 1 (28 days)

Outcome Measure Data

Analysis Population Description

SA set included all enrolled participants who received at least one dose of Crizotinib on Cycle 1 Day 1.

Arm/Group Title	Low Dose Escalation Cohort: Crizotinib 50 mg QD	Low Dose Escalation Cohort: Crizotinib 100 mg QD	Low Dose Escalation Cohort: Crizotinib 200 mg QD	Low Dose Escalation Cohort: Crizotinib 200 mg BID	Low Dose Escalation Cohort: Crizotinib 250 mg BID	Low Dose Escalation Cohort: Crizotinib 300 mg BID	High Dose Escalation Cohort: Crizotinib 300 mg QD	High Dose Escalation Cohort: Crizotinib 400 mg QD	High Dose Escalation Cohort: Crizotinib 500 mg QD	High Dose Escalation Cohort: Crizotinib 650 mg QD	High Dose Escalation Cohort: Crizotinib 800 mg QD
Arm/Group Description:	Participants received Crizotinib 50 milligram (mg) capsule or tablet orally once daily (QD) for up to 34 cycles (each cycle 28 days).	Participants received Crizotinib 100 mg capsule or tablet orally QD for up to 34 cycles (each cycle 28 days) and 2 mg oral dose of Midazolam along with Crizotinib 100 mg on Cycle 2 Day 1 only. Participants who did not receive Crizotinib on Day -7, received single 2 mg oral dose of Midazolam on Day -7.	Participants received Crizotinib 200 mg (2 capsules/tablet of 100 mg each) capsule/tablet orally QD for up to 34 cycles (each cycle 28 days).	Participants received Crizotinib 200 mg (2 capsules/tablet of 100 mg each) capsule/tablet orally twice daily (BID) for up to 34 cycles (each cycle 28 days).	Participants received Crizotinib 250 mg (2 capsules/tablet of 100 mg each + 1 capsule/tablet of 50 mg) capsule/tablet BID for up to 34 cycles (each cycle 28 days).	Participants received Crizotinib 300 mg (3 capsules/tablet of 100 mg each) capsule/tablet orally BID for up to 34 cycles (each cycle 28 days) and 2 mg oral dose of Midazolam along with Crizotinib 300 mg on Cycle 2 Day 1 only. Participants who did not receive Crizotinib on Day -7, received single 2 mg oral dose of Midazolam on Day -7.	Participants received Crizotinib 300 mg (3 capsules/tablet of 100 mg each) capsule/tablet QD for up to 7 cycles (each cycle 28 days).	Participants received Crizotinib 400 mg (4 capsules/tablet of 100 mg each) capsule/tablet QD for up to 7 cycles (each cycle 28 days).	Participants received Crizotinib 500 mg (5 capsules/tablet of 100 mg each) capsule/tablet QD for up to 7 cycles (each cycle 28 days).	Participants received Crizotinib 650 mg (6 capsules/tablet of 100 mg each + 1 capsule/tablet of 50 mg) capsule/tablet twice daily (BID) for up to 7 cycles (each cycle 28 days).	Participants received Crizotinib 800 mg (8 capsules/tablet of 100 mg each) capsule/tablet QD for up to 7 cycles (each cycle 28 days).
Overall Number of Participants Analyzed	3	4	8	7	8	6	6	5	3	6	9
Measure Type: Count of Participants; Unit of Measure: Participants
	0 0.0%	0 0.0%	1 12.5%	0 0.0%	0 0.0%	2 33.3%	0 0.0%	0 0.0%	0 0.0%	0 0.0%	0 0.0%

21. Primary Outcome

Title	Midazolam Interaction Cohort: Maximum Observed Plasma Concentration (Cmax) of Midazolam When Taken Alone or Taken With Crizotinib
Description	Cmax is defined as the observed maximum plasma concentration post drug administration.
Time Frame	pre-dose, 0.5, 1, 2, 4, 6, 8, 9, and 24 hours post dose on Day -7 (midazolam alone arm), pre-dose, 0.5, 1, 2, 4, 6, 8, 9, and 24 hours post dose on Cycle 2 Day 1 (midazolam with crizotinib arm)

Outcome Measure Data

Analysis Population Description

The PK concentration population of midazolam included all participants treated with midazolam (including Day -7 dose) who have at least 1 concentration of midazolam.

Arm/Group Title	Low Dose Escalation Cohort: Crizotinib 100 mg QD (Midazolam Alone)	Low Dose Escalation Cohort: Crizotinib 100 mg QD + Midazolam	Low Dose Escalation Cohort: Crizotinib 300 mg BID (Midazolam Alone)	Low Dose Escalation Cohort: Crizotinib 300 mg BID + Midazolam	RP2D Cohort: Crizotinib 250 mg (Midazolam Alone)	RP2D Cohort: Crizotinib 250 mg + Midazolam
Arm/Group Description:	Participants who did not receive Crizotinib on Day -7, received single 2 mg oral dose of Midazolam on Day -7.	Participants received Crizotinib 100 mg capsule or tablet orally QD along with single 2 mg oral dose of Midazolam on Cycle 2 Day 1.	Participants who did not receive Crizotinib 300 mg (3 capsules/tablet of 100 mg each) capsule/tablet BID on Day -7, received single 2 mg oral dose of Midazolam on Day -7.	Participants received Crizotinib 300 mg (3 capsules/tablet of 100 mg each) capsule/tablet orally BID along with 2 mg oral dose of Midazolam on Cycle 2 Day 1.	Participants who did not receive Crizotinib 250 mg (2 capsules/tablet of 100 mg each + 1 capsule/tablet of 50 mg) capsule/tablet on Day -7, received single 2 mg oral dose of Midazolam on Day -7.	Participants received Crizotinib 250 mg (2 capsules/tablet of 100 mg each + 1 capsule/tablet of 50 mg) BID along with single 2 mg oral dose of Midazolam on Cycle 2 Day 1.
Overall Number of Participants Analyzed	4	3	5	2	14	8
Geometric Mean (Geometric Coefficient of Variation); Unit of Measure: nanogram per milliliter
	14.98; (19%)	19.26; (38%)	13.65; (10%)	32.62; (40%)	12.78; (41%)	25.37; (67%)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Low Dose Escalation Cohort: Crizotinib 100 mg QD (Midazolam Alone), Low Dose Escalation Cohort: Crizotinib 100 mg QD + Midazolam
	Comments	[Not Specified]
	Type of Statistical Test	Superiority
	Comments	[Not Specified]
Method of Estimation	Estimation Parameter	Ratio of adjusted geometric means
	Estimated Value	131.72
	Confidence Interval	(2-Sided) 90%; 96.59 to 179.63
	Estimation Comments	[Not Specified]

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Low Dose Escalation Cohort: Crizotinib 300 mg BID (Midazolam Alone), Low Dose Escalation Cohort: Crizotinib 300 mg BID + Midazolam
	Comments	[Not Specified]
	Type of Statistical Test	Superiority
	Comments	[Not Specified]
Method of Estimation	Estimation Parameter	Ratio of adjusted geometric means
	Estimated Value	239.03
	Confidence Interval	(2-Sided) 90%; 172.14 to 331.93
	Estimation Comments	[Not Specified]

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	RP2D Cohort: Crizotinib 250 mg (Midazolam Alone), RP2D Cohort: Crizotinib 250 mg + Midazolam
	Comments	[Not Specified]
	Type of Statistical Test	Superiority
	Comments	[Not Specified]
Method of Estimation	Estimation Parameter	Ratio of adjusted geometric means
	Estimated Value	201.56
	Confidence Interval	(2-Sided) 90%; 139.33 to 291.58
	Estimation Comments	[Not Specified]

22. Primary Outcome

Title	Area Under the Curve From Time Zero to Extrapolated Infinite Time (AUCinf) of Midazolam When Taken Alone or Taken With Crizotinib
Description	AUCinf = Area under the plasma concentration versus time curve (AUC) from time zero (pre-dose) to extrapolated infinite time (0-inf).
Time Frame	pre-dose, 0.5, 1, 2, 4, 6, 8, 9, and 24 hours post dose on Day -7 (midazolam alone arm), pre-dose, 0.5, 1, 2, 4, 6, 8, 9, and 24 hours post dose on Cycle 2 Day 1 (midazolam with crizotinib arm)

Outcome Measure Data

Analysis Population Description

The PK concentration population of midazolam included all participants treated with midazolam (including Day -7 dose) who have at least 1 concentration of midazolam.

Arm/Group Title	Low Dose Escalation Cohort: Crizotinib 100 mg QD (Midazolam Alone)	Low Dose Escalation Cohort: Crizotinib 100 mg QD + Midazolam	Low Dose Escalation Cohort: Crizotinib 300 mg BID (Midazolam Alone)	Low Dose Escalation Cohort: Crizotinib 300 mg BID + Midazolam	RP2D Cohort: Crizotinib 250 mg (Midazolam Alone)	RP2D Cohort: Crizotinib 250 mg +Midazolam
Arm/Group Description:	Participants who did not receive Crizotinib on Day -7, received single 2 mg oral dose of Midazolam on Day -7.	Participants received Crizotinib 100 mg capsule or tablet orally QD along with single 2 mg oral dose of Midazolam on Cycle 2 Day 1.	Participants who did not receive Crizotinib 300 mg (3 capsules/tablet of 100 mg each) capsule/tablet BID on Day -7, received single 2 mg oral dose of Midazolam on Day -7.	Participants received Crizotinib 300 mg (3 capsules/tablet of 100 mg each) capsule/tablet orally BID along with 2 mg oral dose of Midazolam on Cycle 2 Day 1.	Participants who did not receive Crizotinib 250 mg (2 capsules/tablet of 100 mg each + 1 capsule/tablet of 50 mg) capsule/tablet on Day -7, received single 2 mg oral dose of Midazolam on Day -7	Participants received Crizotinib 250 mg (2 capsules/tablet of 100 mg each + 1 capsule/tablet of 50 mg) BID along with single 2 mg oral dose of Midazolam on Cycle 2 Day 1.
Overall Number of Participants Analyzed	4	3	5	2	14	8
Geometric Mean (Geometric Coefficient of Variation); Unit of Measure: nanogram*hour per milliliter
	41.77; (27%)	90.78; (33%)	37.71; (38%)	151.45; (31%)	32.10; (36%)	112.78; (87%)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Low Dose Escalation Cohort: Crizotinib 100 mg QD (Midazolam Alone), Low Dose Escalation Cohort: Crizotinib 100 mg QD + Midazolam
	Comments	[Not Specified]
	Type of Statistical Test	Superiority
	Comments	[Not Specified]
Method of Estimation	Estimation Parameter	Ratio of adjusted geometric means
	Estimated Value	216.19
	Confidence Interval	(2-Sided) 90%; 161.41 to 289.56
	Estimation Comments	[Not Specified]

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Low Dose Escalation Cohort: Crizotinib 300 mg BID (Midazolam Alone), Low Dose Escalation Cohort: Crizotinib 300 mg BID + Midazolam
	Comments	[Not Specified]
	Type of Statistical Test	Superiority
	Comments	[Not Specified]
Method of Estimation	Estimation Parameter	Ratio of adjusted geometric means
	Estimated Value	350.00
	Confidence Interval	(2-Sided) 90%; 141.09 to 868.23
	Estimation Comments	[Not Specified]

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	RP2D Cohort: Crizotinib 250 mg (Midazolam Alone), RP2D Cohort: Crizotinib 250 mg +Midazolam
	Comments	[Not Specified]
	Type of Statistical Test	Superiority
	Comments	[Not Specified]
Method of Estimation	Estimation Parameter	Ratio of adjusted geometric means
	Estimated Value	365.43
	Confidence Interval	(2-Sided) 90%; 263.22 to 507.31
	Estimation Comments	[Not Specified]

23. Primary Outcome

Title	RP2D Cohort: Area Under the Curve From Time Zero to Last Quantifiable Concentration [AUC (0-24)] of Crizotinib When Taken With Food
Description	AUC0-24 of Crizotinib was defined as the area under the free plasma concentration time curve from time 0 to 24 hours post-dose.
Time Frame	pre-dose, 1, 2, 4, 6, 8, 9, and 24 hours post-dose on Day -7

Outcome Measure Data

Analysis Population Description

The food effect analysis set included all participants treated (including Day -7 dose) and in the RP2D cohort who had received a dose of crizotinib under fed conditions and for which at least 1 PK parameter of interest (Cmax or AUC) was available. Here, "Overall number of participants analyzed" signifies number of participants evaluable for this outcome measure.

Arm/Group Title	RP2D Cohort: Crizotinib 250 mg With Food
Arm/Group Description:	Participants who were enrolled in enriched RP2D cohort received single dose of Crizotinib 250 mg tablet/capsule (2 capsules/tablet of 100 mg each + 1 capsule/tablet of 50 mg) orally with food on Day -7.
Overall Number of Participants Analyzed	8
Geometric Mean (Geometric Coefficient of Variation); Unit of Measure: nanogram*hour per milliliter
	1212.86; (46%)

24. Primary Outcome

Title	RP2D Cohort: Maximum Observed Plasma Concentration (Cmax) of Crizotinib When Taken With Food
Description	Cmax is defined as the observed maximum plasma concentration post drug administration.
Time Frame	pre-dose, 1, 2, 4, 6, 8, 9, and 24 hours post-dose on Day -7

Outcome Measure Data

Analysis Population Description

The food effect analysis set included all participants treated (including Day -7 dose) and in the RP2D cohort who had received a dose of crizotinib under fed conditions and for which at least 1 PK parameter of interest (Cmax or AUC) was available. Here, "Overall number of participants analyzed" signifies number of participants evaluable for this outcome measure.

Arm/Group Title	RP2D Cohort: Crizotinib 250 mg With Food
Arm/Group Description:	Participants who were enrolled in enriched RP2D cohort received single dose of Crizotinib 250 mg tablet/capsule (2 capsules/tablet of 100 mg each + 1 capsule/tablet of 50 mg) orally with food on Day -7.
Overall Number of Participants Analyzed	11
Geometric Mean (Geometric Coefficient of Variation); Unit of Measure: nanogram per milliliter
	106.24; (51%)

25. Primary Outcome

Title	Area Under the Curve From Time Zero to End of Dosing Interval (AUCtau) of Crizotinib Alone and When Taken With Rifampin
Description	Area under the plasma concentration versus time curve from time 0 to end of dosing interval (AUCtau).
Time Frame	pre-dose, 2, 4, 6, 8 and 10 hours on Cycle 1 Day 15 (Crizotinib alone arm) and Cycle 2 Day 1 (Crizotinib with Rifampin arm)

Outcome Measure Data

Analysis Population Description

PK parameter population was defined as all participants in the Rifampin interaction cohort safety population who satisfied following criteria for Cycle 1 Day 15 or Cycle 2 Day 1: a) had at least 1 of the primary PK parameters of Crizotinib (AUCtau and Cmax). b) received adequate dosing prior to PK sampling. Here, "Overall number of participants analyzed" signifies number of participants evaluable for this outcome measure.

Arm/Group Title	RP2D Cohort: Rifampin Interaction: Crizotinib 250 mg Alone	RP2D Cohort: Rifampin Interaction: Crizotinib 250 mg With Rifampin
Arm/Group Description:	Participants received Crizotinib 250 mg (2 capsules/tablet of 100 mg each + 1 capsule/tablet of 50 mg) capsule/tablet twice daily (BID) with or without food from Cycle 1 Day 1 up to 13 cycles (each cycle 28 days).	Participants received Crizotinib 250 mg (2 capsules/tablet of 100 mg each + 1 capsule/tablet of 50 mg) capsule/tablet twice daily (BID) form Cycle 1Day 1 up to 13 cycles (each cycle 28 days). Participants also received commercially available Rifampin 650 mg QD from Cycle 1 Day 16 to Cycle 2 Day 1 (14 days) either one hour before or 2 hours after a meal.
Overall Number of Participants Analyzed	10	7
Geometric Mean (Geometric Coefficient of Variation); Unit of Measure: nanogram*hour per milliliter
	3110; (49%)	509.6; (35%)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	RP2D Cohort: Rifampin Interaction: Crizotinib 250 mg Alone, RP2D Cohort: Rifampin Interaction: Crizotinib 250 mg With Rifampin
	Comments	[Not Specified]
	Type of Statistical Test	Superiority
	Comments	[Not Specified]
Method of Estimation	Estimation Parameter	Ratio of adjusted geometric mean
	Estimated Value	15.57
	Confidence Interval	(2-Sided) 90%; 10.89 to 22.26
	Estimation Comments	[Not Specified]

26. Primary Outcome

Title	Rifampin Cohort: Maximum Observed Plasma Concentration (Cmax) of Crizotinib Alone and When Taken With Rifampin
Description	[Not Specified]
Time Frame	pre-dose, 2, 4, 6, 8 and 10 hours on Cycle 1 Day 15 (Crizotinib alone) and Cycle 2 Day 1 (Crizotinib with Rifampin)

Outcome Measure Data

Analysis Population Description

PK parameter population was defined as all participants in the Rifampin interaction cohort safety population who satisfied following criteria for Cycle 1 Day 15 or Cycle 2 Day 1: a) had at least 1 of the primary PK parameters of Crizotinib (AUCtau and Cmax). b) Received adequate dosing prior to PK sampling. Here, "Overall number of participants analyzed" signifies number of participants evaluable for this outcome measure.

Arm/Group Title	RP2D Cohort: Rifampin Interaction: Crizotinib 250 mg Alone	RP2D Cohort: Rifampin Interaction: Crizotinib 250 mg With Rifampin
Arm/Group Description:	Participants received Crizotinib 250 mg (2 capsules/tablet of 100 mg each + 1 capsule/tablet of 50 mg) capsule/tablet twice daily (BID) with or without food from Cycle 1 Day 1 up to 13 cycles (each cycle 28 days).	Participants received Crizotinib 250 mg (2 capsules/tablet of 100 mg each + 1 capsule/tablet of 50 mg) capsule/tablet twice daily (BID) form Cycle 1Day 1 up to 13 cycles (each cycle 28 days). Participants also received commercially available Rifampin 650 mg QD from Cycle 1 Day 16 to Cycle 2 Day 1 (14 days) either one hour before or 2 hours after a meal.
Overall Number of Participants Analyzed	10	7
Geometric Mean (Geometric Coefficient of Variation); Unit of Measure: nanogram per milliliter
	326.4; (48%)	71.53; (49%)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	RP2D Cohort: Rifampin Interaction: Crizotinib 250 mg Alone, RP2D Cohort: Rifampin Interaction: Crizotinib 250 mg With Rifampin
	Comments	[Not Specified]
	Type of Statistical Test	Superiority
	Comments	[Not Specified]
Method of Estimation	Estimation Parameter	Ratio of adjusted geometric mean
	Estimated Value	20.64
	Confidence Interval	(2-Sided) 90%; 14.59 to 29.18
	Estimation Comments	[Not Specified]

27. Primary Outcome

Title	Rifampin Cohort: Ctrough of Crizotinib Alone and When Taken With Rifampin
Description	Ctrough refers to plasma concentration of Crizotinib observed just before treatment administration.
Time Frame	pre-dose on Cycle 1 Day 15 (Crizotinib alone arm) and Cycle 2 Day 1 (Crizotinib with Rifampin arm)

Outcome Measure Data

Analysis Population Description

PK parameter population was defined as all participants in the Rifampin interaction cohort safety population who satisfied following criteria for Cycle 1 Day 15 or Cycle 2 Day 1: a) had at least 1 of the primary PK parameters of Crizotinib (AUCtau and Cmax). b) Received adequate dosing prior to PK sampling. Here, "Overall number of participants analyzed" signifies number of participants evaluable for this outcome measure.

Arm/Group Title	RP2D Cohort: Rifampin Interaction: Crizotinib 250 mg Alone	RP2D Cohort: Rifampin Interaction: Crizotinib 250 mg With Rifampin
Arm/Group Description:	Participants received Crizotinib 250 mg (2 capsules/tablet of 100 mg each + 1 capsule/tablet of 50 mg) capsule/tablet twice daily (BID) with or without food from Cycle 1 Day 1 up to 13 cycles (each cycle 28 days).	Participants received Crizotinib 250 mg (2 capsules/tablet of 100 mg each + 1 capsule/tablet of 50 mg) capsule/tablet twice daily (BID) form Cycle 1Day 1 up to 13 cycles (each cycle 28 days). Participants also received commercially available Rifampin 650 mg QD from Cycle 1 Day 16 to Cycle 2 Day 1 (14 days) either one hour before or 2 hours after a meal.
Overall Number of Participants Analyzed	9	7
Geometric Mean (Geometric Coefficient of Variation); Unit of Measure: nanogram per milliliter
	251.7; (46%)	26.67; (50%)

28. Primary Outcome

Title	Itraconazole Cohort: Area Under the Curve From Time Zero to End of Dosing Interval (AUCtau) of Crizotinib When Taken Alone and When Taken With Itraconazole
Description	Area under the plasma concentration versus time curve from time 0 to end of dosing interval (AUCtau), where dosing interval is 24 hours.
Time Frame	pre-dose, 1, 2, 4, 6, 8, 9 and 24 hours post dose on Cycle 1 Day 15 (Crizotinib with itraconazole) and Cycle 2 Day 1 (itraconazole alone)

Outcome Measure Data

Analysis Population Description

PK parameter evaluable population included participants who had at least 1 of the PK parameters of Crizotinib (AUCtau or Cmax) and had received 10 consecutive doses of both Crizotinib 250 mg QD and itraconazole 200 mg QD immediately prior to end of Crizotinib 250 mg + Itraconazole treatment as well as 10 consecutive doses of Crizotinib 250 mg QD prior to end of Crizotinib 250 mg + Itraconazole treatment. Overall number of participants analyzed =participants evaluable for this outcome measure.

Arm/Group Title	RP2D Cohort: Itraconazole Interaction: Crizotinib 250 mg Alone	Itraconazole Interaction Cohort: Crizotinib 250 mg + Itraconazole
Arm/Group Description:	Participants received with or without food Crizotinib 250 mg (2 capsules/tablet of 100 mg each + 1 capsule/tablet of 50 mg) capsule/tablet QD from Cycle 1Day1 to Cycle 2 Day1 thereafter 250 mg BID from Cycle 2 Day 2 up to 58 cycles (each cycle 28 days).	Participants received Crizotinib 250 mg (2 capsules/tablet of 100 mg each + 1 capsule/tablet of 50 mg) capsule/tablet QD from Cycle 1Day1 to Cycle 2 Day1 thereafter 250 mg BID from Cycle 2 Day 2 up to 58 cycles (each cycle 28 days). Participants also received Itraconazole 200 mg QD from Cycle 1 Day 1 to Cycle 1 Day 16. (each cycle 28 days).
Overall Number of Participants Analyzed	10	10
Geometric Mean (Geometric Coefficient of Variation); Unit of Measure: nanogram*hour per milliliter
	4102; (31%)	6665; (16%)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	RP2D Cohort: Itraconazole Interaction: Crizotinib 250 mg Alone, Itraconazole Interaction Cohort: Crizotinib 250 mg + Itraconazole
	Comments	[Not Specified]
	Type of Statistical Test	Superiority
	Comments	[Not Specified]
Method of Estimation	Estimation Parameter	Ratio of adjusted geometric means
	Estimated Value	157.40
	Confidence Interval	(2-Sided) 90%; 136.89 to 180.97
	Estimation Comments	[Not Specified]

29. Primary Outcome

Title	Itraconazole Cohort: Maximum Observed Plasma Concentration (Cmax) of Crizotinib When Taken Alone and When Taken With Itraconazole
Description	[Not Specified]
Time Frame	pre-dose, 1, 2, 4, 6, 8, 9 and 24 hours post dose on Cycle 1 Day 15 (Crizotinib with itraconazole) and Cycle 2 Day 1 (itraconazole alone)

Outcome Measure Data

Analysis Population Description

PK parameter evaluable population included participants who had at least 1 of the PK parameters of Crizotinib (AUCtau or Cmax) and had received 10 consecutive doses of both Crizotinib 250 mg QD and itraconazole 200 mg QD immediately prior to end of Crizotinib 250 mg + Itraconazole treatment as well as 10 consecutive doses of Crizotinib 250 mg QD prior to end of Crizotinib 250 mg + Itraconazole treatment. Overall number of participants analyzed =participants evaluable for this outcome measure.

Arm/Group Title	RP2D Cohort: Itraconazole Interaction: Crizotinib 250 mg Alone	RP2D Cohort: Itraconazole Interaction: Crizotinib 250 mg With Itraconazole
Arm/Group Description:	Participants received with or without food Crizotinib 250 mg (2 capsules/tablet of 100 mg each + 1 capsule/tablet of 50 mg) capsule/tablet QD from Cycle 1Day1 to Cycle 2 Day1 thereafter 250 mg BID from Cycle 2 Day 2 up to 58 cycles (each cycle 28 days).	Participants received Crizotinib 250 mg (2 capsules/tablet of 100 mg each + 1 capsule/tablet of 50 mg) capsule/tablet QD from Cycle 1Day1 to Cycle 2 Day1 thereafter 250 mg BID from Cycle 2 Day 2 up to 58 cycles (each cycle 28 days). Participants also received Itraconazole 200 mg QD from Cycle 1 Day 1 to Cycle 1 Day 16. (each cycle 28 days).
Overall Number of Participants Analyzed	10	10
Geometric Mean (Geometric Coefficient of Variation); Unit of Measure: nanogram per milliliter
	259.9; (23%)	353.2; (14%)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	RP2D Cohort: Itraconazole Interaction: Crizotinib 250 mg Alone, RP2D Cohort: Itraconazole Interaction: Crizotinib 250 mg With Itraconazole
	Comments	[Not Specified]
	Type of Statistical Test	Superiority
	Comments	[Not Specified]
Method of Estimation	Estimation Parameter	Ratio of adjusted geometric means
	Estimated Value	132.81
	Confidence Interval	(2-Sided) 90%; 119.10 to 148.10
	Estimation Comments	[Not Specified]

30. Primary Outcome

Title	Itraconazole Cohort: Trough Plasma Concentration (Ctrough) of Crizotinib When Taken Alone and When Taken With Itraconazole
Description	Ctrough refers to plasma concentration of Crizotinib observed just before treatment administration.
Time Frame	pre-dose on Cycle 1 Day 15 (crizotinib with itraconazole) and Cycle 2 Day 1 (itraconazole alone)

Outcome Measure Data

Analysis Population Description

PK parameter evaluable population included participants who had at least 1 of the PK parameters of Crizotinib (AUCtau or Cmax) and had received 10 consecutive doses of both Crizotinib 250 mg QD and itraconazole 200 mg QD immediately prior to end of Crizotinib 250 mg + Itraconazole treatment as well as 10 consecutive doses of Crizotinib 250 mg QD prior to end of Crizotinib 250 mg + Itraconazole treatment. Overall number of participants analyzed =participants evaluable for this outcome measure.

Arm/Group Title	RP2D Cohort: Itraconazole Interaction: Crizotinib 250 mg Alone	RP2D Cohort: Itraconazole Interaction: Crizotinib 250 mg With Itraconazole
Arm/Group Description:	Participants received with or without food Crizotinib 250 mg (2 capsules/tablet of 100 mg each + 1 capsule/tablet of 50 mg) capsule/tablet QD from Cycle 1Day1 to Cycle 2 Day1 thereafter 250 mg BID from Cycle 2 Day 2 up to 58 cycles (each cycle 28 days).	Participants received Crizotinib 250 mg (2 capsules/tablet of 100 mg each + 1 capsule/tablet of 50 mg) capsule/tablet QD from Cycle 1Day1 to Cycle 2 Day1 thereafter 250 mg BID from Cycle 2 Day 2 up to 58 cycles (each cycle 28 days). Participants also received Itraconazole 200 mg QD from Cycle 1 Day 1 to Cycle 1 Day 16. (each cycle 28 days).
Overall Number of Participants Analyzed	7	9
Geometric Mean (Geometric Coefficient of Variation); Unit of Measure: nanogram per milliliter
	136.0; (36%)	214.0; (30%)

31. Primary Outcome

Title	Recommended Phase 2 Dose (RP2D) Cohort: Percentage of Participants With Objective Response (OR)
Description	ORR was defined as participants with a best overall response of complete response (CR) or partial response (PR) divided by the total number of evaluable participants per RECIST version 1.0 (RECIST1.1 for ALK-negative NSCLC cohort 1 and ALK-negative NSCLC cohort 2). CR: Disappearance of all target and non-target lesions, normalization of tumor marker levels, and no appearance of new lesions indicated complete response. PR: At least a 30% decrease in the sum of the longest diameters of target lesions (taking as reference the baseline sum), without progression of non-target lesions and no appearance of new lesions indicated partial response.
Time Frame	Baseline up to 172 months

Outcome Measure Data

Analysis Population Description

Response-evaluable population was defined as all participants in the SA set who had an adequate baseline disease assessment and had met 1 of the following 2 criteria: a) Had at least one post-baseline disease assessment b) withdrew from the trial or experienced progression/death at any time on study. Here, "Overall number of participants Analyzed" signifies number of participants evaluable for this outcome measure. Data was planned to be analyzed for reported arms only.

Arm/Group Title	RP2D Cohort: ROS1-Positive NSCLC: Crizotinib 250 mg	RP2D Cohort: MET Exon 14 Alterations NSCLC: Crizotinib 250 mg	RP2D Cohort: MET Amplification NSCLC: Crizotinib 250 mg	RP2D Cohort: ALK-Negative Cohort 2, NSCLC: Crizotinib 250 mg	RP2D Cohort: ALK-Positive Cohort, NSCLC: Crizotinib 250 mg	RP2D Cohort: Enriched Other: Crizotinib 250 mg
Arm/Group Description:	Participants received Crizotinib 250 mg (2 capsules/tablet of 100 mg each + 1 capsule/tablet of 50 mg) capsule/tablet orally twice daily (BID) with or without food for up to 105 cycles (each cycle 28 days).	Participants received Crizotinib 250 mg (2 capsules/tablet of 100 mg each + 1 capsule/tablet of 50 mg) capsule/tablet orally twice daily (BID) with or without food for up to 55 cycles (each cycle 28 days).	Participants received Crizotinib 250 mg (2 capsules/tablet of 100 mg each + 1 capsule/tablet of 50 mg) capsule/tablet orally twice daily (BID) with or without food for up to 101 cycles (each cycle 28 days).	Participants received Crizotinib 250 mg (2 capsules/tablet of 100 mg each + 1 capsule/tablet of 50 mg) capsule/tablet orally BID with or without food for up to 70 cycles (each cycle 21 days).	Participants received Crizotinib 250 mg (2 capsules/tablet of 100 mg each + 1 capsule/tablet of 50 mg) capsule/tablet twice daily (BID) with or without food for up to 133 cycles (each cycle 28 days).	Participants received Crizotinib 250 mg (2 capsules/tablet of 100 mg each + 1 capsule/tablet of 50 mg) capsule/tablet orally twice daily (BID) with or without food for up to 54 cycles (each cycle 28 days).
Overall Number of Participants Analyzed	53	65	38	18	116	66
Measure Type: Number; Number (95% Confidence Interval); Unit of Measure: percentage of participants
	71.7; (57.7 to 83.2)	32.3; (21.2 to 45.1)	31.6; (17.5 to 48.7)	19.0; (5.4 to 41.9)	61.2; (51.7 to 70.1)	8.3; (0.2 to 38.5)

32. Primary Outcome

Title	Recommended Phase 2 Dose (RP2D) Cohort: Duration of Response (DOR)
Description	Duration of response (DoR) was the time from first documentation of PR or CR to date of first documentation of progressive disease (PD) or death due to any cause. PR: At least a 30% decrease in the sum of the longest diameters of target lesions (taking as reference the baseline sum), without progression of non-target lesions and no appearance of new lesions indicated partial response. CR: Disappearance of all target and non-target lesions, normalization of tumor marker levels, and no appearance of new lesions indicated complete response. PD: >=20% increase in the sum of the longest diameter of target lesions taking as references the smallest sum longest diameter recorded since the treatment started, unequivocal progression of existing non-target lesions, or the appearance of 1 or more new lesions.
Time Frame	From first documentation of response to date of PD or death due to any cause (up to 172 months)

Outcome Measure Data

Analysis Population Description

Response-evaluable population was defined as all participants in the SA set who had an adequate baseline disease assessment and had met 1 of the following 2 criteria: a) Had at least one post-baseline disease assessment b) withdrew from the trial or experienced progression/death at any time on study. Here, "Overall number of participants analyzed" signifies number of participants who were objective responders. Data was planned to be analyzed for reported arms only.

Arm/Group Title	RP2D Cohort: ROS1-Positive NSCLC: Crizotinib 250 mg	RP2D Cohort: MET Exon 14 Alterations NSCLC: Crizotinib 250 mg	RP2D Cohort: MET Amplification NSCLC: Crizotinib 250 mg	RP2D Cohort: ALK-Positive Cohort, NSCLC: Crizotinib 250 mg
Arm/Group Description:	Participants received Crizotinib 250 mg (2 capsules/tablet of 100 mg each + 1 capsule/tablet of 50 mg) capsule/tablet orally twice daily (BID) with or without food for up to 105 cycles (each cycle 28 days).	Participants received Crizotinib 250 mg (2 capsules/tablet of 100 mg each + 1 capsule/tablet of 50 mg) capsule/tablet orally twice daily (BID) with or without food for up to 55 cycles (each cycle 28 days).	Participants received Crizotinib 250 mg (2 capsules/tablet of 100 mg each + 1 capsule/tablet of 50 mg) capsule/tablet orally twice daily (BID) with or without food for up to 101 cycles (each cycle 28 days).	Participants received Crizotinib 250 mg (2 capsules/tablet of 100 mg each + 1 capsule/tablet of 50 mg) capsule/tablet twice daily (BID) with or without food for up to 133 cycles (each cycle 28 days).
Overall Number of Participants Analyzed	38	33	12	71
Median (Full Range); Unit of Measure: Weeks
	14.5; (2.8 to 45.4)	6.8; (2.8 to 13.4)	5.2; (3.8 to 12.2)	26.2; (8.1 to 72.9)

33. Primary Outcome

Title	Recommended Phase 2 Dose (RP2D) Cohort: Time to Response (TTR)
Description	TTR: time between first dose until first documented response of PR or CR. PR: At least a 30% decrease in the sum of the longest diameters of target lesions (taking as reference the baseline sum), without progression of non-target lesions and no appearance of new lesions indicated partial response. CR: Disappearance of all target and non-target lesions, normalization of tumor marker levels, and no appearance of new lesions indicated complete response.
Time Frame	From first dose until first documented response of PR or CR (up to 172 months)

Outcome Measure Data

Analysis Population Description

Response-evaluable population was defined as all participants in the SA set who had an adequate baseline disease assessment and had met 1 of the following 2 criteria: a) Had at least one post-baseline disease assessment b) withdrew from the trial or experienced progression/death at any time on study. Here, "Overall number of participants analyzed" signifies number of participants who were objective responders. Data was planned to be analyzed for reported arms only.

Arm/Group Title	RP2D Cohort: ROS1-Positive NSCLC: Crizotinib 250 mg	RP2D Cohort: MET Exon 14 Alterations NSCLC: Crizotinib 250 mg	RP2D Cohort: MET Amplification NSCLC: Crizotinib 250 mg	RP2D Cohort: ALK-Positive Cohort, NSCLC: Crizotinib 250 mg
Arm/Group Description:	Participants received Crizotinib 250 mg (2 capsules/tablet of 100 mg each + 1 capsule/tablet of 50 mg) capsule/tablet orally twice daily (BID) with or without food for up to 105 cycles (each cycle 28 days).	Participants received Crizotinib 250 mg (2 capsules/tablet of 100 mg each + 1 capsule/tablet of 50 mg) capsule/tablet orally twice daily (BID) with or without food for up to 55 cycles (each cycle 28 days).	Participants received Crizotinib 250 mg (2 capsules/tablet of 100 mg each + 1 capsule/tablet of 50 mg) capsule/tablet orally twice daily (BID) with or without food for up to 101 cycles (each cycle 28 days).	Participants received Crizotinib 250 mg (2 capsules/tablet of 100 mg each + 1 capsule/tablet of 50 mg) capsule/tablet twice daily (BID) with or without food for up to 133 cycles (each cycle 28 days).
Overall Number of Participants Analyzed	38	33	12	71
Median (Full Range); Unit of Measure: Weeks
	7.9; (4.3 to 103.6)	7.6; (3.7 to 47.3)	8.0; (7.1 to 23.6)	7.7; (4.3 to 39.6)

34. Primary Outcome

Title	Recommended Phase 2 Dose (RP2D) Cohort: Percentage of Participants With Disease Control at Week 8
Description	Disease control was defined as the percentage of participants with a confirmed CR, PR, or stable disease (SD) per RECIST version 1.0 (RECIST1.1 for ALK-negative NSCLC cohort 1 and ALK-negative NSCLC cohort 2). PR: At least a 30% decrease in the sum of the longest diameters of target lesions (taking as reference the baseline sum), without progression of non-target lesions and no appearance of new lesions indicated partial response. CR: Disappearance of all target and non-target lesions, normalization of tumor marker levels, and no appearance of new lesions indicated complete response. SD was defined as neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD, taking as reference the smallest sum diameters while on study.
Time Frame	Week 8

Outcome Measure Data

Analysis Population Description

Response-evaluable population was defined as all participants in the SA set who had an adequate baseline disease assessment and had met 1 of the following 2 criteria: a) Had at least one post-baseline disease assessment b) withdrew from the trial or experienced progression/death at any time on study. Here, "Overall number of participants analyzed" signifies number of participants evaluable for this outcome measure. Data was planned to be analyzed for reported arms only.

Arm/Group Title	RP2D Cohort: ROS1-Positive NSCLC: Crizotinib 250 mg	RP2D Cohort: MET Exon 14 Alterations NSCLC: Crizotinib 250 mg	RP2D Cohort: ALK-Positive Cohort, NSCLC: Crizotinib 250 mg	RP2D Cohort: ALK-Negative Cohort 2, NSCLC: Crizotinib 250 mg
Arm/Group Description:	Participants received Crizotinib 250 mg (2 capsules/tablet of 100 mg each + 1 capsule/tablet of 50 mg) capsule/tablet orally twice daily (BID) with or without food for up to 105 cycles (each cycle 28 days).	Participants received Crizotinib 250 mg (2 capsules/tablet of 100 mg each + 1 capsule/tablet of 50 mg) capsule/tablet orally twice daily (BID) with or without food for up to 55 cycles (each cycle 28 days).	Participants received Crizotinib 250 mg (2 capsules/tablet of 100 mg each + 1 capsule/tablet of 50 mg) capsule/tablet twice daily (BID) with or without food for up to 133 cycles (each cycle 28 days).	Participants received Crizotinib 250 mg (2 capsules/tablet of 100 mg each + 1 capsule/tablet of 50 mg) capsule/tablet orally BID with or without food for up to 70 cycles (each cycle 21 days).
Overall Number of Participants Analyzed	53	85	116	18
Measure Type: Number; Number (95% Confidence Interval); Unit of Measure: percentage of participants
	86.8; (74.7 to 94.5)	71.8; (61.0 to 81.0)	79.3; (70.8 to 86.3)	47.6; (25.7 to 70.2)

35. Primary Outcome

Title	Recommended Phase 2 Dose (RP2D) Cohort: Percentage of Participants With Disease Control at Week 16
Description	Disease control was defined as the percentage of participants with a confirmed CR, PR, or stable disease (SD) per RECIST version 1.0 (RECIST1.1 for ALK-negative NSCLC cohort 1 and ALK-negative NSCLC cohort 2). PR: At least a 30% decrease in the sum of the longest diameters of target lesions (taking as reference the baseline sum), without progression of non-target lesions and no appearance of new lesions indicated partial response. CR: Disappearance of all target and non-target lesions, normalization of tumor marker levels, and no appearance of new lesions indicated complete response. SD was defined as neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD, taking as reference the smallest sum diameters while on study.
Time Frame	Week 16

Outcome Measure Data

Analysis Population Description

Response-evaluable population was defined as all participants in the SA set who had an adequate baseline disease assessment and had met 1 of the following 2 criteria: a) Had at least one post-baseline disease assessment b) withdrew from the trial or experienced progression/death at any time on study. Here, "Overall number of participants analyzed" signifies number of participants evaluable for this outcome measure. Data was planned to be analyzed for reported arms only.

Arm/Group Title	RP2D Cohort: ROS1-Positive NSCLC: Crizotinib 250 mg	RP2D Cohort: MET Exon 14 Alterations NSCLC: Crizotinib 250 mg	RP2D Cohort: ALK-Positive Cohort, NSCLC: Crizotinib 250 mg	RP2D Cohort: ALK-Negative Cohort 2, NSCLC: Crizotinib 250 mg
Arm/Group Description:	Participants received Crizotinib 250 mg (2 capsules/tablet of 100 mg each + 1 capsule/tablet of 50 mg) capsule/tablet orally twice daily (BID) with or without food for up to 105 cycles (each cycle 28 days).	Participants received Crizotinib 250 mg (2 capsules/tablet of 100 mg each + 1 capsule/tablet of 50 mg) capsule/tablet orally twice daily (BID) with or without food for up to 55 cycles (each cycle 28 days).	Participants received Crizotinib 250 mg (2 capsules/tablet of 100 mg each + 1 capsule/tablet of 50 mg) capsule/tablet twice daily (BID) with or without food for up to 133 cycles (each cycle 28 days).	Participants received Crizotinib 250 mg (2 capsules/tablet of 100 mg each + 1 capsule/tablet of 50 mg) capsule/tablet orally BID with or without food for up to 70 cycles (each cycle 21 days).
Overall Number of Participants Analyzed	53	85	116	18
Measure Type: Number; Number (95% Confidence Interval); Unit of Measure: percentage of participants
	79.2; (65.9 to 89.2)	51.8; (40.7 to 62.7)	67.2; (57.9 to 75.7)	42.9; (21.8 to 66.0)

36. Primary Outcome

Title	Recommended Phase 2 Dose (RP2D) Cohort: Progression Free Survival (PFS)
Description	Progression free survival (PFS) was the time from randomization date to date of first documentation of PD or death due to any cause RECIST version 1.0 (RECIST1.1 for ALK-negative NSCLC cohort 1 and ALK-negative NSCLC cohort 2). PD: >=20% increase in the sum of the longest diameter of target lesions taking as references the smallest sum longest diameter recorded since the treatment started, unequivocal progression of existing non-target lesions, or the appearance of 1 or more new lesions.
Time Frame	From randomization until PD or death, whichever occurred first (up to 172 months)

Outcome Measure Data

Analysis Population Description

SA set included all enrolled participants who received at least one dose of Crizotinib on Cycle 1 Day 1. Here, "Overall number of participants analyzed" signifies number of participants evaluable for this outcome measure. Data was planned to be analyzed for reported arms only.

Arm/Group Title	RP2D Cohort: ROS1-Positive NSCLC: Crizotinib 250 mg	RP2D Cohort: MET Exon 14 Alterations NSCLC: Crizotinib 250 mg	RP2D Cohort: MET Amplification NSCLC: Crizotinib 250 mg	RP2D Cohort: ALK-Positive Cohort, NSCLC: Crizotinib 250 mg
Arm/Group Description:	Participants received Crizotinib 250 mg (2 capsules/tablet of 100 mg each + 1 capsule/tablet of 50 mg) capsule/tablet orally twice daily (BID) with or without food for up to 105 cycles (each cycle 28 days).	Participants received Crizotinib 250 mg (2 capsules/tablet of 100 mg each + 1 capsule/tablet of 50 mg) capsule/tablet orally twice daily (BID) with or without food for up to 55 cycles (each cycle 28 days).	Participants received Crizotinib 250 mg (2 capsules/tablet of 100 mg each + 1 capsule/tablet of 50 mg) capsule/tablet orally twice daily (BID) with or without food for up to 101 cycles (each cycle 28 days).	Participants received Crizotinib 250 mg (2 capsules/tablet of 100 mg each + 1 capsule/tablet of 50 mg) capsule/tablet twice daily (BID) with or without food for up to 133 cycles (each cycle 28 days).
Overall Number of Participants Analyzed	53	85	41	119
Median (95% Confidence Interval); Unit of Measure: Months
	19.3; (15.2 to 39.1)	7.6; (5.6 to 9.1)	4.0; (1.9 to 6.9)	10.0; (8.2 to 14.7)

37. Primary Outcome

Title	Recommended Phase 2 Dose (RP2D) Cohort: Probability of Being Event Free at Month 6
Description	Probability of being event free (event defined as PD or death due to any cause) at 6 months after the first dose of crizotinib was reported. PD: >=20% increase in the sum of the longest diameter of target lesions taking as references the smallest sum longest diameter recorded since the treatment started, unequivocal progression of existing non-target lesions, or the appearance of 1 or more new lesions.
Time Frame	From randomization to 6 months

Outcome Measure Data

Analysis Population Description

SA set included all enrolled participants who received at least one dose of Crizotinib on Cycle 1 Day 1. Here, "Overall Number of Participants Analyzed" signifies number of participants evaluable for this outcome measure. Data was planned to be analyzed for reported arms only.

Arm/Group Title	RP2D Cohort: ROS1-Positive NSCLC: Crizotinib 250 mg	RP2D Cohort: MET Exon 14 Alterations NSCLC: Crizotinib 250 mg	RP2D Cohort: MET Amplification NSCLC: Crizotinib 250 mg	RP2D Cohort: ALK-Positive Cohort, NSCLC: Crizotinib 250 mg
Arm/Group Description:	Participants received Crizotinib 250 mg (2 capsules/tablet of 100 mg each + 1 capsule/tablet of 50 mg) capsule/tablet orally twice daily (BID) with or without food for up to 105 cycles (each cycle 28 days).	Participants received Crizotinib 250 mg (2 capsules/tablet of 100 mg each + 1 capsule/tablet of 50 mg) capsule/tablet orally twice daily (BID) with or without food for up to 55 cycles (each cycle 28 days).	Participants received Crizotinib 250 mg (2 capsules/tablet of 100 mg each + 1 capsule/tablet of 50 mg) capsule/tablet orally twice daily (BID) with or without food for up to 101 cycles (each cycle 28 days).	Participants received Crizotinib 250 mg (2 capsules/tablet of 100 mg each + 1 capsule/tablet of 50 mg) capsule/tablet twice daily (BID) with or without food for up to 133 cycles (each cycle 28 days).
Overall Number of Participants Analyzed	53	85	41	119
Measure Type: Number; Number (95% Confidence Interval); Unit of Measure: Probability of being event-free
	76.9; (62.8 to 86.1)	57.5; (45.3 to 68.0)	39.0; (22.8 to 54.9)	71.9; (61.8 to 79.7)

38. Primary Outcome

Title	Recommended Phase 2 Dose (RP2D) Cohort: Overall Survival (OS)
Description	OS was defined as the time from randomization to death due to any cause.
Time Frame	From randomization date to the date of death (up to 172 Months)

Outcome Measure Data

Analysis Population Description

SA set included all enrolled participants who received at least one dose of Crizotinib on Cycle 1 Day 1. Here, "Overall number of participants analyzed" signifies number of participants evaluable for this outcome measure. Data was planned to be analyzed for reported arms only.

Arm/Group Title	RP2D Cohort: ROS1-Positive NSCLC: Crizotinib 250 mg	RP2D Cohort: MET Exon 14 Alterations NSCLC: Crizotinib 250 mg	RP2D Cohort: MET Amplification NSCLC: Crizotinib 250 mg	RP2D Cohort: ALK-Positive Cohort, NSCLC: Crizotinib 250 mg
Arm/Group Description:	Participants received Crizotinib 250 mg (2 capsules/tablet of 100 mg each + 1 capsule/tablet of 50 mg) capsule/tablet orally twice daily (BID) with or without food for up to 105 cycles (each cycle 28 days).	Participants received Crizotinib 250 mg (2 capsules/tablet of 100 mg each + 1 capsule/tablet of 50 mg) capsule/tablet orally twice daily (BID) with or without food for up to 55 cycles (each cycle 28 days).	Participants received Crizotinib 250 mg (2 capsules/tablet of 100 mg each + 1 capsule/tablet of 50 mg) capsule/tablet orally twice daily (BID) with or without food for up to 101 cycles (each cycle 28 days).	Participants received Crizotinib 250 mg (2 capsules/tablet of 100 mg each + 1 capsule/tablet of 50 mg) capsule/tablet twice daily (BID) with or without food for up to 133 cycles (each cycle 28 days).
Overall Number of Participants Analyzed	53	85	41	119
Median (95% Confidence Interval); Unit of Measure: Months
	51.4 [1]; (29.3 to NA)	20.0; (13.2 to 25.7)	10.1; (7.1 to 12.9)	NA [2]; (NA to NA)

[1]

Upper limit of 95% CI could not be estimable due to low number of participants with events.

[2]

Median and 95% CI could not be estimable due to low number of participants with events.

39. Primary Outcome

Title	Probability of Participant Survival at Month 6
Description	Probability of survival was defined as the probability of being alive at Month 6.
Time Frame	Month 6

Outcome Measure Data

Analysis Population Description

SA set included all enrolled participants who received at least one dose of Crizotinib on Cycle 1 Day 1. Here, "Overall number of participants analyzed" signifies number of participants evaluable for this outcome measure. Data was planned to be analyzed for reported arms only.

Arm/Group Title	RP2D Cohort: ROS1-Positive NSCLC: Crizotinib 250 mg	RP2D Cohort: MET Exon 14 Alterations NSCLC: Crizotinib 250 mg	RP2D Cohort: MET Amplification NSCLC: Crizotinib 250 mg	RP2D Cohort: ALK-Positive Cohort, NSCLC: Crizotinib 250 mg
Arm/Group Description:	Participants received Crizotinib 250 mg (2 capsules/tablet of 100 mg each + 1 capsule/tablet of 50 mg) capsule/tablet orally twice daily (BID) with or without food for up to 105 cycles (each cycle 28 days).	Participants received Crizotinib 250 mg (2 capsules/tablet of 100 mg each + 1 capsule/tablet of 50 mg) capsule/tablet orally twice daily (BID) with or without food for up to 55 cycles (each cycle 28 days).	Participants received Crizotinib 250 mg (2 capsules/tablet of 100 mg each + 1 capsule/tablet of 50 mg) capsule/tablet orally twice daily (BID) with or without food for up to 101 cycles (each cycle 28 days).	Participants received Crizotinib 250 mg (2 capsules/tablet of 100 mg each + 1 capsule/tablet of 50 mg) capsule/tablet twice daily (BID) with or without food for up to 133 cycles (each cycle 28 days).
Overall Number of Participants Analyzed	53	85	41	119
Measure Type: Number; Number (95% Confidence Interval); Unit of Measure: Probability of participants survival
	90.5; (78.7 to 95.9)	86.7; (77.3 to 92.4)	67.8; (51.1 to 79.9)	90.0; (82.7 to 94.4)

40. Primary Outcome

Title	Probability of Participant Survival at Month 12
Description	Probability of survival was defined as the probability of being alive at Month 12.
Time Frame	Month 12

Outcome Measure Data

Analysis Population Description

SA set included all enrolled participants who received at least one dose of Crizotinib on Cycle 1 Day 1. Here, "Overall Number of Participants Analyzed" signifies number of participants evaluable for this outcome measure. Data was planned to be analyzed for reported arms only.

Arm/Group Title	RP2D Cohort: ROS1-Positive NSCLC: Crizotinib 250 mg	RP2D Cohort: MET Exon 14 Alterations NSCLC: Crizotinib 250 mg	RP2D Cohort: MET Amplification NSCLC: Crizotinib 250 mg	RP2D Cohort: ALK-Positive Cohort, NSCLC: Crizotinib 250 mg
Arm/Group Description:	Participants received Crizotinib 250 mg (2 capsules/tablet of 100 mg each + 1 capsule/tablet of 50 mg) capsule/tablet orally twice daily (BID) with or without food for up to 105 cycles (each cycle 28 days).	Participants received Crizotinib 250 mg (2 capsules/tablet of 100 mg each + 1 capsule/tablet of 50 mg) capsule/tablet orally twice daily (BID) with or without food for up to 55 cycles (each cycle 28 days).	Participants received Crizotinib 250 mg (2 capsules/tablet of 100 mg each + 1 capsule/tablet of 50 mg) capsule/tablet orally twice daily (BID) with or without food for up to 101 cycles (each cycle 28 days).	Participants received Crizotinib 250 mg (2 capsules/tablet of 100 mg each + 1 capsule/tablet of 50 mg) capsule/tablet twice daily (BID) with or without food for up to 133 cycles (each cycle 28 days).
Overall Number of Participants Analyzed	53	85	41	119
Measure Type: Number; Number (95% Confidence Interval); Unit of Measure: probability of participants survival
	78.8; (65.0 to 87.7)	66.0; (54.0 to 75.5)	37.1; (22.4 to 51.8)	80.5; (70.9 to 87.2)

41. Primary Outcome

Title	Geometric Mean of Ratio of Total Testosterone, Free Testosterone, Sex Hormone Binding Globulin (SHBG), Luteinizing Hormone, Follicle Stimulating Hormone, Dihydroepiandrosterone Sulfate, Estradiol and Prolactin Levels in Males at Cycle 1 Day 15
Description	Geometric mean of ratio (Cycle1Day15/Baseline) of hypogonadism parameters (total testosterone, free testosterone, sex hormone binding globulin, luteinizing hormone, follicle stimulating hormone, dihydroepiandrosterone sulfate, estradiol and prolactin) levels in males was analyzed. Data for this outcome measure was planned to be collected for combined RP2D Cohort only, excluding arms of low and high dose escalation cohorts.
Time Frame	Baseline, Cycle 1 Day 15

Outcome Measure Data

Analysis Population Description

Hypogonadism test evaluable population: Male participants who had completed screening, had received at least 1 dose of crizotinib on Cycle 1 Day 1, had at least 1 post baseline visit data for at least total testosterone, free testosterone, SHBG and included male participants of MET amplification and enriched other Cohort following approval of protocol amendment number 21. "N" =participants evaluable for this OM and 'number analyzed' =participants with available data for each specified category.

Arm/Group Title		RP2D Cohort: Crizotinib 250 mg
Arm/Group Description:		Participants received Crizotinib 250 mg tablet/capsule (2 capsules/tablet of 100 mg each + 1 capsule/tablet of 50 mg) orally BID up to 124 months.
Overall Number of Participants Analyzed		28
Geometric Mean (95% Confidence Interval); Unit of Measure: Ratio
Testosterone	Number Analyzed	22 participants
		0.46; (0.34 to 0.62)
Estradiol	Number Analyzed	19 participants
		0.53; (0.42 to 0.66)
Prolactin	Number Analyzed	22 participants
		1.19; (0.91 to 1.55)
Luteinizing Hormone (LH) Serum	Number Analyzed	22 participants
		0.58; (0.47 to 0.73)
Follicle Stimulating Hormone	Number Analyzed	22 participants
		0.77; (0.66 to 0.91)
Free Testosterone	Number Analyzed	22 participants
		0.96; (0.66 to 1.40)
Sex Hormone Binding Globulin	Number Analyzed	28 participants
		0.36; (0.32 to 0.41)
Dihydroepiandrosterone Sulfate	Number Analyzed	21 participants
		0.97; (0.85 to 1.11)

42. Primary Outcome

Title	Geometric Mean of Ratio of Total Testosterone, Free Testosterone, Sex Hormone Binding Globulin (SHBG), Luteinizing Hormone, Follicle Stimulating Hormone, Dihydroepiandrosterone Sulfate, Estradiol and Prolactin Levels in Males at Cycle 2 Day 1
Description	Geometric mean of ratio (Cycle 2 Day 1/Baseline) of hypogonadism parameters (total testosterone, free testosterone, sex hormone binding globulin, luteinizing hormone, follicle stimulating hormone, dihydroepiandrosterone sulfate, estradiol and prolactin) levels in males was analyzed. Data for this outcome measure was planned to be collected for combined RP2D Cohort only, excluding arms of low and high dose escalation cohorts.
Time Frame	Baseline, Cycle 2 Day 1

Outcome Measure Data

Analysis Population Description

Hypogonadism test evaluable population: Male participants who had completed screening, had received at least 1 dose of crizotinib on Cycle 1 Day 1, had at least 1 post baseline visit data for at least total testosterone, free testosterone, SHBG and included male participants of MET amplification and enriched other Cohort following approval of protocol amendment number 21. "N" =participants evaluable for this OM and 'number analyzed' =participants with available data for each specified category.

Arm/Group Title		RP2D Cohort: Crizotinib 250 mg
Arm/Group Description:		Participants received Crizotinib 250 mg tablet/capsule (2 capsules/tablet of 100 mg each + 1 capsule/tablet of 50 mg) orally BID up to 124 months.
Overall Number of Participants Analyzed		25
Geometric Mean (95% Confidence Interval); Unit of Measure: Ratio
Testosterone	Number Analyzed	24 participants
		0.47; (0.38 to 0.58)
Estradiol	Number Analyzed	22 participants
		0.72; (0.56 to 0.93)
Prolactin	Number Analyzed	25 participants
		0.89; (0.71 to 1.12)
LH Serum	Number Analyzed	23 participants
		0.42; (0.26 to 0.70)
Follicle Stimulating Hormone	Number Analyzed	23 participants
		0.69; (0.48 to 1.00)
Free Testosterone	Number Analyzed	24 participants
		1.31; (0.97 to 1.77)
Sex Hormone Binding Globulin	Number Analyzed	17 participants
		0.24; (0.18 to 0.31)
Dihydroepiandrosterone Sulfate	Number Analyzed	25 participants
		0.85; (0.75 to 0.96)

43. Primary Outcome

Title	Geometric Mean of Ratio of Total Testosterone, Free Testosterone, Sex Hormone Binding Globulin (SHBG), Luteinizing Hormone, Follicle Stimulating Hormone, Dihydroepiandrosterone Sulfate, Estradiol and Prolactin Levels in Males at Cycle 4 Day 1
Description	Geometric mean of ratio (Cycle 4 Day 1/Baseline) of hypogonadism parameters (total testosterone, free testosterone, sex hormone binding globulin, luteinizing hormone, follicle stimulating hormone, dihydroepiandrosterone sulfate, estradiol and prolactin) levels in males was analyzed. Data for this outcome measure was planned to be collected for combined RP2D Cohort only, excluding arms of low and high dose escalation cohorts.
Time Frame	Baseline, Cycle 4 Day 1

Outcome Measure Data

Analysis Population Description

Hypogonadism test evaluable population: Male participants who had completed screening, had received at least 1 dose of crizotinib on Cycle 1 Day 1, had at least 1 post baseline visit data for at least total testosterone, free testosterone, SHBG and included male participants of MET amplification and enriched other Cohort following approval of protocol amendment number 21. "N" =participants evaluable for this OM and 'number analyzed' =participants with available data for each specified category.

Arm/Group Title		RP2D Cohort: Crizotinib 250 mg
Arm/Group Description:		Participants received Crizotinib 250 mg tablet/capsule (2 capsules/tablet of 100 mg each + 1 capsule/tablet of 50 mg) orally BID up to 124 months.
Overall Number of Participants Analyzed		10
Geometric Mean (95% Confidence Interval); Unit of Measure: Ratio
Testosterone	Number Analyzed	10 participants
		0.48; (0.27 to 0.84)
Estradiol	Number Analyzed	8 participants
		0.66; (0.49 to 0.89)
Prolactin	Number Analyzed	10 participants
		0.84; (0.55 to 1.28)
LH Serum	Number Analyzed	10 participants
		0.75; (0.57 to 1.00)
Follicle Stimulating Hormone	Number Analyzed	10 participants
		0.88; (0.68 to 1.15)
Free Testosterone	Number Analyzed	10 participants
		1.63; (0.88 to 3.01)
Sex Hormone Binding Globulin	Number Analyzed	8 participants
		0.22; (0.18 to 0.28)
Dihydroepiandrosterone Sulfate	Number Analyzed	10 participants
		0.81; (0.69 to 0.97)

44. Primary Outcome

Title	Geometric Mean of Ratio of Total Testosterone, Free Testosterone, Sex Hormone Binding Globulin (SHBG), Luteinizing Hormone, Follicle Stimulating Hormone, Dihydroepiandrosterone Sulfate, Estradiol and Prolactin Levels in Males at Cycle 6 Day 1
Description	Geometric mean of ratio (Cycle 6 Day 1/Baseline) of hypogonadism parameters (total testosterone, free testosterone, sex hormone binding globulin, luteinizing hormone, follicle stimulating hormone, dihydroepiandrosterone sulfate, estradiol and prolactin) levels in males was analyzed. Data for this outcome measure was planned to be collected for combined RP2D Cohort only, excluding arms of low and high dose escalation cohorts.
Time Frame	Baseline, Cycle 6 Day 1

Outcome Measure Data

Analysis Population Description

Hypogonadism test evaluable population: Male participants who had completed screening, had received at least 1 dose of crizotinib on Cycle 1 Day 1, had at least 1 post baseline visit data for at least total testosterone, free testosterone, SHBG and included male participants of MET amplification and enriched other Cohort following approval of protocol amendment number 21. "N" =participants evaluable for this OM and 'number analyzed' =participants with available data for each specified category.

Arm/Group Title		RP2D Cohort: Crizotinib 250 mg
Arm/Group Description:		Participants received Crizotinib 250 mg tablet/capsule (2 capsules/tablet of 100 mg each + 1 capsule/tablet of 50 mg) orally BID up to 124 months.
Overall Number of Participants Analyzed		10
Geometric Mean (95% Confidence Interval); Unit of Measure: Ratio
Testosterone	Number Analyzed	10 participants
		0.49; (0.24 to 1.01)
Estradiol	Number Analyzed	8 participants
		0.75; (0.58 to 0.97)
Prolactin	Number Analyzed	10 participants
		0.69; (0.48 to 1.00)
LH Serum	Number Analyzed	10 participants
		0.78; (0.60 to 1.02)
Follicle Stimulating Hormone	Number Analyzed	10 participants
		1.07; (0.78 to 1.46)
Free Testosterone	Number Analyzed	10 participants
		1.71; (1.01 to 2.90)
Sex Hormone Binding Globulin	Number Analyzed	7 participants
		0.25; (0.15 to 0.43)
Dihydroepiandrosterone Sulfate	Number Analyzed	9 participants
		0.87; (0.68 to 1.12)

45. Primary Outcome

Title	Geometric Mean of Ratio of Total Testosterone, Free Testosterone, Sex Hormone Binding Globulin (SHBG), Luteinizing Hormone, Follicle Stimulating Hormone, Dihydroepiandrosterone Sulfate, Estradiol and Prolactin Levels in Males at Cycle 9 Day 1
Description	Geometric mean of ratio (Cycle 9 Day 1/Baseline) of hypogonadism parameters (total testosterone, free testosterone, sex hormone binding globulin, luteinizing hormone, follicle stimulating hormone, dihydroepiandrosterone sulfate, estradiol and prolactin) levels in males was analyzed. Data for this outcome measure was planned to be collected for combined RP2D Cohort only, excluding arms of low and high dose escalation cohorts. 95% CI should be interpreted with cautions due to the limited sample size at this time point.
Time Frame	Baseline, Cycle 9 Day 1

Outcome Measure Data

Analysis Population Description

Hypogonadism test evaluable population: Male participants who had completed screening, had received at least 1 dose of crizotinib on Cycle 1 Day 1, had at least 1 post baseline visit data for at least total testosterone, free testosterone, SHBG and included male participants of MET amplification and enriched other Cohort following approval of protocol amendment number 21. "N" =participants evaluable for this OM and 'number analyzed' =participants with available data for each specified category.

Arm/Group Title		RP2D Cohort: Crizotinib 250 mg
Arm/Group Description:		Participants received Crizotinib 250 mg tablet/capsule (2 capsules/tablet of 100 mg each + 1 capsule/tablet of 50 mg) orally BID up to 124 months.
Overall Number of Participants Analyzed		6
Geometric Mean (95% Confidence Interval); Unit of Measure: Ratio
Testosterone	Number Analyzed	6 participants
		0.38; (0.26 to 0.57)
Estradiol	Number Analyzed	6 participants
		0.56; (0.49 to 0.65)
Prolactin	Number Analyzed	6 participants
		1.19; (0.65 to 2.18)
LH Serum	Number Analyzed	6 participants
		0.72; (0.56 to 0.93)
Follicle Stimulating Hormone	Number Analyzed	6 participants
		0.83; (0.67 to 1.03)
Free Testosterone	Number Analyzed	6 participants
		1.23; (1.08 to 1.40)
Sex Hormone Binding Globulin	Number Analyzed	4 participants
		0.19; (0.09 to 0.39)
Dihydroepiandrosterone Sulfate	Number Analyzed	6 participants
		0.72; (0.51 to 1.00)

46. Primary Outcome

Title	Geometric Mean of Ratio of Total Testosterone, Free Testosterone, Sex Hormone Binding Globulin (SHBG), Luteinizing Hormone, Follicle Stimulating Hormone, Dihydroepiandrosterone Sulfate, Estradiol and Prolactin Levels in Males at Cycle 12 Day 1
Description	Geometric mean of ratio (Cycle 12 Day 1/Baseline) of hypogonadism parameters (total testosterone, free testosterone, sex hormone binding globulin, luteinizing hormone, follicle stimulating hormone, dihydroepiandrosterone sulfate, estradiol and prolactin) levels in males was analyzed. Data for this outcome measure was planned to be collected for combined RP2D Cohort only, excluding arms of low and high dose escalation cohorts. 95% CI should be interpreted with cautions due to the limited sample size at this time point.
Time Frame	Baseline, Cycle 12 Day 1

Outcome Measure Data

Analysis Population Description

Hypogonadism test evaluable population: Male participants who had completed screening, had received at least 1 dose of crizotinib on Cycle 1 Day 1, had at least 1 post baseline visit data for at least total testosterone, free testosterone, SHBG and included male participants of MET amplification and enriched other Cohort following approval of protocol amendment number 21. "N" =participants evaluable for this OM and 'number analyzed' =participants with available data for each specified category.

Arm/Group Title		RP2D Cohort: Crizotinib 250 mg
Arm/Group Description:		Participants received Crizotinib 250 mg tablet/capsule (2 capsules/tablet of 100 mg each + 1 capsule/tablet of 50 mg) orally BID up to 124 months.
Overall Number of Participants Analyzed		6
Geometric Mean (95% Confidence Interval); Unit of Measure: Ratio
Testosterone	Number Analyzed	6 participants
		0.38; (0.14 to 1.04)
Estradiol	Number Analyzed	5 participants
		0.66; (0.32 to 1.37)
Prolactin	Number Analyzed	6 participants
		1.06; (0.72 to 1.57)
LH Serum	Number Analyzed	6 participants
		0.88; (0.59 to 1.32)
Follicle Stimulating Hormone	Number Analyzed	6 participants
		1.02; (0.63 to 1.65)
Free Testosterone	Number Analyzed	6 participants
		1.39; (0.68 to 2.86)
Sex Hormone Binding Globulin	Number Analyzed	5 participants
		0.23; (0.11 to 0.46)
Dihydroepiandrosterone Sulfate	Number Analyzed	5 participants
		0.75; (0.42 to 1.34)

47. Primary Outcome

Title	Geometric Mean of Ratio of Total Testosterone, Free Testosterone, Sex Hormone Binding Globulin (SHBG), Luteinizing Hormone, Follicle Stimulating Hormone, Dihydroepiandrosterone Sulfate, Estradiol and Prolactin Levels in Males at Cycle 15 Day 1
Description	Geometric mean of ratio (Cycle 15 Day 1/Baseline) of hypogonadism parameters (total testosterone, free testosterone, sex hormone binding globulin, luteinizing hormone, follicle stimulating hormone, dihydroepiandrosterone sulfate, estradiol and prolactin) levels in males was analyzed. Data for this outcome measure was planned to be collected for combined RP2D Cohort only, excluding arms of low and high dose escalation cohorts. 95% CI should be interpreted with cautions due to the limited sample size at this time point.
Time Frame	Baseline, Cycle 15 Day 1

Outcome Measure Data

Analysis Population Description

Hypogonadism test evaluable population: Male participants who had completed screening, had received at least 1 dose of crizotinib on Cycle 1 Day 1, had at least 1 post baseline visit data for at least total testosterone, free testosterone, SHBG and included male participants of MET amplification and enriched other Cohort following approval of protocol amendment number 21. "N" =participants evaluable for this outcome measure.

Arm/Group Title	RP2D Cohort: Crizotinib 250 mg
Arm/Group Description:	Participants received Crizotinib 250 mg tablet/capsule (2 capsules/tablet of 100 mg each + 1 capsule/tablet of 50 mg) orally BID up to 124 months.
Overall Number of Participants Analyzed	4
Geometric Mean (95% Confidence Interval); Unit of Measure: Ratio
Testosterone	0.49; (0.21 to 1.14)
Estradiol	1.03; (0.47 to 2.25)
Prolactin	1.32; (0.86 to 2.03)
LH Serum	0.90; (0.56 to 1.45)
Follicle Stimulating Hormone	0.81; (0.53 to 1.22)
Free Testosterone	1.71; (0.57 to 5.13)
Sex Hormone Binding Globulin	0.24; (0.12 to 0.49)
Dihydroepiandrosterone Sulfate	0.76; (0.57 to 0.99)

48. Primary Outcome

Title	Geometric Mean of Ratio of Total Testosterone, Free Testosterone, Sex Hormone Binding Globulin (SHBG), Luteinizing Hormone, Follicle Stimulating Hormone, Dihydroepiandrosterone Sulfate, Estradiol and Prolactin Levels in Males at Cycle 18 Day 1
Description	Geometric mean of ratio (Cycle 18 Day 1/Baseline) of hypogonadism parameters (total testosterone, free testosterone, sex hormone binding globulin, luteinizing hormone, follicle stimulating hormone, dihydroepiandrosterone sulfate, estradiol and prolactin) levels in males was analyzed. Data for this outcome measure was planned to be collected for combined RP2D Cohort only, excluding arms of low and high dose escalation cohorts. 95% CI should be interpreted with cautions due to the limited sample size at this time point.
Time Frame	Baseline, Cycle 18 Day 1

Outcome Measure Data

Analysis Population Description

Hypogonadism test evaluable population: Male participants who had completed screening, had received at least 1 dose of crizotinib on Cycle 1 Day 1, had at least 1 post baseline visit data for at least total testosterone, free testosterone, SHBG and included male participants of MET amplification and enriched other Cohort following approval of protocol amendment number 21. "N" =participants evaluable for this OM and 'number analyzed' =participants with available data for each specified category.

Arm/Group Title		RP2D Cohort: Crizotinib 250 mg
Arm/Group Description:		Participants received Crizotinib 250 mg tablet/capsule (2 capsules/tablet of 100 mg each + 1 capsule/tablet of 50 mg) orally BID up to 124 months.
Overall Number of Participants Analyzed		3
Geometric Mean (95% Confidence Interval); Unit of Measure: Ratio
Testosterone	Number Analyzed	3 participants
		0.32; (0.22 to 0.48)
Estradiol	Number Analyzed	2 participants
		0.55; (0.03 to 8.69)
Prolactin	Number Analyzed	3 participants
		1.64; (1.12 to 2.39)
LH Serum	Number Analyzed	3 participants
		0.69; (0.58 to 0.82)
Follicle Stimulating Hormone	Number Analyzed	3 participants
		0.89; (0.53 to 1.47)
Free Testosterone	Number Analyzed	3 participants
		1.10; (0.42 to 2.91)
Sex Hormone Binding Globulin	Number Analyzed	2 participants
		0.18; (0.07 to 0.45)
Dihydroepiandrosterone Sulfate	Number Analyzed	3 participants
		0.69; (0.20 to 2.35)

49. Primary Outcome

Title	Geometric Mean of Ratio of Total Testosterone, Free Testosterone, Sex Hormone Binding Globulin (SHBG), Luteinizing Hormone, Follicle Stimulating Hormone, Dihydroepiandrosterone Sulfate, Estradiol and Prolactin Levels in Males at Cycle 21 Day 1
Description	Geometric mean of ratio (Cycle 21 Day 1/Baseline) of hypogonadism parameters (total testosterone, free testosterone, sex hormone binding globulin, luteinizing hormone, follicle stimulating hormone, dihydroepiandrosterone sulfate, estradiol and prolactin) levels in males was analyzed. Data for this outcome measure was planned to be collected for combined RP2D Cohort only, excluding arms of low and high dose escalation cohorts. 95% CI should be interpreted with cautions due to the limited sample size at this time point.
Time Frame	Baseline, Cycle 21 Day 1

Outcome Measure Data

Analysis Population Description

Hypogonadism test evaluable population: Male participants who had completed screening, had received at least 1 dose of crizotinib on Cycle 1 Day 1, had at least 1 post baseline visit data for at least total testosterone, free testosterone, SHBG and included male participants of MET amplification and enriched other Cohort following approval of protocol amendment number 21. "N" =participants evaluable for this OM and 'number analyzed' =participants with available data for each specified category.

Arm/Group Title		RP2D Cohort: Crizotinib 250 mg
Arm/Group Description:		Participants received Crizotinib 250 mg tablet/capsule (2 capsules/tablet of 100 mg each + 1 capsule/tablet of 50 mg) orally BID up to 124 months.
Overall Number of Participants Analyzed		2
Geometric Mean (95% Confidence Interval); Unit of Measure: Ratio
Testosterone	Number Analyzed	2 participants
		0.23; (0.09 to 0.60)
Estradiol	Number Analyzed	1 participants
		0.48
Prolactin	Number Analyzed	2 participants
		1.46; (0.62 to 3.41)
LH Serum	Number Analyzed	2 participants
		0.53; (0.12 to 2.42)
Follicle Stimulating Hormone	Number Analyzed	2 participants
		0.77; (0.44 to 1.33)
Free Testosterone	Number Analyzed	2 participants
		1.23; (0.00 to 797.68)
Sex Hormone Binding Globulin	Number Analyzed	2 participants
		0.15; (0.00 to 20.43)
Dihydroepiandrosterone Sulfate	Number Analyzed	2 participants
		0.72; (0.09 to 5.76)

50. Primary Outcome

Title	Geometric Mean of Ratio of Total Testosterone, Free Testosterone, Sex Hormone Binding Globulin (SHBG), Luteinizing Hormone, Follicle Stimulating Hormone, Dihydroepiandrosterone Sulfate, Estradiol and Prolactin Levels in Males at Cycle 24 Day 1
Description	Geometric mean of ratio (Cycle 24 Day 1/Baseline) of hypogonadism parameters (total testosterone, free testosterone, sex hormone binding globulin, luteinizing hormone, follicle stimulating hormone, dihydroepiandrosterone sulfate, estradiol and prolactin) levels in males was analyzed. Data for this outcome measure was planned to be collected for combined RP2D Cohort only, excluding arms of low and high dose escalation cohorts. 95% CI should be interpreted with cautions due to the limited sample size at this time point.
Time Frame	Baseline, Cycle 24 Day 1

Outcome Measure Data

Analysis Population Description

Hypogonadism test evaluable population: Male participants who had completed screening, had received at least 1 dose of crizotinib on Cycle 1 Day 1, had at least 1 post baseline visit data for at least total testosterone, free testosterone, SHBG and included male participants of MET amplification and enriched other Cohort following approval of protocol amendment number 21. "N" =participants evaluable for this OM and 'number analyzed' =participants with available data for each specified category.

Arm/Group Title		RP2D Cohort: Crizotinib 250 mg
Arm/Group Description:		Participants received Crizotinib 250 mg tablet/capsule (2 capsules/tablet of 100 mg each + 1 capsule/tablet of 50 mg) orally BID up to 124 months.
Overall Number of Participants Analyzed		2
Geometric Mean (95% Confidence Interval); Unit of Measure: Ratio
Testosterone	Number Analyzed	2 participants
		0.39; (0.00 to 70772.27)
Estradiol	Number Analyzed	2 participants
		0.70; (0.00 to 11581.59)
Prolactin	Number Analyzed	2 participants
		1.13; (0.10 to 12.55)
LH Serum	Number Analyzed	2 participants
		0.69; (0.09 to 5.23)
Follicle Stimulating Hormone	Number Analyzed	2 participants
		0.53; (0.07 to 3.81)
Free Testosterone	Number Analyzed	1 participants
		2.35
Sex Hormone Binding Globulin	Number Analyzed	2 participants
		0.20; (0.00 to 33217.86)
Dihydroepiandrosterone Sulfate	Number Analyzed	2 participants
		0.90; (0.48 to 1.66)

51. Primary Outcome

Title	Geometric Mean of Ratio of Total Testosterone, Free Testosterone, Sex Hormone Binding Globulin (SHBG), Luteinizing Hormone, Follicle Stimulating Hormone, Dihydroepiandrosterone Sulfate, Estradiol and Prolactin Levels in Males at Cycle 27 Day 1
Description	Geometric mean of ratio (Cycle 27 Day 1/Baseline) of hypogonadism parameters (total testosterone, free testosterone, sex hormone binding globulin, luteinizing hormone, follicle stimulating hormone, dihydroepiandrosterone sulfate, estradiol and prolactin) levels in males was analyzed. Data for this outcome measure was planned to be collected for combined RP2D Cohort only, excluding arms of low and high dose escalation cohorts. 95% CI should be interpreted with cautions due to the limited sample size at this time point.
Time Frame	Baseline, Cycle 27 Day 1

Outcome Measure Data

Analysis Population Description

Hypogonadism test evaluable population: Male participants who had completed screening, had received at least 1 dose of crizotinib on Cycle 1 Day 1, had at least 1 post baseline visit data for at least total testosterone, free testosterone, SHBG and included male participants of MET amplification and enriched other Cohort following approval of protocol amendment number 21. "N" =participants evaluable for this outcome measure.

Arm/Group Title	RP2D Cohort: Crizotinib 250 mg
Arm/Group Description:	Participants received Crizotinib 250 mg tablet/capsule (2 capsules/tablet of 100 mg each + 1 capsule/tablet of 50 mg) orally BID up to 124 months.
Overall Number of Participants Analyzed	2
Geometric Mean (95% Confidence Interval); Unit of Measure: Ratio
Testosterone	0.46; (0.00 to 61000.31)
Estradiol	0.97; (0.00 to 9022.66)
Prolactin	1.48; (0.11 to 20.69)
LH Serum	0.70; (0.11 to 4.50)
Follicle Stimulating Hormone	0.66; (0.06 to 7.53)
Free Testosterone	1.86; (0.02 to 147.95)
Sex Hormone Binding Globulin	0.24; (0.00 to 22059.61)
Dihydroepiandrosterone Sulfate	0.95; (0.24 to 3.78)

52. Primary Outcome

Title	Geometric Mean of Ratio of Total Testosterone, Free Testosterone, Sex Hormone Binding Globulin (SHBG), Luteinizing Hormone, Follicle Stimulating Hormone, Dihydroepiandrosterone Sulfate, Estradiol and Prolactin Levels in Males at Cycle 30 Day 1
Description	Geometric mean of ratio (Cycle 30 Day 1/Baseline) of hypogonadism parameters (total testosterone, free testosterone, sex hormone binding globulin, luteinizing hormone, follicle stimulating hormone, dihydroepiandrosterone sulfate, estradiol and prolactin) levels in males was analyzed. Data for this outcome measure was planned to be collected for combined RP2D Cohort only, excluding arms of low and high dose escalation cohorts. 95% CI should be interpreted with cautions due to the limited sample size at this time point.
Time Frame	Baseline, Cycle 30 Day 1

Outcome Measure Data

Analysis Population Description

Hypogonadism test evaluable population: Male participants who had completed screening, had received at least 1 dose of crizotinib on Cycle 1 Day 1, had at least 1 post baseline visit data for at least total testosterone, free testosterone, SHBG and included male participants of MET amplification and enriched other Cohort following approval of protocol amendment number 21. "N" =participants evaluable for this outcome measure.

Arm/Group Title	RP2D Cohort: Crizotinib 250 mg
Arm/Group Description:	Participants received Crizotinib 250 mg tablet/capsule (2 capsules/tablet of 100 mg each + 1 capsule/tablet of 50 mg) orally BID up to 124 months.
Overall Number of Participants Analyzed	1
Geometric Mean (95% Confidence Interval); Unit of Measure: Ratio
Testosterone	0.16
Estradiol	0.38
Prolactin	1.14
LH Serum	0.85
Follicle Stimulating Hormone	0.80
Free Testosterone	1.25
Sex Hormone Binding Globulin	0.09
Dihydroepiandrosterone Sulfate	0.71

53. Primary Outcome

Title	Geometric Mean of Ratio of Total Testosterone, Free Testosterone, Sex Hormone Binding Globulin (SHBG), Luteinizing Hormone, Follicle Stimulating Hormone, Dihydroepiandrosterone Sulfate, Estradiol and Prolactin Levels in Males at End of Treatment
Description	Geometric mean of ratio (End of treatment/Baseline) of hypogonadism parameters (total testosterone, free testosterone, sex hormone binding globulin, luteinizing hormone, follicle stimulating hormone, dihydroepiandrosterone sulfate, estradiol and prolactin) levels in males was analyzed. Data for this outcome measure was planned to be collected for combined RP2D Cohort only, excluding arms of low and high dose escalation cohorts. 95% CI should be interpreted with cautions due to the limited sample size at this time point.
Time Frame	Baseline, End of Treatment (28 days post last dose)

Outcome Measure Data

Analysis Population Description

Hypogonadism test evaluable population: Male participants who had completed screening, had received at least 1 dose of crizotinib on Cycle 1 Day 1, had at least 1 post baseline visit data for at least total testosterone, free testosterone, SHBG and included male participants of MET amplification and enriched other Cohort following approval of protocol amendment number 21. "N" =participants evaluable for this OM and 'number analyzed' =participants with available data for each specified category.

Arm/Group Title		RP2D Cohort: Crizotinib 250 mg
Arm/Group Description:		Participants received Crizotinib 250 mg tablet/capsule (2 capsules/tablet of 100 mg each + 1 capsule/tablet of 50 mg) orally BID up to 124 months.
Overall Number of Participants Analyzed		5
Geometric Mean (95% Confidence Interval); Unit of Measure: Ratio
Testosterone	Number Analyzed	5 participants
		0.40; (0.08 to 2.08)
Estradiol	Number Analyzed	5 participants
		0.66; (0.39 to 1.13)
Prolactin	Number Analyzed	5 participants
		1.48; (0.49 to 4.50)
LH Serum	Number Analyzed	5 participants
		0.52; (0.14 to 1.98)
Follicle Stimulating Hormone	Number Analyzed	5 participants
		0.85; (0.26 to 2.72)
Free Testosterone	Number Analyzed	5 participants
		0.62; (0.20 to 1.93)
Sex Hormone Binding Globulin	Number Analyzed	5 participants
		0.64; (0.24 to 1.71)
Dihydroepiandrosterone Sulfate	Number Analyzed	4 participants
		0.41; (0.21 to 0.78)

Adverse Events

Time Frame

Up to maximum of 189 months

Adverse Event Reporting Description

Same event may appear as both an AE and SAE. However, what is presented are distinct events. An event may be categorized as serious in one participant and as non-serious in another, or a participant may have experienced both a serious and non-serious event. Analysis performed on safety analysis set.

Arm/Group Title

Low Dose Escalation Cohort: Crizotinib 50 mg QD

Low Dose Escalation Cohort: Crizotinib 100 mg QD

Low Dose Escalation Cohort: Crizotinib 200 mg QD

Low Dose Escalation Cohort: Crizotinib 200 mg BID

Low Dose Escalation Cohort: Crizotinib 250 mg BID

Low Dose Escalation Cohort: Crizotinib 300 mg BID

High Dose Escalation Cohort: Crizotinib 300 mg QD

High Dose Escalation Cohort: Crizotinib 400 mg QD

High Dose Escalation Cohort: Crizotinib 500 mg QD

High Dose Escalation Cohort: Crizotinib 650 mg QD

High Dose Escalation Cohort: Crizotinib 800 mg QD

RP2D Cohort: ROS1-Positive NSCLC: Crizotinib 250 mg

RP2D Cohort: MET Exon 14 Alterations NSCLC: Crizotinib 250 mg

RP2D Cohort: MET Amplification NSCLC: Crizotinib 250 mg

RP2D Cohort: ALK-Negative Cohort 1, NSCLC: Crizotinib 250 mg

RP2D Cohort: ALK-Negative Cohort 2, NSCLC: Crizotinib 250 mg

RP2D Cohort: ALK-Positive Cohort, NSCLC: Crizotinib 250 mg

RP2D Cohort: Enriched Other: Crizotinib 250 mg

Itraconazole Interaction Sub-study: Crizotinib 250 mg

RP2D Cohort: Rifampin Interaction: Crizotinib 250 mg +Rifampin

Midazolam Interaction Cohort: Crizotinib 250

Arm/Group Description

Participants received Crizotinib 50 milligram (mg) capsule or tablet orally once daily (QD) for up to 34 cycles (each cycle 28 days).

Participants received Crizotinib 100 mg capsule or tablet orally QD for up to 34 cycles (each cycle 28 days) and 2 mg oral dose of Midazolam along with Crizotinib 100 mg on Cycle 2 Day 1 only. Participants who did not receive Crizotinib on Day -7, received single 2 mg oral dose of Midazolam on Day -7.

Participants received Crizotinib 200 mg (2 capsules/tablet of 100 mg each) capsule/tablet orally QD for up to 34 cycles (each cycle 28 days).

Participants received Crizotinib 200 mg (2 capsules/tablet of 100 mg each) capsule/tablet orally twice daily (BID) for up to 34 cycles (each cycle 28 days).

Participants received Crizotinib 250 mg (2 capsules/tablet of 100 mg each + 1 capsule/tablet of 50 mg) capsule/tablet BID for up to 34 cycles (each cycle 28 days).

Participants received Crizotinib 300 mg (3 capsules/tablet of 100 mg each) capsule/tablet orally BID for up to 34 cycles (each cycle 28 days) and 2 mg oral dose of Midazolam along with Crizotinib 300 mg on Cycle 2 Day 1 only. Participants who did not receive Crizotinib on Day -7, received single 2 mg oral dose of Midazolam on Day -7.

Participants received Crizotinib 300 mg (3 capsules/tablet of 100 mg each) capsule/tablet QD for up to 7 cycles (each cycle 28 days).

Participants received Crizotinib 400 mg (4 capsules/tablet of 100 mg each) capsule/tablet QD for up to 7 cycles (each cycle 28 days).

Participants received Crizotinib 500 mg (5 capsules/tablet of 100 mg each) capsule/tablet QD for up to 7 cycles (each cycle 28 days).

Participants received Crizotinib 650 mg (6 capsules/tablet of 100 mg each + 1 capsule/tablet of 50 mg) capsule/tablet twice daily (BID) for up to 7 cycles (each cycle 28 days).

Participants received Crizotinib 800 mg (8 capsules/tablet of 100 mg each) capsule/tablet QD for up to 7 cycles (each cycle 28 days).

Participants received Crizotinib 250 mg (2 capsules/tablet of 100 mg each + 1 capsule/tablet of 50 mg) capsule/tablet orally twice daily (BID) with or without food for up to 105 cycles (each cycle 28 days).

Participants received Crizotinib 250 mg (2 capsules/tablet of 100 mg each + 1 capsule/tablet of 50 mg) capsule/tablet orally twice daily (BID) with or without food for up to 55 cycles (each cycle 28 days).

Participants received Crizotinib 250 mg (2 capsules/tablet of 100 mg each + 1 capsule/tablet of 50 mg) capsule/tablet orally twice daily (BID) with or without food for up to 101 cycles (each cycle 28 days).

Participants received Crizotinib 250 mg (2 capsules/tablet of 100 mg each + 1 capsule/tablet of 50 mg) capsule/tablet twice daily (BID) with or without food for up to 70 cycles (each cycle 21 days).

Participants received Crizotinib 250 mg (2 capsules/tablet of 100 mg each + 1 capsule/tablet of 50 mg) capsule/tablet orally BID with or without food for up to 70 cycles (each cycle 21 days).

Participants received Crizotinib 250 mg (2 capsules/tablet of 100 mg each + 1 capsule/tablet of 50 mg) capsule/tablet twice daily (BID) with or without food for up to 133 cycles (each cycle 28 days).

Participants received Crizotinib 250 mg (2 capsules/tablet of 100 mg each + 1 capsule/tablet of 50 mg) capsule/tablet orally twice daily (BID) with or without food for up to 54 cycles (each cycle 28 days).

Participants received Crizotinib 250 mg (2 capsules/tablet of 100 mg each + 1 capsule/tablet of 50 mg) capsule/tablet QD from Cycle 1Day1 to Cycle 2 Day1 thereafter 250 mg BID from Cycle 2 Day 2 up to 58 cycles (each cycle 28 days). Participants also received Itraconazole 200 mg QD from Cycle 1 Day 1 to Cycle 1 Day 16.

Participants received Crizotinib 250 mg (2 capsules/tablet of 100 mg each + 1 capsule/tablet of 50 mg) capsule/tablet twice daily (BID) with or without food from Cycle 1 Day 1 up to 13 cycles (each cycle 28 days). Participants also received commercially available Rifampin 650 mg QD from Cycle 1 Day 16 to Cycle 2 Day 1 (14 days) either one hour before or 2 hours after food.

Participants received Crizotinib 250 mg tablet/capsule (2 capsules/tablet of 100 mg each + 1 capsule/tablet of 50 mg) orally BID from Day 1Cycle 1 up to p to 133 cycles (each cycle 28 days). Participants also received single 2 mg oral dose of Midazolam on Day -7 and another single 2-mg oral dose of Midazolam concurrently with Crizotinib on Cycle 2 Day 1.

All-Cause Mortality

Low Dose Escalation Cohort: Crizotinib 50 mg QD

Low Dose Escalation Cohort: Crizotinib 100 mg QD

Low Dose Escalation Cohort: Crizotinib 200 mg QD

Low Dose Escalation Cohort: Crizotinib 200 mg BID

Low Dose Escalation Cohort: Crizotinib 250 mg BID

Low Dose Escalation Cohort: Crizotinib 300 mg BID

High Dose Escalation Cohort: Crizotinib 300 mg QD

High Dose Escalation Cohort: Crizotinib 400 mg QD

High Dose Escalation Cohort: Crizotinib 500 mg QD

High Dose Escalation Cohort: Crizotinib 650 mg QD

High Dose Escalation Cohort: Crizotinib 800 mg QD

RP2D Cohort: ROS1-Positive NSCLC: Crizotinib 250 mg

RP2D Cohort: MET Exon 14 Alterations NSCLC: Crizotinib 250 mg

RP2D Cohort: MET Amplification NSCLC: Crizotinib 250 mg

RP2D Cohort: ALK-Negative Cohort 1, NSCLC: Crizotinib 250 mg

RP2D Cohort: ALK-Negative Cohort 2, NSCLC: Crizotinib 250 mg

RP2D Cohort: ALK-Positive Cohort, NSCLC: Crizotinib 250 mg

RP2D Cohort: Enriched Other: Crizotinib 250 mg

Itraconazole Interaction Sub-study: Crizotinib 250 mg

RP2D Cohort: Rifampin Interaction: Crizotinib 250 mg +Rifampin

Midazolam Interaction Cohort: Crizotinib 250

Affected / at Risk (%)

Affected / at Risk (%)

Affected / at Risk (%)

Affected / at Risk (%)

Affected / at Risk (%)

Affected / at Risk (%)

Affected / at Risk (%)

Affected / at Risk (%)

Affected / at Risk (%)

Affected / at Risk (%)

Affected / at Risk (%)

Affected / at Risk (%)

Affected / at Risk (%)

Affected / at Risk (%)

Affected / at Risk (%)

Affected / at Risk (%)

Affected / at Risk (%)

Affected / at Risk (%)

Affected / at Risk (%)

Affected / at Risk (%)

Affected / at Risk (%)

Total

0/3 (0.00%)

0/4 (0.00%)

0/8 (0.00%)

0/7 (0.00%)

0/8 (0.00%)

0/6 (0.00%)

1/6 (16.67%)

0/5 (0.00%)

1/3 (33.33%)

1/6 (16.67%)

1/9 (11.11%)

10/53 (18.87%)

15/85 (17.65%)

8/41 (19.51%)

13/48 (27.08%)

9/18 (50.00%)

25/154 (16.23%)

15/66 (22.73%)

0/18 (0.00%)

1/18 (5.56%)

4/12 (33.33%)

Serious Adverse Events

Low Dose Escalation Cohort: Crizotinib 50 mg QD

Low Dose Escalation Cohort: Crizotinib 100 mg QD

Low Dose Escalation Cohort: Crizotinib 200 mg QD

Low Dose Escalation Cohort: Crizotinib 200 mg BID

Low Dose Escalation Cohort: Crizotinib 250 mg BID

Low Dose Escalation Cohort: Crizotinib 300 mg BID

High Dose Escalation Cohort: Crizotinib 300 mg QD

High Dose Escalation Cohort: Crizotinib 400 mg QD

High Dose Escalation Cohort: Crizotinib 500 mg QD

High Dose Escalation Cohort: Crizotinib 650 mg QD

High Dose Escalation Cohort: Crizotinib 800 mg QD

RP2D Cohort: ROS1-Positive NSCLC: Crizotinib 250 mg

RP2D Cohort: MET Exon 14 Alterations NSCLC: Crizotinib 250 mg

RP2D Cohort: MET Amplification NSCLC: Crizotinib 250 mg

RP2D Cohort: ALK-Negative Cohort 1, NSCLC: Crizotinib 250 mg

RP2D Cohort: ALK-Negative Cohort 2, NSCLC: Crizotinib 250 mg

RP2D Cohort: ALK-Positive Cohort, NSCLC: Crizotinib 250 mg

RP2D Cohort: Enriched Other: Crizotinib 250 mg

Itraconazole Interaction Sub-study: Crizotinib 250 mg

RP2D Cohort: Rifampin Interaction: Crizotinib 250 mg +Rifampin

Midazolam Interaction Cohort: Crizotinib 250

Affected / at Risk (%)

# Events

Affected / at Risk (%)

# Events

Affected / at Risk (%)

# Events

Affected / at Risk (%)

# Events

Affected / at Risk (%)

# Events

Affected / at Risk (%)

# Events

Affected / at Risk (%)

# Events

Affected / at Risk (%)

# Events

Affected / at Risk (%)

# Events

Affected / at Risk (%)

# Events

Affected / at Risk (%)

# Events

Affected / at Risk (%)

# Events

Affected / at Risk (%)

# Events

Affected / at Risk (%)

# Events

Affected / at Risk (%)

# Events

Affected / at Risk (%)

# Events

Affected / at Risk (%)

# Events

Affected / at Risk (%)

# Events

Affected / at Risk (%)

# Events

Affected / at Risk (%)

# Events

Affected / at Risk (%)

# Events

Total

0/3 (0.00%)

0/4 (0.00%)

1/8 (12.50%)

2/7 (28.57%)

4/8 (50.00%)

2/6 (33.33%)

2/6 (33.33%)

2/5 (40.00%)

1/3 (33.33%)

2/6 (33.33%)

4/9 (44.44%)

24/53 (45.28%)

54/85 (63.53%)

25/41 (60.98%)

22/48 (45.83%)

9/18 (50.00%)

75/154 (48.70%)

29/66 (43.94%)

7/18 (38.89%)

6/18 (33.33%)

6/12 (50.00%)

Blood and lymphatic system disorders

Anaemia * 1

0/3 (0.00%)

0/4 (0.00%)

0/8 (0.00%)

0/7 (0.00%)

1/8 (12.50%)

0/6 (0.00%)

0/6 (0.00%)

0/5 (0.00%)

0/3 (0.00%)

0/6 (0.00%)

0/9 (0.00%)

0/53 (0.00%)

1/85 (1.18%)

2/41 (4.88%)

1/48 (2.08%)

0/18 (0.00%)

2/154 (1.30%)

3/66 (4.55%)

0/18 (0.00%)

0/18 (0.00%)

0/12 (0.00%)

Disseminated intravascular coagulation * 1

0/3 (0.00%)

0/4 (0.00%)

0/8 (0.00%)

0/7 (0.00%)

0/8 (0.00%)

0/6 (0.00%)

0/6 (0.00%)

0/5 (0.00%)

0/3 (0.00%)

0/6 (0.00%)

0/9 (0.00%)

0/53 (0.00%)

0/85 (0.00%)

0/41 (0.00%)

0/48 (0.00%)

0/18 (0.00%)

1/154 (0.65%)

0/66 (0.00%)

0/18 (0.00%)

0/18 (0.00%)

0/12 (0.00%)

Febrile neutropenia * 1

0/3 (0.00%)

0/4 (0.00%)

0/8 (0.00%)

0/7 (0.00%)

0/8 (0.00%)

0/6 (0.00%)

0/6 (0.00%)

0/5 (0.00%)

0/3 (0.00%)

0/6 (0.00%)

0/9 (0.00%)

0/53 (0.00%)

0/85 (0.00%)

1/41 (2.44%)

0/48 (0.00%)

0/18 (0.00%)

0/154 (0.00%)

1/66 (1.52%)

0/18 (0.00%)

0/18 (0.00%)

0/12 (0.00%)

Thrombocytopenia * 1

0/3 (0.00%)

0/4 (0.00%)

0/8 (0.00%)

0/7 (0.00%)

0/8 (0.00%)

0/6 (0.00%)

0/6 (0.00%)

0/5 (0.00%)

0/3 (0.00%)

0/6 (0.00%)

0/9 (0.00%)

0/53 (0.00%)

0/85 (0.00%)

0/41 (0.00%)

0/48 (0.00%)

0/18 (0.00%)

0/154 (0.00%)

0/66 (0.00%)

1/18 (5.56%)

0/18 (0.00%)

0/12 (0.00%)

Cardiac disorders

Bradycardia * 1

0/3 (0.00%)

0/4 (0.00%)

0/8 (0.00%)

0/7 (0.00%)

0/8 (0.00%)

0/6 (0.00%)

0/6 (0.00%)

0/5 (0.00%)

0/3 (0.00%)

0/6 (0.00%)

0/9 (0.00%)

1/53 (1.89%)

1/85 (1.18%)

1/41 (2.44%)

0/48 (0.00%)

1/18 (5.56%)

1/154 (0.65%)

0/66 (0.00%)

0/18 (0.00%)

0/18 (0.00%)

0/12 (0.00%)

Pericardial effusion * 1

0/3 (0.00%)

0/4 (0.00%)

0/8 (0.00%)

0/7 (0.00%)

0/8 (0.00%)

0/6 (0.00%)

0/6 (0.00%)

0/5 (0.00%)

0/3 (0.00%)

0/6 (0.00%)

0/9 (0.00%)

1/53 (1.89%)

0/85 (0.00%)

1/41 (2.44%)

0/48 (0.00%)

0/18 (0.00%)

1/154 (0.65%)

0/66 (0.00%)

0/18 (0.00%)

0/18 (0.00%)

0/12 (0.00%)

Arrhythmia supraventricular * 1

0/3 (0.00%)

0/4 (0.00%)

0/8 (0.00%)

0/7 (0.00%)

0/8 (0.00%)

0/6 (0.00%)

0/6 (0.00%)

0/5 (0.00%)

0/3 (0.00%)

0/6 (0.00%)

0/9 (0.00%)

0/53 (0.00%)

0/85 (0.00%)

1/41 (2.44%)

0/48 (0.00%)

0/18 (0.00%)

0/154 (0.00%)

0/66 (0.00%)

0/18 (0.00%)

0/18 (0.00%)

0/12 (0.00%)

Atrial fibrillation * 1

0/3 (0.00%)

0/4 (0.00%)

0/8 (0.00%)

0/7 (0.00%)

0/8 (0.00%)

0/6 (0.00%)

0/6 (0.00%)

0/5 (0.00%)

0/3 (0.00%)

0/6 (0.00%)

0/9 (0.00%)

0/53 (0.00%)

1/85 (1.18%)

0/41 (0.00%)

0/48 (0.00%)

1/18 (5.56%)

3/154 (1.95%)

0/66 (0.00%)

1/18 (5.56%)

0/18 (0.00%)

0/12 (0.00%)

Atrial thrombosis * 1

0/3 (0.00%)

0/4 (0.00%)

0/8 (0.00%)

0/7 (0.00%)

0/8 (0.00%)

0/6 (0.00%)

0/6 (0.00%)

0/5 (0.00%)

0/3 (0.00%)

0/6 (0.00%)

0/9 (0.00%)

0/53 (0.00%)

0/85 (0.00%)

1/41 (2.44%)

0/48 (0.00%)

0/18 (0.00%)

0/154 (0.00%)

0/66 (0.00%)

0/18 (0.00%)

0/18 (0.00%)

0/12 (0.00%)

Cardiac arrest * 1

0/3 (0.00%)

0/4 (0.00%)

0/8 (0.00%)

0/7 (0.00%)

0/8 (0.00%)

0/6 (0.00%)

0/6 (0.00%)

0/5 (0.00%)

1/3 (33.33%)

0/6 (0.00%)

0/9 (0.00%)

0/53 (0.00%)

1/85 (1.18%)

0/41 (0.00%)

0/48 (0.00%)

0/18 (0.00%)

0/154 (0.00%)

0/66 (0.00%)

0/18 (0.00%)

0/18 (0.00%)

0/12 (0.00%)

Cardiac failure * 1

0/3 (0.00%)

0/4 (0.00%)

0/8 (0.00%)

0/7 (0.00%)

0/8 (0.00%)

0/6 (0.00%)

0/6 (0.00%)

0/5 (0.00%)

0/3 (0.00%)

0/6 (0.00%)

0/9 (0.00%)

0/53 (0.00%)

2/85 (2.35%)

0/41 (0.00%)

0/48 (0.00%)

0/18 (0.00%)

0/154 (0.00%)

0/66 (0.00%)

0/18 (0.00%)

0/18 (0.00%)

0/12 (0.00%)

Cardiac tamponade * 1

0/3 (0.00%)

0/4 (0.00%)

0/8 (0.00%)

0/7 (0.00%)

0/8 (0.00%)

0/6 (0.00%)

0/6 (0.00%)

0/5 (0.00%)

0/3 (0.00%)

0/6 (0.00%)

0/9 (0.00%)

0/53 (0.00%)

0/85 (0.00%)

1/41 (2.44%)

0/48 (0.00%)

0/18 (0.00%)

0/154 (0.00%)

0/66 (0.00%)

0/18 (0.00%)

0/18 (0.00%)

0/12 (0.00%)

Cardio-respiratory arrest * 1

0/3 (0.00%)

0/4 (0.00%)

0/8 (0.00%)

0/7 (0.00%)

0/8 (0.00%)

0/6 (0.00%)

0/6 (0.00%)

0/5 (0.00%)

0/3 (0.00%)

0/6 (0.00%)

0/9 (0.00%)

0/53 (0.00%)

1/85 (1.18%)

0/41 (0.00%)

1/48 (2.08%)

0/18 (0.00%)

0/154 (0.00%)

0/66 (0.00%)

0/18 (0.00%)

0/18 (0.00%)

0/12 (0.00%)

Left ventricular dysfunction * 1

0/3 (0.00%)

0/4 (0.00%)

0/8 (0.00%)

0/7 (0.00%)

0/8 (0.00%)

0/6 (0.00%)

0/6 (0.00%)

0/5 (0.00%)

0/3 (0.00%)

0/6 (0.00%)

0/9 (0.00%)

0/53 (0.00%)

1/85 (1.18%)

0/41 (0.00%)

0/48 (0.00%)

0/18 (0.00%)

0/154 (0.00%)

0/66 (0.00%)

0/18 (0.00%)

0/18 (0.00%)

0/12 (0.00%)

Myocardial infarction * 1

0/3 (0.00%)

0/4 (0.00%)

0/8 (0.00%)

0/7 (0.00%)

0/8 (0.00%)

0/6 (0.00%)

0/6 (0.00%)

0/5 (0.00%)

0/3 (0.00%)

0/6 (0.00%)

0/9 (0.00%)

0/53 (0.00%)

0/85 (0.00%)

0/41 (0.00%)

1/48 (2.08%)

0/18 (0.00%)

0/154 (0.00%)

1/66 (1.52%)

0/18 (0.00%)

0/18 (0.00%)

0/12 (0.00%)

Sinus bradycardia * 1

0/3 (0.00%)

0/4 (0.00%)

0/8 (0.00%)

0/7 (0.00%)

0/8 (0.00%)

0/6 (0.00%)

0/6 (0.00%)

0/5 (0.00%)

0/3 (0.00%)

0/6 (0.00%)

0/9 (0.00%)

0/53 (0.00%)

1/85 (1.18%)

0/41 (0.00%)

0/48 (0.00%)

0/18 (0.00%)

0/154 (0.00%)

0/66 (0.00%)

0/18 (0.00%)

0/18 (0.00%)

0/12 (0.00%)

Syncope * 1

0/3 (0.00%)

0/4 (0.00%)

0/8 (0.00%)

0/7 (0.00%)

0/8 (0.00%)

0/6 (0.00%)

0/6 (0.00%)

0/5 (0.00%)

0/3 (0.00%)

0/6 (0.00%)

0/9 (0.00%)

0/53 (0.00%)

3/85 (3.53%)

0/41 (0.00%)

0/48 (0.00%)

0/18 (0.00%)

4/154 (2.60%)

1/66 (1.52%)

0/18 (0.00%)

0/18 (0.00%)

0/12 (0.00%)

Endocrine disorders

Adrenal insufficiency * 1

0/3 (0.00%)

0/4 (0.00%)

0/8 (0.00%)

0/7 (0.00%)

0/8 (0.00%)

0/6 (0.00%)

0/6 (0.00%)

0/5 (0.00%)

0/3 (0.00%)

0/6 (0.00%)

0/9 (0.00%)

1/53 (1.89%)

0/85 (0.00%)

0/41 (0.00%)

0/48 (0.00%)

0/18 (0.00%)

0/154 (0.00%)

0/66 (0.00%)

0/18 (0.00%)

0/18 (0.00%)

0/12 (0.00%)

Autoimmune thyroiditis * 1

0/3 (0.00%)

0/4 (0.00%)

0/8 (0.00%)

0/7 (0.00%)

0/8 (0.00%)

0/6 (0.00%)

0/6 (0.00%)

0/5 (0.00%)

0/3 (0.00%)

0/6 (0.00%)

0/9 (0.00%)

0/53 (0.00%)

0/85 (0.00%)

0/41 (0.00%)

0/48 (0.00%)

0/18 (0.00%)

0/154 (0.00%)

1/66 (1.52%)

0/18 (0.00%)

0/18 (0.00%)

0/12 (0.00%)

Eye disorders

Papilloedema * 1

0/3 (0.00%)

0/4 (0.00%)

0/8 (0.00%)

0/7 (0.00%)

0/8 (0.00%)

0/6 (0.00%)

0/6 (0.00%)

0/5 (0.00%)

0/3 (0.00%)

0/6 (0.00%)

0/9 (0.00%)

0/53 (0.00%)

0/85 (0.00%)

0/41 (0.00%)

0/48 (0.00%)

1/18 (5.56%)

0/154 (0.00%)

0/66 (0.00%)

0/18 (0.00%)

0/18 (0.00%)

0/12 (0.00%)

Gastrointestinal disorders

Abdominal pain upper * 1

0/3 (0.00%)

0/4 (0.00%)

0/8 (0.00%)

0/7 (0.00%)

0/8 (0.00%)

0/6 (0.00%)

0/6 (0.00%)

0/5 (0.00%)

0/3 (0.00%)

0/6 (0.00%)

0/9 (0.00%)

1/53 (1.89%)

0/85 (0.00%)

0/41 (0.00%)

0/48 (0.00%)

0/18 (0.00%)

0/154 (0.00%)

0/66 (0.00%)

0/18 (0.00%)

0/18 (0.00%)

0/12 (0.00%)

Gastrointestinal amyloidosis * 1

0/3 (0.00%)

0/4 (0.00%)

0/8 (0.00%)

0/7 (0.00%)

0/8 (0.00%)

0/6 (0.00%)

0/6 (0.00%)

0/5 (0.00%)

0/3 (0.00%)

0/6 (0.00%)

0/9 (0.00%)

1/53 (1.89%)

0/85 (0.00%)

0/41 (0.00%)

0/48 (0.00%)

0/18 (0.00%)

0/154 (0.00%)

0/66 (0.00%)

0/18 (0.00%)

0/18 (0.00%)

0/12 (0.00%)

Large intestine perforation * 1

0/3 (0.00%)

0/4 (0.00%)

0/8 (0.00%)

0/7 (0.00%)

0/8 (0.00%)

0/6 (0.00%)

0/6 (0.00%)

0/5 (0.00%)

0/3 (0.00%)

0/6 (0.00%)

0/9 (0.00%)

1/53 (1.89%)

0/85 (0.00%)

0/41 (0.00%)

0/48 (0.00%)

0/18 (0.00%)

0/154 (0.00%)

0/66 (0.00%)

0/18 (0.00%)

0/18 (0.00%)

0/12 (0.00%)

Nausea * 1

0/3 (0.00%)

0/4 (0.00%)

0/8 (0.00%)

0/7 (0.00%)

0/8 (0.00%)

0/6 (0.00%)

0/6 (0.00%)

0/5 (0.00%)

0/3 (0.00%)

0/6 (0.00%)

0/9 (0.00%)

2/53 (3.77%)

2/85 (2.35%)

0/41 (0.00%)

0/48 (0.00%)

0/18 (0.00%)

2/154 (1.30%)

0/66 (0.00%)

1/18 (5.56%)

0/18 (0.00%)

0/12 (0.00%)

Vomiting * 1

0/3 (0.00%)

0/4 (0.00%)

0/8 (0.00%)

1/7 (14.29%)

1/8 (12.50%)

0/6 (0.00%)

0/6 (0.00%)

0/5 (0.00%)

0/3 (0.00%)

0/6 (0.00%)

0/9 (0.00%)

1/53 (1.89%)

0/85 (0.00%)

0/41 (0.00%)

0/48 (0.00%)

0/18 (0.00%)

3/154 (1.95%)

1/66 (1.52%)

2/18 (11.11%)

0/18 (0.00%)

0/12 (0.00%)

Abdominal pain * 1

0/3 (0.00%)

0/4 (0.00%)

0/8 (0.00%)

0/7 (0.00%)

0/8 (0.00%)

0/6 (0.00%)

0/6 (0.00%)

0/5 (0.00%)

0/3 (0.00%)

0/6 (0.00%)

0/9 (0.00%)

0/53 (0.00%)

1/85 (1.18%)

0/41 (0.00%)

0/48 (0.00%)

0/18 (0.00%)

1/154 (0.65%)

1/66 (1.52%)

0/18 (0.00%)

1/18 (5.56%)

0/12 (0.00%)

Ascites * 1

0/3 (0.00%)

0/4 (0.00%)

0/8 (0.00%)

0/7 (0.00%)

0/8 (0.00%)

0/6 (0.00%)

0/6 (0.00%)

0/5 (0.00%)

0/3 (0.00%)

0/6 (0.00%)

0/9 (0.00%)

0/53 (0.00%)

0/85 (0.00%)

0/41 (0.00%)

0/48 (0.00%)

0/18 (0.00%)

0/154 (0.00%)

1/66 (1.52%)

0/18 (0.00%)

0/18 (0.00%)

0/12 (0.00%)

Constipation * 1

0/3 (0.00%)

0/4 (0.00%)

0/8 (0.00%)

0/7 (0.00%)

0/8 (0.00%)

0/6 (0.00%)

0/6 (0.00%)

1/5 (20.00%)

0/3 (0.00%)

0/6 (0.00%)

0/9 (0.00%)

0/53 (0.00%)

1/85 (1.18%)

1/41 (2.44%)

0/48 (0.00%)

0/18 (0.00%)

3/154 (1.95%)

0/66 (0.00%)

0/18 (0.00%)

0/18 (0.00%)

0/12 (0.00%)

Diarrhoea * 1

0/3 (0.00%)

0/4 (0.00%)

0/8 (0.00%)

0/7 (0.00%)

1/8 (12.50%)

0/6 (0.00%)

0/6 (0.00%)

0/5 (0.00%)

0/3 (0.00%)

0/6 (0.00%)

0/9 (0.00%)

0/53 (0.00%)

0/85 (0.00%)

0/41 (0.00%)

0/48 (0.00%)

0/18 (0.00%)

0/154 (0.00%)

0/66 (0.00%)

0/18 (0.00%)

0/18 (0.00%)

0/12 (0.00%)

Dysphagia * 1

0/3 (0.00%)

0/4 (0.00%)

0/8 (0.00%)

0/7 (0.00%)

0/8 (0.00%)

0/6 (0.00%)

0/6 (0.00%)

0/5 (0.00%)

0/3 (0.00%)

0/6 (0.00%)

0/9 (0.00%)

0/53 (0.00%)

0/85 (0.00%)

1/41 (2.44%)

0/48 (0.00%)

0/18 (0.00%)

0/154 (0.00%)

0/66 (0.00%)

0/18 (0.00%)

0/18 (0.00%)

0/12 (0.00%)

Gastric haemorrhage * 1

0/3 (0.00%)

0/4 (0.00%)

0/8 (0.00%)

0/7 (0.00%)

0/8 (0.00%)

0/6 (0.00%)

0/6 (0.00%)

0/5 (0.00%)

0/3 (0.00%)

0/6 (0.00%)

0/9 (0.00%)

0/53 (0.00%)

0/85 (0.00%)

0/41 (0.00%)

0/48 (0.00%)

0/18 (0.00%)

0/154 (0.00%)

0/66 (0.00%)

1/18 (5.56%)

0/18 (0.00%)

0/12 (0.00%)

Gastrointestinal haemorrhage * 1

0/3 (0.00%)

0/4 (0.00%)

0/8 (0.00%)

0/7 (0.00%)

0/8 (0.00%)

0/6 (0.00%)

0/6 (0.00%)

0/5 (0.00%)

0/3 (0.00%)

0/6 (0.00%)

0/9 (0.00%)

0/53 (0.00%)

1/85 (1.18%)

0/41 (0.00%)

0/48 (0.00%)

0/18 (0.00%)

0/154 (0.00%)

1/66 (1.52%)

0/18 (0.00%)

0/18 (0.00%)

0/12 (0.00%)

Gastrointestinal necrosis * 1

0/3 (0.00%)

0/4 (0.00%)

0/8 (0.00%)

0/7 (0.00%)

0/8 (0.00%)

0/6 (0.00%)

0/6 (0.00%)

0/5 (0.00%)

1/3 (33.33%)

0/6 (0.00%)

0/9 (0.00%)

0/53 (0.00%)

0/85 (0.00%)

0/41 (0.00%)

0/48 (0.00%)

0/18 (0.00%)

0/154 (0.00%)

0/66 (0.00%)

0/18 (0.00%)

0/18 (0.00%)

0/12 (0.00%)

Gastrointestinal perforation * 1

0/3 (0.00%)

0/4 (0.00%)

0/8 (0.00%)

0/7 (0.00%)

0/8 (0.00%)

0/6 (0.00%)

0/6 (0.00%)

0/5 (0.00%)

0/3 (0.00%)

0/6 (0.00%)

0/9 (0.00%)

0/53 (0.00%)

0/85 (0.00%)

0/41 (0.00%)

0/48 (0.00%)

0/18 (0.00%)

1/154 (0.65%)

0/66 (0.00%)

0/18 (0.00%)

0/18 (0.00%)

0/12 (0.00%)

Gastrooesophageal reflux disease * 1

0/3 (0.00%)

0/4 (0.00%)

0/8 (0.00%)

0/7 (0.00%)

0/8 (0.00%)

0/6 (0.00%)

0/6 (0.00%)

0/5 (0.00%)

0/3 (0.00%)

0/6 (0.00%)

0/9 (0.00%)

0/53 (0.00%)

0/85 (0.00%)

0/41 (0.00%)

0/48 (0.00%)

0/18 (0.00%)

0/154 (0.00%)

0/66 (0.00%)

0/18 (0.00%)

1/18 (5.56%)

0/12 (0.00%)

Intestinal obstruction * 1

0/3 (0.00%)

0/4 (0.00%)

0/8 (0.00%)

0/7 (0.00%)

0/8 (0.00%)

0/6 (0.00%)

0/6 (0.00%)

0/5 (0.00%)

1/3 (33.33%)

0/6 (0.00%)

0/9 (0.00%)

0/53 (0.00%)

0/85 (0.00%)

0/41 (0.00%)

0/48 (0.00%)

0/18 (0.00%)

0/154 (0.00%)

0/66 (0.00%)

0/18 (0.00%)

1/18 (5.56%)

0/12 (0.00%)

Large intestinal obstruction * 1

0/3 (0.00%)

0/4 (0.00%)

0/8 (0.00%)

0/7 (0.00%)

0/8 (0.00%)

0/6 (0.00%)

0/6 (0.00%)

0/5 (0.00%)

0/3 (0.00%)

0/6 (0.00%)

0/9 (0.00%)

0/53 (0.00%)

1/85 (1.18%)

0/41 (0.00%)

0/48 (0.00%)

0/18 (0.00%)

0/154 (0.00%)

0/66 (0.00%)

0/18 (0.00%)

0/18 (0.00%)

0/12 (0.00%)

Megacolon * 1

0/3 (0.00%)

0/4 (0.00%)

0/8 (0.00%)

0/7 (0.00%)

0/8 (0.00%)

0/6 (0.00%)

0/6 (0.00%)

0/5 (0.00%)

1/3 (33.33%)

0/6 (0.00%)

0/9 (0.00%)

0/53 (0.00%)

0/85 (0.00%)

0/41 (0.00%)

0/48 (0.00%)

0/18 (0.00%)

0/154 (0.00%)

0/66 (0.00%)

0/18 (0.00%)

0/18 (0.00%)

0/12 (0.00%)

Oesophageal ulcer * 1

0/3 (0.00%)

0/4 (0.00%)

0/8 (0.00%)

0/7 (0.00%)

0/8 (0.00%)

0/6 (0.00%)

0/6 (0.00%)

0/5 (0.00%)

0/3 (0.00%)

0/6 (0.00%)

0/9 (0.00%)

0/53 (0.00%)

0/85 (0.00%)

0/41 (0.00%)

0/48 (0.00%)

0/18 (0.00%)

1/154 (0.65%)

0/66 (0.00%)

0/18 (0.00%)

0/18 (0.00%)

0/12 (0.00%)

Small intestinal obstruction * 1

0/3 (0.00%)

0/4 (0.00%)

1/8 (12.50%)

0/7 (0.00%)

0/8 (0.00%)

0/6 (0.00%)

0/6 (0.00%)

0/5 (0.00%)

0/3 (0.00%)

1/6 (16.67%)

0/9 (0.00%)

0/53 (0.00%)

0/85 (0.00%)

0/41 (0.00%)

0/48 (0.00%)

0/18 (0.00%)

0/154 (0.00%)

1/66 (1.52%)

0/18 (0.00%)

0/18 (0.00%)

0/12 (0.00%)

Small intestinal perforation * 1

0/3 (0.00%)

0/4 (0.00%)

0/8 (0.00%)

0/7 (0.00%)

0/8 (0.00%)

0/6 (0.00%)

0/6 (0.00%)

0/5 (0.00%)

0/3 (0.00%)

0/6 (0.00%)

0/9 (0.00%)

0/53 (0.00%)

0/85 (0.00%)

0/41 (0.00%)

1/48 (2.08%)

0/18 (0.00%)

0/154 (0.00%)

0/66 (0.00%)

0/18 (0.00%)

0/18 (0.00%)

0/12 (0.00%)

General disorders

Chest discomfort * 1

0/3 (0.00%)

0/4 (0.00%)

0/8 (0.00%)

0/7 (0.00%)

0/8 (0.00%)

0/6 (0.00%)

0/6 (0.00%)

0/5 (0.00%)

0/3 (0.00%)

0/6 (0.00%)

0/9 (0.00%)

1/53 (1.89%)

0/85 (0.00%)

0/41 (0.00%)

0/48 (0.00%)

0/18 (0.00%)

0/154 (0.00%)

0/66 (0.00%)

0/18 (0.00%)

0/18 (0.00%)

0/12 (0.00%)

Disease progression * 1

0/3 (0.00%)

0/4 (0.00%)

0/8 (0.00%)

0/7 (0.00%)

2/8 (25.00%)

1/6 (16.67%)

1/6 (16.67%)

0/5 (0.00%)

0/3 (0.00%)

1/6 (16.67%)

1/9 (11.11%)

10/53 (18.87%)

8/85 (9.41%)

6/41 (14.63%)

8/48 (16.67%)

1/18 (5.56%)

19/154 (12.34%)

12/66 (18.18%)

0/18 (0.00%)

0/18 (0.00%)

4/12 (33.33%)

Asthenia * 1

0/3 (0.00%)

0/4 (0.00%)

0/8 (0.00%)

0/7 (0.00%)

0/8 (0.00%)

0/6 (0.00%)

0/6 (0.00%)

0/5 (0.00%)

0/3 (0.00%)

0/6 (0.00%)

0/9 (0.00%)

0/53 (0.00%)

1/85 (1.18%)

0/41 (0.00%)

0/48 (0.00%)

0/18 (0.00%)

1/154 (0.65%)

0/66 (0.00%)

0/18 (0.00%)

0/18 (0.00%)

0/12 (0.00%)

Chest pain * 1

0/3 (0.00%)

0/4 (0.00%)

0/8 (0.00%)

0/7 (0.00%)

1/8 (12.50%)

0/6 (0.00%)

0/6 (0.00%)

0/5 (0.00%)

0/3 (0.00%)

0/6 (0.00%)

0/9 (0.00%)

0/53 (0.00%)

1/85 (1.18%)

0/41 (0.00%)

1/48 (2.08%)

0/18 (0.00%)

0/154 (0.00%)

0/66 (0.00%)

0/18 (0.00%)

1/18 (5.56%)

0/12 (0.00%)

Death * 1

0/3 (0.00%)

0/4 (0.00%)

0/8 (0.00%)

0/7 (0.00%)

0/8 (0.00%)

0/6 (0.00%)

0/6 (0.00%)

0/5 (0.00%)

0/3 (0.00%)

0/6 (0.00%)

0/9 (0.00%)

0/53 (0.00%)

0/85 (0.00%)

0/41 (0.00%)

1/48 (2.08%)

0/18 (0.00%)

0/154 (0.00%)

0/66 (0.00%)

0/18 (0.00%)

0/18 (0.00%)

0/12 (0.00%)

Fatigue * 1

0/3 (0.00%)

0/4 (0.00%)

0/8 (0.00%)

0/7 (0.00%)

0/8 (0.00%)

0/6 (0.00%)

0/6 (0.00%)

0/5 (0.00%)

0/3 (0.00%)

0/6 (0.00%)

0/9 (0.00%)

0/53 (0.00%)

0/85 (0.00%)

1/41 (2.44%)

0/48 (0.00%)

1/18 (5.56%)

0/154 (0.00%)

0/66 (0.00%)

0/18 (0.00%)

0/18 (0.00%)

0/12 (0.00%)

Gait disturbance * 1

0/3 (0.00%)

0/4 (0.00%)

0/8 (0.00%)

0/7 (0.00%)

0/8 (0.00%)

0/6 (0.00%)

0/6 (0.00%)

0/5 (0.00%)

0/3 (0.00%)

0/6 (0.00%)

0/9 (0.00%)

0/53 (0.00%)

2/85 (2.35%)

0/41 (0.00%)

0/48 (0.00%)

0/18 (0.00%)

0/154 (0.00%)

0/66 (0.00%)

0/18 (0.00%)

0/18 (0.00%)

0/12 (0.00%)

Impaired healing * 1

0/3 (0.00%)

0/4 (0.00%)

0/8 (0.00%)

0/7 (0.00%)

0/8 (0.00%)

0/6 (0.00%)

0/6 (0.00%)

0/5 (0.00%)

0/3 (0.00%)

0/6 (0.00%)

0/9 (0.00%)

0/53 (0.00%)

1/85 (1.18%)

0/41 (0.00%)

0/48 (0.00%)

0/18 (0.00%)

0/154 (0.00%)

0/66 (0.00%)

0/18 (0.00%)

0/18 (0.00%)

0/12 (0.00%)

Localised oedema * 1

0/3 (0.00%)

0/4 (0.00%)

0/8 (0.00%)

0/7 (0.00%)

0/8 (0.00%)

0/6 (0.00%)

0/6 (0.00%)

0/5 (0.00%)

0/3 (0.00%)

0/6 (0.00%)

0/9 (0.00%)

0/53 (0.00%)

0/85 (0.00%)

1/41 (2.44%)

0/48 (0.00%)

0/18 (0.00%)

0/154 (0.00%)

0/66 (0.00%)

0/18 (0.00%)

0/18 (0.00%)

0/12 (0.00%)

Oedema * 1

0/3 (0.00%)

0/4 (0.00%)

0/8 (0.00%)

0/7 (0.00%)

0/8 (0.00%)

0/6 (0.00%)

0/6 (0.00%)

0/5 (0.00%)

0/3 (0.00%)

0/6 (0.00%)

0/9 (0.00%)

0/53 (0.00%)

1/85 (1.18%)

0/41 (0.00%)

0/48 (0.00%)

0/18 (0.00%)

0/154 (0.00%)

0/66 (0.00%)

0/18 (0.00%)

0/18 (0.00%)

0/12 (0.00%)

Oedema peripheral * 1

0/3 (0.00%)

0/4 (0.00%)

0/8 (0.00%)

0/7 (0.00%)

0/8 (0.00%)

0/6 (0.00%)

0/6 (0.00%)

0/5 (0.00%)

0/3 (0.00%)

0/6 (0.00%)

0/9 (0.00%)

0/53 (0.00%)

0/85 (0.00%)

0/41 (0.00%)

0/48 (0.00%)

0/18 (0.00%)

1/154 (0.65%)

1/66 (1.52%)

0/18 (0.00%)

1/18 (5.56%)

0/12 (0.00%)

Pain * 1

0/3 (0.00%)

0/4 (0.00%)

0/8 (0.00%)

0/7 (0.00%)

0/8 (0.00%)

0/6 (0.00%)

0/6 (0.00%)

0/5 (0.00%)

0/3 (0.00%)

0/6 (0.00%)

0/9 (0.00%)

0/53 (0.00%)

1/85 (1.18%)

0/41 (0.00%)

0/48 (0.00%)

0/18 (0.00%)

0/154 (0.00%)

1/66 (1.52%)

0/18 (0.00%)

0/18 (0.00%)

0/12 (0.00%)

Physical deconditioning * 1

0/3 (0.00%)

0/4 (0.00%)

0/8 (0.00%)

0/7 (0.00%)

0/8 (0.00%)

0/6 (0.00%)

0/6 (0.00%)

0/5 (0.00%)

0/3 (0.00%)

0/6 (0.00%)

0/9 (0.00%)

0/53 (0.00%)

0/85 (0.00%)

0/41 (0.00%)

0/48 (0.00%)

0/18 (0.00%)

1/154 (0.65%)

0/66 (0.00%)

0/18 (0.00%)

0/18 (0.00%)

0/12 (0.00%)

Pyrexia * 1

0/3 (0.00%)

0/4 (0.00%)

0/8 (0.00%)

0/7 (0.00%)

0/8 (0.00%)

0/6 (0.00%)

1/6 (16.67%)

0/5 (0.00%)

0/3 (0.00%)

0/6 (0.00%)

0/9 (0.00%)

0/53 (0.00%)

4/85 (4.71%)

1/41 (2.44%)

0/48 (0.00%)

0/18 (0.00%)

2/154 (1.30%)

1/66 (1.52%)

0/18 (0.00%)

0/18 (0.00%)

1/12 (8.33%)

Fat necrosis * 1

0/3 (0.00%)

0/4 (0.00%)

0/8 (0.00%)

0/7 (0.00%)

0/8 (0.00%)

0/6 (0.00%)

0/6 (0.00%)

0/5 (0.00%)

0/3 (0.00%)

0/6 (0.00%)

0/9 (0.00%)

0/53 (0.00%)

0/85 (0.00%)

0/41 (0.00%)

0/48 (0.00%)

0/18 (0.00%)

0/154 (0.00%)

0/66 (0.00%)

0/18 (0.00%)

0/18 (0.00%)

1/12 (8.33%)

Hepatobiliary disorders

Cholangitis acute * 1

0/3 (0.00%)

0/4 (0.00%)

0/8 (0.00%)

0/7 (0.00%)

0/8 (0.00%)

0/6 (0.00%)

0/6 (0.00%)

0/5 (0.00%)

0/3 (0.00%)

0/6 (0.00%)

0/9 (0.00%)

1/53 (1.89%)

0/85 (0.00%)

0/41 (0.00%)

0/48 (0.00%)

0/18 (0.00%)

0/154 (0.00%)

0/66 (0.00%)

0/18 (0.00%)

0/18 (0.00%)

0/12 (0.00%)

Drug-induced liver injury * 1

0/3 (0.00%)

0/4 (0.00%)

0/8 (0.00%)

0/7 (0.00%)

0/8 (0.00%)

0/6 (0.00%)

0/6 (0.00%)

0/5 (0.00%)

0/3 (0.00%)

0/6 (0.00%)

0/9 (0.00%)

1/53 (1.89%)

0/85 (0.00%)

0/41 (0.00%)

0/48 (0.00%)

0/18 (0.00%)

1/154 (0.65%)

0/66 (0.00%)

0/18 (0.00%)

0/18 (0.00%)

0/12 (0.00%)

Cholangitis * 1

0/3 (0.00%)

0/4 (0.00%)

0/8 (0.00%)

0/7 (0.00%)

0/8 (0.00%)

0/6 (0.00%)

0/6 (0.00%)

0/5 (0.00%)

0/3 (0.00%)

0/6 (0.00%)

0/9 (0.00%)

0/53 (0.00%)

0/85 (0.00%)

0/41 (0.00%)

0/48 (0.00%)

0/18 (0.00%)

1/154 (0.65%)

0/66 (0.00%)

0/18 (0.00%)

0/18 (0.00%)

0/12 (0.00%)

Hyperbilirubinaemia * 1

0/3 (0.00%)

0/4 (0.00%)

0/8 (0.00%)

0/7 (0.00%)

0/8 (0.00%)

0/6 (0.00%)

0/6 (0.00%)

0/5 (0.00%)

0/3 (0.00%)

0/6 (0.00%)

0/9 (0.00%)

0/53 (0.00%)

0/85 (0.00%)

0/41 (0.00%)

0/48 (0.00%)

0/18 (0.00%)

0/154 (0.00%)

1/66 (1.52%)

0/18 (0.00%)

0/18 (0.00%)

0/12 (0.00%)

Immune system disorders

Anaphylactic reaction * 1

0/3 (0.00%)

0/4 (0.00%)

0/8 (0.00%)

0/7 (0.00%)

0/8 (0.00%)

0/6 (0.00%)

0/6 (0.00%)

0/5 (0.00%)

0/3 (0.00%)

0/6 (0.00%)

0/9 (0.00%)

0/53 (0.00%)

1/85 (1.18%)

0/41 (0.00%)

0/48 (0.00%)

0/18 (0.00%)

0/154 (0.00%)

0/66 (0.00%)

0/18 (0.00%)

0/18 (0.00%)

0/12 (0.00%)

Infections and infestations

Bronchitis * 1

0/3 (0.00%)

0/4 (0.00%)

0/8 (0.00%)

0/7 (0.00%)

0/8 (0.00%)

0/6 (0.00%)

0/6 (0.00%)

0/5 (0.00%)

0/3 (0.00%)

0/6 (0.00%)

0/9 (0.00%)

1/53 (1.89%)

0/85 (0.00%)

0/41 (0.00%)

0/48 (0.00%)

0/18 (0.00%)

0/154 (0.00%)

0/66 (0.00%)

0/18 (0.00%)

0/18 (0.00%)

0/12 (0.00%)

Gastroenteritis viral * 1

0/3 (0.00%)

0/4 (0.00%)

0/8 (0.00%)

0/7 (0.00%)

0/8 (0.00%)

0/6 (0.00%)

0/6 (0.00%)

0/5 (0.00%)

0/3 (0.00%)

0/6 (0.00%)

0/9 (0.00%)

1/53 (1.89%)

0/85 (0.00%)

0/41 (0.00%)

0/48 (0.00%)

0/18 (0.00%)

0/154 (0.00%)

0/66 (0.00%)

0/18 (0.00%)

0/18 (0.00%)

0/12 (0.00%)

Influenza * 1

0/3 (0.00%)

0/4 (0.00%)

0/8 (0.00%)

0/7 (0.00%)

0/8 (0.00%)

0/6 (0.00%)

0/6 (0.00%)

0/5 (0.00%)

0/3 (0.00%)

0/6 (0.00%)

0/9 (0.00%)

1/53 (1.89%)

0/85 (0.00%)

1/41 (2.44%)

0/48 (0.00%)

0/18 (0.00%)

1/154 (0.65%)

0/66 (0.00%)

0/18 (0.00%)

0/18 (0.00%)

0/12 (0.00%)

Oesophageal candidiasis * 1

0/3 (0.00%)

0/4 (0.00%)

0/8 (0.00%)

0/7 (0.00%)

0/8 (0.00%)

0/6 (0.00%)

0/6 (0.00%)

0/5 (0.00%)

0/3 (0.00%)

0/6 (0.00%)

0/9 (0.00%)

1/53 (1.89%)

0/85 (0.00%)

0/41 (0.00%)

0/48 (0.00%)

0/18 (0.00%)

0/154 (0.00%)

0/66 (0.00%)

0/18 (0.00%)

0/18 (0.00%)

0/12 (0.00%)

Pneumocystis jirovecii pneumonia * 1

0/3 (0.00%)

0/4 (0.00%)

0/8 (0.00%)

0/7 (0.00%)

0/8 (0.00%)

0/6 (0.00%)

0/6 (0.00%)

0/5 (0.00%)

0/3 (0.00%)

0/6 (0.00%)

0/9 (0.00%)

1/53 (1.89%)

0/85 (0.00%)

0/41 (0.00%)

0/48 (0.00%)

0/18 (0.00%)

0/154 (0.00%)

0/66 (0.00%)

0/18 (0.00%)

0/18 (0.00%)

0/12 (0.00%)

Pneumonia * 1

0/3 (0.00%)

0/4 (0.00%)

0/8 (0.00%)

0/7 (0.00%)

0/8 (0.00%)

0/6 (0.00%)

0/6 (0.00%)

0/5 (0.00%)

0/3 (0.00%)

0/6 (0.00%)

1/9 (11.11%)

3/53 (5.66%)

11/85 (12.94%)

3/41 (7.32%)

2/48 (4.17%)

0/18 (0.00%)

15/154 (9.74%)

3/66 (4.55%)

0/18 (0.00%)

0/18 (0.00%)

1/12 (8.33%)

Scrub typhus * 1

0/3 (0.00%)

0/4 (0.00%)

0/8 (0.00%)

0/7 (0.00%)

0/8 (0.00%)

0/6 (0.00%)

0/6 (0.00%)

0/5 (0.00%)

0/3 (0.00%)

0/6 (0.00%)

0/9 (0.00%)

1/53 (1.89%)

0/85 (0.00%)

0/41 (0.00%)

0/48 (0.00%)

0/18 (0.00%)

0/154 (0.00%)

0/66 (0.00%)

0/18 (0.00%)

0/18 (0.00%)

0/12 (0.00%)

Skin infection * 1

0/3 (0.00%)

0/4 (0.00%)

0/8 (0.00%)

0/7 (0.00%)

0/8 (0.00%)

0/6 (0.00%)

0/6 (0.00%)

0/5 (0.00%)

0/3 (0.00%)

0/6 (0.00%)

0/9 (0.00%)

1/53 (1.89%)

1/85 (1.18%)

0/41 (0.00%)

0/48 (0.00%)

0/18 (0.00%)

0/154 (0.00%)

0/66 (0.00%)

0/18 (0.00%)

0/18 (0.00%)

0/12 (0.00%)

Appendicitis * 1

0/3 (0.00%)

0/4 (0.00%)

0/8 (0.00%)

0/7 (0.00%)

0/8 (0.00%)

0/6 (0.00%)

0/6 (0.00%)

0/5 (0.00%)

0/3 (0.00%)

0/6 (0.00%)

0/9 (0.00%)

0/53 (0.00%)

1/85 (1.18%)

0/41 (0.00%)

0/48 (0.00%)

0/18 (0.00%)

0/154 (0.00%)

0/66 (0.00%)

0/18 (0.00%)

0/18 (0.00%)

0/12 (0.00%)

Aspergillus infection * 1

0/3 (0.00%)

0/4 (0.00%)

0/8 (0.00%)

0/7 (0.00%)

0/8 (0.00%)

0/6 (0.00%)

0/6 (0.00%)

0/5 (0.00%)

0/3 (0.00%)

0/6 (0.00%)

0/9 (0.00%)

0/53 (0.00%)

0/85 (0.00%)

0/41 (0.00%)

0/48 (0.00%)

0/18 (0.00%)

1/154 (0.65%)

0/66 (0.00%)

0/18 (0.00%)

0/18 (0.00%)

0/12 (0.00%)

Bacteraemia * 1

0/3 (0.00%)

0/4 (0.00%)

0/8 (0.00%)

0/7 (0.00%)

0/8 (0.00%)

0/6 (0.00%)

0/6 (0.00%)

0/5 (0.00%)

0/3 (0.00%)

0/6 (0.00%)

0/9 (0.00%)

0/53 (0.00%)

0/85 (0.00%)

0/41 (0.00%)

0/48 (0.00%)

0/18 (0.00%)

1/154 (0.65%)

0/66 (0.00%)

0/18 (0.00%)

0/18 (0.00%)

0/12 (0.00%)

Candida infection * 1

0/3 (0.00%)

0/4 (0.00%)

0/8 (0.00%)

0/7 (0.00%)

0/8 (0.00%)

0/6 (0.00%)

0/6 (0.00%)

0/5 (0.00%)

0/3 (0.00%)

0/6 (0.00%)

0/9 (0.00%)

0/53 (0.00%)

0/85 (0.00%)

0/41 (0.00%)

0/48 (0.00%)

0/18 (0.00%)

0/154 (0.00%)

1/66 (1.52%)

0/18 (0.00%)

0/18 (0.00%)

0/12 (0.00%)

Cellulitis * 1

0/3 (0.00%)

0/4 (0.00%)

0/8 (0.00%)

0/7 (0.00%)

0/8 (0.00%)

0/6 (0.00%)

0/6 (0.00%)

0/5 (0.00%)

0/3 (0.00%)

0/6 (0.00%)

0/9 (0.00%)

0/53 (0.00%)

1/85 (1.18%)

1/41 (2.44%)

1/48 (2.08%)

0/18 (0.00%)

3/154 (1.95%)

2/66 (3.03%)

0/18 (0.00%)

0/18 (0.00%)

0/12 (0.00%)

Chest wall abscess * 1

0/3 (0.00%)

0/4 (0.00%)

0/8 (0.00%)

0/7 (0.00%)

0/8 (0.00%)

0/6 (0.00%)

0/6 (0.00%)

0/5 (0.00%)

0/3 (0.00%)

0/6 (0.00%)

0/9 (0.00%)

0/53 (0.00%)

0/85 (0.00%)

0/41 (0.00%)

1/48 (2.08%)

0/18 (0.00%)

0/154 (0.00%)

0/66 (0.00%)

0/18 (0.00%)

0/18 (0.00%)

0/12 (0.00%)

Diverticulitis * 1

0/3 (0.00%)

0/4 (0.00%)

0/8 (0.00%)

0/7 (0.00%)

0/8 (0.00%)

0/6 (0.00%)

0/6 (0.00%)

0/5 (0.00%)

0/3 (0.00%)

0/6 (0.00%)

0/9 (0.00%)

0/53 (0.00%)

0/85 (0.00%)

0/41 (0.00%)

0/48 (0.00%)

0/18 (0.00%)

1/154 (0.65%)

0/66 (0.00%)

0/18 (0.00%)

0/18 (0.00%)

0/12 (0.00%)

Enterocolitis infectious * 1

0/3 (0.00%)

0/4 (0.00%)

0/8 (0.00%)

0/7 (0.00%)

0/8 (0.00%)

0/6 (0.00%)

0/6 (0.00%)

0/5 (0.00%)

0/3 (0.00%)

0/6 (0.00%)

0/9 (0.00%)

0/53 (0.00%)

1/85 (1.18%)

0/41 (0.00%)

0/48 (0.00%)

0/18 (0.00%)

0/154 (0.00%)

0/66 (0.00%)

0/18 (0.00%)

0/18 (0.00%)

0/12 (0.00%)

Fungal infection * 1

0/3 (0.00%)

0/4 (0.00%)

0/8 (0.00%)

0/7 (0.00%)

0/8 (0.00%)

0/6 (0.00%)

0/6 (0.00%)

0/5 (0.00%)

0/3 (0.00%)

0/6 (0.00%)

0/9 (0.00%)

0/53 (0.00%)

0/85 (0.00%)

0/41 (0.00%)

0/48 (0.00%)

0/18 (0.00%)

1/154 (0.65%)

0/66 (0.00%)

0/18 (0.00%)

0/18 (0.00%)

0/12 (0.00%)

Gastroenteritis * 1

0/3 (0.00%)

0/4 (0.00%)

0/8 (0.00%)

0/7 (0.00%)

0/8 (0.00%)

0/6 (0.00%)

0/6 (0.00%)

0/5 (0.00%)

0/3 (0.00%)

0/6 (0.00%)

0/9 (0.00%)

0/53 (0.00%)

0/85 (0.00%)

0/41 (0.00%)

0/48 (0.00%)

0/18 (0.00%)

1/154 (0.65%)

0/66 (0.00%)

0/18 (0.00%)

0/18 (0.00%)

0/12 (0.00%)

Gastrointestinal infection * 1

0/3 (0.00%)

0/4 (0.00%)

0/8 (0.00%)

0/7 (0.00%)

0/8 (0.00%)

0/6 (0.00%)

0/6 (0.00%)

0/5 (0.00%)

0/3 (0.00%)

0/6 (0.00%)

0/9 (0.00%)

0/53 (0.00%)

1/85 (1.18%)

0/41 (0.00%)

0/48 (0.00%)

0/18 (0.00%)

0/154 (0.00%)

0/66 (0.00%)

0/18 (0.00%)

0/18 (0.00%)

0/12 (0.00%)

Graft infection * 1

0/3 (0.00%)

0/4 (0.00%)

0/8 (0.00%)

0/7 (0.00%)

0/8 (0.00%)

0/6 (0.00%)

0/6 (0.00%)

0/5 (0.00%)

0/3 (0.00%)

0/6 (0.00%)

0/9 (0.00%)

0/53 (0.00%)

1/85 (1.18%)

0/41 (0.00%)

0/48 (0.00%)

0/18 (0.00%)

0/154 (0.00%)

0/66 (0.00%)

0/18 (0.00%)

0/18 (0.00%)

0/12 (0.00%)

H1N1 influenza * 1

0/3 (0.00%)

0/4 (0.00%)

0/8 (0.00%)

0/7 (0.00%)

0/8 (0.00%)

0/6 (0.00%)

0/6 (0.00%)

0/5 (0.00%)

0/3 (0.00%)

0/6 (0.00%)

0/9 (0.00%)

0/53 (0.00%)

0/85 (0.00%)

0/41 (0.00%)

0/48 (0.00%)

0/18 (0.00%)

0/154 (0.00%)

1/66 (1.52%)

0/18 (0.00%)

0/18 (0.00%)

0/12 (0.00%)

Herpes zoster * 1

0/3 (0.00%)

0/4 (0.00%)

0/8 (0.00%)

0/7 (0.00%)

0/8 (0.00%)

0/6 (0.00%)

0/6 (0.00%)

0/5 (0.00%)

0/3 (0.00%)

0/6 (0.00%)

0/9 (0.00%)

0/53 (0.00%)

0/85 (0.00%)

0/41 (0.00%)

0/48 (0.00%)

0/18 (0.00%)

1/154 (0.65%)

0/66 (0.00%)

0/18 (0.00%)

0/18 (0.00%)

0/12 (0.00%)

Infection * 1

0/3 (0.00%)

0/4 (0.00%)

0/8 (0.00%)

0/7 (0.00%)

0/8 (0.00%)

0/6 (0.00%)

0/6 (0.00%)

0/5 (0.00%)

0/3 (0.00%)

0/6 (0.00%)

0/9 (0.00%)

0/53 (0.00%)

0/85 (0.00%)

0/41 (0.00%)

0/48 (0.00%)

0/18 (0.00%)

0/154 (0.00%)

1/66 (1.52%)

0/18 (0.00%)

0/18 (0.00%)

0/12 (0.00%)

Lower respiratory tract infection * 1

0/3 (0.00%)

0/4 (0.00%)

0/8 (0.00%)

0/7 (0.00%)

0/8 (0.00%)

0/6 (0.00%)

0/6 (0.00%)

0/5 (0.00%)

0/3 (0.00%)

0/6 (0.00%)

0/9 (0.00%)

0/53 (0.00%)

0/85 (0.00%)

0/41 (0.00%)

0/48 (0.00%)

0/18 (0.00%)

1/154 (0.65%)

2/66 (3.03%)

0/18 (0.00%)

0/18 (0.00%)

0/12 (0.00%)

Meningitis * 1

0/3 (0.00%)

0/4 (0.00%)

0/8 (0.00%)

0/7 (0.00%)

0/8 (0.00%)

0/6 (0.00%)

0/6 (0.00%)

0/5 (0.00%)

0/3 (0.00%)

0/6 (0.00%)

0/9 (0.00%)

0/53 (0.00%)

0/85 (0.00%)

1/41 (2.44%)

0/48 (0.00%)

0/18 (0.00%)

0/154 (0.00%)

0/66 (0.00%)

0/18 (0.00%)

0/18 (0.00%)

0/12 (0.00%)

Mesenteric abscess * 1

0/3 (0.00%)

0/4 (0.00%)

0/8 (0.00%)

0/7 (0.00%)

0/8 (0.00%)

0/6 (0.00%)

0/6 (0.00%)

0/5 (0.00%)

0/3 (0.00%)

0/6 (0.00%)

0/9 (0.00%)

0/53 (0.00%)

0/85 (0.00%)

0/41 (0.00%)

0/48 (0.00%)

0/18 (0.00%)

0/154 (0.00%)

0/66 (0.00%)

0/18 (0.00%)

2/18 (11.11%)

0/12 (0.00%)

Nasal abscess * 1

0/3 (0.00%)

0/4 (0.00%)

0/8 (0.00%)

0/7 (0.00%)

0/8 (0.00%)

0/6 (0.00%)

0/6 (0.00%)

0/5 (0.00%)

0/3 (0.00%)

0/6 (0.00%)

0/9 (0.00%)

0/53 (0.00%)

0/85 (0.00%)

0/41 (0.00%)

0/48 (0.00%)

0/18 (0.00%)

1/154 (0.65%)

0/66 (0.00%)

0/18 (0.00%)

0/18 (0.00%)

0/12 (0.00%)

Parainfluenzae virus infection * 1

0/3 (0.00%)

0/4 (0.00%)

0/8 (0.00%)

0/7 (0.00%)

0/8 (0.00%)

0/6 (0.00%)

0/6 (0.00%)

0/5 (0.00%)

0/3 (0.00%)

0/6 (0.00%)

0/9 (0.00%)

0/53 (0.00%)

1/85 (1.18%)

0/41 (0.00%)

0/48 (0.00%)

0/18 (0.00%)

0/154 (0.00%)

0/66 (0.00%)

0/18 (0.00%)

0/18 (0.00%)

0/12 (0.00%)

Pleural infection * 1

0/3 (0.00%)

0/4 (0.00%)

0/8 (0.00%)

0/7 (0.00%)

0/8 (0.00%)

0/6 (0.00%)

0/6 (0.00%)

0/5 (0.00%)

0/3 (0.00%)

0/6 (0.00%)

0/9 (0.00%)

0/53 (0.00%)

0/85 (0.00%)

0/41 (0.00%)

0/48 (0.00%)

0/18 (0.00%)

1/154 (0.65%)

0/66 (0.00%)

0/18 (0.00%)

0/18 (0.00%)

0/12 (0.00%)

Pneumonia pneumococcal * 1

0/3 (0.00%)

0/4 (0.00%)

0/8 (0.00%)

0/7 (0.00%)

0/8 (0.00%)

0/6 (0.00%)

0/6 (0.00%)

0/5 (0.00%)

0/3 (0.00%)

0/6 (0.00%)

0/9 (0.00%)

0/53 (0.00%)

1/85 (1.18%)

0/41 (0.00%)

0/48 (0.00%)

0/18 (0.00%)

0/154 (0.00%)

0/66 (0.00%)

0/18 (0.00%)

0/18 (0.00%)

0/12 (0.00%)

Respiratory syncytial virus bronchitis * 1

0/3 (0.00%)

0/4 (0.00%)

0/8 (0.00%)

0/7 (0.00%)

0/8 (0.00%)

0/6 (0.00%)

0/6 (0.00%)

0/5 (0.00%)

0/3 (0.00%)

0/6 (0.00%)

0/9 (0.00%)

0/53 (0.00%)

1/85 (1.18%)

0/41 (0.00%)

0/48 (0.00%)

0/18 (0.00%)

0/154 (0.00%)

0/66 (0.00%)

0/18 (0.00%)

0/18 (0.00%)

0/12 (0.00%)

Sepsis * 1

0/3 (0.00%)

0/4 (0.00%)

0/8 (0.00%)

0/7 (0.00%)

0/8 (0.00%)

0/6 (0.00%)

0/6 (0.00%)

0/5 (0.00%)

0/3 (0.00%)

0/6 (0.00%)

0/9 (0.00%)

0/53 (0.00%)

0/85 (0.00%)

0/41 (0.00%)

0/48 (0.00%)

1/18 (5.56%)

0/154 (0.00%)

0/66 (0.00%)

0/18 (0.00%)

0/18 (0.00%)

0/12 (0.00%)

Septic arthritis streptococcal * 1

0/3 (0.00%)

0/4 (0.00%)

0/8 (0.00%)

0/7 (0.00%)

0/8 (0.00%)

0/6 (0.00%)

0/6 (0.00%)

0/5 (0.00%)

0/3 (0.00%)

0/6 (0.00%)

0/9 (0.00%)

0/53 (0.00%)

0/85 (0.00%)

0/41 (0.00%)

0/48 (0.00%)

0/18 (0.00%)

1/154 (0.65%)

0/66 (0.00%)

0/18 (0.00%)

0/18 (0.00%)

0/12 (0.00%)

Septic shock * 1

0/3 (0.00%)

0/4 (0.00%)

0/8 (0.00%)

0/7 (0.00%)

0/8 (0.00%)

0/6 (0.00%)

0/6 (0.00%)

0/5 (0.00%)

0/3 (0.00%)

0/6 (0.00%)

0/9 (0.00%)

0/53 (0.00%)

0/85 (0.00%)

1/41 (2.44%)

0/48 (0.00%)

0/18 (0.00%)

0/154 (0.00%)

1/66 (1.52%)

0/18 (0.00%)

0/18 (0.00%)

0/12 (0.00%)

Subcutaneous abscess * 1

0/3 (0.00%)

0/4 (0.00%)

0/8 (0.00%)

0/7 (0.00%)

0/8 (0.00%)

0/6 (0.00%)

0/6 (0.00%)

0/5 (0.00%)

0/3 (0.00%)

0/6 (0.00%)

0/9 (0.00%)

0/53 (0.00%)

1/85 (1.18%)

0/41 (0.00%)

0/48 (0.00%)

0/18 (0.00%)

0/154 (0.00%)

0/66 (0.00%)

0/18 (0.00%)

0/18 (0.00%)

0/12 (0.00%)

Upper respiratory tract infection * 1

0/3 (0.00%)

0/4 (0.00%)

0/8 (0.00%)

0/7 (0.00%)

1/8 (12.50%)

0/6 (0.00%)

0/6 (0.00%)

0/5 (0.00%)

0/3 (0.00%)

0/6 (0.00%)

0/9 (0.00%)

0/53 (0.00%)

1/85 (1.18%)

1/41 (2.44%)

0/48 (0.00%)

0/18 (0.00%)

0/154 (0.00%)

0/66 (0.00%)

0/18 (0.00%)

0/18 (0.00%)

0/12 (0.00%)

Urinary tract infection * 1

0/3 (0.00%)

0/4 (0.00%)

0/8 (0.00%)

0/7 (0.00%)

0/8 (0.00%)

0/6 (0.00%)

0/6 (0.00%)

0/5 (0.00%)

0/3 (0.00%)

0/6 (0.00%)

0/9 (0.00%)

0/53 (0.00%)

1/85 (1.18%)

1/41 (2.44%)

0/48 (0.00%)

0/18 (0.00%)

0/154 (0.00%)

0/66 (0.00%)

0/18 (0.00%)

0/18 (0.00%)

0/12 (0.00%)

Urosepsis * 1

0/3 (0.00%)

0/4 (0.00%)

0/8 (0.00%)

0/7 (0.00%)

0/8 (0.00%)

0/6 (0.00%)

0/6 (0.00%)

0/5 (0.00%)

0/3 (0.00%)

0/6 (0.00%)

0/9 (0.00%)

0/53 (0.00%)

0/85 (0.00%)

0/41 (0.00%)

0/48 (0.00%)

0/18 (0.00%)

1/154 (0.65%)

0/66 (0.00%)

0/18 (0.00%)

0/18 (0.00%)

0/12 (0.00%)

Injury, poisoning and procedural complications

Ankle fracture * 1

0/3 (0.00%)

0/4 (0.00%)

0/8 (0.00%)

0/7 (0.00%)

0/8 (0.00%)

0/6 (0.00%)

0/6 (0.00%)

0/5 (0.00%)

0/3 (0.00%)

0/6 (0.00%)

0/9 (0.00%)

0/53 (0.00%)

0/85 (0.00%)

0/41 (0.00%)

0/48 (0.00%)

0/18 (0.00%)

1/154 (0.65%)

0/66 (0.00%)

0/18 (0.00%)

0/18 (0.00%)

0/12 (0.00%)

Clavicle fracture * 1

0/3 (0.00%)

0/4 (0.00%)

0/8 (0.00%)

0/7 (0.00%)

0/8 (0.00%)

0/6 (0.00%)

0/6 (0.00%)

0/5 (0.00%)

0/3 (0.00%)

0/6 (0.00%)

0/9 (0.00%)

0/53 (0.00%)

0/85 (0.00%)

0/41 (0.00%)

1/48 (2.08%)

0/18 (0.00%)

0/154 (0.00%)

0/66 (0.00%)

0/18 (0.00%)

0/18 (0.00%)

0/12 (0.00%)

Compression fracture * 1

0/3 (0.00%)

0/4 (0.00%)

0/8 (0.00%)

0/7 (0.00%)

0/8 (0.00%)

0/6 (0.00%)

0/6 (0.00%)

0/5 (0.00%)

0/3 (0.00%)

0/6 (0.00%)

0/9 (0.00%)

0/53 (0.00%)

0/85 (0.00%)

0/41 (0.00%)

0/48 (0.00%)

0/18 (0.00%)

1/154 (0.65%)

0/66 (0.00%)

0/18 (0.00%)

0/18 (0.00%)

0/12 (0.00%)

Fall * 1

0/3 (0.00%)

0/4 (0.00%)

0/8 (0.00%)

0/7 (0.00%)

0/8 (0.00%)

0/6 (0.00%)

0/6 (0.00%)

0/5 (0.00%)

0/3 (0.00%)

0/6 (0.00%)

0/9 (0.00%)

0/53 (0.00%)

1/85 (1.18%)

0/41 (0.00%)

0/48 (0.00%)

0/18 (0.00%)

0/154 (0.00%)

0/66 (0.00%)

0/18 (0.00%)

0/18 (0.00%)

0/12 (0.00%)

Femoral neck fracture * 1

0/3 (0.00%)

0/4 (0.00%)

0/8 (0.00%)

0/7 (0.00%)

0/8 (0.00%)

0/6 (0.00%)

0/6 (0.00%)

0/5 (0.00%)

0/3 (0.00%)

0/6 (0.00%)

0/9 (0.00%)

0/53 (0.00%)

0/85 (0.00%)

0/41 (0.00%)

1/48 (2.08%)

0/18 (0.00%)

0/154 (0.00%)

0/66 (0.00%)

0/18 (0.00%)

0/18 (0.00%)

0/12 (0.00%)

Foetal exposure during pregnancy * 1

0/3 (0.00%)

0/4 (0.00%)

0/8 (0.00%)

0/7 (0.00%)

0/8 (0.00%)

0/6 (0.00%)

0/6 (0.00%)

0/5 (0.00%)

0/3 (0.00%)

0/6 (0.00%)

0/9 (0.00%)

0/53 (0.00%)

0/85 (0.00%)

0/41 (0.00%)

0/48 (0.00%)

0/18 (0.00%)

1/154 (0.65%)

0/66 (0.00%)

0/18 (0.00%)

0/18 (0.00%)

0/12 (0.00%)

Hip fracture * 1

0/3 (0.00%)

0/4 (0.00%)

0/8 (0.00%)

0/7 (0.00%)

0/8 (0.00%)

0/6 (0.00%)

0/6 (0.00%)

0/5 (0.00%)

0/3 (0.00%)

0/6 (0.00%)

0/9 (0.00%)

0/53 (0.00%)

0/85 (0.00%)

0/41 (0.00%)

0/48 (0.00%)

0/18 (0.00%)

1/154 (0.65%)

0/66 (0.00%)

0/18 (0.00%)

0/18 (0.00%)

0/12 (0.00%)

Pelvic fracture * 1

0/3 (0.00%)

0/4 (0.00%)

0/8 (0.00%)

0/7 (0.00%)

0/8 (0.00%)

0/6 (0.00%)

0/6 (0.00%)

0/5 (0.00%)

0/3 (0.00%)

0/6 (0.00%)

0/9 (0.00%)

0/53 (0.00%)

0/85 (0.00%)

0/41 (0.00%)

0/48 (0.00%)

0/18 (0.00%)

1/154 (0.65%)

0/66 (0.00%)

0/18 (0.00%)

0/18 (0.00%)

0/12 (0.00%)

Post-traumatic pain * 1

0/3 (0.00%)

0/4 (0.00%)

0/8 (0.00%)

0/7 (0.00%)

0/8 (0.00%)

0/6 (0.00%)

0/6 (0.00%)

0/5 (0.00%)

0/3 (0.00%)

0/6 (0.00%)

0/9 (0.00%)

0/53 (0.00%)

0/85 (0.00%)

1/41 (2.44%)

0/48 (0.00%)

0/18 (0.00%)

0/154 (0.00%)

0/66 (0.00%)

0/18 (0.00%)

0/18 (0.00%)

0/12 (0.00%)

Spinal compression fracture * 1

0/3 (0.00%)

0/4 (0.00%)

0/8 (0.00%)

0/7 (0.00%)

0/8 (0.00%)

0/6 (0.00%)

0/6 (0.00%)

0/5 (0.00%)

0/3 (0.00%)

0/6 (0.00%)

0/9 (0.00%)

0/53 (0.00%)

1/85 (1.18%)

1/41 (2.44%)

0/48 (0.00%)

0/18 (0.00%)

1/154 (0.65%)

0/66 (0.00%)

0/18 (0.00%)

0/18 (0.00%)

0/12 (0.00%)

Subcutaneous haematoma * 1

0/3 (0.00%)

0/4 (0.00%)

0/8 (0.00%)

0/7 (0.00%)

0/8 (0.00%)

0/6 (0.00%)

0/6 (0.00%)

0/5 (0.00%)

0/3 (0.00%)

0/6 (0.00%)

0/9 (0.00%)

0/53 (0.00%)

0/85 (0.00%)

0/41 (0.00%)

0/48 (0.00%)

0/18 (0.00%)

1/154 (0.65%)

0/66 (0.00%)

0/18 (0.00%)

0/18 (0.00%)

0/12 (0.00%)

Subdural haematoma * 1

0/3 (0.00%)

0/4 (0.00%)

0/8 (0.00%)

0/7 (0.00%)

0/8 (0.00%)

0/6 (0.00%)

0/6 (0.00%)

0/5 (0.00%)

0/3 (0.00%)

0/6 (0.00%)

0/9 (0.00%)

0/53 (0.00%)

1/85 (1.18%)

0/41 (0.00%)

0/48 (0.00%)

0/18 (0.00%)

0/154 (0.00%)

0/66 (0.00%)

0/18 (0.00%)

0/18 (0.00%)

0/12 (0.00%)

Tendon rupture * 1

0/3 (0.00%)

0/4 (0.00%)

0/8 (0.00%)

0/7 (0.00%)

0/8 (0.00%)

0/6 (0.00%)

0/6 (0.00%)

0/5 (0.00%)

0/3 (0.00%)

0/6 (0.00%)

0/9 (0.00%)

0/53 (0.00%)

0/85 (0.00%)

0/41 (0.00%)

0/48 (0.00%)

0/18 (0.00%)

1/154 (0.65%)

0/66 (0.00%)

0/18 (0.00%)

0/18 (0.00%)

0/12 (0.00%)

Wrist fracture * 1

0/3 (0.00%)

0/4 (0.00%)

0/8 (0.00%)

0/7 (0.00%)

0/8 (0.00%)

0/6 (0.00%)

0/6 (0.00%)

0/5 (0.00%)

0/3 (0.00%)

0/6 (0.00%)

0/9 (0.00%)

0/53 (0.00%)

0/85 (0.00%)

0/41 (0.00%)

0/48 (0.00%)

0/18 (0.00%)

0/154 (0.00%)

0/66 (0.00%)

0/18 (0.00%)

0/18 (0.00%)

1/12 (8.33%)

Investigations

Alanine aminotransferase increased * 1

0/3 (0.00%)

0/4 (0.00%)

0/8 (0.00%)

0/7 (0.00%)

0/8 (0.00%)

0/6 (0.00%)

0/6 (0.00%)

0/5 (0.00%)

0/3 (0.00%)

0/6 (0.00%)

0/9 (0.00%)

0/53 (0.00%)

1/85 (1.18%)

0/41 (0.00%)

0/48 (0.00%)

0/18 (0.00%)

2/154 (1.30%)

1/66 (1.52%)

0/18 (0.00%)

0/18 (0.00%)

0/12 (0.00%)

Aspartate aminotransferase increased * 1

0/3 (0.00%)

0/4 (0.00%)

0/8 (0.00%)

0/7 (0.00%)

0/8 (0.00%)

0/6 (0.00%)

0/6 (0.00%)

0/5 (0.00%)

0/3 (0.00%)

0/6 (0.00%)

0/9 (0.00%)

0/53 (0.00%)

1/85 (1.18%)

0/41 (0.00%)

0/48 (0.00%)

0/18 (0.00%)

2/154 (1.30%)

1/66 (1.52%)

0/18 (0.00%)

0/18 (0.00%)

0/12 (0.00%)

Blood creatinine increased * 1

0/3 (0.00%)

0/4 (0.00%)

0/8 (0.00%)

0/7 (0.00%)

0/8 (0.00%)

0/6 (0.00%)

0/6 (0.00%)

0/5 (0.00%)

0/3 (0.00%)

0/6 (0.00%)

0/9 (0.00%)

0/53 (0.00%)

2/85 (2.35%)

0/41 (0.00%)

0/48 (0.00%)

0/18 (0.00%)

0/154 (0.00%)

0/66 (0.00%)

0/18 (0.00%)

0/18 (0.00%)

0/12 (0.00%)

Electrocardiogram QT prolonged * 1

0/3 (0.00%)

0/4 (0.00%)

0/8 (0.00%)

0/7 (0.00%)

0/8 (0.00%)

0/6 (0.00%)

0/6 (0.00%)

0/5 (0.00%)

0/3 (0.00%)

0/6 (0.00%)

0/9 (0.00%)

0/53 (0.00%)

0/85 (0.00%)

1/41 (2.44%)

0/48 (0.00%)

0/18 (0.00%)

0/154 (0.00%)

1/66 (1.52%)

0/18 (0.00%)

0/18 (0.00%)

0/12 (0.00%)

Liver function test increased * 1

0/3 (0.00%)

0/4 (0.00%)

0/8 (0.00%)

0/7 (0.00%)

0/8 (0.00%)

0/6 (0.00%)

0/6 (0.00%)

0/5 (0.00%)

0/3 (0.00%)

0/6 (0.00%)

0/9 (0.00%)

0/53 (0.00%)

1/85 (1.18%)

0/41 (0.00%)

0/48 (0.00%)

0/18 (0.00%)

0/154 (0.00%)

0/66 (0.00%)

0/18 (0.00%)

0/18 (0.00%)

0/12 (0.00%)

Metabolism and nutrition disorders

Adult failure to thrive * 1

0/3 (0.00%)

0/4 (0.00%)

0/8 (0.00%)

0/7 (0.00%)

0/8 (0.00%)

0/6 (0.00%)

0/6 (0.00%)

0/5 (0.00%)

0/3 (0.00%)

0/6 (0.00%)

0/9 (0.00%)

0/53 (0.00%)

1/85 (1.18%)

0/41 (0.00%)

0/48 (0.00%)

0/18 (0.00%)

0/154 (0.00%)

0/66 (0.00%)

0/18 (0.00%)

0/18 (0.00%)

0/12 (0.00%)

Decreased appetite * 1

0/3 (0.00%)

0/4 (0.00%)

0/8 (0.00%)

0/7 (0.00%)

0/8 (0.00%)

0/6 (0.00%)

0/6 (0.00%)

0/5 (0.00%)

0/3 (0.00%)

0/6 (0.00%)

0/9 (0.00%)

0/53 (0.00%)

1/85 (1.18%)

0/41 (0.00%)

0/48 (0.00%)

0/18 (0.00%)

0/154 (0.00%)

0/66 (0.00%)

0/18 (0.00%)

0/18 (0.00%)

0/12 (0.00%)

Dehydration * 1

0/3 (0.00%)

0/4 (0.00%)

0/8 (0.00%)

0/7 (0.00%)

1/8 (12.50%)

0/6 (0.00%)

0/6 (0.00%)

0/5 (0.00%)

0/3 (0.00%)

0/6 (0.00%)

0/9 (0.00%)

0/53 (0.00%)

1/85 (1.18%)

0/41 (0.00%)

0/48 (0.00%)

0/18 (0.00%)

2/154 (1.30%)

1/66 (1.52%)

0/18 (0.00%)

0/18 (0.00%)

0/12 (0.00%)

Failure to thrive * 1

0/3 (0.00%)

0/4 (0.00%)

0/8 (0.00%)

0/7 (0.00%)

0/8 (0.00%)

0/6 (0.00%)

0/6 (0.00%)

0/5 (0.00%)

0/3 (0.00%)

0/6 (0.00%)

0/9 (0.00%)

0/53 (0.00%)

1/85 (1.18%)

0/41 (0.00%)

0/48 (0.00%)

0/18 (0.00%)

0/154 (0.00%)

1/66 (1.52%)

0/18 (0.00%)

0/18 (0.00%)

0/12 (0.00%)

Hypercalcaemia * 1

0/3 (0.00%)

0/4 (0.00%)

0/8 (0.00%)

0/7 (0.00%)

0/8 (0.00%)

0/6 (0.00%)

0/6 (0.00%)

0/5 (0.00%)

0/3 (0.00%)

0/6 (0.00%)

0/9 (0.00%)

0/53 (0.00%)

0/85 (0.00%)

0/41 (0.00%)

0/48 (0.00%)

0/18 (0.00%)

0/154 (0.00%)

1/66 (1.52%)

0/18 (0.00%)

0/18 (0.00%)

0/12 (0.00%)

Hypokalaemia * 1

0/3 (0.00%)

0/4 (0.00%)

0/8 (0.00%)

0/7 (0.00%)

0/8 (0.00%)

0/6 (0.00%)

0/6 (0.00%)

0/5 (0.00%)

0/3 (0.00%)

0/6 (0.00%)

0/9 (0.00%)

0/53 (0.00%)

0/85 (0.00%)

0/41 (0.00%)

0/48 (0.00%)

0/18 (0.00%)

1/154 (0.65%)

0/66 (0.00%)

0/18 (0.00%)

0/18 (0.00%)

0/12 (0.00%)

Hyponatraemia * 1

0/3 (0.00%)

0/4 (0.00%)

0/8 (0.00%)

0/7 (0.00%)

0/8 (0.00%)

0/6 (0.00%)

0/6 (0.00%)

0/5 (0.00%)

0/3 (0.00%)

0/6 (0.00%)

0/9 (0.00%)

0/53 (0.00%)

1/85 (1.18%)

1/41 (2.44%)

0/48 (0.00%)

0/18 (0.00%)

1/154 (0.65%)

0/66 (0.00%)

0/18 (0.00%)

0/18 (0.00%)

0/12 (0.00%)

Musculoskeletal and connective tissue disorders

Back pain * 1

0/3 (0.00%)

0/4 (0.00%)

0/8 (0.00%)

0/7 (0.00%)

0/8 (0.00%)

0/6 (0.00%)

0/6 (0.00%)

0/5 (0.00%)

0/3 (0.00%)

0/6 (0.00%)

0/9 (0.00%)

1/53 (1.89%)

1/85 (1.18%)

1/41 (2.44%)

0/48 (0.00%)

1/18 (5.56%)

1/154 (0.65%)

2/66 (3.03%)

0/18 (0.00%)

0/18 (0.00%)

0/12 (0.00%)

Arthralgia * 1

0/3 (0.00%)

0/4 (0.00%)

0/8 (0.00%)

0/7 (0.00%)

0/8 (0.00%)

0/6 (0.00%)

0/6 (0.00%)

0/5 (0.00%)

0/3 (0.00%)

0/6 (0.00%)

0/9 (0.00%)

0/53 (0.00%)

0/85 (0.00%)

0/41 (0.00%)

0/48 (0.00%)

0/18 (0.00%)

2/154 (1.30%)

1/66 (1.52%)

0/18 (0.00%)

0/18 (0.00%)

0/12 (0.00%)

Bone pain * 1

0/3 (0.00%)

0/4 (0.00%)

0/8 (0.00%)

0/7 (0.00%)

0/8 (0.00%)

0/6 (0.00%)

0/6 (0.00%)

0/5 (0.00%)

0/3 (0.00%)

0/6 (0.00%)

0/9 (0.00%)

0/53 (0.00%)

0/85 (0.00%)

0/41 (0.00%)

0/48 (0.00%)

0/18 (0.00%)

1/154 (0.65%)

0/66 (0.00%)

0/18 (0.00%)

0/18 (0.00%)

0/12 (0.00%)

Fracture pain * 1

0/3 (0.00%)

0/4 (0.00%)

0/8 (0.00%)

0/7 (0.00%)

0/8 (0.00%)

0/6 (0.00%)

0/6 (0.00%)

0/5 (0.00%)

0/3 (0.00%)

0/6 (0.00%)

0/9 (0.00%)

0/53 (0.00%)

1/85 (1.18%)

0/41 (0.00%)

0/48 (0.00%)

0/18 (0.00%)

0/154 (0.00%)

0/66 (0.00%)

0/18 (0.00%)

0/18 (0.00%)

0/12 (0.00%)

Haemarthrosis * 1

0/3 (0.00%)

0/4 (0.00%)

0/8 (0.00%)

0/7 (0.00%)

0/8 (0.00%)

0/6 (0.00%)

0/6 (0.00%)

0/5 (0.00%)

0/3 (0.00%)

0/6 (0.00%)

0/9 (0.00%)

0/53 (0.00%)

0/85 (0.00%)

0/41 (0.00%)

0/48 (0.00%)

0/18 (0.00%)

1/154 (0.65%)

0/66 (0.00%)

0/18 (0.00%)

0/18 (0.00%)

0/12 (0.00%)

Muscular weakness * 1

0/3 (0.00%)

0/4 (0.00%)

0/8 (0.00%)

0/7 (0.00%)

0/8 (0.00%)

0/6 (0.00%)

0/6 (0.00%)

0/5 (0.00%)

0/3 (0.00%)

0/6 (0.00%)

0/9 (0.00%)

0/53 (0.00%)

1/85 (1.18%)

2/41 (4.88%)

0/48 (0.00%)

0/18 (0.00%)

1/154 (0.65%)

0/66 (0.00%)

0/18 (0.00%)

0/18 (0.00%)

0/12 (0.00%)

Musculoskeletal pain * 1

0/3 (0.00%)

0/4 (0.00%)

0/8 (0.00%)

0/7 (0.00%)

0/8 (0.00%)

0/6 (0.00%)

0/6 (0.00%)

0/5 (0.00%)

0/3 (0.00%)

0/6 (0.00%)

0/9 (0.00%)

0/53 (0.00%)

0/85 (0.00%)

1/41 (2.44%)

0/48 (0.00%)

0/18 (0.00%)

0/154 (0.00%)

0/66 (0.00%)

0/18 (0.00%)

0/18 (0.00%)

0/12 (0.00%)

Osteonecrosis * 1

0/3 (0.00%)

0/4 (0.00%)

0/8 (0.00%)

0/7 (0.00%)

0/8 (0.00%)

0/6 (0.00%)

0/6 (0.00%)

0/5 (0.00%)

0/3 (0.00%)

0/6 (0.00%)

0/9 (0.00%)

0/53 (0.00%)

0/85 (0.00%)

0/41 (0.00%)

0/48 (0.00%)

0/18 (0.00%)

1/154 (0.65%)

0/66 (0.00%)

0/18 (0.00%)

0/18 (0.00%)

0/12 (0.00%)

Pain in extremity * 1

0/3 (0.00%)

0/4 (0.00%)

0/8 (0.00%)

0/7 (0.00%)

0/8 (0.00%)

0/6 (0.00%)

0/6 (0.00%)

0/5 (0.00%)

0/3 (0.00%)

0/6 (0.00%)

0/9 (0.00%)

0/53 (0.00%)

0/85 (0.00%)

0/41 (0.00%)

0/48 (0.00%)

0/18 (0.00%)

0/154 (0.00%)

2/66 (3.03%)

0/18 (0.00%)

0/18 (0.00%)

0/12 (0.00%)

Pathological fracture * 1

0/3 (0.00%)

0/4 (0.00%)

0/8 (0.00%)

0/7 (0.00%)

0/8 (0.00%)

0/6 (0.00%)

0/6 (0.00%)

0/5 (0.00%)

0/3 (0.00%)

0/6 (0.00%)

0/9 (0.00%)

0/53 (0.00%)

1/85 (1.18%)

0/41 (0.00%)

0/48 (0.00%)

0/18 (0.00%)

0/154 (0.00%)

0/66 (0.00%)

0/18 (0.00%)

0/18 (0.00%)

0/12 (0.00%)

Rhabdomyolysis * 1

0/3 (0.00%)

0/4 (0.00%)

0/8 (0.00%)

0/7 (0.00%)

0/8 (0.00%)

0/6 (0.00%)

0/6 (0.00%)

0/5 (0.00%)

0/3 (0.00%)

0/6 (0.00%)

0/9 (0.00%)

0/53 (0.00%)

0/85 (0.00%)

0/41 (0.00%)

0/48 (0.00%)

0/18 (0.00%)

1/154 (0.65%)

0/66 (0.00%)

0/18 (0.00%)

0/18 (0.00%)

0/12 (0.00%)

Soft tissue disorder * 1

0/3 (0.00%)

0/4 (0.00%)

0/8 (0.00%)

0/7 (0.00%)

0/8 (0.00%)

0/6 (0.00%)

0/6 (0.00%)

0/5 (0.00%)

0/3 (0.00%)

0/6 (0.00%)

0/9 (0.00%)

0/53 (0.00%)

1/85 (1.18%)

0/41 (0.00%)

0/48 (0.00%)

0/18 (0.00%)

0/154 (0.00%)

0/66 (0.00%)

0/18 (0.00%)

0/18 (0.00%)

0/12 (0.00%)

Neoplasms benign, malignant and unspecified (incl cysts and polyps)

Bladder cancer recurrent * 1

0/3 (0.00%)

0/4 (0.00%)

0/8 (0.00%)

0/7 (0.00%)

0/8 (0.00%)

0/6 (0.00%)

0/6 (0.00%)

0/5 (0.00%)

0/3 (0.00%)

0/6 (0.00%)

0/9 (0.00%)

0/53 (0.00%)

1/85 (1.18%)

0/41 (0.00%)

0/48 (0.00%)

0/18 (0.00%)

0/154 (0.00%)

0/66 (0.00%)

0/18 (0.00%)

0/18 (0.00%)

0/12 (0.00%)

Chronic lymphocytic leukaemia * 1

0/3 (0.00%)

0/4 (0.00%)

0/8 (0.00%)

0/7 (0.00%)

0/8 (0.00%)

0/6 (0.00%)

0/6 (0.00%)

0/5 (0.00%)

0/3 (0.00%)

0/6 (0.00%)

0/9 (0.00%)

0/53 (0.00%)

1/85 (1.18%)

0/41 (0.00%)

0/48 (0.00%)

0/18 (0.00%)

0/154 (0.00%)

0/66 (0.00%)

0/18 (0.00%)

0/18 (0.00%)

0/12 (0.00%)

Malignant melanoma * 1

0/3 (0.00%)

0/4 (0.00%)

0/8 (0.00%)

0/7 (0.00%)

0/8 (0.00%)

0/6 (0.00%)

0/6 (0.00%)

0/5 (0.00%)

0/3 (0.00%)

0/6 (0.00%)

0/9 (0.00%)

0/53 (0.00%)

0/85 (0.00%)

0/41 (0.00%)

1/48 (2.08%)

0/18 (0.00%)

1/154 (0.65%)

1/66 (1.52%)

0/18 (0.00%)

0/18 (0.00%)

0/12 (0.00%)

Prostate cancer * 1

0/3 (0.00%)

0/4 (0.00%)

0/8 (0.00%)

0/7 (0.00%)

0/8 (0.00%)

0/6 (0.00%)

0/6 (0.00%)

0/5 (0.00%)

0/3 (0.00%)

0/6 (0.00%)

0/9 (0.00%)

0/53 (0.00%)

0/85 (0.00%)

0/41 (0.00%)

0/48 (0.00%)

0/18 (0.00%)

1/154 (0.65%)

0/66 (0.00%)

0/18 (0.00%)

0/18 (0.00%)

0/12 (0.00%)

Small cell lung cancer * 1

0/3 (0.00%)

0/4 (0.00%)

0/8 (0.00%)

0/7 (0.00%)

0/8 (0.00%)

0/6 (0.00%)

0/6 (0.00%)

0/5 (0.00%)

0/3 (0.00%)

0/6 (0.00%)

0/9 (0.00%)

0/53 (0.00%)

0/85 (0.00%)

0/41 (0.00%)

1/48 (2.08%)

0/18 (0.00%)

0/154 (0.00%)

0/66 (0.00%)

0/18 (0.00%)

0/18 (0.00%)

0/12 (0.00%)

Squamous cell carcinoma * 1

0/3 (0.00%)

0/4 (0.00%)

0/8 (0.00%)

0/7 (0.00%)

0/8 (0.00%)

0/6 (0.00%)

0/6 (0.00%)

0/5 (0.00%)

0/3 (0.00%)

0/6 (0.00%)

0/9 (0.00%)

0/53 (0.00%)

0/85 (0.00%)

0/41 (0.00%)

0/48 (0.00%)

0/18 (0.00%)

1/154 (0.65%)

0/66 (0.00%)

0/18 (0.00%)

0/18 (0.00%)

0/12 (0.00%)

Nervous system disorders

Aphasia * 1

0/3 (0.00%)

0/4 (0.00%)

0/8 (0.00%)

0/7 (0.00%)

0/8 (0.00%)

0/6 (0.00%)

0/6 (0.00%)

0/5 (0.00%)

0/3 (0.00%)

0/6 (0.00%)

0/9 (0.00%)

1/53 (1.89%)

0/85 (0.00%)

0/41 (0.00%)

0/48 (0.00%)

0/18 (0.00%)

0/154 (0.00%)

0/66 (0.00%)

0/18 (0.00%)

0/18 (0.00%)

0/12 (0.00%)

Haemorrhage intracranial * 1

0/3 (0.00%)

0/4 (0.00%)

0/8 (0.00%)

0/7 (0.00%)

0/8 (0.00%)

0/6 (0.00%)

0/6 (0.00%)

0/5 (0.00%)

0/3 (0.00%)

0/6 (0.00%)

0/9 (0.00%)

1/53 (1.89%)

0/85 (0.00%)

1/41 (2.44%)

0/48 (0.00%)

0/18 (0.00%)

0/154 (0.00%)

0/66 (0.00%)

0/18 (0.00%)

0/18 (0.00%)

0/12 (0.00%)

Headache * 1

0/3 (0.00%)

0/4 (0.00%)

0/8 (0.00%)

1/7 (14.29%)

0/8 (0.00%)

0/6 (0.00%)

0/6 (0.00%)

0/5 (0.00%)

0/3 (0.00%)

0/6 (0.00%)

0/9 (0.00%)

1/53 (1.89%)

0/85 (0.00%)

0/41 (0.00%)

0/48 (0.00%)

0/18 (0.00%)

2/154 (1.30%)

0/66 (0.00%)

0/18 (0.00%)

0/18 (0.00%)

0/12 (0.00%)

Brain oedema * 1

0/3 (0.00%)

0/4 (0.00%)

0/8 (0.00%)

0/7 (0.00%)

0/8 (0.00%)

0/6 (0.00%)

0/6 (0.00%)

0/5 (0.00%)

0/3 (0.00%)

0/6 (0.00%)

0/9 (0.00%)

0/53 (0.00%)

0/85 (0.00%)

0/41 (0.00%)

0/48 (0.00%)

0/18 (0.00%)

2/154 (1.30%)

0/66 (0.00%)

0/18 (0.00%)

0/18 (0.00%)

0/12 (0.00%)

Central nervous system haemorrhage * 1

0/3 (0.00%)

0/4 (0.00%)

0/8 (0.00%)

0/7 (0.00%)

0/8 (0.00%)

0/6 (0.00%)

0/6 (0.00%)

0/5 (0.00%)

0/3 (0.00%)

0/6 (0.00%)

0/9 (0.00%)

0/53 (0.00%)

0/85 (0.00%)

0/41 (0.00%)

0/48 (0.00%)

0/18 (0.00%)

1/154 (0.65%)

0/66 (0.00%)

0/18 (0.00%)

0/18 (0.00%)

0/12 (0.00%)

Cerebral haematoma * 1

0/3 (0.00%)

0/4 (0.00%)

0/8 (0.00%)

0/7 (0.00%)

0/8 (0.00%)

0/6 (0.00%)

0/6 (0.00%)

1/5 (20.00%)

0/3 (0.00%)

0/6 (0.00%)

0/9 (0.00%)

0/53 (0.00%)

0/85 (0.00%)

0/41 (0.00%)

0/48 (0.00%)

0/18 (0.00%)

1/154 (0.65%)

0/66 (0.00%)

0/18 (0.00%)

0/18 (0.00%)

0/12 (0.00%)

Cerebral haemorrhage * 1

0/3 (0.00%)

0/4 (0.00%)

0/8 (0.00%)

0/7 (0.00%)

0/8 (0.00%)

0/6 (0.00%)

0/6 (0.00%)

0/5 (0.00%)

0/3 (0.00%)

0/6 (0.00%)

0/9 (0.00%)

0/53 (0.00%)

0/85 (0.00%)

0/41 (0.00%)

0/48 (0.00%)

0/18 (0.00%)

1/154 (0.65%)

0/66 (0.00%)

1/18 (5.56%)

0/18 (0.00%)

0/12 (0.00%)

Cerebrovascular accident * 1

0/3 (0.00%)

0/4 (0.00%)

0/8 (0.00%)

0/7 (0.00%)

0/8 (0.00%)

0/6 (0.00%)

0/6 (0.00%)

0/5 (0.00%)

0/3 (0.00%)

0/6 (0.00%)

1/9 (11.11%)

0/53 (0.00%)

2/85 (2.35%)

0/41 (0.00%)

0/48 (0.00%)

0/18 (0.00%)

2/154 (1.30%)

0/66 (0.00%)

0/18 (0.00%)

0/18 (0.00%)

0/12 (0.00%)

Encephalopathy * 1

0/3 (0.00%)

0/4 (0.00%)

0/8 (0.00%)

0/7 (0.00%)

0/8 (0.00%)

0/6 (0.00%)

0/6 (0.00%)

0/5 (0.00%)

0/3 (0.00%)

0/6 (0.00%)

0/9 (0.00%)

0/53 (0.00%)

0/85 (0.00%)

1/41 (2.44%)

0/48 (0.00%)

0/18 (0.00%)

0/154 (0.00%)

0/66 (0.00%)

0/18 (0.00%)

0/18 (0.00%)

0/12 (0.00%)

Hypoxic-ischaemic encephalopathy * 1

0/3 (0.00%)

0/4 (0.00%)

0/8 (0.00%)

0/7 (0.00%)

0/8 (0.00%)

0/6 (0.00%)

0/6 (0.00%)

0/5 (0.00%)

1/3 (33.33%)

0/6 (0.00%)

0/9 (0.00%)

0/53 (0.00%)

0/85 (0.00%)

0/41 (0.00%)

0/48 (0.00%)

0/18 (0.00%)

0/154 (0.00%)

0/66 (0.00%)

0/18 (0.00%)

0/18 (0.00%)

0/12 (0.00%)

Intracranial pressure increased * 1

0/3 (0.00%)

0/4 (0.00%)

0/8 (0.00%)

0/7 (0.00%)

0/8 (0.00%)

0/6 (0.00%)

0/6 (0.00%)

0/5 (0.00%)

0/3 (0.00%)

0/6 (0.00%)

0/9 (0.00%)

0/53 (0.00%)

0/85 (0.00%)

0/41 (0.00%)

0/48 (0.00%)

1/18 (5.56%)

0/154 (0.00%)

0/66 (0.00%)

0/18 (0.00%)

0/18 (0.00%)

0/12 (0.00%)

Seizure * 1

0/3 (0.00%)

0/4 (0.00%)

0/8 (0.00%)

0/7 (0.00%)

0/8 (0.00%)

0/6 (0.00%)

0/6 (0.00%)

0/5 (0.00%)

0/3 (0.00%)

0/6 (0.00%)

0/9 (0.00%)

0/53 (0.00%)

1/85 (1.18%)

2/41 (4.88%)

0/48 (0.00%)

0/18 (0.00%)

5/154 (3.25%)

0/66 (0.00%)

0/18 (0.00%)

0/18 (0.00%)

0/12 (0.00%)

Spinal cord compression * 1

0/3 (0.00%)

0/4 (0.00%)

0/8 (0.00%)

1/7 (14.29%)

0/8 (0.00%)

0/6 (0.00%)

0/6 (0.00%)

0/5 (0.00%)

0/3 (0.00%)

0/6 (0.00%)

0/9 (0.00%)

0/53 (0.00%)

0/85 (0.00%)

0/41 (0.00%)

0/48 (0.00%)

0/18 (0.00%)

0/154 (0.00%)

0/66 (0.00%)

0/18 (0.00%)

0/18 (0.00%)

0/12 (0.00%)

Transient ischaemic attack * 1

0/3 (0.00%)

0/4 (0.00%)

0/8 (0.00%)

0/7 (0.00%)

0/8 (0.00%)

0/6 (0.00%)

0/6 (0.00%)

0/5 (0.00%)

0/3 (0.00%)

0/6 (0.00%)

0/9 (0.00%)

0/53 (0.00%)

0/85 (0.00%)

0/41 (0.00%)

0/48 (0.00%)

2/18 (11.11%)

1/154 (0.65%)

0/66 (0.00%)

0/18 (0.00%)

0/18 (0.00%)

0/12 (0.00%)

Pregnancy, puerperium and perinatal conditions

Abortion spontaneous * 1

0/3 (0.00%)

0/4 (0.00%)

0/8 (0.00%)

0/7 (0.00%)

0/8 (0.00%)

0/6 (0.00%)

0/6 (0.00%)

0/5 (0.00%)

0/3 (0.00%)

0/6 (0.00%)

0/9 (0.00%)

0/53 (0.00%)

0/85 (0.00%)

0/41 (0.00%)

0/48 (0.00%)

0/18 (0.00%)

1/154 (0.65%)

0/66 (0.00%)

0/18 (0.00%)

0/18 (0.00%)

0/12 (0.00%)

Psychiatric disorders

Mental status changes * 1

0/3 (0.00%)

0/4 (0.00%)

0/8 (0.00%)

0/7 (0.00%)

0/8 (0.00%)

0/6 (0.00%)

0/6 (0.00%)

0/5 (0.00%)

0/3 (0.00%)

0/6 (0.00%)

0/9 (0.00%)

1/53 (1.89%)

1/85 (1.18%)

0/41 (0.00%)

0/48 (0.00%)

0/18 (0.00%)

2/154 (1.30%)

0/66 (0.00%)

0/18 (0.00%)

0/18 (0.00%)

0/12 (0.00%)

Anxiety * 1

0/3 (0.00%)

0/4 (0.00%)

0/8 (0.00%)

0/7 (0.00%)

0/8 (0.00%)

0/6 (0.00%)

0/6 (0.00%)

0/5 (0.00%)

0/3 (0.00%)

0/6 (0.00%)

0/9 (0.00%)

0/53 (0.00%)

0/85 (0.00%)

1/41 (2.44%)

0/48 (0.00%)

0/18 (0.00%)

0/154 (0.00%)

0/66 (0.00%)

0/18 (0.00%)

0/18 (0.00%)

0/12 (0.00%)

Confusional state * 1

0/3 (0.00%)

0/4 (0.00%)

0/8 (0.00%)

0/7 (0.00%)

0/8 (0.00%)

0/6 (0.00%)

0/6 (0.00%)

0/5 (0.00%)

0/3 (0.00%)

0/6 (0.00%)

0/9 (0.00%)

0/53 (0.00%)

1/85 (1.18%)

0/41 (0.00%)

0/48 (0.00%)

0/18 (0.00%)

0/154 (0.00%)

0/66 (0.00%)

0/18 (0.00%)

0/18 (0.00%)

0/12 (0.00%)

Drug abuse * 1

0/3 (0.00%)

0/4 (0.00%)

0/8 (0.00%)

0/7 (0.00%)

0/8 (0.00%)

0/6 (0.00%)

0/6 (0.00%)

0/5 (0.00%)

0/3 (0.00%)

0/6 (0.00%)

0/9 (0.00%)

0/53 (0.00%)

0/85 (0.00%)

0/41 (0.00%)

0/48 (0.00%)

0/18 (0.00%)

1/154 (0.65%)

0/66 (0.00%)

0/18 (0.00%)

0/18 (0.00%)

0/12 (0.00%)

Suicidal ideation * 1

0/3 (0.00%)

0/4 (0.00%)

0/8 (0.00%)

0/7 (0.00%)

0/8 (0.00%)

0/6 (0.00%)

0/6 (0.00%)

0/5 (0.00%)

0/3 (0.00%)

0/6 (0.00%)

0/9 (0.00%)

0/53 (0.00%)

0/85 (0.00%)

1/41 (2.44%)

0/48 (0.00%)

0/18 (0.00%)

0/154 (0.00%)

0/66 (0.00%)

0/18 (0.00%)

0/18 (0.00%)

0/12 (0.00%)

Renal and urinary disorders

Renal cyst * 1

0/3 (0.00%)

0/4 (0.00%)

0/8 (0.00%)

0/7 (0.00%)

0/8 (0.00%)

0/6 (0.00%)

0/6 (0.00%)

0/5 (0.00%)

0/3 (0.00%)

0/6 (0.00%)

0/9 (0.00%)

1/53 (1.89%)

0/85 (0.00%)

1/41 (2.44%)

0/48 (0.00%)

0/18 (0.00%)

2/154 (1.30%)

0/66 (0.00%)

0/18 (0.00%)

0/18 (0.00%)

0/12 (0.00%)

Urinary retention * 1

0/3 (0.00%)

0/4 (0.00%)

0/8 (0.00%)

0/7 (0.00%)

0/8 (0.00%)

0/6 (0.00%)

0/6 (0.00%)

0/5 (0.00%)

0/3 (0.00%)

0/6 (0.00%)

0/9 (0.00%)

1/53 (1.89%)

1/85 (1.18%)

0/41 (0.00%)

0/48 (0.00%)

0/18 (0.00%)

0/154 (0.00%)

0/66 (0.00%)

0/18 (0.00%)

0/18 (0.00%)

0/12 (0.00%)

Acute kidney injury * 1

0/3 (0.00%)

0/4 (0.00%)

0/8 (0.00%)

0/7 (0.00%)

0/8 (0.00%)

0/6 (0.00%)

0/6 (0.00%)

0/5 (0.00%)

0/3 (0.00%)

0/6 (0.00%)

0/9 (0.00%)

0/53 (0.00%)

1/85 (1.18%)

4/41 (9.76%)

0/48 (0.00%)

0/18 (0.00%)

1/154 (0.65%)

1/66 (1.52%)

1/18 (5.56%)

0/18 (0.00%)

0/12 (0.00%)

Haematuria * 1

0/3 (0.00%)

0/4 (0.00%)

0/8 (0.00%)

0/7 (0.00%)

0/8 (0.00%)

0/6 (0.00%)

0/6 (0.00%)

0/5 (0.00%)

0/3 (0.00%)

0/6 (0.00%)

0/9 (0.00%)

0/53 (0.00%)

0/85 (0.00%)

0/41 (0.00%)

0/48 (0.00%)

0/18 (0.00%)

1/154 (0.65%)

0/66 (0.00%)

0/18 (0.00%)

0/18 (0.00%)

0/12 (0.00%)

Nephrolithiasis * 1

0/3 (0.00%)

0/4 (0.00%)

0/8 (0.00%)

0/7 (0.00%)

0/8 (0.00%)

0/6 (0.00%)

0/6 (0.00%)

0/5 (0.00%)

0/3 (0.00%)

0/6 (0.00%)

0/9 (0.00%)

0/53 (0.00%)

0/85 (0.00%)

0/41 (0.00%)

0/48 (0.00%)

0/18 (0.00%)

2/154 (1.30%)

0/66 (0.00%)

0/18 (0.00%)

0/18 (0.00%)

0/12 (0.00%)

Reproductive system and breast disorders

Pelvic pain * 1

0/3 (0.00%)

0/4 (0.00%)

0/8 (0.00%)

0/7 (0.00%)

0/8 (0.00%)

0/6 (0.00%)

0/6 (0.00%)

0/5 (0.00%)

0/3 (0.00%)

0/6 (0.00%)

0/9 (0.00%)

0/53 (0.00%)

1/85 (1.18%)

0/41 (0.00%)

0/48 (0.00%)

0/18 (0.00%)

0/154 (0.00%)

0/66 (0.00%)

0/18 (0.00%)

0/18 (0.00%)

0/12 (0.00%)

Vaginal haemorrhage * 1

0/3 (0.00%)

0/4 (0.00%)

0/8 (0.00%)

0/7 (0.00%)

0/8 (0.00%)

0/6 (0.00%)

0/6 (0.00%)

0/5 (0.00%)

0/3 (0.00%)

0/6 (0.00%)

0/9 (0.00%)

0/53 (0.00%)

0/85 (0.00%)

0/41 (0.00%)

0/48 (0.00%)

0/18 (0.00%)

1/154 (0.65%)

0/66 (0.00%)

0/18 (0.00%)

0/18 (0.00%)

0/12 (0.00%)

Respiratory, thoracic and mediastinal disorders

Dyspnoea * 1

0/3 (0.00%)

0/4 (0.00%)

0/8 (0.00%)

0/7 (0.00%)

0/8 (0.00%)

0/6 (0.00%)

0/6 (0.00%)

0/5 (0.00%)

0/3 (0.00%)

0/6 (0.00%)

1/9 (11.11%)

1/53 (1.89%)

6/85 (7.06%)

2/41 (4.88%)

4/48 (8.33%)

0/18 (0.00%)

7/154 (4.55%)

1/66 (1.52%)

0/18 (0.00%)

0/18 (0.00%)

0/12 (0.00%)

Hypoxia * 1

0/3 (0.00%)

0/4 (0.00%)

0/8 (0.00%)

0/7 (0.00%)

0/8 (0.00%)

0/6 (0.00%)

0/6 (0.00%)

0/5 (0.00%)

0/3 (0.00%)

0/6 (0.00%)

0/9 (0.00%)

1/53 (1.89%)

3/85 (3.53%)

2/41 (4.88%)

0/48 (0.00%)

0/18 (0.00%)

2/154 (1.30%)

0/66 (0.00%)

0/18 (0.00%)

0/18 (0.00%)

1/12 (8.33%)

Pneumothorax * 1

0/3 (0.00%)

0/4 (0.00%)

0/8 (0.00%)

0/7 (0.00%)

0/8 (0.00%)

0/6 (0.00%)

0/6 (0.00%)

0/5 (0.00%)

0/3 (0.00%)

0/6 (0.00%)

0/9 (0.00%)

1/53 (1.89%)

0/85 (0.00%)

0/41 (0.00%)

2/48 (4.17%)

0/18 (0.00%)

0/154 (0.00%)

0/66 (0.00%)

0/18 (0.00%)

0/18 (0.00%)

0/12 (0.00%)

Pulmonary embolism * 1

0/3 (0.00%)

0/4 (0.00%)

0/8 (0.00%)

1/7 (14.29%)

0/8 (0.00%)

0/6 (0.00%)

0/6 (0.00%)

0/5 (0.00%)

0/3 (0.00%)

0/6 (0.00%)

0/9 (0.00%)

2/53 (3.77%)

2/85 (2.35%)

4/41 (9.76%)

1/48 (2.08%)

1/18 (5.56%)

10/154 (6.49%)

1/66 (1.52%)

0/18 (0.00%)

0/18 (0.00%)

0/12 (0.00%)

Acute respiratory failure * 1

0/3 (0.00%)

0/4 (0.00%)

0/8 (0.00%)

0/7 (0.00%)

0/8 (0.00%)

0/6 (0.00%)

0/6 (0.00%)

0/5 (0.00%)

0/3 (0.00%)

0/6 (0.00%)

0/9 (0.00%)

0/53 (0.00%)

0/85 (0.00%)

0/41 (0.00%)

0/48 (0.00%)

1/18 (5.56%)

0/154 (0.00%)

0/66 (0.00%)

0/18 (0.00%)

0/18 (0.00%)

0/12 (0.00%)

Bronchial obstruction * 1

0/3 (0.00%)

0/4 (0.00%)

0/8 (0.00%)

0/7 (0.00%)

0/8 (0.00%)

0/6 (0.00%)

0/6 (0.00%)

0/5 (0.00%)

0/3 (0.00%)

0/6 (0.00%)

0/9 (0.00%)

0/53 (0.00%)

0/85 (0.00%)

0/41 (0.00%)

0/48 (0.00%)

0/18 (0.00%)

1/154 (0.65%)

0/66 (0.00%)

0/18 (0.00%)

0/18 (0.00%)

0/12 (0.00%)

Bronchospasm * 1

0/3 (0.00%)

0/4 (0.00%)

0/8 (0.00%)

0/7 (0.00%)

0/8 (0.00%)

0/6 (0.00%)

0/6 (0.00%)

0/5 (0.00%)

0/3 (0.00%)

0/6 (0.00%)

0/9 (0.00%)

0/53 (0.00%)

1/85 (1.18%)

0/41 (0.00%)

0/48 (0.00%)

0/18 (0.00%)

0/154 (0.00%)

0/66 (0.00%)

0/18 (0.00%)

0/18 (0.00%)

0/12 (0.00%)

Chronic obstructive pulmonary disease * 1

0/3 (0.00%)

0/4 (0.00%)

0/8 (0.00%)

0/7 (0.00%)

0/8 (0.00%)

0/6 (0.00%)

0/6 (0.00%)

0/5 (0.00%)

0/3 (0.00%)

0/6 (0.00%)

0/9 (0.00%)

0/53 (0.00%)

0/85 (0.00%)

1/41 (2.44%)

0/48 (0.00%)

0/18 (0.00%)

0/154 (0.00%)

0/66 (0.00%)

0/18 (0.00%)

0/18 (0.00%)

0/12 (0.00%)

Cough * 1

0/3 (0.00%)

0/4 (0.00%)

0/8 (0.00%)

1/7 (14.29%)

0/8 (0.00%)

0/6 (0.00%)

0/6 (0.00%)

0/5 (0.00%)

0/3 (0.00%)

0/6 (0.00%)

0/9 (0.00%)

0/53 (0.00%)

1/85 (1.18%)

0/41 (0.00%)

0/48 (0.00%)

0/18 (0.00%)

0/154 (0.00%)

0/66 (0.00%)

0/18 (0.00%)

0/18 (0.00%)

0/12 (0.00%)

Haemoptysis * 1

0/3 (0.00%)

0/4 (0.00%)

0/8 (0.00%)

1/7 (14.29%)

0/8 (0.00%)

0/6 (0.00%)

0/6 (0.00%)

0/5 (0.00%)

0/3 (0.00%)

0/6 (0.00%)

0/9 (0.00%)

0/53 (0.00%)

0/85 (0.00%)

0/41 (0.00%)

0/48 (0.00%)

0/18 (0.00%)

3/154 (1.95%)

0/66 (0.00%)

0/18 (0.00%)

0/18 (0.00%)

0/12 (0.00%)

Pleural effusion * 1

0/3 (0.00%)

0/4 (0.00%)

0/8 (0.00%)

0/7 (0.00%)

0/8 (0.00%)

0/6 (0.00%)

0/6 (0.00%)

0/5 (0.00%)

0/3 (0.00%)

0/6 (0.00%)

0/9 (0.00%)

0/53 (0.00%)

5/85 (5.88%)

2/41 (4.88%)

1/48 (2.08%)

0/18 (0.00%)

2/154 (1.30%)

1/66 (1.52%)

1/18 (5.56%)

0/18 (0.00%)

0/12 (0.00%)

Pneumonia aspiration * 1

0/3 (0.00%)

0/4 (0.00%)

0/8 (0.00%)

0/7 (0.00%)

0/8 (0.00%)

0/6 (0.00%)

0/6 (0.00%)

0/5 (0.00%)

0/3 (0.00%)

0/6 (0.00%)

0/9 (0.00%)

0/53 (0.00%)

0/85 (0.00%)

1/41 (2.44%)

0/48 (0.00%)

1/18 (5.56%)

0/154 (0.00%)

0/66 (0.00%)

0/18 (0.00%)

0/18 (0.00%)

0/12 (0.00%)

Pneumonitis * 1

0/3 (0.00%)

0/4 (0.00%)

0/8 (0.00%)

0/7 (0.00%)

0/8 (0.00%)

0/6 (0.00%)

0/6 (0.00%)

0/5 (0.00%)

0/3 (0.00%)

0/6 (0.00%)

0/9 (0.00%)

0/53 (0.00%)

6/85 (7.06%)

1/41 (2.44%)

0/48 (0.00%)

0/18 (0.00%)

1/154 (0.65%)

0/66 (0.00%)

1/18 (5.56%)

0/18 (0.00%)

0/12 (0.00%)

Pulmonary haemorrhage * 1

0/3 (0.00%)

0/4 (0.00%)

0/8 (0.00%)

0/7 (0.00%)

0/8 (0.00%)

0/6 (0.00%)

0/6 (0.00%)

0/5 (0.00%)

0/3 (0.00%)

0/6 (0.00%)

0/9 (0.00%)

0/53 (0.00%)

0/85 (0.00%)

0/41 (0.00%)

0/48 (0.00%)

0/18 (0.00%)

1/154 (0.65%)

0/66 (0.00%)

0/18 (0.00%)

0/18 (0.00%)

0/12 (0.00%)

Respiratory arrest * 1

0/3 (0.00%)

0/4 (0.00%)

0/8 (0.00%)

0/7 (0.00%)

0/8 (0.00%)

0/6 (0.00%)

0/6 (0.00%)

0/5 (0.00%)

0/3 (0.00%)

0/6 (0.00%)

0/9 (0.00%)

0/53 (0.00%)

1/85 (1.18%)

0/41 (0.00%)

0/48 (0.00%)

0/18 (0.00%)

0/154 (0.00%)

0/66 (0.00%)

0/18 (0.00%)

0/18 (0.00%)

0/12 (0.00%)

Respiratory failure * 1

0/3 (0.00%)

0/4 (0.00%)

0/8 (0.00%)

0/7 (0.00%)

0/8 (0.00%)

1/6 (16.67%)

0/6 (0.00%)

0/5 (0.00%)

0/3 (0.00%)

0/6 (0.00%)

0/9 (0.00%)

0/53 (0.00%)

2/85 (2.35%)

1/41 (2.44%)

0/48 (0.00%)

1/18 (5.56%)

1/154 (0.65%)

0/66 (0.00%)

0/18 (0.00%)

0/18 (0.00%)

0/12 (0.00%)

Skin and subcutaneous tissue disorders

Stasis dermatitis * 1

0/3 (0.00%)

0/4 (0.00%)

0/8 (0.00%)

0/7 (0.00%)

0/8 (0.00%)

0/6 (0.00%)

0/6 (0.00%)

0/5 (0.00%)

0/3 (0.00%)

0/6 (0.00%)

0/9 (0.00%)

0/53 (0.00%)

0/85 (0.00%)

0/41 (0.00%)

0/48 (0.00%)

0/18 (0.00%)

0/154 (0.00%)

1/66 (1.52%)

0/18 (0.00%)

0/18 (0.00%)

0/12 (0.00%)

Subcutaneous emphysema * 1

0/3 (0.00%)

0/4 (0.00%)

0/8 (0.00%)

0/7 (0.00%)

0/8 (0.00%)

0/6 (0.00%)

0/6 (0.00%)

0/5 (0.00%)

0/3 (0.00%)

0/6 (0.00%)

0/9 (0.00%)

0/53 (0.00%)

0/85 (0.00%)

0/41 (0.00%)

0/48 (0.00%)

0/18 (0.00%)

1/154 (0.65%)

0/66 (0.00%)

0/18 (0.00%)

0/18 (0.00%)

0/12 (0.00%)

0

Vascular disorders

Deep vein thrombosis * 1

0/3 (0.00%)

0/4 (0.00%)

0/8 (0.00%)

0/7 (0.00%)

0/8 (0.00%)

0/6 (0.00%)

0/6 (0.00%)

0/5 (0.00%)

0/3 (0.00%)

0/6 (0.00%)

0/9 (0.00%)

1/53 (1.89%)

0/85 (0.00%)

1/41 (2.44%)

0/48 (0.00%)

0/18 (0.00%)

6/154 (3.90%)

0/66 (0.00%)

1/18 (5.56%)

0/18 (0.00%)

0/12 (0.00%)

Aortic stenosis * 1

0/3 (0.00%)

0/4 (0.00%)

0/8 (0.00%)

0/7 (0.00%)

0/8 (0.00%)

0/6 (0.00%)

0/6 (0.00%)

0/5 (0.00%)

0/3 (0.00%)

0/6 (0.00%)

0/9 (0.00%)

0/53 (0.00%)

0/85 (0.00%)

0/41 (0.00%)

0/48 (0.00%)

0/18 (0.00%)

1/154 (0.65%)

0/66 (0.00%)

0/18 (0.00%)

0/18 (0.00%)

0/12 (0.00%)

Embolism * 1

0/3 (0.00%)

0/4 (0.00%)

0/8 (0.00%)

0/7 (0.00%)

0/8 (0.00%)

0/6 (0.00%)

0/6 (0.00%)

0/5 (0.00%)

0/3 (0.00%)

0/6 (0.00%)

0/9 (0.00%)

0/53 (0.00%)

2/85 (2.35%)

0/41 (0.00%)

0/48 (0.00%)

0/18 (0.00%)

0/154 (0.00%)

0/66 (0.00%)

0/18 (0.00%)

0/18 (0.00%)

0/12 (0.00%)

Haematoma * 1

0/3 (0.00%)

0/4 (0.00%)

0/8 (0.00%)

0/7 (0.00%)

0/8 (0.00%)

0/6 (0.00%)

0/6 (0.00%)

0/5 (0.00%)

0/3 (0.00%)

0/6 (0.00%)

0/9 (0.00%)

0/53 (0.00%)

0/85 (0.00%)

1/41 (2.44%)

0/48 (0.00%)

0/18 (0.00%)

0/154 (0.00%)

0/66 (0.00%)

0/18 (0.00%)

0/18 (0.00%)

0/12 (0.00%)

Haemorrhage * 1

0/3 (0.00%)

0/4 (0.00%)

0/8 (0.00%)

0/7 (0.00%)

0/8 (0.00%)

0/6 (0.00%)

0/6 (0.00%)

0/5 (0.00%)

0/3 (0.00%)

0/6 (0.00%)

0/9 (0.00%)

0/53 (0.00%)

0/85 (0.00%)

0/41 (0.00%)

0/48 (0.00%)

0/18 (0.00%)

1/154 (0.65%)

1/66 (1.52%)

0/18 (0.00%)

0/18 (0.00%)

0/12 (0.00%)

Hypotension * 1

0/3 (0.00%)

0/4 (0.00%)

0/8 (0.00%)

0/7 (0.00%)

0/8 (0.00%)

0/6 (0.00%)

0/6 (0.00%)

0/5 (0.00%)

0/3 (0.00%)

0/6 (0.00%)

0/9 (0.00%)

0/53 (0.00%)

1/85 (1.18%)

0/41 (0.00%)

0/48 (0.00%)

0/18 (0.00%)

0/154 (0.00%)

0/66 (0.00%)

0/18 (0.00%)

0/18 (0.00%)

0/12 (0.00%)

Jugular vein thrombosis * 1

0/3 (0.00%)

0/4 (0.00%)

0/8 (0.00%)

0/7 (0.00%)

0/8 (0.00%)

0/6 (0.00%)

0/6 (0.00%)

0/5 (0.00%)

0/3 (0.00%)

0/6 (0.00%)

0/9 (0.00%)

0/53 (0.00%)

0/85 (0.00%)

0/41 (0.00%)

0/48 (0.00%)

0/18 (0.00%)

1/154 (0.65%)

0/66 (0.00%)

0/18 (0.00%)

0/18 (0.00%)

0/12 (0.00%)

Peripheral embolism * 1

0/3 (0.00%)

0/4 (0.00%)

0/8 (0.00%)

0/7 (0.00%)

0/8 (0.00%)

0/6 (0.00%)

0/6 (0.00%)

0/5 (0.00%)

0/3 (0.00%)

0/6 (0.00%)

0/9 (0.00%)

0/53 (0.00%)

1/85 (1.18%)

0/41 (0.00%)

0/48 (0.00%)

0/18 (0.00%)

0/154 (0.00%)

0/66 (0.00%)

0/18 (0.00%)

0/18 (0.00%)

0/12 (0.00%)

Shock * 1

0/3 (0.00%)

0/4 (0.00%)

0/8 (0.00%)

0/7 (0.00%)

0/8 (0.00%)

0/6 (0.00%)

0/6 (0.00%)

0/5 (0.00%)

0/3 (0.00%)

0/6 (0.00%)

0/9 (0.00%)

0/53 (0.00%)

1/85 (1.18%)

0/41 (0.00%)

0/48 (0.00%)

0/18 (0.00%)

0/154 (0.00%)

0/66 (0.00%)

0/18 (0.00%)

0/18 (0.00%)

0/12 (0.00%)

Thrombosis * 1

0/3 (0.00%)

0/4 (0.00%)

0/8 (0.00%)

0/7 (0.00%)

0/8 (0.00%)

0/6 (0.00%)

0/6 (0.00%)

0/5 (0.00%)

0/3 (0.00%)

0/6 (0.00%)

0/9 (0.00%)

0/53 (0.00%)

1/85 (1.18%)

0/41 (0.00%)

0/48 (0.00%)

0/18 (0.00%)

0/154 (0.00%)

0/66 (0.00%)

0/18 (0.00%)

0/18 (0.00%)

0/12 (0.00%)

Vena cava thrombosis * 1

0/3 (0.00%)

0/4 (0.00%)

0/8 (0.00%)

0/7 (0.00%)

0/8 (0.00%)

0/6 (0.00%)

0/6 (0.00%)

0/5 (0.00%)

0/3 (0.00%)

0/6 (0.00%)

0/9 (0.00%)

0/53 (0.00%)

0/85 (0.00%)

0/41 (0.00%)

0/48 (0.00%)

0/18 (0.00%)

1/154 (0.65%)

0/66 (0.00%)

0/18 (0.00%)

0/18 (0.00%)

0/12 (0.00%)

1 Term from vocabulary, MedDRA 23.0; * Indicates events were collected by non-systematic assessment

Other (Not Including Serious) Adverse Events

Frequency Threshold for Reporting Other Adverse Events

5%

Low Dose Escalation Cohort: Crizotinib 50 mg QD

Low Dose Escalation Cohort: Crizotinib 100 mg QD

Low Dose Escalation Cohort: Crizotinib 200 mg QD

Low Dose Escalation Cohort: Crizotinib 200 mg BID

Low Dose Escalation Cohort: Crizotinib 250 mg BID

Low Dose Escalation Cohort: Crizotinib 300 mg BID

High Dose Escalation Cohort: Crizotinib 300 mg QD

High Dose Escalation Cohort: Crizotinib 400 mg QD

High Dose Escalation Cohort: Crizotinib 500 mg QD

High Dose Escalation Cohort: Crizotinib 650 mg QD

High Dose Escalation Cohort: Crizotinib 800 mg QD

RP2D Cohort: ROS1-Positive NSCLC: Crizotinib 250 mg

RP2D Cohort: MET Exon 14 Alterations NSCLC: Crizotinib 250 mg

RP2D Cohort: MET Amplification NSCLC: Crizotinib 250 mg

RP2D Cohort: ALK-Negative Cohort 1, NSCLC: Crizotinib 250 mg

RP2D Cohort: ALK-Negative Cohort 2, NSCLC: Crizotinib 250 mg

RP2D Cohort: ALK-Positive Cohort, NSCLC: Crizotinib 250 mg

RP2D Cohort: Enriched Other: Crizotinib 250 mg

Itraconazole Interaction Sub-study: Crizotinib 250 mg

RP2D Cohort: Rifampin Interaction: Crizotinib 250 mg +Rifampin

Midazolam Interaction Cohort: Crizotinib 250

Affected / at Risk (%)

# Events

Affected / at Risk (%)

# Events

Affected / at Risk (%)

# Events

Affected / at Risk (%)

# Events

Affected / at Risk (%)

# Events

Affected / at Risk (%)

# Events

Affected / at Risk (%)

# Events

Affected / at Risk (%)

# Events

Affected / at Risk (%)

# Events

Affected / at Risk (%)

# Events

Affected / at Risk (%)

# Events

Affected / at Risk (%)

# Events

Affected / at Risk (%)

# Events

Affected / at Risk (%)

# Events

Affected / at Risk (%)

# Events

Affected / at Risk (%)

# Events

Affected / at Risk (%)

# Events

Affected / at Risk (%)

# Events

Affected / at Risk (%)

# Events

Affected / at Risk (%)

# Events

Affected / at Risk (%)

# Events

Total

3/3 (100.00%)

4/4 (100.00%)

8/8 (100.00%)

7/7 (100.00%)

8/8 (100.00%)

6/6 (100.00%)

6/6 (100.00%)

4/5 (80.00%)

3/3 (100.00%)

6/6 (100.00%)

9/9 (100.00%)

53/53 (100.00%)

85/85 (100.00%)

41/41 (100.00%)

46/48 (95.83%)

18/18 (100.00%)

154/154 (100.00%)

66/66 (100.00%)

18/18 (100.00%)

18/18 (100.00%)

12/12 (100.00%)

Blood and lymphatic system disorders

Anaemia * 1

0/3 (0.00%)

0/4 (0.00%)

2/8 (25.00%)

1/7 (14.29%)

0/8 (0.00%)

1/6 (16.67%)

2/6 (33.33%)

1/5 (20.00%)

0/3 (0.00%)

1/6 (16.67%)

3/9 (33.33%)

8/53 (15.09%)

14/85 (16.47%)

8/41 (19.51%)

2/48 (4.17%)

2/18 (11.11%)

17/154 (11.04%)

15/66 (22.73%)

4/18 (22.22%)

4/18 (22.22%)

1/12 (8.33%)

Leukopenia * 1

0/3 (0.00%)

0/4 (0.00%)

0/8 (0.00%)

1/7 (14.29%)

0/8 (0.00%)

0/6 (0.00%)

0/6 (0.00%)

0/5 (0.00%)

0/3 (0.00%)

0/6 (0.00%)

0/9 (0.00%)

3/53 (5.66%)

1/85 (1.18%)

1/41 (2.44%)

3/48 (6.25%)

1/18 (5.56%)

14/154 (9.09%)

1/66 (1.52%)

0/18 (0.00%)

0/18 (0.00%)

0/12 (0.00%)

Neutropenia * 1

0/3 (0.00%)

0/4 (0.00%)

1/8 (12.50%)

0/7 (0.00%)

0/8 (0.00%)

0/6 (0.00%)

0/6 (0.00%)

0/5 (0.00%)

0/3 (0.00%)

1/6 (16.67%)

1/9 (11.11%)

9/53 (16.98%)

2/85 (2.35%)

2/41 (4.88%)

5/48 (10.42%)

2/18 (11.11%)

26/154 (16.88%)

5/66 (7.58%)

1/18 (5.56%)

0/18 (0.00%)

0/12 (0.00%)

Thrombocytopenia * 1

0/3 (0.00%)

0/4 (0.00%)

1/8 (12.50%)

0/7 (0.00%)

0/8 (0.00%)

0/6 (0.00%)

0/6 (0.00%)

0/5 (0.00%)

0/3 (0.00%)

0/6 (0.00%)

0/9 (0.00%)

4/53 (7.55%)

2/85 (2.35%)

1/41 (2.44%)

0/48 (0.00%)

1/18 (5.56%)

6/154 (3.90%)

3/66 (4.55%)

1/18 (5.56%)

0/18 (0.00%)

0/12 (0.00%)

Leukocytosis * 1

0/3 (0.00%)

0/4 (0.00%)

0/8 (0.00%)

0/7 (0.00%)

0/8 (0.00%)

0/6 (0.00%)

0/6 (0.00%)

0/5 (0.00%)

0/3 (0.00%)

0/6 (0.00%)

0/9 (0.00%)

1/53 (1.89%)

2/85 (2.35%)

0/41 (0.00%)

3/48 (6.25%)

0/18 (0.00%)

3/154 (1.95%)

1/66 (1.52%)

0/18 (0.00%)

1/18 (5.56%)

0/12 (0.00%)

Lymphopenia * 1

0/3 (0.00%)

0/4 (0.00%)

0/8 (0.00%)

0/7 (0.00%)

0/8 (0.00%)

0/6 (0.00%)

0/6 (0.00%)

0/5 (0.00%)

0/3 (0.00%)

0/6 (0.00%)

0/9 (0.00%)

0/53 (0.00%)

0/85 (0.00%)

2/41 (4.88%)

1/48 (2.08%)

1/18 (5.56%)

11/154 (7.14%)

7/66 (10.61%)

0/18 (0.00%)

0/18 (0.00%)

0/12 (0.00%)

Cardiac disorders

Bradycardia * 1

0/3 (0.00%)

0/4 (0.00%)

0/8 (0.00%)

0/7 (0.00%)

0/8 (0.00%)

0/6 (0.00%)

0/6 (0.00%)

0/5 (0.00%)

0/3 (0.00%)

1/6 (16.67%)

0/9 (0.00%)

7/53 (13.21%)

13/85 (15.29%)

2/41 (4.88%)

2/48 (4.17%)

1/18 (5.56%)

13/154 (8.44%)

2/66 (3.03%)

1/18 (5.56%)

0/18 (0.00%)

0/12 (0.00%)

Sinus bradycardia * 1

0/3 (0.00%)

0/4 (0.00%)

0/8 (0.00%)

0/7 (0.00%)

0/8 (0.00%)

0/6 (0.00%)

0/6 (0.00%)

0/5 (0.00%)

0/3 (0.00%)

1/6 (16.67%)

1/9 (11.11%)

5/53 (9.43%)

11/85 (12.94%)

4/41 (9.76%)

5/48 (10.42%)

0/18 (0.00%)

9/154 (5.84%)

3/66 (4.55%)

0/18 (0.00%)

0/18 (0.00%)

0/0

Syncope * 1

0/3 (0.00%)

0/4 (0.00%)

0/8 (0.00%)

0/7 (0.00%)

0/8 (0.00%)

0/6 (0.00%)

0/6 (0.00%)

0/5 (0.00%)

0/3 (0.00%)

0/6 (0.00%)

1/9 (11.11%)

3/53 (5.66%)

3/85 (3.53%)

1/41 (2.44%)

2/48 (4.17%)

0/18 (0.00%)

9/154 (5.84%)

2/66 (3.03%)

0/18 (0.00%)

0/18 (0.00%)

0/12 (0.00%)

Arrhythmia supraventricular * 1

0/3 (0.00%)

0/4 (0.00%)

0/8 (0.00%)

0/7 (0.00%)

0/8 (0.00%)

0/6 (0.00%)

0/6 (0.00%)

0/5 (0.00%)

0/3 (0.00%)

0/6 (0.00%)

1/9 (11.11%)

0/53 (0.00%)

1/85 (1.18%)

0/41 (0.00%)

0/48 (0.00%)

0/18 (0.00%)

0/154 (0.00%)

1/66 (1.52%)

0/18 (0.00%)

0/18 (0.00%)

0/12 (0.00%)

Atrial fibrillation * 1

0/3 (0.00%)

0/4 (0.00%)

0/8 (0.00%)

0/7 (0.00%)

0/8 (0.00%)

0/6 (0.00%)

0/6 (0.00%)

0/5 (0.00%)

0/3 (0.00%)

0/6 (0.00%)

0/9 (0.00%)

1/53 (1.89%)

2/85 (2.35%)

3/41 (7.32%)

2/48 (4.17%)

0/18 (0.00%)

5/154 (3.25%)

0/66 (0.00%)

0/18 (0.00%)

0/18 (0.00%)

0/12 (0.00%)

Atrioventricular block first degree * 1

0/3 (0.00%)

1/4 (25.00%)

0/8 (0.00%)

0/7 (0.00%)

0/8 (0.00%)

0/6 (0.00%)

0/6 (0.00%)

0/5 (0.00%)

0/3 (0.00%)

0/6 (0.00%)

0/9 (0.00%)

0/53 (0.00%)

0/85 (0.00%)

0/41 (0.00%)

0/48 (0.00%)

0/18 (0.00%)

0/154 (0.00%)

0/66 (0.00%)

0/18 (0.00%)

0/18 (0.00%)

0/12 (0.00%)

Cardiac arrest * 1

0/3 (0.00%)

0/4 (0.00%)

0/8 (0.00%)

0/7 (0.00%)

0/8 (0.00%)

0/6 (0.00%)

0/6 (0.00%)

0/5 (0.00%)

0/3 (0.00%)

0/6 (0.00%)

1/9 (11.11%)

0/53 (0.00%)

0/85 (0.00%)

0/41 (0.00%)

0/48 (0.00%)

0/18 (0.00%)

0/154 (0.00%)

0/66 (0.00%)

0/18 (0.00%)

0/18 (0.00%)

0/12 (0.00%)

Palpitations * 1

0/3 (0.00%)

0/4 (0.00%)

0/8 (0.00%)

0/7 (0.00%)

0/8 (0.00%)

0/6 (0.00%)

0/6 (0.00%)

0/5 (0.00%)

0/3 (0.00%)

0/6 (0.00%)

0/9 (0.00%)

0/53 (0.00%)

4/85 (4.71%)

0/41 (0.00%)

0/48 (0.00%)

1/18 (5.56%)

1/154 (0.65%)

1/66 (1.52%)

1/18 (5.56%)

0/18 (0.00%)

0/12 (0.00%)

Pericardial effusion * 1

0/3 (0.00%)

0/4 (0.00%)

0/8 (0.00%)

0/7 (0.00%)

0/8 (0.00%)

0/6 (0.00%)

0/6 (0.00%)

0/5 (0.00%)

0/3 (0.00%)

0/6 (0.00%)

0/9 (0.00%)

1/53 (1.89%)

3/85 (3.53%)

0/41 (0.00%)

0/48 (0.00%)

1/18 (5.56%)

2/154 (1.30%)

0/66 (0.00%)

0/18 (0.00%)

0/18 (0.00%)

0/12 (0.00%)

Supraventricular tachycardia * 1

0/3 (0.00%)

0/4 (0.00%)

0/8 (0.00%)

0/7 (0.00%)

0/8 (0.00%)

0/6 (0.00%)

0/6 (0.00%)

0/5 (0.00%)

0/3 (0.00%)

0/6 (0.00%)

1/9 (11.11%)

0/53 (0.00%)

0/85 (0.00%)

0/41 (0.00%)

0/48 (0.00%)

0/18 (0.00%)

0/154 (0.00%)

0/66 (0.00%)

0/18 (0.00%)

0/18 (0.00%)

0/12 (0.00%)

Tachycardia * 1

0/3 (0.00%)

0/4 (0.00%)

0/8 (0.00%)

0/7 (0.00%)

0/8 (0.00%)

0/6 (0.00%)

0/6 (0.00%)

0/5 (0.00%)

0/3 (0.00%)

1/6 (16.67%)

0/9 (0.00%)

0/53 (0.00%)

2/85 (2.35%)

0/41 (0.00%)

2/48 (4.17%)

0/18 (0.00%)

6/154 (3.90%)

3/66 (4.55%)

1/18 (5.56%)

0/18 (0.00%)

0/12 (0.00%)

Ear and labyrinth disorders

Tinnitus * 1

0/3 (0.00%)

0/4 (0.00%)

0/8 (0.00%)

0/7 (0.00%)

0/8 (0.00%)

0/6 (0.00%)

0/6 (0.00%)

0/5 (0.00%)

0/3 (0.00%)

0/6 (0.00%)

0/9 (0.00%)

5/53 (9.43%)

1/85 (1.18%)

0/41 (0.00%)

0/48 (0.00%)

1/18 (5.56%)

3/154 (1.95%)

1/66 (1.52%)

1/18 (5.56%)

0/18 (0.00%)

0/12 (0.00%)

Ear discomfort * 1

0/3 (0.00%)

0/4 (0.00%)

0/8 (0.00%)

0/7 (0.00%)

0/8 (0.00%)

0/6 (0.00%)

0/6 (0.00%)

0/5 (0.00%)

0/3 (0.00%)

0/6 (0.00%)

0/9 (0.00%)

0/53 (0.00%)

1/85 (1.18%)

0/41 (0.00%)

0/48 (0.00%)

0/18 (0.00%)

1/154 (0.65%)

0/66 (0.00%)

1/18 (5.56%)

0/18 (0.00%)

0/12 (0.00%)

Excessive cerumen production * 1

0/3 (0.00%)

0/4 (0.00%)

0/8 (0.00%)

0/7 (0.00%)

0/8 (0.00%)

0/6 (0.00%)

0/6 (0.00%)

0/5 (0.00%)

0/3 (0.00%)

1/6 (16.67%)

0/9 (0.00%)

0/53 (0.00%)

0/85 (0.00%)

0/41 (0.00%)

0/48 (0.00%)

0/18 (0.00%)

0/154 (0.00%)

0/66 (0.00%)

0/18 (0.00%)

0/18 (0.00%)

0/12 (0.00%)

Hypoacusis * 1

0/3 (0.00%)

0/4 (0.00%)

1/8 (12.50%)

0/7 (0.00%)

0/8 (0.00%)

0/6 (0.00%)

0/6 (0.00%)

0/5 (0.00%)

0/3 (0.00%)

0/6 (0.00%)

0/9 (0.00%)

1/53 (1.89%)

2/85 (2.35%)

0/41 (0.00%)

0/48 (0.00%)

0/18 (0.00%)

1/154 (0.65%)

0/66 (0.00%)

0/18 (0.00%)

0/18 (0.00%)

0/12 (0.00%)

Eye disorders

Cataract * 1

0/3 (0.00%)

0/4 (0.00%)

0/8 (0.00%)

0/7 (0.00%)

0/8 (0.00%)

0/6 (0.00%)

0/6 (0.00%)

0/5 (0.00%)

0/3 (0.00%)

0/6 (0.00%)

0/9 (0.00%)

5/53 (9.43%)

1/85 (1.18%)

0/41 (0.00%)

1/48 (2.08%)

0/18 (0.00%)

4/154 (2.60%)

0/66 (0.00%)

0/18 (0.00%)

0/18 (0.00%)

0/0

Vision blurred * 1

0/3 (0.00%)

0/4 (0.00%)

0/8 (0.00%)

0/7 (0.00%)

0/8 (0.00%)

0/6 (0.00%)

0/6 (0.00%)

1/5 (20.00%)

0/3 (0.00%)

0/6 (0.00%)

0/9 (0.00%)

7/53 (13.21%)

8/85 (9.41%)

5/41 (12.20%)

3/48 (6.25%)

0/18 (0.00%)

8/154 (5.19%)

3/66 (4.55%)

1/18 (5.56%)

2/18 (11.11%)

1/12 (8.33%)

Visual impairment * 1

0/3 (0.00%)

0/4 (0.00%)

0/8 (0.00%)

1/7 (14.29%)

0/8 (0.00%)

0/6 (0.00%)

1/6 (16.67%)

2/5 (40.00%)

0/3 (0.00%)

4/6 (66.67%)

3/9 (33.33%)

43/53 (81.13%)

11/85 (12.94%)

6/41 (14.63%)

26/48 (54.17%)

9/18 (50.00%)

92/154 (59.74%)

22/66 (33.33%)

3/18 (16.67%)

10/18 (55.56%)

1/12 (8.33%)

Vitreous detachment * 1

0/3 (0.00%)

0/4 (0.00%)

0/8 (0.00%)

0/7 (0.00%)

0/8 (0.00%)

0/6 (0.00%)

0/6 (0.00%)

0/5 (0.00%)

0/3 (0.00%)

0/6 (0.00%)

0/9 (0.00%)

3/53 (5.66%)

0/85 (0.00%)

0/41 (0.00%)

0/48 (0.00%)

0/18 (0.00%)

0/154 (0.00%)

0/66 (0.00%)

0/18 (0.00%)

0/18 (0.00%)

0/12 (0.00%)

Conjunctival haemorrhage * 1

0/3 (0.00%)

0/4 (0.00%)

0/8 (0.00%)

0/7 (0.00%)

0/8 (0.00%)

0/6 (0.00%)

0/6 (0.00%)

0/5 (0.00%)

0/3 (0.00%)

0/6 (0.00%)

0/9 (0.00%)

1/53 (1.89%)

1/85 (1.18%)

0/41 (0.00%)

0/48 (0.00%)

0/18 (0.00%)

1/154 (0.65%)

0/66 (0.00%)

0/18 (0.00%)

1/18 (5.56%)

0/12 (0.00%)

Diplopia * 1

0/3 (0.00%)

0/4 (0.00%)

0/8 (0.00%)

0/7 (0.00%)

0/8 (0.00%)

0/6 (0.00%)

0/6 (0.00%)

0/5 (0.00%)

0/3 (0.00%)

0/6 (0.00%)

0/9 (0.00%)

0/53 (0.00%)

2/85 (2.35%)

2/41 (4.88%)

0/48 (0.00%)

1/18 (5.56%)

3/154 (1.95%)

3/66 (4.55%)

1/18 (5.56%)

0/18 (0.00%)

0/12 (0.00%)

Dry eye * 1

0/3 (0.00%)

0/4 (0.00%)

0/8 (0.00%)

0/7 (0.00%)

0/8 (0.00%)

0/6 (0.00%)

0/6 (0.00%)

0/5 (0.00%)

0/3 (0.00%)

0/6 (0.00%)

0/9 (0.00%)

0/53 (0.00%)

1/85 (1.18%)

0/41 (0.00%)

2/48 (4.17%)

1/18 (5.56%)

3/154 (1.95%)

1/66 (1.52%)

1/18 (5.56%)

0/18 (0.00%)

0/12 (0.00%)

Eye pain * 1

0/3 (0.00%)

0/4 (0.00%)

0/8 (0.00%)

0/7 (0.00%)

0/8 (0.00%)

0/6 (0.00%)

0/6 (0.00%)

0/5 (0.00%)

0/3 (0.00%)

0/6 (0.00%)

0/9 (0.00%)

0/53 (0.00%)

2/85 (2.35%)

0/41 (0.00%)

1/48 (2.08%)

1/18 (5.56%)

2/154 (1.30%)

0/66 (0.00%)

0/18 (0.00%)

0/18 (0.00%)

0/12 (0.00%)

Eyelid oedema * 1

0/3 (0.00%)

0/4 (0.00%)

0/8 (0.00%)

0/7 (0.00%)

0/8 (0.00%)

0/6 (0.00%)

0/6 (0.00%)

0/5 (0.00%)

0/3 (0.00%)

0/6 (0.00%)

0/9 (0.00%)

0/53 (0.00%)

0/85 (0.00%)

0/41 (0.00%)

0/48 (0.00%)

0/18 (0.00%)

0/154 (0.00%)

0/66 (0.00%)

2/18 (11.11%)

0/18 (0.00%)

0/12 (0.00%)

Glaucoma * 1

0/3 (0.00%)

0/4 (0.00%)

0/8 (0.00%)

0/7 (0.00%)

0/8 (0.00%)

0/6 (0.00%)

0/6 (0.00%)

0/5 (0.00%)

0/3 (0.00%)

0/6 (0.00%)

0/9 (0.00%)

0/53 (0.00%)

1/85 (1.18%)

0/41 (0.00%)

0/48 (0.00%)

0/18 (0.00%)

1/154 (0.65%)

0/66 (0.00%)

0/18 (0.00%)

1/18 (5.56%)

0/12 (0.00%)

Lacrimation increased * 1

0/3 (0.00%)

0/4 (0.00%)

0/8 (0.00%)

0/7 (0.00%)

0/8 (0.00%)

0/6 (0.00%)

0/6 (0.00%)

0/5 (0.00%)

0/3 (0.00%)

0/6 (0.00%)

0/9 (0.00%)

0/53 (0.00%)

3/85 (3.53%)

1/41 (2.44%)

1/48 (2.08%)

0/18 (0.00%)

0/154 (0.00%)

0/66 (0.00%)

1/18 (5.56%)

0/18 (0.00%)

0/12 (0.00%)

Periorbital oedema * 1

0/3 (0.00%)

0/4 (0.00%)

0/8 (0.00%)

0/7 (0.00%)

0/8 (0.00%)

0/6 (0.00%)

0/6 (0.00%)

0/5 (0.00%)

0/3 (0.00%)

0/6 (0.00%)

0/9 (0.00%)

0/53 (0.00%)

1/85 (1.18%)

1/41 (2.44%)

0/48 (0.00%)

0/18 (0.00%)

10/154 (6.49%)

1/66 (1.52%)

2/18 (11.11%)

0/18 (0.00%)

0/12 (0.00%)

Photophobia * 1

0/3 (0.00%)

0/4 (0.00%)

0/8 (0.00%)

0/7 (0.00%)

1/8 (12.50%)

0/6 (0.00%)

0/6 (0.00%)

0/5 (0.00%)

0/3 (0.00%)

0/6 (0.00%)

0/9 (0.00%)

1/53 (1.89%)

3/85 (3.53%)

1/41 (2.44%)

1/48 (2.08%)

0/18 (0.00%)

2/154 (1.30%)

0/66 (0.00%)

0/18 (0.00%)

0/18 (0.00%)

0/12 (0.00%)

Photopsia * 1

0/3 (0.00%)

0/4 (0.00%)

0/8 (0.00%)

0/7 (0.00%)

0/8 (0.00%)

0/6 (0.00%)

0/6 (0.00%)

1/5 (20.00%)

0/3 (0.00%)

0/6 (0.00%)

1/9 (11.11%)

2/53 (3.77%)

8/85 (9.41%)

1/41 (2.44%)

1/48 (2.08%)

1/18 (5.56%)

13/154 (8.44%)

2/66 (3.03%)

2/18 (11.11%)

2/18 (11.11%)

1/12 (8.33%)

Retinal degeneration * 1

0/3 (0.00%)

0/4 (0.00%)

0/8 (0.00%)

0/7 (0.00%)

0/8 (0.00%)

0/6 (0.00%)

0/6 (0.00%)

0/5 (0.00%)

0/3 (0.00%)

1/6 (16.67%)

0/9 (0.00%)

0/53 (0.00%)

0/85 (0.00%)

0/41 (0.00%)

0/48 (0.00%)

0/18 (0.00%)

1/154 (0.65%)

0/66 (0.00%)

0/18 (0.00%)

0/18 (0.00%)

0/12 (0.00%)

Retinal drusen * 1

0/3 (0.00%)

0/4 (0.00%)

0/8 (0.00%)

0/7 (0.00%)

0/8 (0.00%)

0/6 (0.00%)

0/6 (0.00%)

0/5 (0.00%)

0/3 (0.00%)

0/6 (0.00%)

0/9 (0.00%)

0/53 (0.00%)

0/85 (0.00%)

0/41 (0.00%)

0/48 (0.00%)

0/18 (0.00%)

1/154 (0.65%)

0/66 (0.00%)

0/18 (0.00%)

1/18 (5.56%)

0/12 (0.00%)

Swelling of eyelid * 1

0/3 (0.00%)

0/4 (0.00%)

0/8 (0.00%)

0/7 (0.00%)

0/8 (0.00%)

0/6 (0.00%)

0/6 (0.00%)

0/5 (0.00%)

0/3 (0.00%)

0/6 (0.00%)

0/9 (0.00%)

0/53 (0.00%)

0/85 (0.00%)

0/41 (0.00%)

0/48 (0.00%)

0/18 (0.00%)

1/154 (0.65%)

0/66 (0.00%)

1/18 (5.56%)

0/18 (0.00%)

0/12 (0.00%)

Visual acuity reduced * 1

0/3 (0.00%)

0/4 (0.00%)

1/8 (12.50%)

0/7 (0.00%)

0/8 (0.00%)

0/6 (0.00%)

0/6 (0.00%)

0/5 (0.00%)

0/3 (0.00%)

0/6 (0.00%)

0/9 (0.00%)

0/53 (0.00%)

0/85 (0.00%)

0/41 (0.00%)

1/48 (2.08%)

0/18 (0.00%)

0/154 (0.00%)

0/66 (0.00%)

0/18 (0.00%)

0/18 (0.00%)

0/12 (0.00%)

Visual brightness * 1

0/3 (0.00%)

0/4 (0.00%)

0/8 (0.00%)

0/7 (0.00%)

0/8 (0.00%)

0/6 (0.00%)

0/6 (0.00%)

0/5 (0.00%)

0/3 (0.00%)

0/6 (0.00%)

0/9 (0.00%)

0/53 (0.00%)

0/85 (0.00%)

0/41 (0.00%)

0/48 (0.00%)

1/18 (5.56%)

1/154 (0.65%)

0/66 (0.00%)

0/18 (0.00%)

0/18 (0.00%)

0/12 (0.00%)

Vitreous degeneration * 1

0/3 (0.00%)

0/4 (0.00%)

0/8 (0.00%)

0/7 (0.00%)

0/8 (0.00%)

0/6 (0.00%)

0/6 (0.00%)

0/5 (0.00%)

0/3 (0.00%)

1/6 (16.67%)

0/9 (0.00%)

1/53 (1.89%)

0/85 (0.00%)

0/41 (0.00%)

0/48 (0.00%)

0/18 (0.00%)

0/154 (0.00%)

0/66 (0.00%)

0/18 (0.00%)

0/18 (0.00%)

0/12 (0.00%)

Vitreous floaters * 1

0/3 (0.00%)

0/4 (0.00%)

0/8 (0.00%)

0/7 (0.00%)

0/8 (0.00%)

1/6 (16.67%)

1/6 (16.67%)

0/5 (0.00%)

0/3 (0.00%)

0/6 (0.00%)

0/9 (0.00%)

1/53 (1.89%)

19/85 (22.35%)

3/41 (7.32%)

0/48 (0.00%)

0/18 (0.00%)

4/154 (2.60%)

4/66 (6.06%)

3/18 (16.67%)

1/18 (5.56%)

0/12 (0.00%)

Eyelid ptosis * 1

0/3 (0.00%)

0/4 (0.00%)

0/8 (0.00%)

0/7 (0.00%)

0/8 (0.00%)

0/6 (0.00%)

0/6 (0.00%)

0/5 (0.00%)

0/3 (0.00%)

0/6 (0.00%)

0/9 (0.00%)

0/53 (0.00%)

0/85 (0.00%)

0/41 (0.00%)

0/48 (0.00%)

0/18 (0.00%)

0/154 (0.00%)

0/66 (0.00%)

0/18 (0.00%)

0/18 (0.00%)

1/12 (8.33%)

Gastrointestinal disorders

Abdominal discomfort * 1

0/3 (0.00%)

0/4 (0.00%)

0/8 (0.00%)

0/7 (0.00%)

0/8 (0.00%)

0/6 (0.00%)

0/6 (0.00%)

0/5 (0.00%)

0/3 (0.00%)

1/6 (16.67%)

0/9 (0.00%)

3/53 (5.66%)

3/85 (3.53%)

0/41 (0.00%)

1/48 (2.08%)

0/18 (0.00%)

12/154 (7.79%)

1/66 (1.52%)

1/18 (5.56%)

0/18 (0.00%)

0/12 (0.00%)

Abdominal distension * 1

0/3 (0.00%)

0/4 (0.00%)

0/8 (0.00%)

1/7 (14.29%)

1/8 (12.50%)

1/6 (16.67%)

1/6 (16.67%)

0/5 (0.00%)

0/3 (0.00%)

2/6 (33.33%)

0/9 (0.00%)

3/53 (5.66%)

7/85 (8.24%)

0/41 (0.00%)

1/48 (2.08%)

1/18 (5.56%)

10/154 (6.49%)

3/66 (4.55%)

3/18 (16.67%)

0/18 (0.00%)

0/12 (0.00%)

Abdominal pain * 1

0/3 (0.00%)

0/4 (0.00%)

1/8 (12.50%)

2/7 (28.57%)

0/8 (0.00%)

0/6 (0.00%)

0/6 (0.00%)

1/5 (20.00%)

1/3 (33.33%)

1/6 (16.67%)

0/9 (0.00%)

8/53 (15.09%)

11/85 (12.94%)

7/41 (17.07%)

2/48 (4.17%)

2/18 (11.11%)

8/154 (5.19%)

7/66 (10.61%)

2/18 (11.11%)

1/18 (5.56%)

2/12 (16.67%)

Abdominal pain upper * 1

0/3 (0.00%)

0/4 (0.00%)

2/8 (25.00%)

0/7 (0.00%)

0/8 (0.00%)

0/6 (0.00%)

0/6 (0.00%)

0/5 (0.00%)

1/3 (33.33%)

0/6 (0.00%)

0/9 (0.00%)

3/53 (5.66%)

4/85 (4.71%)

3/41 (7.32%)

4/48 (8.33%)

1/18 (5.56%)

19/154 (12.34%)

2/66 (3.03%)

0/18 (0.00%)

1/18 (5.56%)

0/12 (0.00%)

Constipation * 1

0/3 (0.00%)

0/4 (0.00%)

1/8 (12.50%)

2/7 (28.57%)

3/8 (37.50%)

2/6 (33.33%)

3/6 (50.00%)

3/5 (60.00%)

2/3 (66.67%)

4/6 (66.67%)

4/9 (44.44%)

24/53 (45.28%)

45/85 (52.94%)

10/41 (24.39%)

21/48 (43.75%)

11/18 (61.11%)

68/154 (44.16%)

15/66 (22.73%)

11/18 (61.11%)

7/18 (38.89%)

1/12 (8.33%)

Diarrhoea * 1

2/3 (66.67%)

0/4 (0.00%)

2/8 (25.00%)

1/7 (14.29%)

1/8 (12.50%)

1/6 (16.67%)

1/6 (16.67%)

1/5 (20.00%)

0/3 (0.00%)

3/6 (50.00%)

2/9 (22.22%)

25/53 (47.17%)

50/85 (58.82%)

17/41 (41.46%)

17/48 (35.42%)

5/18 (27.78%)

93/154 (60.39%)

32/66 (48.48%)

7/18 (38.89%)

7/18 (38.89%)

4/12 (33.33%)

Dyspepsia * 1

0/3 (0.00%)

1/4 (25.00%)

2/8 (25.00%)

1/7 (14.29%)

0/8 (0.00%)

3/6 (50.00%)

0/6 (0.00%)

0/5 (0.00%)

0/3 (0.00%)

1/6 (16.67%)

0/9 (0.00%)

6/53 (11.32%)

5/85 (5.88%)

2/41 (4.88%)

3/48 (6.25%)

1/18 (5.56%)

19/154 (12.34%)

4/66 (6.06%)

4/18 (22.22%)

0/18 (0.00%)

3/12 (25.00%)

Dysphagia * 1

0/3 (0.00%)

1/4 (25.00%)

0/8 (0.00%)

1/7 (14.29%)

0/8 (0.00%)

0/6 (0.00%)

1/6 (16.67%)

0/5 (0.00%)

0/3 (0.00%)

0/6 (0.00%)

0/9 (0.00%)

3/53 (5.66%)

10/85 (11.76%)

5/41 (12.20%)

1/48 (2.08%)

0/18 (0.00%)

12/154 (7.79%)

1/66 (1.52%)

2/18 (11.11%)

1/18 (5.56%)

0/12 (0.00%)

Flatulence * 1

0/3 (0.00%)

0/4 (0.00%)

0/8 (0.00%)

0/7 (0.00%)

0/8 (0.00%)

0/6 (0.00%)

0/6 (0.00%)

0/5 (0.00%)

0/3 (0.00%)

0/6 (0.00%)

0/9 (0.00%)

4/53 (7.55%)

5/85 (5.88%)

1/41 (2.44%)

0/48 (0.00%)

1/18 (5.56%)

2/154 (1.30%)

1/66 (1.52%)

1/18 (5.56%)

1/18 (5.56%)

0/12 (0.00%)

Gastrooesophageal reflux disease * 1

0/3 (0.00%)

0/4 (0.00%)

0/8 (0.00%)

0/7 (0.00%)

0/8 (0.00%)

0/6 (0.00%)

0/6 (0.00%)

1/5 (20.00%)

0/3 (0.00%)

0/6 (0.00%)

2/9 (22.22%)

3/53 (5.66%)

7/85 (8.24%)

1/41 (2.44%)

3/48 (6.25%)

0/18 (0.00%)

17/154 (11.04%)

5/66 (7.58%)

2/18 (11.11%)

0/18 (0.00%)

0/12 (0.00%)

Nausea * 1

1/3 (33.33%)

3/4 (75.00%)

6/8 (75.00%)

3/7 (42.86%)

3/8 (37.50%)

3/6 (50.00%)

2/6 (33.33%)

1/5 (20.00%)

3/3 (100.00%)

3/6 (50.00%)

5/9 (55.56%)

33/53 (62.26%)

49/85 (57.65%)

14/41 (34.15%)

20/48 (41.67%)

10/18 (55.56%)

97/154 (62.99%)

41/66 (62.12%)

10/18 (55.56%)

12/18 (66.67%)

7/12 (58.33%)

Vomiting * 1

2/3 (66.67%)

2/4 (50.00%)

5/8 (62.50%)

4/7 (57.14%)

4/8 (50.00%)

1/6 (16.67%)

3/6 (50.00%)

2/5 (40.00%)

1/3 (33.33%)

2/6 (33.33%)

5/9 (55.56%)

28/53 (52.83%)

35/85 (41.18%)

15/41 (36.59%)

26/48 (54.17%)

9/18 (50.00%)

81/154 (52.60%)

34/66 (51.52%)

8/18 (44.44%)

10/18 (55.56%)

8/12 (66.67%)

Abdominal mass * 1

0/3 (0.00%)

0/4 (0.00%)

0/8 (0.00%)

0/7 (0.00%)

0/8 (0.00%)

0/6 (0.00%)

0/6 (0.00%)

0/5 (0.00%)

0/3 (0.00%)

0/6 (0.00%)

0/9 (0.00%)

0/53 (0.00%)

0/85 (0.00%)

0/41 (0.00%)

0/48 (0.00%)

0/18 (0.00%)

0/154 (0.00%)

0/66 (0.00%)

1/18 (5.56%)

0/18 (0.00%)

0/12 (0.00%)

Abdominal pain lower * 1

0/3 (0.00%)

0/4 (0.00%)

0/8 (0.00%)

0/7 (0.00%)

0/8 (0.00%)

0/6 (0.00%)

1/6 (16.67%)

0/5 (0.00%)

0/3 (0.00%)

0/6 (0.00%)

0/9 (0.00%)

0/53 (0.00%)

0/85 (0.00%)

0/41 (0.00%)

0/48 (0.00%)

0/18 (0.00%)

2/154 (1.30%)

2/66 (3.03%)

1/18 (5.56%)

0/18 (0.00%)

0/12 (0.00%)

Ascites * 1

0/3 (0.00%)

0/4 (0.00%)

0/8 (0.00%)

0/7 (0.00%)

0/8 (0.00%)

1/6 (16.67%)

0/6 (0.00%)

0/5 (0.00%)

0/3 (0.00%)

1/6 (16.67%)

0/9 (0.00%)

0/53 (0.00%)

2/85 (2.35%)

1/41 (2.44%)

0/48 (0.00%)

0/18 (0.00%)

1/154 (0.65%)

3/66 (4.55%)

5/18 (27.78%)

2/18 (11.11%)

0/12 (0.00%)

Diarrhoea haemorrhagic * 1

0/3 (0.00%)

0/4 (0.00%)

0/8 (0.00%)

0/7 (0.00%)

1/8 (12.50%)

0/6 (0.00%)

0/6 (0.00%)

0/5 (0.00%)

0/3 (0.00%)

0/6 (0.00%)

0/9 (0.00%)

0/53 (0.00%)

0/85 (0.00%)

0/41 (0.00%)

0/48 (0.00%)

0/18 (0.00%)

0/154 (0.00%)

0/66 (0.00%)

0/18 (0.00%)

0/18 (0.00%)

0/12 (0.00%)

Dry mouth * 1

0/3 (0.00%)

0/4 (0.00%)

0/8 (0.00%)

0/7 (0.00%)

0/8 (0.00%)

0/6 (0.00%)

1/6 (16.67%)

0/5 (0.00%)

0/3 (0.00%)

1/6 (16.67%)

0/9 (0.00%)

1/53 (1.89%)

3/85 (3.53%)

3/41 (7.32%)

2/48 (4.17%)

0/18 (0.00%)

4/154 (2.60%)

0/66 (0.00%)

3/18 (16.67%)

2/18 (11.11%)

0/12 (0.00%)

Duodenogastric reflux * 1

0/3 (0.00%)

0/4 (0.00%)

0/8 (0.00%)

0/7 (0.00%)

0/8 (0.00%)

1/6 (16.67%)

0/6 (0.00%)

0/5 (0.00%)

0/3 (0.00%)

0/6 (0.00%)

0/9 (0.00%)

0/53 (0.00%)

0/85 (0.00%)

0/41 (0.00%)

0/48 (0.00%)

0/18 (0.00%)

0/154 (0.00%)

0/66 (0.00%)

0/18 (0.00%)

0/18 (0.00%)

0/12 (0.00%)

Eructation * 1

0/3 (0.00%)

0/4 (0.00%)

0/8 (0.00%)

0/7 (0.00%)

0/8 (0.00%)

0/6 (0.00%)

0/6 (0.00%)

0/5 (0.00%)

0/3 (0.00%)

2/6 (33.33%)

0/9 (0.00%)

1/53 (1.89%)

1/85 (1.18%)

1/41 (2.44%)

1/48 (2.08%)

0/18 (0.00%)

0/154 (0.00%)

2/66 (3.03%)

0/18 (0.00%)

0/18 (0.00%)

0/12 (0.00%)

Gastritis * 1

0/3 (0.00%)

0/4 (0.00%)

0/8 (0.00%)

0/7 (0.00%)

0/8 (0.00%)

0/6 (0.00%)

0/6 (0.00%)

0/5 (0.00%)

0/3 (0.00%)

0/6 (0.00%)

0/9 (0.00%)

0/53 (0.00%)

2/85 (2.35%)

1/41 (2.44%)

0/48 (0.00%)

0/18 (0.00%)

1/154 (0.65%)

0/66 (0.00%)

1/18 (5.56%)

0/18 (0.00%)

0/12 (0.00%)

Gastrointestinal sounds abnormal * 1

0/3 (0.00%)

0/4 (0.00%)

0/8 (0.00%)

0/7 (0.00%)

0/8 (0.00%)

0/6 (0.00%)

0/6 (0.00%)

0/5 (0.00%)

0/3 (0.00%)

0/6 (0.00%)

0/9 (0.00%)

0/53 (0.00%)

0/85 (0.00%)

0/41 (0.00%)

0/48 (0.00%)

0/18 (0.00%)

0/154 (0.00%)

0/66 (0.00%)

0/18 (0.00%)

1/18 (5.56%)

0/12 (0.00%)

Gingival discomfort * 1

0/3 (0.00%)

0/4 (0.00%)

0/8 (0.00%)

0/7 (0.00%)

0/8 (0.00%)

0/6 (0.00%)

0/6 (0.00%)

0/5 (0.00%)

0/3 (0.00%)

0/6 (0.00%)

0/9 (0.00%)

0/53 (0.00%)

0/85 (0.00%)

0/41 (0.00%)

0/48 (0.00%)

0/18 (0.00%)

0/154 (0.00%)

0/66 (0.00%)

0/18 (0.00%)

1/18 (5.56%)

0/12 (0.00%)

Haemorrhoids * 1

0/3 (0.00%)

0/4 (0.00%)

0/8 (0.00%)

0/7 (0.00%)

0/8 (0.00%)

0/6 (0.00%)

0/6 (0.00%)

0/5 (0.00%)

0/3 (0.00%)

1/6 (16.67%)

0/9 (0.00%)

0/53 (0.00%)

1/85 (1.18%)

0/41 (0.00%)

0/48 (0.00%)

0/18 (0.00%)

2/154 (1.30%)

0/66 (0.00%)

0/18 (0.00%)

0/18 (0.00%)

0/12 (0.00%)

Intestinal obstruction * 1

0/3 (0.00%)

0/4 (0.00%)

1/8 (12.50%)

0/7 (0.00%)

0/8 (0.00%)

0/6 (0.00%)

0/6 (0.00%)

0/5 (0.00%)

0/3 (0.00%)

0/6 (0.00%)

0/9 (0.00%)

0/53 (0.00%)

0/85 (0.00%)

0/41 (0.00%)

0/48 (0.00%)

0/18 (0.00%)

0/154 (0.00%)

0/66 (0.00%)

0/18 (0.00%)

0/18 (0.00%)

0/12 (0.00%)

Lip oedema * 1

0/3 (0.00%)

0/4 (0.00%)

0/8 (0.00%)

0/7 (0.00%)

0/8 (0.00%)

0/6 (0.00%)

0/6 (0.00%)

0/5 (0.00%)

0/3 (0.00%)

0/6 (0.00%)

1/9 (11.11%)

0/53 (0.00%)

0/85 (0.00%)

0/41 (0.00%)

0/48 (0.00%)

0/18 (0.00%)

0/154 (0.00%)

0/66 (0.00%)

0/18 (0.00%)

0/18 (0.00%)

0/12 (0.00%)

Oral blood blister * 1

0/3 (0.00%)

0/4 (0.00%)

0/8 (0.00%)

0/7 (0.00%)

0/8 (0.00%)

0/6 (0.00%)

0/6 (0.00%)

0/5 (0.00%)

0/3 (0.00%)

0/6 (0.00%)

0/9 (0.00%)

0/53 (0.00%)

0/85 (0.00%)

0/41 (0.00%)

0/48 (0.00%)

0/18 (0.00%)

0/154 (0.00%)

0/66 (0.00%)

1/18 (5.56%)

0/18 (0.00%)

0/12 (0.00%)

Oral disorder * 1

0/3 (0.00%)

0/4 (0.00%)

0/8 (0.00%)

0/7 (0.00%)

0/8 (0.00%)

0/6 (0.00%)

0/6 (0.00%)

0/5 (0.00%)

0/3 (0.00%)

0/6 (0.00%)

0/9 (0.00%)

1/53 (1.89%)

0/85 (0.00%)

0/41 (0.00%)

0/48 (0.00%)

0/18 (0.00%)

0/154 (0.00%)

0/66 (0.00%)

1/18 (5.56%)

0/18 (0.00%)

0/12 (0.00%)

Pancreatitis * 1

0/3 (0.00%)

0/4 (0.00%)

0/8 (0.00%)

0/7 (0.00%)

0/8 (0.00%)

0/6 (0.00%)

0/6 (0.00%)

0/5 (0.00%)

0/3 (0.00%)

0/6 (0.00%)

0/9 (0.00%)

0/53 (0.00%)

0/85 (0.00%)

0/41 (0.00%)

0/48 (0.00%)

0/18 (0.00%)

0/154 (0.00%)

0/66 (0.00%)

0/18 (0.00%)

1/18 (5.56%)

1/12 (8.33%)

Paraesthesia oral * 1

0/3 (0.00%)

0/4 (0.00%)

0/8 (0.00%)

0/7 (0.00%)

0/8 (0.00%)

0/6 (0.00%)

0/6 (0.00%)

0/5 (0.00%)

0/3 (0.00%)

0/6 (0.00%)

0/9 (0.00%)

0/53 (0.00%)

0/85 (0.00%)

0/41 (0.00%)

0/48 (0.00%)

0/18 (0.00%)

0/154 (0.00%)

0/66 (0.00%)

1/18 (5.56%)

0/18 (0.00%)

0/12 (0.00%)

Rectal haemorrhage * 1

0/3 (0.00%)

0/4 (0.00%)

0/8 (0.00%)

0/7 (0.00%)

0/8 (0.00%)

0/6 (0.00%)

0/6 (0.00%)

0/5 (0.00%)

0/3 (0.00%)

0/6 (0.00%)

0/9 (0.00%)

1/53 (1.89%)

3/85 (3.53%)

0/41 (0.00%)

0/48 (0.00%)

0/18 (0.00%)

2/154 (1.30%)

1/66 (1.52%)

1/18 (5.56%)

0/18 (0.00%)

0/12 (0.00%)

Retching * 1

0/3 (0.00%)

0/4 (0.00%)

0/8 (0.00%)

0/7 (0.00%)

0/8 (0.00%)

1/6 (16.67%)

0/6 (0.00%)

0/5 (0.00%)

0/3 (0.00%)

0/6 (0.00%)

1/9 (11.11%)

0/53 (0.00%)

1/85 (1.18%)

1/41 (2.44%)

0/48 (0.00%)

0/18 (0.00%)

1/154 (0.65%)

1/66 (1.52%)

0/18 (0.00%)

2/18 (11.11%)

0/12 (0.00%)

Salivary gland disorder * 1

0/3 (0.00%)

0/4 (0.00%)

0/8 (0.00%)

1/7 (14.29%)

0/8 (0.00%)

0/6 (0.00%)

0/6 (0.00%)

0/5 (0.00%)

0/3 (0.00%)

0/6 (0.00%)

0/9 (0.00%)

0/53 (0.00%)

0/85 (0.00%)

0/41 (0.00%)

0/48 (0.00%)

0/18 (0.00%)

0/154 (0.00%)

0/66 (0.00%)

0/18 (0.00%)

0/18 (0.00%)

0/12 (0.00%)

Stomatitis * 1

0/3 (0.00%)

0/4 (0.00%)

0/8 (0.00%)

0/7 (0.00%)

0/8 (0.00%)

1/6 (16.67%)

0/6 (0.00%)

0/5 (0.00%)

0/3 (0.00%)

0/6 (0.00%)

0/9 (0.00%)

1/53 (1.89%)

2/85 (2.35%)

1/41 (2.44%)

1/48 (2.08%)

0/18 (0.00%)

2/154 (1.30%)

2/66 (3.03%)

0/18 (0.00%)

0/18 (0.00%)

0/12 (0.00%)

Swollen tongue * 1

0/3 (0.00%)

0/4 (0.00%)

0/8 (0.00%)

0/7 (0.00%)

0/8 (0.00%)

0/6 (0.00%)

0/6 (0.00%)

0/5 (0.00%)

0/3 (0.00%)

0/6 (0.00%)

0/9 (0.00%)

0/53 (0.00%)

0/85 (0.00%)

0/41 (0.00%)

0/48 (0.00%)

0/18 (0.00%)

0/154 (0.00%)

0/66 (0.00%)

1/18 (5.56%)

0/18 (0.00%)

0/12 (0.00%)

Tongue disorder * 1

0/3 (0.00%)

0/4 (0.00%)

0/8 (0.00%)

0/7 (0.00%)

0/8 (0.00%)

0/6 (0.00%)

0/6 (0.00%)

0/5 (0.00%)

0/3 (0.00%)

0/6 (0.00%)

0/9 (0.00%)

0/53 (0.00%)

0/85 (0.00%)

0/41 (0.00%)

0/48 (0.00%)

0/18 (0.00%)

1/154 (0.65%)

0/66 (0.00%)

1/18 (5.56%)

0/18 (0.00%)

0/12 (0.00%)

Tongue oedema * 1

0/3 (0.00%)

0/4 (0.00%)

0/8 (0.00%)

0/7 (0.00%)

0/8 (0.00%)

0/6 (0.00%)

0/6 (0.00%)

0/5 (0.00%)

0/3 (0.00%)

0/6 (0.00%)

1/9 (11.11%)

0/53 (0.00%)

0/85 (0.00%)

0/41 (0.00%)

0/48 (0.00%)

0/18 (0.00%)

0/154 (0.00%)

0/66 (0.00%)

0/18 (0.00%)

0/18 (0.00%)

0/12 (0.00%)

Umbilical hernia * 1

0/3 (0.00%)

0/4 (0.00%)

0/8 (0.00%)

0/7 (0.00%)

0/8 (0.00%)

0/6 (0.00%)

0/6 (0.00%)

0/5 (0.00%)

0/3 (0.00%)

0/6 (0.00%)

0/9 (0.00%)

0/53 (0.00%)

0/85 (0.00%)

0/41 (0.00%)

0/48 (0.00%)

1/18 (5.56%)

0/154 (0.00%)

0/66 (0.00%)

0/18 (0.00%)

0/18 (0.00%)

0/12 (0.00%)

Epigastric discomfort * 1

0/3 (0.00%)

0/4 (0.00%)

0/8 (0.00%)

0/7 (0.00%)

0/8 (0.00%)

0/6 (0.00%)

0/6 (0.00%)

0/5 (0.00%)

0/3 (0.00%)

0/6 (0.00%)

0/9 (0.00%)

0/53 (0.00%)

1/85 (1.18%)

0/41 (0.00%)

0/48 (0.00%)

0/18 (0.00%)

0/154 (0.00%)

0/66 (0.00%)

0/18 (0.00%)

0/18 (0.00%)

1/12 (8.33%)

General disorders

Asthenia * 1

0/3 (0.00%)

0/4 (0.00%)

0/8 (0.00%)

0/7 (0.00%)

0/8 (0.00%)

0/6 (0.00%)

0/6 (0.00%)

0/5 (0.00%)

0/3 (0.00%)

0/6 (0.00%)

0/9 (0.00%)

6/53 (11.32%)

3/85 (3.53%)

3/41 (7.32%)

3/48 (6.25%)

1/18 (5.56%)

14/154 (9.09%)

4/66 (6.06%)

0/18 (0.00%)

0/18 (0.00%)

6/12 (50.00%)

Chest pain * 1

1/3 (33.33%)

0/4 (0.00%)

0/8 (0.00%)

0/7 (0.00%)

0/8 (0.00%)

0/6 (0.00%)

0/6 (0.00%)

0/5 (0.00%)

0/3 (0.00%)

0/6 (0.00%)

1/9 (11.11%)

5/53 (9.43%)

5/85 (5.88%)

4/41 (9.76%)

3/48 (6.25%)

0/18 (0.00%)

16/154 (10.39%)

5/66 (7.58%)

0/18 (0.00%)

0/18 (0.00%)

0/12 (0.00%)

Chills * 1

0/3 (0.00%)

1/4 (25.00%)

0/8 (0.00%)

0/7 (0.00%)

0/8 (0.00%)

0/6 (0.00%)

0/6 (0.00%)

0/5 (0.00%)

0/3 (0.00%)

1/6 (16.67%)

0/9 (0.00%)

4/53 (7.55%)

12/85 (14.12%)

1/41 (2.44%)

1/48 (2.08%)

0/18 (0.00%)

7/154 (4.55%)

5/66 (7.58%)

1/18 (5.56%)

0/18 (0.00%)

0/12 (0.00%)

Face oedema * 1

0/3 (0.00%)

0/4 (0.00%)

0/8 (0.00%)

0/7 (0.00%)

0/8 (0.00%)

0/6 (0.00%)

0/6 (0.00%)

0/5 (0.00%)

0/3 (0.00%)

0/6 (0.00%)

0/9 (0.00%)

3/53 (5.66%)

0/85 (0.00%)

1/41 (2.44%)

0/48 (0.00%)

0/18 (0.00%)

6/154 (3.90%)

1/66 (1.52%)

1/18 (5.56%)

0/18 (0.00%)

0/12 (0.00%)

Fatigue * 1

2/3 (66.67%)

2/4 (50.00%)

3/8 (37.50%)

3/7 (42.86%)

4/8 (50.00%)

3/6 (50.00%)

3/6 (50.00%)

1/5 (20.00%)

2/3 (66.67%)

2/6 (33.33%)

3/9 (33.33%)

20/53 (37.74%)

35/85 (41.18%)

11/41 (26.83%)

23/48 (47.92%)

8/18 (44.44%)

59/154 (38.31%)

26/66 (39.39%)

8/18 (44.44%)

6/18 (33.33%)

5/12 (41.67%)

Malaise * 1

0/3 (0.00%)

0/4 (0.00%)

0/8 (0.00%)

0/7 (0.00%)

0/8 (0.00%)

0/6 (0.00%)

0/6 (0.00%)

0/5 (0.00%)

0/3 (0.00%)

0/6 (0.00%)

0/9 (0.00%)

3/53 (5.66%)

3/85 (3.53%)

2/41 (4.88%)

0/48 (0.00%)

0/18 (0.00%)

2/154 (1.30%)

0/66 (0.00%)

0/18 (0.00%)

0/18 (0.00%)

0/12 (0.00%)

Oedema * 1

0/3 (0.00%)

0/4 (0.00%)

0/8 (0.00%)

1/7 (14.29%)

1/8 (12.50%)

1/6 (16.67%)

0/6 (0.00%)

0/5 (0.00%)

0/3 (0.00%)

0/6 (0.00%)

0/9 (0.00%)

8/53 (15.09%)

4/85 (4.71%)

2/41 (4.88%)

1/48 (2.08%)

0/18 (0.00%)

14/154 (9.09%)

3/66 (4.55%)

2/18 (11.11%)

0/18 (0.00%)

0/12 (0.00%)

Oedema peripheral * 1

0/3 (0.00%)

0/4 (0.00%)

0/8 (0.00%)

2/7 (28.57%)

1/8 (12.50%)

0/6 (0.00%)

2/6 (33.33%)

1/5 (20.00%)

0/3 (0.00%)

2/6 (33.33%)

0/9 (0.00%)

27/53 (50.94%)

49/85 (57.65%)

14/41 (34.15%)

15/48 (31.25%)

4/18 (22.22%)

69/154 (44.81%)

18/66 (27.27%)

3/18 (16.67%)

5/18 (27.78%)

1/12 (8.33%)

Pain * 1

0/3 (0.00%)

0/4 (0.00%)

0/8 (0.00%)

0/7 (0.00%)

1/8 (12.50%)

0/6 (0.00%)

0/6 (0.00%)

0/5 (0.00%)

0/3 (0.00%)

0/6 (0.00%)

0/9 (0.00%)

5/53 (9.43%)

3/85 (3.53%)

3/41 (7.32%)

6/48 (12.50%)

1/18 (5.56%)

12/154 (7.79%)

5/66 (7.58%)

2/18 (11.11%)

2/18 (11.11%)

0/12 (0.00%)

Pyrexia * 1

1/3 (33.33%)

3/4 (75.00%)

1/8 (12.50%)

0/7 (0.00%)

0/8 (0.00%)

0/6 (0.00%)

0/6 (0.00%)

0/5 (0.00%)

0/3 (0.00%)

2/6 (33.33%)

2/9 (22.22%)

15/53 (28.30%)

12/85 (14.12%)

2/41 (4.88%)

6/48 (12.50%)

2/18 (11.11%)

34/154 (22.08%)

3/66 (4.55%)

3/18 (16.67%)

3/18 (16.67%)

1/12 (8.33%)

Breakthrough pain * 1

0/3 (0.00%)

0/4 (0.00%)

0/8 (0.00%)

0/7 (0.00%)

0/8 (0.00%)

0/6 (0.00%)

0/6 (0.00%)

0/5 (0.00%)

0/3 (0.00%)

0/6 (0.00%)

1/9 (11.11%)

0/53 (0.00%)

0/85 (0.00%)

0/41 (0.00%)

0/48 (0.00%)

0/18 (0.00%)

0/154 (0.00%)

0/66 (0.00%)

0/18 (0.00%)

0/18 (0.00%)

0/12 (0.00%)

Chest discomfort * 1

0/3 (0.00%)

0/4 (0.00%)

0/8 (0.00%)

0/7 (0.00%)

0/8 (0.00%)

0/6 (0.00%)

0/6 (0.00%)

0/5 (0.00%)

0/3 (0.00%)

0/6 (0.00%)

0/9 (0.00%)

1/53 (1.89%)

4/85 (4.71%)

2/41 (4.88%)

0/48 (0.00%)

0/18 (0.00%)

13/154 (8.44%)

2/66 (3.03%)

0/18 (0.00%)

0/18 (0.00%)

0/12 (0.00%)

Discomfort * 1

0/3 (0.00%)

0/4 (0.00%)

0/8 (0.00%)

0/7 (0.00%)

0/8 (0.00%)

0/6 (0.00%)

0/6 (0.00%)

0/5 (0.00%)

0/3 (0.00%)

0/6 (0.00%)

0/9 (0.00%)

1/53 (1.89%)

0/85 (0.00%)

0/41 (0.00%)

0/48 (0.00%)

0/18 (0.00%)

0/154 (0.00%)

0/66 (0.00%)

1/18 (5.56%)

0/18 (0.00%)

0/12 (0.00%)

Early satiety * 1

0/3 (0.00%)

0/4 (0.00%)

0/8 (0.00%)

0/7 (0.00%)

0/8 (0.00%)

0/6 (0.00%)

0/6 (0.00%)

0/5 (0.00%)

1/3 (33.33%)

0/6 (0.00%)

0/9 (0.00%)

0/53 (0.00%)

0/85 (0.00%)

1/41 (2.44%)

0/48 (0.00%)

1/18 (5.56%)

0/154 (0.00%)

1/66 (1.52%)

0/18 (0.00%)

1/18 (5.56%)

0/12 (0.00%)

Facial pain * 1

0/3 (0.00%)

1/4 (25.00%)

0/8 (0.00%)

0/7 (0.00%)

0/8 (0.00%)

0/6 (0.00%)

0/6 (0.00%)

0/5 (0.00%)

0/3 (0.00%)

0/6 (0.00%)

0/9 (0.00%)

1/53 (1.89%)

0/85 (0.00%)

0/41 (0.00%)

0/48 (0.00%)

0/18 (0.00%)

1/154 (0.65%)

0/66 (0.00%)

0/18 (0.00%)

0/18 (0.00%)

0/12 (0.00%)

Gait disturbance * 1 [1]

0/3 (0.00%)

0/4 (0.00%)

0/8 (0.00%)

0/7 (0.00%)

0/8 (0.00%)

0/6 (0.00%)

0/6 (0.00%)

0/5 (0.00%)

0/3 (0.00%)

0/6 (0.00%)

0/9 (0.00%)

2/53 (3.77%)

7/85 (8.24%)

0/41 (0.00%)

1/48 (2.08%)

0/18 (0.00%)

8/154 (5.19%)

0/66 (0.00%)

2/18 (11.11%)

0/18 (0.00%)

0/12 (0.00%)

Influenza like illness * 1

0/3 (0.00%)

0/4 (0.00%)

0/8 (0.00%)

0/7 (0.00%)

0/8 (0.00%)

0/6 (0.00%)

0/6 (0.00%)

0/5 (0.00%)

0/3 (0.00%)

0/6 (0.00%)

0/9 (0.00%)

1/53 (1.89%)

1/85 (1.18%)

1/41 (2.44%)

0/48 (0.00%)

0/18 (0.00%)

9/154 (5.84%)

0/66 (0.00%)

0/18 (0.00%)

0/18 (0.00%)

0/12 (0.00%)

Infusion site erythema * 1

0/3 (0.00%)

0/4 (0.00%)

0/8 (0.00%)

0/7 (0.00%)

0/8 (0.00%)

0/6 (0.00%)

0/6 (0.00%)

0/5 (0.00%)

0/3 (0.00%)

0/6 (0.00%)

0/9 (0.00%)

0/53 (0.00%)

0/85 (0.00%)

0/41 (0.00%)

0/48 (0.00%)

0/18 (0.00%)

0/154 (0.00%)

0/66 (0.00%)

1/18 (5.56%)

0/18 (0.00%)

0/12 (0.00%)

Localised oedema * 1

0/3 (0.00%)

0/4 (0.00%)

0/8 (0.00%)

0/7 (0.00%)

0/8 (0.00%)

0/6 (0.00%)

0/6 (0.00%)

0/5 (0.00%)

1/3 (33.33%)

0/6 (0.00%)

0/9 (0.00%)

1/53 (1.89%)

1/85 (1.18%)

0/41 (0.00%)

0/48 (0.00%)

0/18 (0.00%)

2/154 (1.30%)

0/66 (0.00%)

0/18 (0.00%)

0/18 (0.00%)

0/12 (0.00%)

Mucosal inflammation * 1

0/3 (0.00%)

1/4 (25.00%)

1/8 (12.50%)

0/7 (0.00%)

0/8 (0.00%)

0/6 (0.00%)

0/6 (0.00%)

0/5 (0.00%)

0/3 (0.00%)

0/6 (0.00%)

0/9 (0.00%)

1/53 (1.89%)

0/85 (0.00%)

0/41 (0.00%)

0/48 (0.00%)

0/18 (0.00%)

2/154 (1.30%)

0/66 (0.00%)

0/18 (0.00%)

0/18 (0.00%)

0/12 (0.00%)

Peripheral swelling * 1

0/3 (0.00%)

1/4 (25.00%)

0/8 (0.00%)

0/7 (0.00%)

0/8 (0.00%)

0/6 (0.00%)

0/6 (0.00%)

0/5 (0.00%)

0/3 (0.00%)

0/6 (0.00%)

0/9 (0.00%)

1/53 (1.89%)

0/85 (0.00%)

1/41 (2.44%)

2/48 (4.17%)

1/18 (5.56%)

17/154 (11.04%)

1/66 (1.52%)

0/18 (0.00%)

0/18 (0.00%)

0/12 (0.00%)

Swelling * 1

0/3 (0.00%)

0/4 (0.00%)

0/8 (0.00%)

0/7 (0.00%)

0/8 (0.00%)

0/6 (0.00%)

0/6 (0.00%)

0/5 (0.00%)

0/3 (0.00%)

0/6 (0.00%)

1/9 (11.11%)

1/53 (1.89%)

1/85 (1.18%)

1/41 (2.44%)

1/48 (2.08%)

0/18 (0.00%)

1/154 (0.65%)

0/66 (0.00%)

0/18 (0.00%)

0/18 (0.00%)

0/12 (0.00%)

Systemic inflammatory response syndrome * 1

0/3 (0.00%)

0/4 (0.00%)

0/8 (0.00%)

0/7 (0.00%)

0/8 (0.00%)

0/6 (0.00%)

0/6 (0.00%)

0/5 (0.00%)

0/3 (0.00%)

0/6 (0.00%)

1/9 (11.11%)

0/53 (0.00%)

0/85 (0.00%)

0/41 (0.00%)

0/48 (0.00%)

0/18 (0.00%)

0/154 (0.00%)

0/66 (0.00%)

0/18 (0.00%)

0/18 (0.00%)

0/12 (0.00%)

Hepatobiliary disorders

Bile duct stenosis * 1

0/3 (0.00%)

0/4 (0.00%)

0/8 (0.00%)

0/7 (0.00%)

0/8 (0.00%)

1/6 (16.67%)

0/6 (0.00%)

0/5 (0.00%)

0/3 (0.00%)

0/6 (0.00%)

0/9 (0.00%)

0/53 (0.00%)

0/85 (0.00%)

0/41 (0.00%)

0/48 (0.00%)

0/18 (0.00%)

0/154 (0.00%)

0/66 (0.00%)

0/18 (0.00%)

0/18 (0.00%)

0/12 (0.00%)

Hyperbilirubinaemia * 1

0/3 (0.00%)

0/4 (0.00%)

0/8 (0.00%)

1/7 (14.29%)

0/8 (0.00%)

1/6 (16.67%)

0/6 (0.00%)

0/5 (0.00%)

0/3 (0.00%)

0/6 (0.00%)

0/9 (0.00%)

1/53 (1.89%)

0/85 (0.00%)

1/41 (2.44%)

0/48 (0.00%)

0/18 (0.00%)

2/154 (1.30%)

2/66 (3.03%)

0/18 (0.00%)

1/18 (5.56%)

0/12 (0.00%)

Jaundice * 1

0/3 (0.00%)

0/4 (0.00%)

0/8 (0.00%)

0/7 (0.00%)

1/8 (12.50%)

0/6 (0.00%)

0/6 (0.00%)

0/5 (0.00%)

0/3 (0.00%)

0/6 (0.00%)

0/9 (0.00%)

0/53 (0.00%)

0/85 (0.00%)

0/41 (0.00%)

0/48 (0.00%)

0/18 (0.00%)

1/154 (0.65%)

0/66 (0.00%)

0/18 (0.00%)

0/18 (0.00%)

0/12 (0.00%)

Immune system disorders

Multiple allergies * 1

0/3 (0.00%)

0/4 (0.00%)

1/8 (12.50%)

0/7 (0.00%)

0/8 (0.00%)

0/6 (0.00%)

0/6 (0.00%)

0/5 (0.00%)

0/3 (0.00%)

0/6 (0.00%)

0/9 (0.00%)

1/53 (1.89%)

0/85 (0.00%)

0/41 (0.00%)

0/48 (0.00%)

0/18 (0.00%)

0/154 (0.00%)

0/66 (0.00%)

0/18 (0.00%)

0/18 (0.00%)

0/12 (0.00%)

Seasonal allergy * 1

0/3 (0.00%)

0/4 (0.00%)

0/8 (0.00%)

0/7 (0.00%)

0/8 (0.00%)

0/6 (0.00%)

0/6 (0.00%)

0/5 (0.00%)

0/3 (0.00%)

0/6 (0.00%)

0/9 (0.00%)

2/53 (3.77%)

1/85 (1.18%)

1/41 (2.44%)

2/48 (4.17%)

0/18 (0.00%)

5/154 (3.25%)

0/66 (0.00%)

1/18 (5.56%)

0/18 (0.00%)

0/12 (0.00%)

Infections and infestations

Herpes zoster * 1

0/3 (0.00%)

0/4 (0.00%)

0/8 (0.00%)

0/7 (0.00%)

0/8 (0.00%)

0/6 (0.00%)

0/6 (0.00%)

0/5 (0.00%)

0/3 (0.00%)

0/6 (0.00%)

0/9 (0.00%)

3/53 (5.66%)

0/85 (0.00%)

1/41 (2.44%)

2/48 (4.17%)

0/18 (0.00%)

3/154 (1.95%)

0/66 (0.00%)

0/18 (0.00%)

0/18 (0.00%)

0/12 (0.00%)

Influenza * 1

0/3 (0.00%)

0/4 (0.00%)

0/8 (0.00%)

0/7 (0.00%)

0/8 (0.00%)

0/6 (0.00%)

0/6 (0.00%)

0/5 (0.00%)

0/3 (0.00%)

0/6 (0.00%)

0/9 (0.00%)

3/53 (5.66%)

1/85 (1.18%)

2/41 (4.88%)

0/48 (0.00%)

0/18 (0.00%)

8/154 (5.19%)

0/66 (0.00%)

0/18 (0.00%)

0/18 (0.00%)

0/12 (0.00%)

Nasopharyngitis * 1

0/3 (0.00%)

0/4 (0.00%)

1/8 (12.50%)

0/7 (0.00%)

0/8 (0.00%)

0/6 (0.00%)

0/6 (0.00%)

0/5 (0.00%)

0/3 (0.00%)

0/6 (0.00%)

0/9 (0.00%)

13/53 (24.53%)

3/85 (3.53%)

1/41 (2.44%)

7/48 (14.58%)

0/18 (0.00%)

26/154 (16.88%)

2/66 (3.03%)

0/18 (0.00%)

0/18 (0.00%)

0/12 (0.00%)

Pneumonia * 1

0/3 (0.00%)

0/4 (0.00%)

0/8 (0.00%)

0/7 (0.00%)

0/8 (0.00%)

0/6 (0.00%)

0/6 (0.00%)

0/5 (0.00%)

0/3 (0.00%)

0/6 (0.00%)

0/9 (0.00%)

7/53 (13.21%)

8/85 (9.41%)

5/41 (12.20%)

3/48 (6.25%)

2/18 (11.11%)

12/154 (7.79%)

1/66 (1.52%)

0/18 (0.00%)

0/18 (0.00%)

0/12 (0.00%)

Sinusitis * 1

0/3 (0.00%)

0/4 (0.00%)

0/8 (0.00%)

1/7 (14.29%)

0/8 (0.00%)

0/6 (0.00%)

0/6 (0.00%)

0/5 (0.00%)

0/3 (0.00%)

0/6 (0.00%)

0/9 (0.00%)

3/53 (5.66%)

4/85 (4.71%)

2/41 (4.88%)

1/48 (2.08%)

0/18 (0.00%)

7/154 (4.55%)

1/66 (1.52%)

0/18 (0.00%)

0/18 (0.00%)

0/12 (0.00%)

Upper respiratory tract infection * 1

1/3 (33.33%)

0/4 (0.00%)

2/8 (25.00%)

1/7 (14.29%)

0/8 (0.00%)

1/6 (16.67%)

0/6 (0.00%)

0/5 (0.00%)

0/3 (0.00%)

0/6 (0.00%)

0/9 (0.00%)

11/53 (20.75%)

15/85 (17.65%)

1/41 (2.44%)

5/48 (10.42%)

4/18 (22.22%)

39/154 (25.32%)

1/66 (1.52%)

3/18 (16.67%)

0/18 (0.00%)

0/12 (0.00%)

Urinary tract infection * 1

0/3 (0.00%)

0/4 (0.00%)

0/8 (0.00%)

0/7 (0.00%)

0/8 (0.00%)

0/6 (0.00%)

0/6 (0.00%)

0/5 (0.00%)

0/3 (0.00%)

0/6 (0.00%)

1/9 (11.11%)

6/53 (11.32%)

11/85 (12.94%)

5/41 (12.20%)

1/48 (2.08%)

1/18 (5.56%)

13/154 (8.44%)

5/66 (7.58%)

1/18 (5.56%)

1/18 (5.56%)

1/12 (8.33%)

Viral infection * 1

1/3 (33.33%)

0/4 (0.00%)

0/8 (0.00%)

0/7 (0.00%)

0/8 (0.00%)

0/6 (0.00%)

0/6 (0.00%)

0/5 (0.00%)

0/3 (0.00%)

0/6 (0.00%)

0/9 (0.00%)

4/53 (7.55%)

2/85 (2.35%)

0/41 (0.00%)

0/48 (0.00%)

0/18 (0.00%)

3/154 (1.95%)

0/66 (0.00%)

0/18 (0.00%)

0/18 (0.00%)

0/12 (0.00%)

Viral upper respiratory tract infection * 1

0/3 (0.00%)

0/4 (0.00%)

0/8 (0.00%)

0/7 (0.00%)

0/8 (0.00%)

0/6 (0.00%)

0/6 (0.00%)

0/5 (0.00%)

0/3 (0.00%)

0/6 (0.00%)

0/9 (0.00%)

3/53 (5.66%)

2/85 (2.35%)

0/41 (0.00%)

2/48 (4.17%)

0/18 (0.00%)

2/154 (1.30%)

1/66 (1.52%)

0/18 (0.00%)

0/18 (0.00%)

0/12 (0.00%)

Bronchitis * 1

0/3 (0.00%)

0/4 (0.00%)

0/8 (0.00%)

2/7 (28.57%)

0/8 (0.00%)

0/6 (0.00%)

0/6 (0.00%)

0/5 (0.00%)

0/3 (0.00%)

0/6 (0.00%)

0/9 (0.00%)

1/53 (1.89%)

4/85 (4.71%)

2/41 (4.88%)

2/48 (4.17%)

0/18 (0.00%)

4/154 (2.60%)

0/66 (0.00%)

2/18 (11.11%)

0/18 (0.00%)

0/12 (0.00%)

Candida infection * 1

0/3 (0.00%)

0/4 (0.00%)

0/8 (0.00%)

0/7 (0.00%)

0/8 (0.00%)

0/6 (0.00%)

0/6 (0.00%)

0/5 (0.00%)

0/3 (0.00%)

0/6 (0.00%)

0/9 (0.00%)

0/53 (0.00%)

3/85 (3.53%)

1/41 (2.44%)

0/48 (0.00%)

0/18 (0.00%)

5/154 (3.25%)

1/66 (1.52%)

0/18 (0.00%)

1/18 (5.56%)

0/12 (0.00%)

Epididymitis * 1

0/3 (0.00%)

0/4 (0.00%)

0/8 (0.00%)

0/7 (0.00%)

0/8 (0.00%)

0/6 (0.00%)

0/6 (0.00%)

0/5 (0.00%)

0/3 (0.00%)

0/6 (0.00%)

1/9 (11.11%)

0/53 (0.00%)

0/85 (0.00%)

0/41 (0.00%)

1/48 (2.08%)

0/18 (0.00%)

0/154 (0.00%)

0/66 (0.00%)

0/18 (0.00%)

0/18 (0.00%)

0/12 (0.00%)

Fungal infection * 1

0/3 (0.00%)

0/4 (0.00%)

0/8 (0.00%)

0/7 (0.00%)

0/8 (0.00%)

0/6 (0.00%)

0/6 (0.00%)

0/5 (0.00%)

0/3 (0.00%)

1/6 (16.67%)

0/9 (0.00%)

1/53 (1.89%)

1/85 (1.18%)

0/41 (0.00%)

1/48 (2.08%)

0/18 (0.00%)

1/154 (0.65%)

0/66 (0.00%)

0/18 (0.00%)

0/18 (0.00%)

0/12 (0.00%)

Infection * 1

0/3 (0.00%)

0/4 (0.00%)

0/8 (0.00%)

0/7 (0.00%)

0/8 (0.00%)

0/6 (0.00%)

0/6 (0.00%)

0/5 (0.00%)

0/3 (0.00%)

1/6 (16.67%)

0/9 (0.00%)

1/53 (1.89%)

0/85 (0.00%)

1/41 (2.44%)

0/48 (0.00%)

0/18 (0.00%)

0/154 (0.00%)

3/66 (4.55%)

0/18 (0.00%)

0/18 (0.00%)

0/12 (0.00%)

Oral candidiasis * 1

0/3 (0.00%)

0/4 (0.00%)

0/8 (0.00%)

1/7 (14.29%)

0/8 (0.00%)

0/6 (0.00%)

0/6 (0.00%)

0/5 (0.00%)

0/3 (0.00%)

0/6 (0.00%)

0/9 (0.00%)

1/53 (1.89%)

1/85 (1.18%)

0/41 (0.00%)

1/48 (2.08%)

0/18 (0.00%)

4/154 (2.60%)

2/66 (3.03%)

1/18 (5.56%)

0/18 (0.00%)

0/12 (0.00%)

Rhinitis * 1

0/3 (0.00%)

0/4 (0.00%)

0/8 (0.00%)

0/7 (0.00%)

0/8 (0.00%)

0/6 (0.00%)

0/6 (0.00%)

0/5 (0.00%)

0/3 (0.00%)

0/6 (0.00%)

0/9 (0.00%)

0/53 (0.00%)

3/85 (3.53%)

0/41 (0.00%)

0/48 (0.00%)

1/18 (5.56%)

5/154 (3.25%)

1/66 (1.52%)

0/18 (0.00%)

0/18 (0.00%)

0/12 (0.00%)

Skin infection * 1

0/3 (0.00%)

0/4 (0.00%)

0/8 (0.00%)

0/7 (0.00%)

0/8 (0.00%)

0/6 (0.00%)

0/6 (0.00%)

0/5 (0.00%)

0/3 (0.00%)

0/6 (0.00%)

0/9 (0.00%)

1/53 (1.89%)

5/85 (5.88%)

0/41 (0.00%)

0/48 (0.00%)

0/18 (0.00%)

0/154 (0.00%)

1/66 (1.52%)

0/18 (0.00%)

0/18 (0.00%)

0/12 (0.00%)

Tinea pedis * 1

0/3 (0.00%)

0/4 (0.00%)

0/8 (0.00%)

0/7 (0.00%)

0/8 (0.00%)

0/6 (0.00%)

0/6 (0.00%)

0/5 (0.00%)

0/3 (0.00%)

1/6 (16.67%)

0/9 (0.00%)

0/53 (0.00%)

0/85 (0.00%)

0/41 (0.00%)

0/48 (0.00%)

0/18 (0.00%)

0/154 (0.00%)

0/66 (0.00%)

0/18 (0.00%)

0/18 (0.00%)

0/12 (0.00%)

Urosepsis * 1

0/3 (0.00%)

0/4 (0.00%)

1/8 (12.50%)

0/7 (0.00%)

0/8 (0.00%)

0/6 (0.00%)

0/6 (0.00%)

0/5 (0.00%)

0/3 (0.00%)

0/6 (0.00%)

0/9 (0.00%)

0/53 (0.00%)

0/85 (0.00%)

0/41 (0.00%)

0/48 (0.00%)

0/18 (0.00%)

0/154 (0.00%)

0/66 (0.00%)

0/18 (0.00%)

0/18 (0.00%)

0/12 (0.00%)

Bacteraemia * 1

0/3 (0.00%)

0/4 (0.00%)

0/8 (0.00%)

0/7 (0.00%)

0/8 (0.00%)

0/6 (0.00%)

0/6 (0.00%)

0/5 (0.00%)

0/3 (0.00%)

0/6 (0.00%)

0/9 (0.00%)

0/53 (0.00%)

0/85 (0.00%)

0/41 (0.00%)

0/48 (0.00%)

0/18 (0.00%)

0/154 (0.00%)

0/66 (0.00%)

0/18 (0.00%)

0/18 (0.00%)

1/12 (8.33%)

Injury, poisoning and procedural complications

Fall * 1

0/3 (0.00%)

0/4 (0.00%)

0/8 (0.00%)

0/7 (0.00%)

1/8 (12.50%)

0/6 (0.00%)

0/6 (0.00%)

1/5 (20.00%)

0/3 (0.00%)

0/6 (0.00%)

1/9 (11.11%)

6/53 (11.32%)

14/85 (16.47%)

5/41 (12.20%)

3/48 (6.25%)

1/18 (5.56%)

19/154 (12.34%)

6/66 (9.09%)

2/18 (11.11%)

1/18 (5.56%)

1/12 (8.33%)

Bone contusion * 1

0/3 (0.00%)

0/4 (0.00%)

0/8 (0.00%)

0/7 (0.00%)

0/8 (0.00%)

0/6 (0.00%)

0/6 (0.00%)

0/5 (0.00%)

0/3 (0.00%)

0/6 (0.00%)

0/9 (0.00%)

0/53 (0.00%)

0/85 (0.00%)

0/41 (0.00%)

0/48 (0.00%)

0/18 (0.00%)

0/154 (0.00%)

0/66 (0.00%)

0/18 (0.00%)

1/18 (5.56%)

0/12 (0.00%)

Contusion * 1

0/3 (0.00%)

0/4 (0.00%)

0/8 (0.00%)

0/7 (0.00%)

0/8 (0.00%)

0/6 (0.00%)

0/6 (0.00%)

0/5 (0.00%)

0/3 (0.00%)

0/6 (0.00%)

0/9 (0.00%)

2/53 (3.77%)

2/85 (2.35%)

2/41 (4.88%)

1/48 (2.08%)

1/18 (5.56%)

4/154 (2.60%)

1/66 (1.52%)

1/18 (5.56%)

1/18 (5.56%)

0/12 (0.00%)

Infusion related reaction * 1

0/3 (0.00%)

0/4 (0.00%)

0/8 (0.00%)

0/7 (0.00%)

0/8 (0.00%)

0/6 (0.00%)

0/6 (0.00%)

0/5 (0.00%)

0/3 (0.00%)

0/6 (0.00%)

0/9 (0.00%)

0/53 (0.00%)

0/85 (0.00%)

0/41 (0.00%)

0/48 (0.00%)

0/18 (0.00%)

1/154 (0.65%)

1/66 (1.52%)

1/18 (5.56%)

0/18 (0.00%)

0/12 (0.00%)

Ligament rupture * 1

0/3 (0.00%)

0/4 (0.00%)

0/8 (0.00%)

0/7 (0.00%)

0/8 (0.00%)

0/6 (0.00%)

0/6 (0.00%)

0/5 (0.00%)

0/3 (0.00%)

0/6 (0.00%)

0/9 (0.00%)

0/53 (0.00%)

0/85 (0.00%)

0/41 (0.00%)

0/48 (0.00%)

0/18 (0.00%)

0/154 (0.00%)

0/66 (0.00%)

1/18 (5.56%)

0/18 (0.00%)

0/12 (0.00%)

Limb injury * 1

0/3 (0.00%)

0/4 (0.00%)

0/8 (0.00%)

0/7 (0.00%)

0/8 (0.00%)

0/6 (0.00%)

0/6 (0.00%)

0/5 (0.00%)

0/3 (0.00%)

0/6 (0.00%)

0/9 (0.00%)

0/53 (0.00%)

2/85 (2.35%)

2/41 (4.88%)

0/48 (0.00%)

1/18 (5.56%)

1/154 (0.65%)

0/66 (0.00%)

0/18 (0.00%)

0/18 (0.00%)

0/12 (0.00%)

Muscle strain * 1

0/3 (0.00%)

0/4 (0.00%)

0/8 (0.00%)

0/7 (0.00%)

0/8 (0.00%)

0/6 (0.00%)

0/6 (0.00%)

0/5 (0.00%)

0/3 (0.00%)

0/6 (0.00%)

0/9 (0.00%)

0/53 (0.00%)

0/85 (0.00%)

0/41 (0.00%)

1/48 (2.08%)

0/18 (0.00%)

0/154 (0.00%)

1/66 (1.52%)

1/18 (5.56%)

0/18 (0.00%)

0/12 (0.00%)

Optic nerve injury * 1

0/3 (0.00%)

0/4 (0.00%)

0/8 (0.00%)

0/7 (0.00%)

0/8 (0.00%)

0/6 (0.00%)

0/6 (0.00%)

0/5 (0.00%)

0/3 (0.00%)

0/6 (0.00%)

0/9 (0.00%)

0/53 (0.00%)

0/85 (0.00%)

0/41 (0.00%)

0/48 (0.00%)

0/18 (0.00%)

0/154 (0.00%)

0/66 (0.00%)

0/18 (0.00%)

1/18 (5.56%)

0/12 (0.00%)

Postoperative ileus * 1

0/3 (0.00%)

0/4 (0.00%)

0/8 (0.00%)

0/7 (0.00%)

0/8 (0.00%)

0/6 (0.00%)

0/6 (0.00%)

0/5 (0.00%)

0/3 (0.00%)

0/6 (0.00%)

0/9 (0.00%)

0/53 (0.00%)

0/85 (0.00%)

0/41 (0.00%)

0/48 (0.00%)

0/18 (0.00%)

0/154 (0.00%)

0/66 (0.00%)

0/18 (0.00%)

1/18 (5.56%)

0/12 (0.00%)

Road traffic accident * 1

0/3 (0.00%)

0/4 (0.00%)

0/8 (0.00%)

0/7 (0.00%)

0/8 (0.00%)

0/6 (0.00%)

0/6 (0.00%)

0/5 (0.00%)

0/3 (0.00%)

0/6 (0.00%)

0/9 (0.00%)

0/53 (0.00%)

1/85 (1.18%)

0/41 (0.00%)

0/48 (0.00%)

0/18 (0.00%)

0/154 (0.00%)

0/66 (0.00%)

0/18 (0.00%)

1/18 (5.56%)

0/12 (0.00%)

Stoma site rash * 1

0/3 (0.00%)

0/4 (0.00%)

0/8 (0.00%)

0/7 (0.00%)

0/8 (0.00%)

0/6 (0.00%)

0/6 (0.00%)

0/5 (0.00%)

0/3 (0.00%)

0/6 (0.00%)

0/9 (0.00%)

0/53 (0.00%)

0/85 (0.00%)

0/41 (0.00%)

0/48 (0.00%)

0/18 (0.00%)

0/154 (0.00%)

0/66 (0.00%)

1/18 (5.56%)

0/18 (0.00%)

0/12 (0.00%)

Skin laceration * 1

0/3 (0.00%)

0/4 (0.00%)

0/8 (0.00%)

0/7 (0.00%)

0/8 (0.00%)

0/6 (0.00%)

0/6 (0.00%)

0/5 (0.00%)

0/3 (0.00%)

0/6 (0.00%)

0/9 (0.00%)

0/53 (0.00%)

0/85 (0.00%)

0/41 (0.00%)

0/48 (0.00%)

0/18 (0.00%)

0/154 (0.00%)

0/66 (0.00%)

0/18 (0.00%)

0/18 (0.00%)

1/12 (8.33%)

Investigations

Alanine aminotransferase increased * 1

0/3 (0.00%)

0/4 (0.00%)

1/8 (12.50%)

0/7 (0.00%)

0/8 (0.00%)

1/6 (16.67%)

1/6 (16.67%)

0/5 (0.00%)

0/3 (0.00%)

0/6 (0.00%)

2/9 (22.22%)

17/53 (32.08%)

19/85 (22.35%)

9/41 (21.95%)

4/48 (8.33%)

0/18 (0.00%)

35/154 (22.73%)

11/66 (16.67%)

3/18 (16.67%)

4/18 (22.22%)

0/12 (0.00%)

Aspartate aminotransferase increased * 1

0/3 (0.00%)

0/4 (0.00%)

1/8 (12.50%)

0/7 (0.00%)

1/8 (12.50%)

1/6 (16.67%)

1/6 (16.67%)

0/5 (0.00%)

0/3 (0.00%)

1/6 (16.67%)

2/9 (22.22%)

16/53 (30.19%)

15/85 (17.65%)

10/41 (24.39%)

8/48 (16.67%)

2/18 (11.11%)

30/154 (19.48%)

10/66 (15.15%)

3/18 (16.67%)

4/18 (22.22%)

0/12 (0.00%)

Blood creatinine increased * 1

0/3 (0.00%)

0/4 (0.00%)

0/8 (0.00%)

0/7 (0.00%)

0/8 (0.00%)

0/6 (0.00%)

0/6 (0.00%)

0/5 (0.00%)

0/3 (0.00%)

1/6 (16.67%)

2/9 (22.22%)

6/53 (11.32%)

11/85 (12.94%)

6/41 (14.63%)

4/48 (8.33%)

1/18 (5.56%)

5/154 (3.25%)

9/66 (13.64%)

3/18 (16.67%)

3/18 (16.67%)

1/12 (8.33%)

Blood testosterone decreased * 1

0/3 (0.00%)

0/4 (0.00%)

0/8 (0.00%)

0/7 (0.00%)

0/8 (0.00%)

0/6 (0.00%)

0/6 (0.00%)

0/5 (0.00%)

0/3 (0.00%)

1/6 (16.67%)

0/9 (0.00%)

5/53 (9.43%)

2/85 (2.35%)

1/41 (2.44%)

1/48 (2.08%)

1/18 (5.56%)

12/154 (7.79%)

0/66 (0.00%)

0/18 (0.00%)

1/18 (5.56%)

0/12 (0.00%)

Weight decreased * 1

0/3 (0.00%)

0/4 (0.00%)

1/8 (12.50%)

1/7 (14.29%)

0/8 (0.00%)

0/6 (0.00%)

1/6 (16.67%)

2/5 (40.00%)

0/3 (0.00%)

1/6 (16.67%)

0/9 (0.00%)

5/53 (9.43%)

11/85 (12.94%)

9/41 (21.95%)

2/48 (4.17%)

2/18 (11.11%)

28/154 (18.18%)

5/66 (7.58%)

1/18 (5.56%)

2/18 (11.11%)

2/12 (16.67%)

Weight increased * 1

0/3 (0.00%)

0/4 (0.00%)

0/8 (0.00%)

0/7 (0.00%)

0/8 (0.00%)

0/6 (0.00%)

1/6 (16.67%)

0/5 (0.00%)

0/3 (0.00%)

0/6 (0.00%)

0/9 (0.00%)

6/53 (11.32%)

6/85 (7.06%)

5/41 (12.20%)

2/48 (4.17%)

1/18 (5.56%)

33/154 (21.43%)

2/66 (3.03%)

2/18 (11.11%)

1/18 (5.56%)

0/12 (0.00%)

Activated partial thromboplastin time prolonged * 1

0/3 (0.00%)

0/4 (0.00%)

0/8 (0.00%)

0/7 (0.00%)

0/8 (0.00%)

0/6 (0.00%)

0/6 (0.00%)

0/5 (0.00%)

0/3 (0.00%)

0/6 (0.00%)

0/9 (0.00%)

0/53 (0.00%)

1/85 (1.18%)

4/41 (9.76%)

0/48 (0.00%)

0/18 (0.00%)

2/154 (1.30%)

0/66 (0.00%)

0/18 (0.00%)

2/18 (11.11%)

0/12 (0.00%)

Bacterial test positive * 1

0/3 (0.00%)

0/4 (0.00%)

0/8 (0.00%)

0/7 (0.00%)

0/8 (0.00%)

0/6 (0.00%)

0/6 (0.00%)

0/5 (0.00%)

0/3 (0.00%)

0/6 (0.00%)

0/9 (0.00%)

0/53 (0.00%)

0/85 (0.00%)

0/41 (0.00%)

0/48 (0.00%)

1/18 (5.56%)

0/154 (0.00%)

0/66 (0.00%)

0/18 (0.00%)

1/18 (5.56%)

0/12 (0.00%)

Bilirubin conjugated increased * 1

0/3 (0.00%)

0/4 (0.00%)

0/8 (0.00%)

0/7 (0.00%)

0/8 (0.00%)

0/6 (0.00%)

0/6 (0.00%)

0/5 (0.00%)

0/3 (0.00%)

0/6 (0.00%)

0/9 (0.00%)

0/53 (0.00%)

0/85 (0.00%)

0/41 (0.00%)

0/48 (0.00%)

0/18 (0.00%)

0/154 (0.00%)

0/66 (0.00%)

1/18 (5.56%)

0/18 (0.00%)

0/12 (0.00%)

Blood albumin decreased * 1

0/3 (0.00%)

0/4 (0.00%)

0/8 (0.00%)

1/7 (14.29%)

0/8 (0.00%)

0/6 (0.00%)

0/6 (0.00%)

0/5 (0.00%)

0/3 (0.00%)

0/6 (0.00%)

0/9 (0.00%)

0/53 (0.00%)

1/85 (1.18%)

0/41 (0.00%)

0/48 (0.00%)

0/18 (0.00%)

5/154 (3.25%)

0/66 (0.00%)

0/18 (0.00%)

0/18 (0.00%)

0/12 (0.00%)

Blood alkaline phosphatase * 1

0/3 (0.00%)

0/4 (0.00%)

0/8 (0.00%)

0/7 (0.00%)

0/8 (0.00%)

0/6 (0.00%)

0/6 (0.00%)

0/5 (0.00%)

0/3 (0.00%)

0/6 (0.00%)

1/9 (11.11%)

0/53 (0.00%)

0/85 (0.00%)

0/41 (0.00%)

0/48 (0.00%)

0/18 (0.00%)

0/154 (0.00%)

0/66 (0.00%)

0/18 (0.00%)

0/18 (0.00%)

0/12 (0.00%)

Blood alkaline phosphatase increased * 1

0/3 (0.00%)

0/4 (0.00%)

0/8 (0.00%)

1/7 (14.29%)

1/8 (12.50%)

2/6 (33.33%)

1/6 (16.67%)

0/5 (0.00%)

0/3 (0.00%)

0/6 (0.00%)

0/9 (0.00%)

2/53 (3.77%)

7/85 (8.24%)

4/41 (9.76%)

4/48 (8.33%)

3/18 (16.67%)

13/154 (8.44%)

4/66 (6.06%)

2/18 (11.11%)

2/18 (11.11%)

1/12 (8.33%)

Blood bilirubin increased * 1

0/3 (0.00%)

0/4 (0.00%)

0/8 (0.00%)

0/7 (0.00%)

1/8 (12.50%)

0/6 (0.00%)

0/6 (0.00%)

0/5 (0.00%)

0/3 (0.00%)

0/6 (0.00%)

0/9 (0.00%)

1/53 (1.89%)

0/85 (0.00%)

0/41 (0.00%)

0/48 (0.00%)

0/18 (0.00%)

2/154 (1.30%)

1/66 (1.52%)

2/18 (11.11%)

0/18 (0.00%)

0/12 (0.00%)

Blood iron decreased * 1

0/3 (0.00%)

0/4 (0.00%)

0/8 (0.00%)

0/7 (0.00%)

0/8 (0.00%)

0/6 (0.00%)

0/6 (0.00%)

0/5 (0.00%)

0/3 (0.00%)

0/6 (0.00%)

0/9 (0.00%)

0/53 (0.00%)

0/85 (0.00%)

0/41 (0.00%)

0/48 (0.00%)

0/18 (0.00%)

0/154 (0.00%)

0/66 (0.00%)

0/18 (0.00%)

1/18 (5.56%)

0/12 (0.00%)

Blood lactate dehydrogenase increased * 1

0/3 (0.00%)

0/4 (0.00%)

0/8 (0.00%)

0/7 (0.00%)

0/8 (0.00%)

0/6 (0.00%)

0/6 (0.00%)

0/5 (0.00%)

0/3 (0.00%)

0/6 (0.00%)

0/9 (0.00%)

0/53 (0.00%)

1/85 (1.18%)

0/41 (0.00%)

0/48 (0.00%)

1/18 (5.56%)

1/154 (0.65%)

2/66 (3.03%)

1/18 (5.56%)

2/18 (11.11%)

0/12 (0.00%)

Blood phosphorus decreased * 1

0/3 (0.00%)

0/4 (0.00%)

1/8 (12.50%)

0/7 (0.00%)

0/8 (0.00%)

0/6 (0.00%)

0/6 (0.00%)

0/5 (0.00%)

0/3 (0.00%)

0/6 (0.00%)

0/9 (0.00%)

1/53 (1.89%)

0/85 (0.00%)

0/41 (0.00%)

0/48 (0.00%)

0/18 (0.00%)

2/154 (1.30%)

0/66 (0.00%)

0/18 (0.00%)

0/18 (0.00%)

0/12 (0.00%)

Blood potassium decreased * 1

0/3 (0.00%)

0/4 (0.00%)

1/8 (12.50%)

0/7 (0.00%)

0/8 (0.00%)

0/6 (0.00%)

0/6 (0.00%)

0/5 (0.00%)

0/3 (0.00%)

0/6 (0.00%)

0/9 (0.00%)

0/53 (0.00%)

1/85 (1.18%)

0/41 (0.00%)

0/48 (0.00%)

0/18 (0.00%)

0/154 (0.00%)

0/66 (0.00%)

0/18 (0.00%)

0/18 (0.00%)

0/12 (0.00%)

Blood pressure systolic increased * 1

0/3 (0.00%)

0/4 (0.00%)

0/8 (0.00%)

0/7 (0.00%)

0/8 (0.00%)

0/6 (0.00%)

0/6 (0.00%)

0/5 (0.00%)

0/3 (0.00%)

0/6 (0.00%)

1/9 (11.11%)

0/53 (0.00%)

0/85 (0.00%)

0/41 (0.00%)

0/48 (0.00%)

0/18 (0.00%)

0/154 (0.00%)

0/66 (0.00%)

0/18 (0.00%)

0/18 (0.00%)

0/12 (0.00%)

Blood urea increased * 1

0/3 (0.00%)

0/4 (0.00%)

0/8 (0.00%)

0/7 (0.00%)

0/8 (0.00%)

0/6 (0.00%)

0/6 (0.00%)

0/5 (0.00%)

0/3 (0.00%)

0/6 (0.00%)

0/9 (0.00%)

1/53 (1.89%)

0/85 (0.00%)

1/41 (2.44%)

0/48 (0.00%)

1/18 (5.56%)

0/154 (0.00%)

1/66 (1.52%)

1/18 (5.56%)

2/18 (11.11%)

0/12 (0.00%)

Blood uric acid increased * 1

0/3 (0.00%)

0/4 (0.00%)

0/8 (0.00%)

0/7 (0.00%)

0/8 (0.00%)

0/6 (0.00%)

0/6 (0.00%)

0/5 (0.00%)

0/3 (0.00%)

0/6 (0.00%)

0/9 (0.00%)

0/53 (0.00%)

0/85 (0.00%)

0/41 (0.00%)

0/48 (0.00%)

0/18 (0.00%)

0/154 (0.00%)

0/66 (0.00%)

0/18 (0.00%)

1/18 (5.56%)

0/12 (0.00%)

Blood urine * 1

0/3 (0.00%)

0/4 (0.00%)

0/8 (0.00%)

0/7 (0.00%)

0/8 (0.00%)

0/6 (0.00%)

0/6 (0.00%)

0/5 (0.00%)

0/3 (0.00%)

0/6 (0.00%)

0/9 (0.00%)

0/53 (0.00%)

0/85 (0.00%)

0/41 (0.00%)

0/48 (0.00%)

0/18 (0.00%)

0/154 (0.00%)

0/66 (0.00%)

0/18 (0.00%)

1/18 (5.56%)

0/12 (0.00%)

Blood urine present * 1

0/3 (0.00%)

0/4 (0.00%)

0/8 (0.00%)

0/7 (0.00%)

0/8 (0.00%)

0/6 (0.00%)

0/6 (0.00%)

0/5 (0.00%)

0/3 (0.00%)

0/6 (0.00%)

0/9 (0.00%)

0/53 (0.00%)

0/85 (0.00%)

0/41 (0.00%)

0/48 (0.00%)

1/18 (5.56%)

1/154 (0.65%)

0/66 (0.00%)

0/18 (0.00%)

1/18 (5.56%)

0/12 (0.00%)

Brain natriuretic peptide increased * 1

0/3 (0.00%)

0/4 (0.00%)

0/8 (0.00%)

0/7 (0.00%)

0/8 (0.00%)

0/6 (0.00%)

0/6 (0.00%)

0/5 (0.00%)

0/3 (0.00%)

0/6 (0.00%)

1/9 (11.11%)

0/53 (0.00%)

0/85 (0.00%)

1/41 (2.44%)

0/48 (0.00%)

0/18 (0.00%)

0/154 (0.00%)

0/66 (0.00%)

0/18 (0.00%)

0/18 (0.00%)

0/12 (0.00%)

Electrocardiogram QT prolonged * 1

0/3 (0.00%)

0/4 (0.00%)

0/8 (0.00%)

0/7 (0.00%)

0/8 (0.00%)

0/6 (0.00%)

0/6 (0.00%)

0/5 (0.00%)

0/3 (0.00%)

0/6 (0.00%)

0/9 (0.00%)

2/53 (3.77%)

3/85 (3.53%)

2/41 (4.88%)

3/48 (6.25%)

0/18 (0.00%)

2/154 (1.30%)

4/66 (6.06%)

1/18 (5.56%)

2/18 (11.11%)

0/12 (0.00%)

Electrocardiogram abnormal * 1

0/3 (0.00%)

0/4 (0.00%)

0/8 (0.00%)

0/7 (0.00%)

0/8 (0.00%)

0/6 (0.00%)

0/6 (0.00%)

0/5 (0.00%)

1/3 (33.33%)

0/6 (0.00%)

0/9 (0.00%)

0/53 (0.00%)

0/85 (0.00%)

0/41 (0.00%)

1/48 (2.08%)

0/18 (0.00%)

0/154 (0.00%)

0/66 (0.00%)

0/18 (0.00%)

0/18 (0.00%)

0/12 (0.00%)

Glucose urine present * 1

0/3 (0.00%)

0/4 (0.00%)

0/8 (0.00%)

0/7 (0.00%)

0/8 (0.00%)

0/6 (0.00%)

1/6 (16.67%)

0/5 (0.00%)

0/3 (0.00%)

0/6 (0.00%)

0/9 (0.00%)

0/53 (0.00%)

0/85 (0.00%)

0/41 (0.00%)

0/48 (0.00%)

0/18 (0.00%)

0/154 (0.00%)

0/66 (0.00%)

0/18 (0.00%)

0/18 (0.00%)

0/12 (0.00%)

Haematocrit decreased * 1

0/3 (0.00%)

0/4 (0.00%)

0/8 (0.00%)

0/7 (0.00%)

0/8 (0.00%)

0/6 (0.00%)

0/6 (0.00%)

0/5 (0.00%)

0/3 (0.00%)

0/6 (0.00%)

0/9 (0.00%)

0/53 (0.00%)

0/85 (0.00%)

0/41 (0.00%)

0/48 (0.00%)

0/18 (0.00%)

1/154 (0.65%)

0/66 (0.00%)

0/18 (0.00%)

1/18 (5.56%)

0/12 (0.00%)

Haemoglobin decreased * 1

0/3 (0.00%)

0/4 (0.00%)

0/8 (0.00%)

0/7 (0.00%)

0/8 (0.00%)

0/6 (0.00%)

0/6 (0.00%)

0/5 (0.00%)

0/3 (0.00%)

0/6 (0.00%)

0/9 (0.00%)

0/53 (0.00%)

0/85 (0.00%)

3/41 (7.32%)

1/48 (2.08%)

0/18 (0.00%)

4/154 (2.60%)

1/66 (1.52%)

0/18 (0.00%)

0/18 (0.00%)

1/12 (8.33%)

Heart rate increased * 1

0/3 (0.00%)

0/4 (0.00%)

0/8 (0.00%)

0/7 (0.00%)

0/8 (0.00%)

0/6 (0.00%)

0/6 (0.00%)

0/5 (0.00%)

0/3 (0.00%)

0/6 (0.00%)

0/9 (0.00%)

1/53 (1.89%)

0/85 (0.00%)

0/41 (0.00%)

1/48 (2.08%)

0/18 (0.00%)

0/154 (0.00%)

0/66 (0.00%)

1/18 (5.56%)

0/18 (0.00%)

0/12 (0.00%)

International normalised ratio increased * 1

0/3 (0.00%)

0/4 (0.00%)

0/8 (0.00%)

0/7 (0.00%)

0/8 (0.00%)

0/6 (0.00%)

0/6 (0.00%)

0/5 (0.00%)

0/3 (0.00%)

0/6 (0.00%)

0/9 (0.00%)

0/53 (0.00%)

0/85 (0.00%)

3/41 (7.32%)

0/48 (0.00%)

0/18 (0.00%)

1/154 (0.65%)

1/66 (1.52%)

0/18 (0.00%)

1/18 (5.56%)

0/12 (0.00%)

Iron binding capacity total decreased * 1

0/3 (0.00%)

0/4 (0.00%)

0/8 (0.00%)

0/7 (0.00%)

0/8 (0.00%)

0/6 (0.00%)

0/6 (0.00%)

0/5 (0.00%)

0/3 (0.00%)

0/6 (0.00%)

0/9 (0.00%)

0/53 (0.00%)

0/85 (0.00%)

0/41 (0.00%)

0/48 (0.00%)

0/18 (0.00%)

0/154 (0.00%)

0/66 (0.00%)

0/18 (0.00%)

1/18 (5.56%)

0/12 (0.00%)

Liver function test increased * 1

0/3 (0.00%)

0/4 (0.00%)

0/8 (0.00%)

1/7 (14.29%)

0/8 (0.00%)

0/6 (0.00%)

0/6 (0.00%)

0/5 (0.00%)

0/3 (0.00%)

0/6 (0.00%)

0/9 (0.00%)

1/53 (1.89%)

1/85 (1.18%)

0/41 (0.00%)

1/48 (2.08%)

0/18 (0.00%)

1/154 (0.65%)

0/66 (0.00%)

0/18 (0.00%)

0/18 (0.00%)

0/12 (0.00%)

Lymphocyte count decreased * 1

0/3 (0.00%)

0/4 (0.00%)

0/8 (0.00%)

0/7 (0.00%)

0/8 (0.00%)

0/6 (0.00%)

0/6 (0.00%)

0/5 (0.00%)

0/3 (0.00%)

0/6 (0.00%)

0/9 (0.00%)

1/53 (1.89%)

3/85 (3.53%)

4/41 (9.76%)

0/48 (0.00%)

0/18 (0.00%)

1/154 (0.65%)

0/66 (0.00%)

0/18 (0.00%)

1/18 (5.56%)

0/12 (0.00%)

Mean cell haemoglobin concentration decreased * 1

0/3 (0.00%)

0/4 (0.00%)

0/8 (0.00%)

0/7 (0.00%)

0/8 (0.00%)

0/6 (0.00%)

0/6 (0.00%)

0/5 (0.00%)

0/3 (0.00%)

0/6 (0.00%)

0/9 (0.00%)

0/53 (0.00%)

0/85 (0.00%)

0/41 (0.00%)

0/48 (0.00%)

0/18 (0.00%)

0/154 (0.00%)

0/66 (0.00%)

0/18 (0.00%)

2/18 (11.11%)

0/12 (0.00%)

Monocyte count increased * 1

0/3 (0.00%)

0/4 (0.00%)

0/8 (0.00%)

0/7 (0.00%)

0/8 (0.00%)

0/6 (0.00%)

0/6 (0.00%)

0/5 (0.00%)

0/3 (0.00%)

0/6 (0.00%)

0/9 (0.00%)

0/53 (0.00%)

0/85 (0.00%)

0/41 (0.00%)

0/48 (0.00%)

0/18 (0.00%)

0/154 (0.00%)

0/66 (0.00%)

0/18 (0.00%)

1/18 (5.56%)

0/12 (0.00%)

Neutrophil count decreased * 1

0/3 (0.00%)

0/4 (0.00%)

0/8 (0.00%)

0/7 (0.00%)

0/8 (0.00%)

0/6 (0.00%)

0/6 (0.00%)

0/5 (0.00%)

0/3 (0.00%)

0/6 (0.00%)

1/9 (11.11%)

2/53 (3.77%)

3/85 (3.53%)

4/41 (9.76%)

0/48 (0.00%)

1/18 (5.56%)

2/154 (1.30%)

3/66 (4.55%)

0/18 (0.00%)

0/18 (0.00%)

0/12 (0.00%)

Nitrite urine present * 1

0/3 (0.00%)

0/4 (0.00%)

0/8 (0.00%)

0/7 (0.00%)

0/8 (0.00%)

0/6 (0.00%)

0/6 (0.00%)

0/5 (0.00%)

0/3 (0.00%)

0/6 (0.00%)

0/9 (0.00%)

0/53 (0.00%)

0/85 (0.00%)

0/41 (0.00%)

0/48 (0.00%)

0/18 (0.00%)

0/154 (0.00%)

0/66 (0.00%)

0/18 (0.00%)

1/18 (5.56%)

0/12 (0.00%)

Oxygen saturation decreased * 1

0/3 (0.00%)

0/4 (0.00%)

0/8 (0.00%)

1/7 (14.29%)

0/8 (0.00%)

0/6 (0.00%)

0/6 (0.00%)

0/5 (0.00%)

0/3 (0.00%)

0/6 (0.00%)

0/9 (0.00%)

0/53 (0.00%)

0/85 (0.00%)

0/41 (0.00%)

0/48 (0.00%)

0/18 (0.00%)

0/154 (0.00%)

0/66 (0.00%)

0/18 (0.00%)

0/18 (0.00%)

0/12 (0.00%)

Platelet count decreased * 1

0/3 (0.00%)

0/4 (0.00%)

0/8 (0.00%)

0/7 (0.00%)

0/8 (0.00%)

0/6 (0.00%)

0/6 (0.00%)

0/5 (0.00%)

0/3 (0.00%)

0/6 (0.00%)

0/9 (0.00%)

0/53 (0.00%)

2/85 (2.35%)

3/41 (7.32%)

0/48 (0.00%)

0/18 (0.00%)

4/154 (2.60%)

1/66 (1.52%)

0/18 (0.00%)

1/18 (5.56%)

0/12 (0.00%)

Protein total decreased * 1

0/3 (0.00%)

0/4 (0.00%)

0/8 (0.00%)

0/7 (0.00%)

0/8 (0.00%)

0/6 (0.00%)

0/6 (0.00%)

0/5 (0.00%)

0/3 (0.00%)

0/6 (0.00%)

0/9 (0.00%)

0/53 (0.00%)

0/85 (0.00%)

0/41 (0.00%)

0/48 (0.00%)

0/18 (0.00%)

1/154 (0.65%)

0/66 (0.00%)

0/18 (0.00%)

1/18 (5.56%)

0/12 (0.00%)

Protein urine present * 1

0/3 (0.00%)

0/4 (0.00%)

0/8 (0.00%)

0/7 (0.00%)

0/8 (0.00%)

0/6 (0.00%)

0/6 (0.00%)

0/5 (0.00%)

0/3 (0.00%)

0/6 (0.00%)

0/9 (0.00%)

0/53 (0.00%)

0/85 (0.00%)

0/41 (0.00%)

0/48 (0.00%)

0/18 (0.00%)

0/154 (0.00%)

0/66 (0.00%)

0/18 (0.00%)

1/18 (5.56%)

0/12 (0.00%)

Prothrombin time prolonged * 1

0/3 (0.00%)

0/4 (0.00%)

0/8 (0.00%)

0/7 (0.00%)

0/8 (0.00%)

0/6 (0.00%)

0/6 (0.00%)

0/5 (0.00%)

0/3 (0.00%)

0/6 (0.00%)

0/9 (0.00%)

0/53 (0.00%)

1/85 (1.18%)

1/41 (2.44%)

0/48 (0.00%)

0/18 (0.00%)

0/154 (0.00%)

0/66 (0.00%)

0/18 (0.00%)

1/18 (5.56%)

0/12 (0.00%)

Red blood cells urine positive * 1

0/3 (0.00%)

0/4 (0.00%)

0/8 (0.00%)

0/7 (0.00%)

0/8 (0.00%)

0/6 (0.00%)

0/6 (0.00%)

0/5 (0.00%)

0/3 (0.00%)

0/6 (0.00%)

0/9 (0.00%)

0/53 (0.00%)

0/85 (0.00%)

0/41 (0.00%)

0/48 (0.00%)

0/18 (0.00%)

0/154 (0.00%)

0/66 (0.00%)

0/18 (0.00%)

1/18 (5.56%)

0/12 (0.00%)

Red cell distribution width increased * 1

0/3 (0.00%)

0/4 (0.00%)

0/8 (0.00%)

0/7 (0.00%)

0/8 (0.00%)

0/6 (0.00%)

0/6 (0.00%)

0/5 (0.00%)

0/3 (0.00%)

0/6 (0.00%)

0/9 (0.00%)

0/53 (0.00%)

0/85 (0.00%)

1/41 (2.44%)

0/48 (0.00%)

0/18 (0.00%)

0/154 (0.00%)

0/66 (0.00%)

0/18 (0.00%)

2/18 (11.11%)

0/12 (0.00%)

Serum ferritin increased * 1

0/3 (0.00%)

0/4 (0.00%)

0/8 (0.00%)

0/7 (0.00%)

0/8 (0.00%)

0/6 (0.00%)

0/6 (0.00%)

0/5 (0.00%)

0/3 (0.00%)

0/6 (0.00%)

0/9 (0.00%)

0/53 (0.00%)

0/85 (0.00%)

0/41 (0.00%)

0/48 (0.00%)

0/18 (0.00%)

0/154 (0.00%)

0/66 (0.00%)

0/18 (0.00%)

1/18 (5.56%)

0/12 (0.00%)

Transferrin saturation decreased * 1

0/3 (0.00%)

0/4 (0.00%)

0/8 (0.00%)

0/7 (0.00%)

0/8 (0.00%)

0/6 (0.00%)

0/6 (0.00%)

0/5 (0.00%)

0/3 (0.00%)

0/6 (0.00%)

0/9 (0.00%)

0/53 (0.00%)

0/85 (0.00%)

0/41 (0.00%)

0/48 (0.00%)

0/18 (0.00%)

0/154 (0.00%)

0/66 (0.00%)

0/18 (0.00%)

1/18 (5.56%)

0/12 (0.00%)

Urine ketone body present * 1

0/3 (0.00%)

0/4 (0.00%)

0/8 (0.00%)

0/7 (0.00%)

0/8 (0.00%)

0/6 (0.00%)

0/6 (0.00%)

0/5 (0.00%)

0/3 (0.00%)

0/6 (0.00%)

0/9 (0.00%)

0/53 (0.00%)

0/85 (0.00%)

0/41 (0.00%)

0/48 (0.00%)

1/18 (5.56%)

0/154 (0.00%)

0/66 (0.00%)

0/18 (0.00%)

0/18 (0.00%)

0/12 (0.00%)

Urine leukocyte esterase positive * 1

0/3 (0.00%)

0/4 (0.00%)

0/8 (0.00%)

0/7 (0.00%)

0/8 (0.00%)

0/6 (0.00%)

0/6 (0.00%)

0/5 (0.00%)

0/3 (0.00%)

0/6 (0.00%)

0/9 (0.00%)

0/53 (0.00%)

0/85 (0.00%)

0/41 (0.00%)

0/48 (0.00%)

0/18 (0.00%)

0/154 (0.00%)

0/66 (0.00%)

0/18 (0.00%)

1/18 (5.56%)

0/12 (0.00%)

Urine output decreased * 1

0/3 (0.00%)

0/4 (0.00%)

0/8 (0.00%)

0/7 (0.00%)

0/8 (0.00%)

0/6 (0.00%)

0/6 (0.00%)

0/5 (0.00%)

1/3 (33.33%)

1/6 (16.67%)

0/9 (0.00%)

0/53 (0.00%)

1/85 (1.18%)

0/41 (0.00%)

0/48 (0.00%)

0/18 (0.00%)

0/154 (0.00%)

0/66 (0.00%)

0/18 (0.00%)

0/18 (0.00%)

0/12 (0.00%)

Vital dye staining cornea present * 1

0/3 (0.00%)

0/4 (0.00%)

0/8 (0.00%)

0/7 (0.00%)

0/8 (0.00%)

0/6 (0.00%)

0/6 (0.00%)

0/5 (0.00%)

0/3 (0.00%)

0/6 (0.00%)

0/9 (0.00%)

0/53 (0.00%)

0/85 (0.00%)

0/41 (0.00%)

0/48 (0.00%)

0/18 (0.00%)

0/154 (0.00%)

0/66 (0.00%)

1/18 (5.56%)

0/18 (0.00%)

0/12 (0.00%)

Waist circumference increased * 1

0/3 (0.00%)

0/4 (0.00%)

0/8 (0.00%)

0/7 (0.00%)

0/8 (0.00%)

0/6 (0.00%)

0/6 (0.00%)

0/5 (0.00%)

0/3 (0.00%)

1/6 (16.67%)

0/9 (0.00%)

0/53 (0.00%)

0/85 (0.00%)

0/41 (0.00%)

0/48 (0.00%)

0/18 (0.00%)

0/154 (0.00%)

0/66 (0.00%)

0/18 (0.00%)

0/18 (0.00%)

0/12 (0.00%)

White blood cell count decreased * 1

0/3 (0.00%)

0/4 (0.00%)

0/8 (0.00%)

0/7 (0.00%)

0/8 (0.00%)

0/6 (0.00%)

0/6 (0.00%)

0/5 (0.00%)

0/3 (0.00%)

0/6 (0.00%)

1/9 (11.11%)

1/53 (1.89%)

5/85 (5.88%)

4/41 (9.76%)

0/48 (0.00%)

0/18 (0.00%)

7/154 (4.55%)

6/66 (9.09%)

0/18 (0.00%)

0/18 (0.00%)

0/12 (0.00%)

Cardiac murmur * 1

0/3 (0.00%)

0/4 (0.00%)

0/8 (0.00%)

0/7 (0.00%)

0/8 (0.00%)

0/6 (0.00%)

0/6 (0.00%)

0/5 (0.00%)

0/3 (0.00%)

0/6 (0.00%)

0/9 (0.00%)

0/53 (0.00%)

0/85 (0.00%)

0/41 (0.00%)

0/48 (0.00%)

0/18 (0.00%)

0/154 (0.00%)

0/66 (0.00%)

0/18 (0.00%)

0/18 (0.00%)

1/12 (8.33%)

Metabolism and nutrition disorders

Decreased appetite * 1

1/3 (33.33%)

2/4 (50.00%)

4/8 (50.00%)

2/7 (28.57%)

2/8 (25.00%)

4/6 (66.67%)

1/6 (16.67%)

1/5 (20.00%)

2/3 (66.67%)

1/6 (16.67%)

3/9 (33.33%)

16/53 (30.19%)

24/85 (28.24%)

7/41 (17.07%)

9/48 (18.75%)

3/18 (16.67%)

50/154 (32.47%)

20/66 (30.30%)

5/18 (27.78%)

6/18 (33.33%)

3/12 (25.00%)

Dehydration * 1

0/3 (0.00%)

2/4 (50.00%)

1/8 (12.50%)

1/7 (14.29%)

2/8 (25.00%)

1/6 (16.67%)

0/6 (0.00%)

1/5 (20.00%)

0/3 (0.00%)

1/6 (16.67%)

2/9 (22.22%)

5/53 (9.43%)

3/85 (3.53%)

6/41 (14.63%)

6/48 (12.50%)

2/18 (11.11%)

13/154 (8.44%)

6/66 (9.09%)

4/18 (22.22%)

1/18 (5.56%)

3/12 (25.00%)

Hyperglycaemia * 1

0/3 (0.00%)

0/4 (0.00%)

0/8 (0.00%)

0/7 (0.00%)

0/8 (0.00%)

0/6 (0.00%)

1/6 (16.67%)

0/5 (0.00%)

0/3 (0.00%)

0/6 (0.00%)

1/9 (11.11%)

3/53 (5.66%)

2/85 (2.35%)

8/41 (19.51%)

3/48 (6.25%)

1/18 (5.56%)

7/154 (4.55%)

1/66 (1.52%)

1/18 (5.56%)

2/18 (11.11%)

0/12 (0.00%)

Hypoalbuminaemia * 1 [1]

0/3 (0.00%)

0/4 (0.00%)

0/8 (0.00%)

0/7 (0.00%)

0/8 (0.00%)

0/6 (0.00%)

0/6 (0.00%)

1/5 (20.00%)

0/3 (0.00%)

2/6 (33.33%)

1/9 (11.11%)

4/53 (7.55%)

9/85 (10.59%)

12/41 (29.27%)

3/48 (6.25%)

2/18 (11.11%)

8/154 (5.19%)

10/66 (15.15%)

3/18 (16.67%)

3/18 (16.67%)

0/12 (0.00%)

Hypocalcaemia * 1

0/3 (0.00%)

0/4 (0.00%)

0/8 (0.00%)

0/7 (0.00%)

0/8 (0.00%)

0/6 (0.00%)

0/6 (0.00%)

0/5 (0.00%)

0/3 (0.00%)

0/6 (0.00%)

1/9 (11.11%)

3/53 (5.66%)

0/85 (0.00%)

5/41 (12.20%)

2/48 (4.17%)

2/18 (11.11%)

8/154 (5.19%)

4/66 (6.06%)

0/18 (0.00%)

1/18 (5.56%)

0/12 (0.00%)

Hyponatraemia * 1

0/3 (0.00%)

0/4 (0.00%)

0/8 (0.00%)

0/7 (0.00%)

0/8 (0.00%)

1/6 (16.67%)

0/6 (0.00%)

0/5 (0.00%)

0/3 (0.00%)

0/6 (0.00%)

2/9 (22.22%)

3/53 (5.66%)

11/85 (12.94%)

12/41 (29.27%)

3/48 (6.25%)

1/18 (5.56%)

10/154 (6.49%)

11/66 (16.67%)

2/18 (11.11%)

2/18 (11.11%)

2/12 (16.67%)

Hypophosphataemia * 1

0/3 (0.00%)

0/4 (0.00%)

0/8 (0.00%)

0/7 (0.00%)

0/8 (0.00%)

0/6 (0.00%)

0/6 (0.00%)

0/5 (0.00%)

0/3 (0.00%)

0/6 (0.00%)

0/9 (0.00%)

10/53 (18.87%)

7/85 (8.24%)

6/41 (14.63%)

5/48 (10.42%)

2/18 (11.11%)

29/154 (18.83%)

10/66 (15.15%)

0/18 (0.00%)

2/18 (11.11%)

1/12 (8.33%)

Vitamin D deficiency * 1

0/3 (0.00%)

0/4 (0.00%)

0/8 (0.00%)

0/7 (0.00%)

0/8 (0.00%)

0/6 (0.00%)

0/6 (0.00%)

0/5 (0.00%)

0/3 (0.00%)

0/6 (0.00%)

0/9 (0.00%)

4/53 (7.55%)

0/85 (0.00%)

0/41 (0.00%)

0/48 (0.00%)

0/18 (0.00%)

0/154 (0.00%)

0/66 (0.00%)

0/18 (0.00%)

0/18 (0.00%)

0/12 (0.00%)

Hyperkalaemia * 1

0/3 (0.00%)

0/4 (0.00%)

0/8 (0.00%)

0/7 (0.00%)

0/8 (0.00%)

1/6 (16.67%)

0/6 (0.00%)

0/5 (0.00%)

0/3 (0.00%)

0/6 (0.00%)

0/9 (0.00%)

2/53 (3.77%)

8/85 (9.41%)

5/41 (12.20%)

0/48 (0.00%)

1/18 (5.56%)

4/154 (2.60%)

1/66 (1.52%)

0/18 (0.00%)

0/18 (0.00%)

0/12 (0.00%)

Hyperuricaemia * 1

0/3 (0.00%)

0/4 (0.00%)

0/8 (0.00%)

0/7 (0.00%)

0/8 (0.00%)

0/6 (0.00%)

0/6 (0.00%)

0/5 (0.00%)

0/3 (0.00%)

0/6 (0.00%)

0/9 (0.00%)

0/53 (0.00%)

3/85 (3.53%)

2/41 (4.88%)

0/48 (0.00%)

0/18 (0.00%)

1/154 (0.65%)

4/66 (6.06%)

2/18 (11.11%)

1/18 (5.56%)

0/12 (0.00%)

Hypoglycaemia * 1

0/3 (0.00%)

0/4 (0.00%)

0/8 (0.00%)

0/7 (0.00%)

0/8 (0.00%)

0/6 (0.00%)

0/6 (0.00%)

0/5 (0.00%)

0/3 (0.00%)

0/6 (0.00%)

0/9 (0.00%)

0/53 (0.00%)

2/85 (2.35%)

0/41 (0.00%)

0/48 (0.00%)

0/18 (0.00%)

1/154 (0.65%)

0/66 (0.00%)

0/18 (0.00%)

1/18 (5.56%)

0/12 (0.00%)

Hypokalaemia * 1

0/3 (0.00%)

0/4 (0.00%)

0/8 (0.00%)

1/7 (14.29%)

0/8 (0.00%)

0/6 (0.00%)

0/6 (0.00%)

0/5 (0.00%)

0/3 (0.00%)

0/6 (0.00%)

0/9 (0.00%)

1/53 (1.89%)

3/85 (3.53%)

3/41 (7.32%)

1/48 (2.08%)

0/18 (0.00%)

8/154 (5.19%)

4/66 (6.06%)

1/18 (5.56%)

4/18 (22.22%)

0/12 (0.00%)

Hypomagnesaemia * 1

0/3 (0.00%)

0/4 (0.00%)

0/8 (0.00%)

0/7 (0.00%)

0/8 (0.00%)

0/6 (0.00%)

0/6 (0.00%)

0/5 (0.00%)

0/3 (0.00%)

0/6 (0.00%)

0/9 (0.00%)

0/53 (0.00%)

2/85 (2.35%)

1/41 (2.44%)

0/48 (0.00%)

0/18 (0.00%)

1/154 (0.65%)

0/66 (0.00%)

0/18 (0.00%)

2/18 (11.11%)

0/12 (0.00%)

Hypophagia * 1

0/3 (0.00%)

0/4 (0.00%)

0/8 (0.00%)

0/7 (0.00%)

0/8 (0.00%)

0/6 (0.00%)

0/6 (0.00%)

0/5 (0.00%)

0/3 (0.00%)

0/6 (0.00%)

0/9 (0.00%)

0/53 (0.00%)

0/85 (0.00%)

0/41 (0.00%)

0/48 (0.00%)

0/18 (0.00%)

0/154 (0.00%)

0/66 (0.00%)

1/18 (5.56%)

0/18 (0.00%)

0/12 (0.00%)

Malnutrition * 1

0/3 (0.00%)

0/4 (0.00%)

0/8 (0.00%)

0/7 (0.00%)

0/8 (0.00%)

0/6 (0.00%)

0/6 (0.00%)

0/5 (0.00%)

0/3 (0.00%)

0/6 (0.00%)

1/9 (11.11%)

0/53 (0.00%)

0/85 (0.00%)

0/41 (0.00%)

1/48 (2.08%)

0/18 (0.00%)

0/154 (0.00%)

0/66 (0.00%)

0/18 (0.00%)

0/18 (0.00%)

0/12 (0.00%)

Metabolic acidosis * 1

0/3 (0.00%)

0/4 (0.00%)

0/8 (0.00%)

0/7 (0.00%)

0/8 (0.00%)

0/6 (0.00%)

0/6 (0.00%)

0/5 (0.00%)

0/3 (0.00%)

0/6 (0.00%)

1/9 (11.11%)

0/53 (0.00%)

1/85 (1.18%)

1/41 (2.44%)

1/48 (2.08%)

0/18 (0.00%)

0/154 (0.00%)

0/66 (0.00%)

0/18 (0.00%)

0/18 (0.00%)

0/12 (0.00%)

Musculoskeletal and connective tissue disorders

Arthralgia * 1

0/3 (0.00%)

1/4 (25.00%)

1/8 (12.50%)

1/7 (14.29%)

0/8 (0.00%)

0/6 (0.00%)

0/6 (0.00%)

0/5 (0.00%)

0/3 (0.00%)

0/6 (0.00%)

0/9 (0.00%)

9/53 (16.98%)

16/85 (18.82%)

4/41 (9.76%)

4/48 (8.33%)

4/18 (22.22%)

22/154 (14.29%)

7/66 (10.61%)

2/18 (11.11%)

1/18 (5.56%)

0/12 (0.00%)

Back pain * 1 [1]

1/3 (33.33%)

0/4 (0.00%)

3/8 (37.50%)

0/7 (0.00%)

1/8 (12.50%)

0/6 (0.00%)

0/6 (0.00%)

0/5 (0.00%)

0/3 (0.00%)

0/6 (0.00%)

0/9 (0.00%)

9/53 (16.98%)

14/85 (16.47%)

12/41 (29.27%)

4/48 (8.33%)

5/18 (27.78%)

32/154 (20.78%)

9/66 (13.64%)

1/18 (5.56%)

2/18 (11.11%)

1/12 (8.33%)

Flank pain * 1

0/3 (0.00%)

0/4 (0.00%)

1/8 (12.50%)

0/7 (0.00%)

0/8 (0.00%)

0/6 (0.00%)

0/6 (0.00%)

0/5 (0.00%)

0/3 (0.00%)

0/6 (0.00%)

0/9 (0.00%)

3/53 (5.66%)

1/85 (1.18%)

1/41 (2.44%)

0/48 (0.00%)

3/18 (16.67%)

6/154 (3.90%)

3/66 (4.55%)

0/18 (0.00%)

0/18 (0.00%)

0/12 (0.00%)

Joint swelling * 1

0/3 (0.00%)

0/4 (0.00%)

1/8 (12.50%)

0/7 (0.00%)

0/8 (0.00%)

0/6 (0.00%)

0/6 (0.00%)

0/5 (0.00%)

0/3 (0.00%)

0/6 (0.00%)

0/9 (0.00%)

3/53 (5.66%)

1/85 (1.18%)

2/41 (4.88%)

5/48 (10.42%)

0/18 (0.00%)

20/154 (12.99%)

1/66 (1.52%)

1/18 (5.56%)

0/18 (0.00%)

0/12 (0.00%)

Muscle spasms * 1

0/3 (0.00%)

0/4 (0.00%)

0/8 (0.00%)

1/7 (14.29%)

0/8 (0.00%)

0/6 (0.00%)

0/6 (0.00%)

0/5 (0.00%)

1/3 (33.33%)

0/6 (0.00%)

0/9 (0.00%)

4/53 (7.55%)

6/85 (7.06%)

1/41 (2.44%)

6/48 (12.50%)

1/18 (5.56%)

27/154 (17.53%)

3/66 (4.55%)

1/18 (5.56%)

0/18 (0.00%)

1/12 (8.33%)

Muscular weakness * 1

1/3 (33.33%)

0/4 (0.00%)

1/8 (12.50%)

0/7 (0.00%)

0/8 (0.00%)

1/6 (16.67%)

0/6 (0.00%)

1/5 (20.00%)

0/3 (0.00%)

0/6 (0.00%)

0/9 (0.00%)

8/53 (15.09%)

16/85 (18.82%)

7/41 (17.07%)

5/48 (10.42%)

0/18 (0.00%)

12/154 (7.79%)

4/66 (6.06%)

0/18 (0.00%)

0/18 (0.00%)

0/12 (0.00%)

Musculoskeletal chest pain * 1

0/3 (0.00%)

0/4 (0.00%)

0/8 (0.00%)

0/7 (0.00%)

0/8 (0.00%)

0/6 (0.00%)

0/6 (0.00%)

0/5 (0.00%)

1/3 (33.33%)

0/6 (0.00%)

0/9 (0.00%)

4/53 (7.55%)

6/85 (7.06%)

1/41 (2.44%)

1/48 (2.08%)

1/18 (5.56%)

8/154 (5.19%)

1/66 (1.52%)

0/18 (0.00%)

0/18 (0.00%)

0/12 (0.00%)

Musculoskeletal pain * 1

0/3 (0.00%)

0/4 (0.00%)

0/8 (0.00%)

0/7 (0.00%)

0/8 (0.00%)

0/6 (0.00%)

0/6 (0.00%)

0/5 (0.00%)

0/3 (0.00%)

0/6 (0.00%)

0/9 (0.00%)

3/53 (5.66%)

6/85 (7.06%)

3/41 (7.32%)

5/48 (10.42%)

0/18 (0.00%)

15/154 (9.74%)

4/66 (6.06%)

0/18 (0.00%)

0/18 (0.00%)

1/12 (8.33%)

Myalgia * 1

0/3 (0.00%)

1/4 (25.00%)

1/8 (12.50%)

0/7 (0.00%)

0/8 (0.00%)

1/6 (16.67%)

0/6 (0.00%)

0/5 (0.00%)

0/3 (0.00%)

0/6 (0.00%)

0/9 (0.00%)

5/53 (9.43%)

12/85 (14.12%)

2/41 (4.88%)

1/48 (2.08%)

2/18 (11.11%)

11/154 (7.14%)

3/66 (4.55%)

1/18 (5.56%)

1/18 (5.56%)

0/12 (0.00%)

Pain in extremity * 1

0/3 (0.00%)

0/4 (0.00%)

0/8 (0.00%)

2/7 (28.57%)

0/8 (0.00%)

0/6 (0.00%)

0/6 (0.00%)

1/5 (20.00%)

0/3 (0.00%)

1/6 (16.67%)

0/9 (0.00%)

7/53 (13.21%)

11/85 (12.94%)

2/41 (4.88%)

2/48 (4.17%)

1/18 (5.56%)

18/154 (11.69%)

3/66 (4.55%)

0/18 (0.00%)

0/18 (0.00%)

0/12 (0.00%)

Groin pain * 1

0/3 (0.00%)

0/4 (0.00%)

0/8 (0.00%)

0/7 (0.00%)

0/8 (0.00%)

1/6 (16.67%)

0/6 (0.00%)

0/5 (0.00%)

0/3 (0.00%)

1/6 (16.67%)

0/9 (0.00%)

1/53 (1.89%)

1/85 (1.18%)

0/41 (0.00%)

0/48 (0.00%)

0/18 (0.00%)

3/154 (1.95%)

0/66 (0.00%)

0/18 (0.00%)

0/18 (0.00%)

0/12 (0.00%)

Limb discomfort * 1

0/3 (0.00%)

0/4 (0.00%)

0/8 (0.00%)

0/7 (0.00%)

0/8 (0.00%)

0/6 (0.00%)

0/6 (0.00%)

0/5 (0.00%)

0/3 (0.00%)

0/6 (0.00%)

0/9 (0.00%)

0/53 (0.00%)

0/85 (0.00%)

0/41 (0.00%)

4/48 (8.33%)

0/18 (0.00%)

3/154 (1.95%)

0/66 (0.00%)

0/18 (0.00%)

0/18 (0.00%)

0/12 (0.00%)

Limb mass * 1

0/3 (0.00%)

0/4 (0.00%)

0/8 (0.00%)

0/7 (0.00%)

0/8 (0.00%)

0/6 (0.00%)

0/6 (0.00%)

0/5 (0.00%)

0/3 (0.00%)

0/6 (0.00%)

0/9 (0.00%)

0/53 (0.00%)

0/85 (0.00%)

0/41 (0.00%)

0/48 (0.00%)

0/18 (0.00%)

0/154 (0.00%)

0/66 (0.00%)

1/18 (5.56%)

0/18 (0.00%)

0/12 (0.00%)

Muscle twitching * 1

0/3 (0.00%)

0/4 (0.00%)

0/8 (0.00%)

0/7 (0.00%)

0/8 (0.00%)

0/6 (0.00%)

0/6 (0.00%)

0/5 (0.00%)

0/3 (0.00%)

1/6 (16.67%)

0/9 (0.00%)

0/53 (0.00%)

0/85 (0.00%)

0/41 (0.00%)

0/48 (0.00%)

0/18 (0.00%)

1/154 (0.65%)

0/66 (0.00%)

0/18 (0.00%)

1/18 (5.56%)

0/12 (0.00%)

Musculoskeletal discomfort * 1

0/3 (0.00%)

0/4 (0.00%)

0/8 (0.00%)

0/7 (0.00%)

0/8 (0.00%)

0/6 (0.00%)

0/6 (0.00%)

0/5 (0.00%)

1/3 (33.33%)

0/6 (0.00%)

0/9 (0.00%)

2/53 (3.77%)

0/85 (0.00%)

1/41 (2.44%)

1/48 (2.08%)

0/18 (0.00%)

6/154 (3.90%)

0/66 (0.00%)

0/18 (0.00%)

0/18 (0.00%)

0/12 (0.00%)

Neck pain * 1

0/3 (0.00%)

0/4 (0.00%)

0/8 (0.00%)

0/7 (0.00%)

0/8 (0.00%)

0/6 (0.00%)

0/6 (0.00%)

0/5 (0.00%)

0/3 (0.00%)

0/6 (0.00%)

0/9 (0.00%)

2/53 (3.77%)

3/85 (3.53%)

2/41 (4.88%)

0/48 (0.00%)

1/18 (5.56%)

10/154 (6.49%)

3/66 (4.55%)

0/18 (0.00%)

0/18 (0.00%)

0/12 (0.00%)

Spinal stenosis * 1

0/3 (0.00%)

0/4 (0.00%)

0/8 (0.00%)

0/7 (0.00%)

0/8 (0.00%)

0/6 (0.00%)

0/6 (0.00%)

0/5 (0.00%)

0/3 (0.00%)

0/6 (0.00%)

0/9 (0.00%)

0/53 (0.00%)

0/85 (0.00%)

1/41 (2.44%)

0/48 (0.00%)

1/18 (5.56%)

0/154 (0.00%)

0/66 (0.00%)

0/18 (0.00%)

0/18 (0.00%)

0/12 (0.00%)

Tendonitis * 1

0/3 (0.00%)

0/4 (0.00%)

0/8 (0.00%)

0/7 (0.00%)

0/8 (0.00%)

0/6 (0.00%)

0/6 (0.00%)

0/5 (0.00%)

0/3 (0.00%)

1/6 (16.67%)

0/9 (0.00%)

1/53 (1.89%)

0/85 (0.00%)

0/41 (0.00%)

1/48 (2.08%)

1/18 (5.56%)

0/154 (0.00%)

0/66 (0.00%)

0/18 (0.00%)

0/18 (0.00%)

0/12 (0.00%)

Neoplasms benign, malignant and unspecified (incl cysts and polyps)

Metastases to central nervous system * 1

0/3 (0.00%)

0/4 (0.00%)

0/8 (0.00%)

0/7 (0.00%)

0/8 (0.00%)

0/6 (0.00%)

0/6 (0.00%)

0/5 (0.00%)

0/3 (0.00%)

0/6 (0.00%)

1/9 (11.11%)

0/53 (0.00%)

0/85 (0.00%)

0/41 (0.00%)

0/48 (0.00%)

0/18 (0.00%)

0/154 (0.00%)

0/66 (0.00%)

0/18 (0.00%)

0/18 (0.00%)

0/12 (0.00%)

Oncologic complication * 1

0/3 (0.00%)

0/4 (0.00%)

0/8 (0.00%)

0/7 (0.00%)

0/8 (0.00%)

0/6 (0.00%)

0/6 (0.00%)

0/5 (0.00%)

1/3 (33.33%)

0/6 (0.00%)

0/9 (0.00%)

0/53 (0.00%)

0/85 (0.00%)

0/41 (0.00%)

0/48 (0.00%)

0/18 (0.00%)

0/154 (0.00%)

0/66 (0.00%)

0/18 (0.00%)

0/18 (0.00%)

0/12 (0.00%)

Nervous system disorders

Dizziness * 1

0/3 (0.00%)

0/4 (0.00%)

2/8 (25.00%)

0/7 (0.00%)

1/8 (12.50%)

0/6 (0.00%)

0/6 (0.00%)

0/5 (0.00%)

0/3 (0.00%)

1/6 (16.67%)

0/9 (0.00%)

21/53 (39.62%)

25/85 (29.41%)

9/41 (21.95%)

12/48 (25.00%)

3/18 (16.67%)

65/154 (42.21%)

15/66 (22.73%)

5/18 (27.78%)

3/18 (16.67%)

1/12 (8.33%)

Dysgeusia * 1

0/3 (0.00%)

0/4 (0.00%)

0/8 (0.00%)

0/7 (0.00%)

0/8 (0.00%)

0/6 (0.00%)

0/6 (0.00%)

0/5 (0.00%)

0/3 (0.00%)

1/6 (16.67%)

1/9 (11.11%)

5/53 (9.43%)

19/85 (22.35%)

4/41 (9.76%)

2/48 (4.17%)

0/18 (0.00%)

7/154 (4.55%)

4/66 (6.06%)

0/18 (0.00%)

2/18 (11.11%)

0/12 (0.00%)

Headache * 1

1/3 (33.33%)

1/4 (25.00%)

1/8 (12.50%)

1/7 (14.29%)

1/8 (12.50%)

0/6 (0.00%)

0/6 (0.00%)

0/5 (0.00%)

0/3 (0.00%)

1/6 (16.67%)

1/9 (11.11%)

15/53 (28.30%)

16/85 (18.82%)

3/41 (7.32%)

7/48 (14.58%)

2/18 (11.11%)

34/154 (22.08%)

8/66 (12.12%)

3/18 (16.67%)

1/18 (5.56%)

0/12 (0.00%)

Hypoaesthesia * 1

0/3 (0.00%)

0/4 (0.00%)

0/8 (0.00%)

1/7 (14.29%)

0/8 (0.00%)

0/6 (0.00%)

0/6 (0.00%)

0/5 (0.00%)

1/3 (33.33%)

0/6 (0.00%)

0/9 (0.00%)

4/53 (7.55%)

0/85 (0.00%)

1/41 (2.44%)

3/48 (6.25%)

2/18 (11.11%)

13/154 (8.44%)

2/66 (3.03%)

1/18 (5.56%)

1/18 (5.56%)

0/12 (0.00%)

Memory impairment * 1

0/3 (0.00%)

0/4 (0.00%)

0/8 (0.00%)

0/7 (0.00%)

0/8 (0.00%)

0/6 (0.00%)

0/6 (0.00%)

0/5 (0.00%)

0/3 (0.00%)

0/6 (0.00%)

0/9 (0.00%)

3/53 (5.66%)

1/85 (1.18%)

1/41 (2.44%)

2/48 (4.17%)

1/18 (5.56%)

6/154 (3.90%)

0/66 (0.00%)

0/18 (0.00%)

0/18 (0.00%)

0/12 (0.00%)

Neuropathy peripheral * 1

0/3 (0.00%)

0/4 (0.00%)

0/8 (0.00%)

1/7 (14.29%)

1/8 (12.50%)

0/6 (0.00%)

0/6 (0.00%)

0/5 (0.00%)

0/3 (0.00%)

0/6 (0.00%)

0/9 (0.00%)

4/53 (7.55%)

2/85 (2.35%)

2/41 (4.88%)

1/48 (2.08%)

0/18 (0.00%)

13/154 (8.44%)

4/66 (6.06%)

1/18 (5.56%)

1/18 (5.56%)

2/12 (16.67%)

Paraesthesia * 1

0/3 (0.00%)

0/4 (0.00%)

0/8 (0.00%)

1/7 (14.29%)

0/8 (0.00%)

0/6 (0.00%)

0/6 (0.00%)

0/5 (0.00%)

0/3 (0.00%)

0/6 (0.00%)

0/9 (0.00%)

8/53 (15.09%)

8/85 (9.41%)

2/41 (4.88%)

6/48 (12.50%)

0/18 (0.00%)

21/154 (13.64%)

3/66 (4.55%)

0/18 (0.00%)

0/18 (0.00%)

0/12 (0.00%)

Taste disorder * 1

0/3 (0.00%)

0/4 (0.00%)

0/8 (0.00%)

0/7 (0.00%)

0/8 (0.00%)

0/6 (0.00%)

0/6 (0.00%)

1/5 (20.00%)

1/3 (33.33%)

0/6 (0.00%)

0/9 (0.00%)

7/53 (13.21%)

3/85 (3.53%)

2/41 (4.88%)

0/48 (0.00%)

0/18 (0.00%)

18/154 (11.69%)

4/66 (6.06%)

1/18 (5.56%)

3/18 (16.67%)

0/12 (0.00%)

Ageusia * 1

0/3 (0.00%)

0/4 (0.00%)

0/8 (0.00%)

0/7 (0.00%)

0/8 (0.00%)

0/6 (0.00%)

0/6 (0.00%)

0/5 (0.00%)

0/3 (0.00%)

0/6 (0.00%)

1/9 (11.11%)

0/53 (0.00%)

0/85 (0.00%)

0/41 (0.00%)

0/48 (0.00%)

0/18 (0.00%)

0/154 (0.00%)

0/66 (0.00%)

0/18 (0.00%)

0/18 (0.00%)

0/12 (0.00%)

Amnesia * 1

0/3 (0.00%)

0/4 (0.00%)

1/8 (12.50%)

0/7 (0.00%)

0/8 (0.00%)

0/6 (0.00%)

0/6 (0.00%)

0/5 (0.00%)

0/3 (0.00%)

0/6 (0.00%)

0/9 (0.00%)

0/53 (0.00%)

0/85 (0.00%)

0/41 (0.00%)

1/48 (2.08%)

0/18 (0.00%)

5/154 (3.25%)

1/66 (1.52%)

0/18 (0.00%)

0/18 (0.00%)

0/12 (0.00%)

Aphasia * 1

0/3 (0.00%)

0/4 (0.00%)

0/8 (0.00%)

1/7 (14.29%)

0/8 (0.00%)

0/6 (0.00%)

0/6 (0.00%)

0/5 (0.00%)

0/3 (0.00%)

0/6 (0.00%)

0/9 (0.00%)

1/53 (1.89%)

2/85 (2.35%)

1/41 (2.44%)

0/48 (0.00%)

0/18 (0.00%)

8/154 (5.19%)

1/66 (1.52%)

0/18 (0.00%)

0/18 (0.00%)

0/12 (0.00%)

Ataxia * 1

0/3 (0.00%)

0/4 (0.00%)

0/8 (0.00%)

0/7 (0.00%)

0/8 (0.00%)

0/6 (0.00%)

0/6 (0.00%)

0/5 (0.00%)

0/3 (0.00%)

0/6 (0.00%)

0/9 (0.00%)

0/53 (0.00%)

3/85 (3.53%)

0/41 (0.00%)

0/48 (0.00%)

0/18 (0.00%)

2/154 (1.30%)

0/66 (0.00%)

1/18 (5.56%)

0/18 (0.00%)

0/12 (0.00%)

Coma * 1

0/3 (0.00%)

0/4 (0.00%)

0/8 (0.00%)

0/7 (0.00%)

0/8 (0.00%)

0/6 (0.00%)

0/6 (0.00%)

0/5 (0.00%)

0/3 (0.00%)

0/6 (0.00%)

1/9 (11.11%)

0/53 (0.00%)

0/85 (0.00%)

0/41 (0.00%)

0/48 (0.00%)

0/18 (0.00%)

0/154 (0.00%)

0/66 (0.00%)

0/18 (0.00%)

0/18 (0.00%)

0/12 (0.00%)

Coordination abnormal * 1

0/3 (0.00%)

0/4 (0.00%)

0/8 (0.00%)

0/7 (0.00%)

0/8 (0.00%)

0/6 (0.00%)

0/6 (0.00%)

0/5 (0.00%)

0/3 (0.00%)

0/6 (0.00%)

0/9 (0.00%)

0/53 (0.00%)

0/85 (0.00%)

0/41 (0.00%)

0/48 (0.00%)

0/18 (0.00%)

1/154 (0.65%)

0/66 (0.00%)

1/18 (5.56%)

0/18 (0.00%)

0/12 (0.00%)

Disturbance in attention * 1

0/3 (0.00%)

0/4 (0.00%)

0/8 (0.00%)

0/7 (0.00%)

0/8 (0.00%)

0/6 (0.00%)

0/6 (0.00%)

0/5 (0.00%)

0/3 (0.00%)

0/6 (0.00%)

0/9 (0.00%)

0/53 (0.00%)

0/85 (0.00%)

0/41 (0.00%)

0/48 (0.00%)

1/18 (5.56%)

2/154 (1.30%)

1/66 (1.52%)

0/18 (0.00%)

0/18 (0.00%)

0/12 (0.00%)

Dizziness postural * 1

0/3 (0.00%)

0/4 (0.00%)

0/8 (0.00%)

0/7 (0.00%)

0/8 (0.00%)

0/6 (0.00%)

0/6 (0.00%)

0/5 (0.00%)

0/3 (0.00%)

0/6 (0.00%)

1/9 (11.11%)

1/53 (1.89%)

1/85 (1.18%)

0/41 (0.00%)

1/48 (2.08%)

0/18 (0.00%)

1/154 (0.65%)

0/66 (0.00%)

0/18 (0.00%)

1/18 (5.56%)

0/12 (0.00%)

Dysarthria * 1

0/3 (0.00%)

0/4 (0.00%)

0/8 (0.00%)

0/7 (0.00%)

0/8 (0.00%)

0/6 (0.00%)

0/6 (0.00%)

0/5 (0.00%)

0/3 (0.00%)

0/6 (0.00%)

0/9 (0.00%)

1/53 (1.89%)

1/85 (1.18%)

1/41 (2.44%)

1/48 (2.08%)

1/18 (5.56%)

4/154 (2.60%)

0/66 (0.00%)

0/18 (0.00%)

0/18 (0.00%)

0/12 (0.00%)

Facial nerve disorder * 1

0/3 (0.00%)

0/4 (0.00%)

0/8 (0.00%)

0/7 (0.00%)

0/8 (0.00%)

1/6 (16.67%)

0/6 (0.00%)

0/5 (0.00%)

0/3 (0.00%)

0/6 (0.00%)

0/9 (0.00%)

0/53 (0.00%)

0/85 (0.00%)

0/41 (0.00%)

0/48 (0.00%)

0/18 (0.00%)

0/154 (0.00%)

0/66 (0.00%)

0/18 (0.00%)

0/18 (0.00%)

0/12 (0.00%)

Haemorrhage intracranial * 1

0/3 (0.00%)

0/4 (0.00%)

0/8 (0.00%)

0/7 (0.00%)

0/8 (0.00%)

0/6 (0.00%)

0/6 (0.00%)

0/5 (0.00%)

0/3 (0.00%)

0/6 (0.00%)

0/9 (0.00%)

0/53 (0.00%)

0/85 (0.00%)

0/41 (0.00%)

0/48 (0.00%)

0/18 (0.00%)

0/154 (0.00%)

0/66 (0.00%)

0/18 (0.00%)

1/18 (5.56%)

0/12 (0.00%)

Hydrocephalus * 1

0/3 (0.00%)

0/4 (0.00%)

0/8 (0.00%)

0/7 (0.00%)

0/8 (0.00%)

0/6 (0.00%)

0/6 (0.00%)

0/5 (0.00%)

0/3 (0.00%)

0/6 (0.00%)

0/9 (0.00%)

0/53 (0.00%)

0/85 (0.00%)

0/41 (0.00%)

0/48 (0.00%)

0/18 (0.00%)

0/154 (0.00%)

0/66 (0.00%)

1/18 (5.56%)

0/18 (0.00%)

0/12 (0.00%)

Hypoxic-ischaemic encephalopathy * 1

0/3 (0.00%)

0/4 (0.00%)

0/8 (0.00%)

0/7 (0.00%)

0/8 (0.00%)

0/6 (0.00%)

0/6 (0.00%)

0/5 (0.00%)

0/3 (0.00%)

0/6 (0.00%)

1/9 (11.11%)

0/53 (0.00%)

0/85 (0.00%)

0/41 (0.00%)

0/48 (0.00%)

0/18 (0.00%)

0/154 (0.00%)

0/66 (0.00%)

0/18 (0.00%)

0/18 (0.00%)

0/12 (0.00%)

Loss of consciousness * 1

0/3 (0.00%)

0/4 (0.00%)

0/8 (0.00%)

0/7 (0.00%)

0/8 (0.00%)

0/6 (0.00%)

0/6 (0.00%)

0/5 (0.00%)

0/3 (0.00%)

0/6 (0.00%)

1/9 (11.11%)

1/53 (1.89%)

0/85 (0.00%)

0/41 (0.00%)

0/48 (0.00%)

0/18 (0.00%)

0/154 (0.00%)

0/66 (0.00%)

0/18 (0.00%)

0/18 (0.00%)

0/12 (0.00%)

Migraine * 1

0/3 (0.00%)

0/4 (0.00%)

0/8 (0.00%)

0/7 (0.00%)

1/8 (12.50%)

0/6 (0.00%)

0/6 (0.00%)

0/5 (0.00%)

0/3 (0.00%)

0/6 (0.00%)

0/9 (0.00%)

1/53 (1.89%)

0/85 (0.00%)

0/41 (0.00%)

1/48 (2.08%)

0/18 (0.00%)

0/154 (0.00%)

0/66 (0.00%)

0/18 (0.00%)

0/18 (0.00%)

0/12 (0.00%)

Migraine with aura * 1

0/3 (0.00%)

0/4 (0.00%)

0/8 (0.00%)

0/7 (0.00%)

0/8 (0.00%)

0/6 (0.00%)

0/6 (0.00%)

0/5 (0.00%)

0/3 (0.00%)

0/6 (0.00%)

0/9 (0.00%)

0/53 (0.00%)

0/85 (0.00%)

0/41 (0.00%)

0/48 (0.00%)

0/18 (0.00%)

0/154 (0.00%)

0/66 (0.00%)

0/18 (0.00%)

1/18 (5.56%)

0/12 (0.00%)

Myoclonus * 1

0/3 (0.00%)

0/4 (0.00%)

0/8 (0.00%)

0/7 (0.00%)

0/8 (0.00%)

0/6 (0.00%)

0/6 (0.00%)

0/5 (0.00%)

0/3 (0.00%)

0/6 (0.00%)

0/9 (0.00%)

0/53 (0.00%)

0/85 (0.00%)

0/41 (0.00%)

0/48 (0.00%)

0/18 (0.00%)

0/154 (0.00%)

0/66 (0.00%)

1/18 (5.56%)

0/18 (0.00%)

0/12 (0.00%)

Neuralgia * 1

0/3 (0.00%)

0/4 (0.00%)

0/8 (0.00%)

0/7 (0.00%)

0/8 (0.00%)

0/6 (0.00%)

0/6 (0.00%)

0/5 (0.00%)

1/3 (33.33%)

0/6 (0.00%)

0/9 (0.00%)

0/53 (0.00%)

0/85 (0.00%)

0/41 (0.00%)

0/48 (0.00%)

1/18 (5.56%)

4/154 (2.60%)

0/66 (0.00%)

0/18 (0.00%)

0/18 (0.00%)

0/12 (0.00%)

Parosmia * 1

0/3 (0.00%)

0/4 (0.00%)

0/8 (0.00%)

0/7 (0.00%)

0/8 (0.00%)

0/6 (0.00%)

0/6 (0.00%)

0/5 (0.00%)

0/3 (0.00%)

0/6 (0.00%)

1/9 (11.11%)

1/53 (1.89%)

0/85 (0.00%)

0/41 (0.00%)

0/48 (0.00%)

0/18 (0.00%)

5/154 (3.25%)

0/66 (0.00%)

0/18 (0.00%)

0/18 (0.00%)

0/12 (0.00%)

Peripheral sensory neuropathy * 1

0/3 (0.00%)

0/4 (0.00%)

0/8 (0.00%)

0/7 (0.00%)

0/8 (0.00%)

0/6 (0.00%)

0/6 (0.00%)

0/5 (0.00%)

0/3 (0.00%)

0/6 (0.00%)

0/9 (0.00%)

1/53 (1.89%)

6/85 (7.06%)

1/41 (2.44%)

0/48 (0.00%)

0/18 (0.00%)

1/154 (0.65%)

3/66 (4.55%)

0/18 (0.00%)

0/18 (0.00%)

0/12 (0.00%)

Seizure * 1

0/3 (0.00%)

0/4 (0.00%)

0/8 (0.00%)

0/7 (0.00%)

0/8 (0.00%)

0/6 (0.00%)

0/6 (0.00%)

0/5 (0.00%)

0/3 (0.00%)

0/6 (0.00%)

1/9 (11.11%)

0/53 (0.00%)

4/85 (4.71%)

1/41 (2.44%)

1/48 (2.08%)

0/18 (0.00%)

7/154 (4.55%)

0/66 (0.00%)

0/18 (0.00%)

0/18 (0.00%)

0/12 (0.00%)

Sinus headache * 1

0/3 (0.00%)

0/4 (0.00%)

0/8 (0.00%)

0/7 (0.00%)

0/8 (0.00%)

0/6 (0.00%)

0/6 (0.00%)

0/5 (0.00%)

0/3 (0.00%)

0/6 (0.00%)

0/9 (0.00%)

0/53 (0.00%)

0/85 (0.00%)

0/41 (0.00%)

0/48 (0.00%)

0/18 (0.00%)

0/154 (0.00%)

0/66 (0.00%)

0/18 (0.00%)

1/18 (5.56%)

0/12 (0.00%)

Tremor * 1

0/3 (0.00%)

0/4 (0.00%)

0/8 (0.00%)

0/7 (0.00%)

0/8 (0.00%)

0/6 (0.00%)

1/6 (16.67%)

0/5 (0.00%)

0/3 (0.00%)

0/6 (0.00%)

0/9 (0.00%)

1/53 (1.89%)

1/85 (1.18%)

1/41 (2.44%)

1/48 (2.08%)

1/18 (5.56%)

8/154 (5.19%)

3/66 (4.55%)

0/18 (0.00%)

0/18 (0.00%)

0/12 (0.00%)

Visual field defect * 1

0/3 (0.00%)

0/4 (0.00%)

0/8 (0.00%)

0/7 (0.00%)

0/8 (0.00%)

0/6 (0.00%)

0/6 (0.00%)

0/5 (0.00%)

0/3 (0.00%)

0/6 (0.00%)

0/9 (0.00%)

1/53 (1.89%)

3/85 (3.53%)

0/41 (0.00%)

0/48 (0.00%)

0/18 (0.00%)

3/154 (1.95%)

1/66 (1.52%)

1/18 (5.56%)

0/18 (0.00%)

0/12 (0.00%)

Visual perseveration * 1

0/3 (0.00%)

0/4 (0.00%)

0/8 (0.00%)

0/7 (0.00%)

0/8 (0.00%)

0/6 (0.00%)

0/6 (0.00%)

0/5 (0.00%)

0/3 (0.00%)

0/6 (0.00%)

0/9 (0.00%)

0/53 (0.00%)

0/85 (0.00%)

0/41 (0.00%)

0/48 (0.00%)

0/18 (0.00%)

0/154 (0.00%)

0/66 (0.00%)

0/18 (0.00%)

1/18 (5.56%)

0/12 (0.00%)

Psychiatric disorders

Anxiety * 1

0/3 (0.00%)

0/4 (0.00%)

0/8 (0.00%)

0/7 (0.00%)

1/8 (12.50%)

1/6 (16.67%)

0/6 (0.00%)

0/5 (0.00%)

0/3 (0.00%)

0/6 (0.00%)

0/9 (0.00%)

3/53 (5.66%)

3/85 (3.53%)

3/41 (7.32%)

3/48 (6.25%)

1/18 (5.56%)

15/154 (9.74%)

4/66 (6.06%)

0/18 (0.00%)

2/18 (11.11%)

0/12 (0.00%)

Depression * 1

0/3 (0.00%)

0/4 (0.00%)

0/8 (0.00%)

0/7 (0.00%)

0/8 (0.00%)

0/6 (0.00%)

0/6 (0.00%)

0/5 (0.00%)

0/3 (0.00%)

0/6 (0.00%)

0/9 (0.00%)

4/53 (7.55%)

3/85 (3.53%)

0/41 (0.00%)

3/48 (6.25%)

0/18 (0.00%)

12/154 (7.79%)

3/66 (4.55%)

0/18 (0.00%)

1/18 (5.56%)

0/12 (0.00%)

Insomnia * 1

0/3 (0.00%)

0/4 (0.00%)

1/8 (12.50%)

0/7 (0.00%)

0/8 (0.00%)

1/6 (16.67%)

0/6 (0.00%)

0/5 (0.00%)

1/3 (33.33%)

0/6 (0.00%)

0/9 (0.00%)

7/53 (13.21%)

11/85 (12.94%)

6/41 (14.63%)

2/48 (4.17%)

0/18 (0.00%)

26/154 (16.88%)

7/66 (10.61%)

1/18 (5.56%)

0/18 (0.00%)

1/12 (8.33%)

Abnormal dreams * 1

0/3 (0.00%)

0/4 (0.00%)

0/8 (0.00%)

0/7 (0.00%)

0/8 (0.00%)

0/6 (0.00%)

0/6 (0.00%)

0/5 (0.00%)

0/3 (0.00%)

0/6 (0.00%)

1/9 (11.11%)

0/53 (0.00%)

0/85 (0.00%)

0/41 (0.00%)

0/48 (0.00%)

0/18 (0.00%)

0/154 (0.00%)

0/66 (0.00%)

0/18 (0.00%)

0/18 (0.00%)

0/12 (0.00%)

Confusional state * 1

0/3 (0.00%)

0/4 (0.00%)

0/8 (0.00%)

0/7 (0.00%)

0/8 (0.00%)

0/6 (0.00%)

0/6 (0.00%)

0/5 (0.00%)

0/3 (0.00%)

0/6 (0.00%)

0/9 (0.00%)

2/53 (3.77%)

8/85 (9.41%)

5/41 (12.20%)

1/48 (2.08%)

1/18 (5.56%)

8/154 (5.19%)

1/66 (1.52%)

1/18 (5.56%)

0/18 (0.00%)

1/12 (8.33%)

Delirium * 1

0/3 (0.00%)

0/4 (0.00%)

0/8 (0.00%)

0/7 (0.00%)

0/8 (0.00%)

0/6 (0.00%)

0/6 (0.00%)

0/5 (0.00%)

0/3 (0.00%)

0/6 (0.00%)

0/9 (0.00%)

0/53 (0.00%)

2/85 (2.35%)

3/41 (7.32%)

1/48 (2.08%)

0/18 (0.00%)

0/154 (0.00%)

0/66 (0.00%)

0/18 (0.00%)

0/18 (0.00%)

0/12 (0.00%)

Hallucination, visual * 1

0/3 (0.00%)

0/4 (0.00%)

0/8 (0.00%)

0/7 (0.00%)

0/8 (0.00%)

0/6 (0.00%)

0/6 (0.00%)

0/5 (0.00%)

0/3 (0.00%)

0/6 (0.00%)

0/9 (0.00%)

0/53 (0.00%)

0/85 (0.00%)

0/41 (0.00%)

0/48 (0.00%)

0/18 (0.00%)

0/154 (0.00%)

0/66 (0.00%)

0/18 (0.00%)

1/18 (5.56%)

0/12 (0.00%)

Psychotic disorder * 1

0/3 (0.00%)

0/4 (0.00%)

0/8 (0.00%)

0/7 (0.00%)

1/8 (12.50%)

0/6 (0.00%)

0/6 (0.00%)

0/5 (0.00%)

0/3 (0.00%)

0/6 (0.00%)

0/9 (0.00%)

0/53 (0.00%)

0/85 (0.00%)

0/41 (0.00%)

0/48 (0.00%)

0/18 (0.00%)

1/154 (0.65%)

0/66 (0.00%)

0/18 (0.00%)

0/18 (0.00%)

0/12 (0.00%)

Renal and urinary disorders

Dysuria * 1

0/3 (0.00%)

0/4 (0.00%)

0/8 (0.00%)

0/7 (0.00%)

0/8 (0.00%)

0/6 (0.00%)

0/6 (0.00%)

0/5 (0.00%)

0/3 (0.00%)

0/6 (0.00%)

1/9 (11.11%)

4/53 (7.55%)

1/85 (1.18%)

0/41 (0.00%)

0/48 (0.00%)

1/18 (5.56%)

9/154 (5.84%)

1/66 (1.52%)

1/18 (5.56%)

1/18 (5.56%)

0/12 (0.00%)

Renal cyst * 1

0/3 (0.00%)

0/4 (0.00%)

0/8 (0.00%)

0/7 (0.00%)

0/8 (0.00%)

0/6 (0.00%)

0/6 (0.00%)

0/5 (0.00%)

0/3 (0.00%)

0/6 (0.00%)

0/9 (0.00%)

3/53 (5.66%)

0/85 (0.00%)

0/41 (0.00%)

0/48 (0.00%)

0/18 (0.00%)

1/154 (0.65%)

1/66 (1.52%)

0/18 (0.00%)

0/18 (0.00%)

0/12 (0.00%)

Acute kidney injury * 1

0/3 (0.00%)

0/4 (0.00%)

0/8 (0.00%)

0/7 (0.00%)

0/8 (0.00%)

0/6 (0.00%)

0/6 (0.00%)

0/5 (0.00%)

0/3 (0.00%)

0/6 (0.00%)

2/9 (22.22%)

0/53 (0.00%)

2/85 (2.35%)

0/41 (0.00%)

0/48 (0.00%)

0/18 (0.00%)

2/154 (1.30%)

1/66 (1.52%)

0/18 (0.00%)

0/18 (0.00%)

0/12 (0.00%)

Chromaturia * 1

0/3 (0.00%)

0/4 (0.00%)

0/8 (0.00%)

0/7 (0.00%)

1/8 (12.50%)

0/6 (0.00%)

0/6 (0.00%)

0/5 (0.00%)

0/3 (0.00%)

1/6 (16.67%)

0/9 (0.00%)

0/53 (0.00%)

0/85 (0.00%)

0/41 (0.00%)

0/48 (0.00%)

0/18 (0.00%)

1/154 (0.65%)

0/66 (0.00%)

0/18 (0.00%)

0/18 (0.00%)

0/12 (0.00%)

Haematuria * 1

0/3 (0.00%)

0/4 (0.00%)

0/8 (0.00%)

0/7 (0.00%)

0/8 (0.00%)

0/6 (0.00%)

0/6 (0.00%)

0/5 (0.00%)

0/3 (0.00%)

0/6 (0.00%)

1/9 (11.11%)

0/53 (0.00%)

0/85 (0.00%)

2/41 (4.88%)

0/48 (0.00%)

0/18 (0.00%)

1/154 (0.65%)

1/66 (1.52%)

0/18 (0.00%)

0/18 (0.00%)

0/12 (0.00%)

Incontinence * 1

0/3 (0.00%)

0/4 (0.00%)

0/8 (0.00%)

0/7 (0.00%)

0/8 (0.00%)

0/6 (0.00%)

0/6 (0.00%)

1/5 (20.00%)

0/3 (0.00%)

0/6 (0.00%)

0/9 (0.00%)

0/53 (0.00%)

0/85 (0.00%)

0/41 (0.00%)

0/48 (0.00%)

0/18 (0.00%)

1/154 (0.65%)

0/66 (0.00%)

0/18 (0.00%)

0/18 (0.00%)

0/12 (0.00%)

Nocturia * 1

0/3 (0.00%)

0/4 (0.00%)

0/8 (0.00%)

0/7 (0.00%)

0/8 (0.00%)

0/6 (0.00%)

0/6 (0.00%)

0/5 (0.00%)

0/3 (0.00%)

0/6 (0.00%)

0/9 (0.00%)

1/53 (1.89%)

1/85 (1.18%)

0/41 (0.00%)

1/48 (2.08%)

1/18 (5.56%)

1/154 (0.65%)

0/66 (0.00%)

0/18 (0.00%)

0/18 (0.00%)

0/12 (0.00%)

Pollakiuria * 1

0/3 (0.00%)

0/4 (0.00%)

0/8 (0.00%)

0/7 (0.00%)

0/8 (0.00%)

0/6 (0.00%)

0/6 (0.00%)

0/5 (0.00%)

0/3 (0.00%)

0/6 (0.00%)

0/9 (0.00%)

0/53 (0.00%)

0/85 (0.00%)

0/41 (0.00%)

2/48 (4.17%)

2/18 (11.11%)

5/154 (3.25%)

1/66 (1.52%)

0/18 (0.00%)

0/18 (0.00%)

0/12 (0.00%)

Proteinuria * 1

0/3 (0.00%)

0/4 (0.00%)

1/8 (12.50%)

0/7 (0.00%)

0/8 (0.00%)

0/6 (0.00%)

0/6 (0.00%)

0/5 (0.00%)

0/3 (0.00%)

0/6 (0.00%)

0/9 (0.00%)

0/53 (0.00%)

1/85 (1.18%)

0/41 (0.00%)

0/48 (0.00%)

1/18 (5.56%)

0/154 (0.00%)

0/66 (0.00%)

0/18 (0.00%)

1/18 (5.56%)

0/12 (0.00%)

Renal failure * 1

0/3 (0.00%)

0/4 (0.00%)

0/8 (0.00%)

0/7 (0.00%)

0/8 (0.00%)

0/6 (0.00%)

0/6 (0.00%)

0/5 (0.00%)

0/3 (0.00%)

0/6 (0.00%)

1/9 (11.11%)

0/53 (0.00%)

0/85 (0.00%)

1/41 (2.44%)

0/48 (0.00%)

0/18 (0.00%)

2/154 (1.30%)

0/66 (0.00%)

0/18 (0.00%)

0/18 (0.00%)

0/12 (0.00%)

Renal pain * 1

0/3 (0.00%)

0/4 (0.00%)

0/8 (0.00%)

0/7 (0.00%)

0/8 (0.00%)

0/6 (0.00%)

0/6 (0.00%)

0/5 (0.00%)

0/3 (0.00%)

0/6 (0.00%)

1/9 (11.11%)

0/53 (0.00%)

0/85 (0.00%)

0/41 (0.00%)

0/48 (0.00%)

0/18 (0.00%)

0/154 (0.00%)

0/66 (0.00%)

0/18 (0.00%)

0/18 (0.00%)

0/12 (0.00%)

Urinary incontinence * 1

0/3 (0.00%)

0/4 (0.00%)

1/8 (12.50%)

1/7 (14.29%)

0/8 (0.00%)

0/6 (0.00%)

0/6 (0.00%)

0/5 (0.00%)

0/3 (0.00%)

0/6 (0.00%)

0/9 (0.00%)

0/53 (0.00%)

8/85 (9.41%)

0/41 (0.00%)

1/48 (2.08%)

0/18 (0.00%)

1/154 (0.65%)

2/66 (3.03%)

0/18 (0.00%)

0/18 (0.00%)

0/12 (0.00%)

Urinary retention * 1

0/3 (0.00%)

0/4 (0.00%)

0/8 (0.00%)

0/7 (0.00%)

0/8 (0.00%)

0/6 (0.00%)

0/6 (0.00%)

0/5 (0.00%)

1/3 (33.33%)

1/6 (16.67%)

2/9 (22.22%)

1/53 (1.89%)

2/85 (2.35%)

1/41 (2.44%)

0/48 (0.00%)

0/18 (0.00%)

4/154 (2.60%)

1/66 (1.52%)

0/18 (0.00%)

1/18 (5.56%)

0/12 (0.00%)

Urinary tract obstruction * 1

0/3 (0.00%)

0/4 (0.00%)

0/8 (0.00%)

0/7 (0.00%)

0/8 (0.00%)

0/6 (0.00%)

0/6 (0.00%)

0/5 (0.00%)

0/3 (0.00%)

0/6 (0.00%)

1/9 (11.11%)

0/53 (0.00%)

1/85 (1.18%)

0/41 (0.00%)

0/48 (0.00%)

0/18 (0.00%)

0/154 (0.00%)

0/66 (0.00%)

0/18 (0.00%)

0/18 (0.00%)

0/12 (0.00%)

Urine abnormality * 1

0/3 (0.00%)

0/4 (0.00%)

0/8 (0.00%)

0/7 (0.00%)

0/8 (0.00%)

0/6 (0.00%)

0/6 (0.00%)

0/5 (0.00%)

0/3 (0.00%)

0/6 (0.00%)

0/9 (0.00%)

0/53 (0.00%)

0/85 (0.00%)

0/41 (0.00%)

0/48 (0.00%)

1/18 (5.56%)

1/154 (0.65%)

0/66 (0.00%)

0/18 (0.00%)

0/18 (0.00%)

0/12 (0.00%)

Urine flow decreased * 1

0/3 (0.00%)

0/4 (0.00%)

0/8 (0.00%)

0/7 (0.00%)

0/8 (0.00%)

0/6 (0.00%)

0/6 (0.00%)

0/5 (0.00%)

0/3 (0.00%)

0/6 (0.00%)

1/9 (11.11%)

0/53 (0.00%)

0/85 (0.00%)

0/41 (0.00%)

0/48 (0.00%)

0/18 (0.00%)

1/154 (0.65%)

0/66 (0.00%)

0/18 (0.00%)

0/18 (0.00%)

0/12 (0.00%)

Reproductive system and breast disorders

Benign prostatic hyperplasia * 1

0/3 (0.00%)

0/4 (0.00%)

0/8 (0.00%)

0/7 (0.00%)

0/8 (0.00%)

0/6 (0.00%)

0/6 (0.00%)

0/5 (0.00%)

0/3 (0.00%)

0/6 (0.00%)

0/9 (0.00%)

0/53 (0.00%)

0/85 (0.00%)

0/41 (0.00%)

0/48 (0.00%)

0/18 (0.00%)

1/154 (0.65%)

0/66 (0.00%)

1/18 (5.56%)

0/18 (0.00%)

0/12 (0.00%)

Erectile dysfunction * 1

0/3 (0.00%)

0/4 (0.00%)

0/8 (0.00%)

0/7 (0.00%)

0/8 (0.00%)

0/6 (0.00%)

0/6 (0.00%)

0/5 (0.00%)

0/3 (0.00%)

0/6 (0.00%)

0/9 (0.00%)

0/53 (0.00%)

2/85 (2.35%)

1/41 (2.44%)

0/48 (0.00%)

1/18 (5.56%)

1/154 (0.65%)

0/66 (0.00%)

0/18 (0.00%)

0/18 (0.00%)

0/12 (0.00%)

Genital haemorrhage * 1

0/3 (0.00%)

0/4 (0.00%)

0/8 (0.00%)

0/7 (0.00%)

0/8 (0.00%)

0/6 (0.00%)

1/6 (16.67%)

0/5 (0.00%)

0/3 (0.00%)

0/6 (0.00%)

0/9 (0.00%)

0/53 (0.00%)

0/85 (0.00%)

0/41 (0.00%)

0/48 (0.00%)

0/18 (0.00%)

0/154 (0.00%)

0/66 (0.00%)

0/18 (0.00%)

0/18 (0.00%)

0/12 (0.00%)

Testicular pain * 1

0/3 (0.00%)

0/4 (0.00%)

0/8 (0.00%)

0/7 (0.00%)

0/8 (0.00%)

0/6 (0.00%)

0/6 (0.00%)

0/5 (0.00%)

0/3 (0.00%)

1/6 (16.67%)

0/9 (0.00%)

0/53 (0.00%)

0/85 (0.00%)

0/41 (0.00%)

0/48 (0.00%)

0/18 (0.00%)

0/154 (0.00%)

0/66 (0.00%)

0/18 (0.00%)

0/18 (0.00%)

0/12 (0.00%)

Vaginal haemorrhage * 1

0/3 (0.00%)

0/4 (0.00%)

0/8 (0.00%)

1/7 (14.29%)

0/8 (0.00%)

0/6 (0.00%)

0/6 (0.00%)

0/5 (0.00%)

0/3 (0.00%)

0/6 (0.00%)

0/9 (0.00%)

1/53 (1.89%)

1/85 (1.18%)

0/41 (0.00%)

0/48 (0.00%)

0/18 (0.00%)

1/154 (0.65%)

1/66 (1.52%)

0/18 (0.00%)

0/18 (0.00%)

0/12 (0.00%)

Vulvovaginal pruritus * 1

0/3 (0.00%)

0/4 (0.00%)

0/8 (0.00%)

0/7 (0.00%)

0/8 (0.00%)

0/6 (0.00%)

0/6 (0.00%)

0/5 (0.00%)

0/3 (0.00%)

0/6 (0.00%)

0/9 (0.00%)

0/53 (0.00%)

0/85 (0.00%)

0/41 (0.00%)

0/48 (0.00%)

0/18 (0.00%)

0/154 (0.00%)

1/66 (1.52%)

1/18 (5.56%)

0/18 (0.00%)

0/12 (0.00%)

Respiratory, thoracic and mediastinal disorders

Cough * 1

0/3 (0.00%)

0/4 (0.00%)

0/8 (0.00%)

0/7 (0.00%)

1/8 (12.50%)

0/6 (0.00%)

0/6 (0.00%)

0/5 (0.00%)

0/3 (0.00%)

0/6 (0.00%)

0/9 (0.00%)

13/53 (24.53%)

24/85 (28.24%)

7/41 (17.07%)

7/48 (14.58%)

4/18 (22.22%)

24/154 (15.58%)

3/66 (4.55%)

5/18 (27.78%)

1/18 (5.56%)

1/12 (8.33%)

Dysphonia * 1

0/3 (0.00%)

0/4 (0.00%)

0/8 (0.00%)

0/7 (0.00%)

0/8 (0.00%)

0/6 (0.00%)

0/6 (0.00%)

0/5 (0.00%)

0/3 (0.00%)

0/6 (0.00%)

0/9 (0.00%)

4/53 (7.55%)

9/85 (10.59%)

2/41 (4.88%)

1/48 (2.08%)

0/18 (0.00%)

10/154 (6.49%)

0/66 (0.00%)

0/18 (0.00%)

1/18 (5.56%)

0/12 (0.00%)

Dyspnoea * 1

2/3 (66.67%)

0/4 (0.00%)

0/8 (0.00%)

2/7 (28.57%)

0/8 (0.00%)

3/6 (50.00%)

2/6 (33.33%)

0/5 (0.00%)

0/3 (0.00%)

0/6 (0.00%)

1/9 (11.11%)

12/53 (22.64%)

27/85 (31.76%)

10/41 (24.39%)

11/48 (22.92%)

4/18 (22.22%)

34/154 (22.08%)

14/66 (21.21%)

8/18 (44.44%)

1/18 (5.56%)

1/12 (8.33%)

Dyspnoea exertional * 1

0/3 (0.00%)

0/4 (0.00%)

0/8 (0.00%)

0/7 (0.00%)

1/8 (12.50%)

0/6 (0.00%)

0/6 (0.00%)

0/5 (0.00%)

0/3 (0.00%)

1/6 (16.67%)

0/9 (0.00%)

7/53 (13.21%)

0/85 (0.00%)

1/41 (2.44%)

3/48 (6.25%)

1/18 (5.56%)

10/154 (6.49%)

1/66 (1.52%)

2/18 (11.11%)

1/18 (5.56%)

0/12 (0.00%)

Hypoxia * 1

0/3 (0.00%)

0/4 (0.00%)

0/8 (0.00%)

0/7 (0.00%)

0/8 (0.00%)

1/6 (16.67%)

0/6 (0.00%)

0/5 (0.00%)

0/3 (0.00%)

0/6 (0.00%)

1/9 (11.11%)

6/53 (11.32%)

8/85 (9.41%)

3/41 (7.32%)

1/48 (2.08%)

1/18 (5.56%)

4/154 (2.60%)

0/66 (0.00%)

2/18 (11.11%)

2/18 (11.11%)

2/12 (16.67%)

Oropharyngeal pain * 1

0/3 (0.00%)

0/4 (0.00%)

0/8 (0.00%)

1/7 (14.29%)

0/8 (0.00%)

0/6 (0.00%)

0/6 (0.00%)

0/5 (0.00%)

0/3 (0.00%)

0/6 (0.00%)

1/9 (11.11%)

4/53 (7.55%)

3/85 (3.53%)

2/41 (4.88%)

6/48 (12.50%)

0/18 (0.00%)

11/154 (7.14%)

2/66 (3.03%)

1/18 (5.56%)

0/18 (0.00%)

1/12 (8.33%)

Pleural effusion * 1

0/3 (0.00%)

0/4 (0.00%)

0/8 (0.00%)

0/7 (0.00%)

0/8 (0.00%)

0/6 (0.00%)

0/6 (0.00%)

0/5 (0.00%)

0/3 (0.00%)

0/6 (0.00%)

0/9 (0.00%)

3/53 (5.66%)

11/85 (12.94%)

4/41 (9.76%)

2/48 (4.17%)

3/18 (16.67%)

8/154 (5.19%)

1/66 (1.52%)

2/18 (11.11%)

1/18 (5.56%)

2/12 (16.67%)

Productive cough * 1

0/3 (0.00%)

0/4 (0.00%)

0/8 (0.00%)

1/7 (14.29%)

0/8 (0.00%)

0/6 (0.00%)

0/6 (0.00%)

0/5 (0.00%)

1/3 (33.33%)

0/6 (0.00%)

0/9 (0.00%)

3/53 (5.66%)

0/85 (0.00%)

0/41 (0.00%)

3/48 (6.25%)

0/18 (0.00%)

9/154 (5.84%)

2/66 (3.03%)

0/18 (0.00%)

0/18 (0.00%)

0/12 (0.00%)

Pulmonary embolism * 1

0/3 (0.00%)

0/4 (0.00%)

0/8 (0.00%)

0/7 (0.00%)

0/8 (0.00%)

0/6 (0.00%)

0/6 (0.00%)

0/5 (0.00%)

0/3 (0.00%)

0/6 (0.00%)

0/9 (0.00%)

9/53 (16.98%)

6/85 (7.06%)

1/41 (2.44%)

2/48 (4.17%)

2/18 (11.11%)

5/154 (3.25%)

0/66 (0.00%)

1/18 (5.56%)

0/18 (0.00%)

0/12 (0.00%)

Rhinorrhoea * 1

0/3 (0.00%)

0/4 (0.00%)

0/8 (0.00%)

0/7 (0.00%)

0/8 (0.00%)

0/6 (0.00%)

0/6 (0.00%)

0/5 (0.00%)

0/3 (0.00%)

0/6 (0.00%)

0/9 (0.00%)

4/53 (7.55%)

6/85 (7.06%)

2/41 (4.88%)

3/48 (6.25%)

1/18 (5.56%)

2/154 (1.30%)

1/66 (1.52%)

0/18 (0.00%)

1/18 (5.56%)

0/12 (0.00%)

Wheezing * 1

0/3 (0.00%)

0/4 (0.00%)

0/8 (0.00%)

1/7 (14.29%)

0/8 (0.00%)

0/6 (0.00%)

0/6 (0.00%)

0/5 (0.00%)

0/3 (0.00%)

0/6 (0.00%)

2/9 (22.22%)

7/53 (13.21%)

5/85 (5.88%)

0/41 (0.00%)

2/48 (4.17%)

1/18 (5.56%)

12/154 (7.79%)

2/66 (3.03%)

2/18 (11.11%)

0/18 (0.00%)

0/12 (0.00%)

Acute respiratory failure * 1

0/3 (0.00%)

0/4 (0.00%)

0/8 (0.00%)

0/7 (0.00%)

0/8 (0.00%)

0/6 (0.00%)

0/6 (0.00%)

0/5 (0.00%)

0/3 (0.00%)

0/6 (0.00%)

1/9 (11.11%)

0/53 (0.00%)

1/85 (1.18%)

0/41 (0.00%)

0/48 (0.00%)

0/18 (0.00%)

1/154 (0.65%)

0/66 (0.00%)

0/18 (0.00%)

0/18 (0.00%)

0/12 (0.00%)

Aspiration * 1

0/3 (0.00%)

0/4 (0.00%)

0/8 (0.00%)

0/7 (0.00%)

0/8 (0.00%)

0/6 (0.00%)

0/6 (0.00%)

0/5 (0.00%)

1/3 (33.33%)

0/6 (0.00%)

0/9 (0.00%)

1/53 (1.89%)

1/85 (1.18%)

0/41 (0.00%)

0/48 (0.00%)

0/18 (0.00%)

1/154 (0.65%)

0/66 (0.00%)

0/18 (0.00%)

0/18 (0.00%)

0/12 (0.00%)

Bronchial secretion retention * 1

0/3 (0.00%)

0/4 (0.00%)

0/8 (0.00%)

0/7 (0.00%)

0/8 (0.00%)

1/6 (16.67%)

0/6 (0.00%)

0/5 (0.00%)

0/3 (0.00%)

0/6 (0.00%)

0/9 (0.00%)

0/53 (0.00%)

0/85 (0.00%)

0/41 (0.00%)

0/48 (0.00%)

0/18 (0.00%)

0/154 (0.00%)

0/66 (0.00%)

0/18 (0.00%)

0/18 (0.00%)

0/12 (0.00%)

Epistaxis * 1

0/3 (0.00%)

0/4 (0.00%)

0/8 (0.00%)

0/7 (0.00%)

0/8 (0.00%)

0/6 (0.00%)

0/6 (0.00%)

0/5 (0.00%)

0/3 (0.00%)

0/6 (0.00%)

1/9 (11.11%)

0/53 (0.00%)

1/85 (1.18%)

1/41 (2.44%)

0/48 (0.00%)

0/18 (0.00%)

5/154 (3.25%)

1/66 (1.52%)

0/18 (0.00%)

0/18 (0.00%)

0/12 (0.00%)

Haemoptysis * 1

0/3 (0.00%)

0/4 (0.00%)

0/8 (0.00%)

1/7 (14.29%)

0/8 (0.00%)

0/6 (0.00%)

0/6 (0.00%)

0/5 (0.00%)

0/3 (0.00%)

0/6 (0.00%)

0/9 (0.00%)

1/53 (1.89%)

2/85 (2.35%)

1/41 (2.44%)

1/48 (2.08%)

1/18 (5.56%)

10/154 (6.49%)

4/66 (6.06%)

0/18 (0.00%)

0/18 (0.00%)

0/12 (0.00%)

Hiccups * 1

0/3 (0.00%)

0/4 (0.00%)

0/8 (0.00%)

0/7 (0.00%)

0/8 (0.00%)

1/6 (16.67%)

0/6 (0.00%)

0/5 (0.00%)

0/3 (0.00%)

0/6 (0.00%)

0/9 (0.00%)

1/53 (1.89%)

1/85 (1.18%)

0/41 (0.00%)

1/48 (2.08%)

0/18 (0.00%)

6/154 (3.90%)

0/66 (0.00%)

0/18 (0.00%)

0/18 (0.00%)

0/12 (0.00%)

Nasal congestion * 1

0/3 (0.00%)

0/4 (0.00%)

0/8 (0.00%)

0/7 (0.00%)

0/8 (0.00%)

0/6 (0.00%)

0/6 (0.00%)

0/5 (0.00%)

0/3 (0.00%)

0/6 (0.00%)

0/9 (0.00%)

1/53 (1.89%)

12/85 (14.12%)

0/41 (0.00%)

1/48 (2.08%)

1/18 (5.56%)

1/154 (0.65%)

0/66 (0.00%)

1/18 (5.56%)

1/18 (5.56%)

0/12 (0.00%)

Paranasal sinus discomfort * 1

0/3 (0.00%)

0/4 (0.00%)

0/8 (0.00%)

0/7 (0.00%)

0/8 (0.00%)

0/6 (0.00%)

0/6 (0.00%)

0/5 (0.00%)

0/3 (0.00%)

0/6 (0.00%)

0/9 (0.00%)

0/53 (0.00%)

0/85 (0.00%)

0/41 (0.00%)

2/48 (4.17%)

0/18 (0.00%)

0/154 (0.00%)

0/66 (0.00%)

0/18 (0.00%)

1/18 (5.56%)

0/12 (0.00%)

Paranasal sinus hypersecretion * 1

0/3 (0.00%)

0/4 (0.00%)

0/8 (0.00%)

0/7 (0.00%)

0/8 (0.00%)

0/6 (0.00%)

0/6 (0.00%)

0/5 (0.00%)

0/3 (0.00%)

0/6 (0.00%)

0/9 (0.00%)

0/53 (0.00%)

0/85 (0.00%)

0/41 (0.00%)

0/48 (0.00%)

0/18 (0.00%)

0/154 (0.00%)

0/66 (0.00%)

1/18 (5.56%)

0/18 (0.00%)

0/12 (0.00%)

Pneumonia aspiration * 1

0/3 (0.00%)

0/4 (0.00%)

0/8 (0.00%)

0/7 (0.00%)

0/8 (0.00%)

0/6 (0.00%)

0/6 (0.00%)

0/5 (0.00%)

0/3 (0.00%)

0/6 (0.00%)

0/9 (0.00%)

0/53 (0.00%)

0/85 (0.00%)

0/41 (0.00%)

0/48 (0.00%)

0/18 (0.00%)

1/154 (0.65%)

0/66 (0.00%)

1/18 (5.56%)

0/18 (0.00%)

0/12 (0.00%)

Pulmonary haemorrhage * 1

0/3 (0.00%)

0/4 (0.00%)

0/8 (0.00%)

0/7 (0.00%)

0/8 (0.00%)

0/6 (0.00%)

0/6 (0.00%)

0/5 (0.00%)

0/3 (0.00%)

0/6 (0.00%)

0/9 (0.00%)

0/53 (0.00%)

5/85 (5.88%)

0/41 (0.00%)

0/48 (0.00%)

0/18 (0.00%)

0/154 (0.00%)

0/66 (0.00%)

0/18 (0.00%)

0/18 (0.00%)

0/12 (0.00%)

Respiratory failure * 1

0/3 (0.00%)

0/4 (0.00%)

0/8 (0.00%)

0/7 (0.00%)

0/8 (0.00%)

0/6 (0.00%)

0/6 (0.00%)

0/5 (0.00%)

0/3 (0.00%)

0/6 (0.00%)

0/9 (0.00%)

1/53 (1.89%)

1/85 (1.18%)

0/41 (0.00%)

0/48 (0.00%)

0/18 (0.00%)

3/154 (1.95%)

0/66 (0.00%)

1/18 (5.56%)

0/18 (0.00%)

0/12 (0.00%)

Rhinitis allergic * 1

0/3 (0.00%)

0/4 (0.00%)

0/8 (0.00%)

0/7 (0.00%)

0/8 (0.00%)

0/6 (0.00%)

0/6 (0.00%)

0/5 (0.00%)

0/3 (0.00%)

0/6 (0.00%)

0/9 (0.00%)

2/53 (3.77%)

3/85 (3.53%)

0/41 (0.00%)

0/48 (0.00%)

0/18 (0.00%)

2/154 (1.30%)

1/66 (1.52%)

2/18 (11.11%)

0/18 (0.00%)

0/12 (0.00%)

Sinus congestion * 1

0/3 (0.00%)

0/4 (0.00%)

0/8 (0.00%)

0/7 (0.00%)

0/8 (0.00%)

0/6 (0.00%)

0/6 (0.00%)

0/5 (0.00%)

0/3 (0.00%)

0/6 (0.00%)

0/9 (0.00%)

0/53 (0.00%)

0/85 (0.00%)

0/41 (0.00%)

1/48 (2.08%)

1/18 (5.56%)

2/154 (1.30%)

0/66 (0.00%)

1/18 (5.56%)

0/18 (0.00%)

0/12 (0.00%)

Tonsillar hypertrophy * 1

0/3 (0.00%)

0/4 (0.00%)

1/8 (12.50%)

0/7 (0.00%)

0/8 (0.00%)

0/6 (0.00%)

0/6 (0.00%)

0/5 (0.00%)

0/3 (0.00%)

0/6 (0.00%)

0/9 (0.00%)

0/53 (0.00%)

0/85 (0.00%)

0/41 (0.00%)

0/48 (0.00%)

0/18 (0.00%)

0/154 (0.00%)

0/66 (0.00%)

0/18 (0.00%)

0/18 (0.00%)

0/12 (0.00%)

Upper-airway cough syndrome * 1

0/3 (0.00%)

0/4 (0.00%)

0/8 (0.00%)

1/7 (14.29%)

0/8 (0.00%)

0/6 (0.00%)

0/6 (0.00%)

0/5 (0.00%)

0/3 (0.00%)

0/6 (0.00%)

0/9 (0.00%)

1/53 (1.89%)

3/85 (3.53%)

0/41 (0.00%)

1/48 (2.08%)

0/18 (0.00%)

1/154 (0.65%)

0/66 (0.00%)

0/18 (0.00%)

0/18 (0.00%)

0/12 (0.00%)

Atelectasis * 1

0/3 (0.00%)

0/4 (0.00%)

0/8 (0.00%)

0/7 (0.00%)

0/8 (0.00%)

0/6 (0.00%)

0/6 (0.00%)

0/5 (0.00%)

0/3 (0.00%)

0/6 (0.00%)

0/9 (0.00%)

0/53 (0.00%)

0/85 (0.00%)

0/41 (0.00%)

0/48 (0.00%)

0/18 (0.00%)

0/154 (0.00%)

0/66 (0.00%)

0/18 (0.00%)

0/18 (0.00%)

1/12 (8.33%)

Skin and subcutaneous tissue disorders

Alopecia * 1

1/3 (33.33%)

0/4 (0.00%)

0/8 (0.00%)

0/7 (0.00%)

0/8 (0.00%)

0/6 (0.00%)

0/6 (0.00%)

0/5 (0.00%)

1/3 (33.33%)

1/6 (16.67%)

0/9 (0.00%)

4/53 (7.55%)

5/85 (5.88%)

1/41 (2.44%)

2/48 (4.17%)

0/18 (0.00%)

19/154 (12.34%)

1/66 (1.52%)

0/18 (0.00%)

0/18 (0.00%)

0/12 (0.00%)

Erythema * 1

0/3 (0.00%)

0/4 (0.00%)

0/8 (0.00%)

0/7 (0.00%)

0/8 (0.00%)

0/6 (0.00%)

0/6 (0.00%)

0/5 (0.00%)

0/3 (0.00%)

0/6 (0.00%)

0/9 (0.00%)

3/53 (5.66%)

3/85 (3.53%)

0/41 (0.00%)

1/48 (2.08%)

0/18 (0.00%)

9/154 (5.84%)

4/66 (6.06%)

1/18 (5.56%)

1/18 (5.56%)

0/12 (0.00%)

Pruritus * 1

0/3 (0.00%)

1/4 (25.00%)

0/8 (0.00%)

0/7 (0.00%)

0/8 (0.00%)

0/6 (0.00%)

0/6 (0.00%)

0/5 (0.00%)

0/3 (0.00%)

0/6 (0.00%)

0/9 (0.00%)

8/53 (15.09%)

8/85 (9.41%)

0/41 (0.00%)

2/48 (4.17%)

0/18 (0.00%)

17/154 (11.04%)

3/66 (4.55%)

4/18 (22.22%)

0/18 (0.00%)

0/12 (0.00%)

Rash * 1

0/3 (0.00%)

1/4 (25.00%)

1/8 (12.50%)

0/7 (0.00%)

0/8 (0.00%)

0/6 (0.00%)

1/6 (16.67%)

0/5 (0.00%)

0/3 (0.00%)

2/6 (33.33%)

0/9 (0.00%)

15/53 (28.30%)

6/85 (7.06%)

2/41 (4.88%)

2/48 (4.17%)

2/18 (11.11%)

41/154 (26.62%)

5/66 (7.58%)

3/18 (16.67%)

2/18 (11.11%)

0/12 (0.00%)

Blister * 1

0/3 (0.00%)

0/4 (0.00%)

0/8 (0.00%)

0/7 (0.00%)

0/8 (0.00%)

0/6 (0.00%)

1/6 (16.67%)

0/5 (0.00%)

0/3 (0.00%)

0/6 (0.00%)

0/9 (0.00%)

0/53 (0.00%)

0/85 (0.00%)

0/41 (0.00%)

0/48 (0.00%)

0/18 (0.00%)

1/154 (0.65%)

0/66 (0.00%)

0/18 (0.00%)

0/18 (0.00%)

0/12 (0.00%)

Cold sweat * 1

0/3 (0.00%)

0/4 (0.00%)

0/8 (0.00%)

0/7 (0.00%)

0/8 (0.00%)

0/6 (0.00%)

0/6 (0.00%)

0/5 (0.00%)

0/3 (0.00%)

0/6 (0.00%)

0/9 (0.00%)

1/53 (1.89%)

0/85 (0.00%)

0/41 (0.00%)

0/48 (0.00%)

0/18 (0.00%)

2/154 (1.30%)

0/66 (0.00%)

0/18 (0.00%)

1/18 (5.56%)

0/12 (0.00%)

Decubitus ulcer * 1

0/3 (0.00%)

0/4 (0.00%)

0/8 (0.00%)

0/7 (0.00%)

0/8 (0.00%)

0/6 (0.00%)

1/6 (16.67%)

0/5 (0.00%)

0/3 (0.00%)

0/6 (0.00%)

0/9 (0.00%)

0/53 (0.00%)

2/85 (2.35%)

0/41 (0.00%)

1/48 (2.08%)

0/18 (0.00%)

2/154 (1.30%)

0/66 (0.00%)

0/18 (0.00%)

0/18 (0.00%)

0/12 (0.00%)

Dermatitis acneiform * 1

0/3 (0.00%)

0/4 (0.00%)

0/8 (0.00%)

0/7 (0.00%)

0/8 (0.00%)

0/6 (0.00%)

1/6 (16.67%)

0/5 (0.00%)

0/3 (0.00%)

0/6 (0.00%)

0/9 (0.00%)

2/53 (3.77%)

1/85 (1.18%)

0/41 (0.00%)

0/48 (0.00%)

0/18 (0.00%)

3/154 (1.95%)

0/66 (0.00%)

0/18 (0.00%)

0/18 (0.00%)

0/12 (0.00%)

Dry skin * 1

0/3 (0.00%)

0/4 (0.00%)

0/8 (0.00%)

0/7 (0.00%)

0/8 (0.00%)

0/6 (0.00%)

0/6 (0.00%)

0/5 (0.00%)

0/3 (0.00%)

0/6 (0.00%)

0/9 (0.00%)

1/53 (1.89%)

8/85 (9.41%)

0/41 (0.00%)

0/48 (0.00%)

0/18 (0.00%)

10/154 (6.49%)

2/66 (3.03%)

3/18 (16.67%)

0/18 (0.00%)

0/12 (0.00%)

Ecchymosis * 1

0/3 (0.00%)

0/4 (0.00%)

0/8 (0.00%)

0/7 (0.00%)

0/8 (0.00%)

0/6 (0.00%)

0/6 (0.00%)

0/5 (0.00%)

0/3 (0.00%)

0/6 (0.00%)

0/9 (0.00%)

0/53 (0.00%)

1/85 (1.18%)

0/41 (0.00%)

2/48 (4.17%)

0/18 (0.00%)

1/154 (0.65%)

0/66 (0.00%)

1/18 (5.56%)

0/18 (0.00%)

0/12 (0.00%)

Hyperhidrosis * 1

0/3 (0.00%)

0/4 (0.00%)

0/8 (0.00%)

0/7 (0.00%)

0/8 (0.00%)

0/6 (0.00%)

0/6 (0.00%)

0/5 (0.00%)

0/3 (0.00%)

0/6 (0.00%)

1/9 (11.11%)

2/53 (3.77%)

1/85 (1.18%)

0/41 (0.00%)

3/48 (6.25%)

0/18 (0.00%)

5/154 (3.25%)

3/66 (4.55%)

0/18 (0.00%)

1/18 (5.56%)

1/12 (8.33%)

Night sweats * 1

0/3 (0.00%)

1/4 (25.00%)

0/8 (0.00%)

0/7 (0.00%)

0/8 (0.00%)

0/6 (0.00%)

0/6 (0.00%)

0/5 (0.00%)

1/3 (33.33%)

1/6 (16.67%)

0/9 (0.00%)

1/53 (1.89%)

2/85 (2.35%)

2/41 (4.88%)

2/48 (4.17%)

1/18 (5.56%)

0/154 (0.00%)

0/66 (0.00%)

1/18 (5.56%)

1/18 (5.56%)

0/12 (0.00%)

Palmar-plantar erythrodysaesthesia syndrome * 1

0/3 (0.00%)

0/4 (0.00%)

0/8 (0.00%)

0/7 (0.00%)

0/8 (0.00%)

0/6 (0.00%)

0/6 (0.00%)

0/5 (0.00%)

0/3 (0.00%)

0/6 (0.00%)

0/9 (0.00%)

0/53 (0.00%)

0/85 (0.00%)

0/41 (0.00%)

0/48 (0.00%)

0/18 (0.00%)

1/154 (0.65%)

0/66 (0.00%)

0/18 (0.00%)

1/18 (5.56%)

0/12 (0.00%)

Petechiae * 1

0/3 (0.00%)

0/4 (0.00%)

0/8 (0.00%)

0/7 (0.00%)

0/8 (0.00%)

0/6 (0.00%)

0/6 (0.00%)

0/5 (0.00%)

0/3 (0.00%)

0/6 (0.00%)

0/9 (0.00%)

0/53 (0.00%)

0/85 (0.00%)

0/41 (0.00%)

1/48 (2.08%)

0/18 (0.00%)

2/154 (1.30%)

0/66 (0.00%)

1/18 (5.56%)

0/18 (0.00%)

0/12 (0.00%)

Photosensitivity reaction * 1

0/3 (0.00%)

1/4 (25.00%)

0/8 (0.00%)

0/7 (0.00%)

0/8 (0.00%)

0/6 (0.00%)

0/6 (0.00%)

0/5 (0.00%)

0/3 (0.00%)

0/6 (0.00%)

0/9 (0.00%)

0/53 (0.00%)

1/85 (1.18%)

0/41 (0.00%)

0/48 (0.00%)

0/18 (0.00%)

0/154 (0.00%)

0/66 (0.00%)

0/18 (0.00%)

1/18 (5.56%)

0/12 (0.00%)

Rash macular * 1

0/3 (0.00%)

1/4 (25.00%)

0/8 (0.00%)

0/7 (0.00%)

0/8 (0.00%)

0/6 (0.00%)

0/6 (0.00%)

0/5 (0.00%)

0/3 (0.00%)

0/6 (0.00%)

0/9 (0.00%)

0/53 (0.00%)

0/85 (0.00%)

0/41 (0.00%)

1/48 (2.08%)

0/18 (0.00%)

2/154 (1.30%)

0/66 (0.00%)

0/18 (0.00%)

0/18 (0.00%)

0/12 (0.00%)

Rash maculo-papular * 1

0/3 (0.00%)

0/4 (0.00%)

0/8 (0.00%)

0/7 (0.00%)

0/8 (0.00%)

0/6 (0.00%)

0/6 (0.00%)

0/5 (0.00%)

0/3 (0.00%)

1/6 (16.67%)

0/9 (0.00%)

1/53 (1.89%)

9/85 (10.59%)

2/41 (4.88%)

1/48 (2.08%)

0/18 (0.00%)

1/154 (0.65%)

1/66 (1.52%)

0/18 (0.00%)

0/18 (0.00%)

0/12 (0.00%)

Skin discolouration * 1

0/3 (0.00%)

0/4 (0.00%)

0/8 (0.00%)

0/7 (0.00%)

0/8 (0.00%)

0/6 (0.00%)

0/6 (0.00%)

0/5 (0.00%)

0/3 (0.00%)

0/6 (0.00%)

1/9 (11.11%)

0/53 (0.00%)

0/85 (0.00%)

0/41 (0.00%)

0/48 (0.00%)

0/18 (0.00%)

1/154 (0.65%)

2/66 (3.03%)

0/18 (0.00%)

0/18 (0.00%)

0/12 (0.00%)

Skin fissures * 1

0/3 (0.00%)

0/4 (0.00%)

0/8 (0.00%)

0/7 (0.00%)

0/8 (0.00%)

0/6 (0.00%)

0/6 (0.00%)

0/5 (0.00%)

0/3 (0.00%)

0/6 (0.00%)

0/9 (0.00%)

0/53 (0.00%)

0/85 (0.00%)

0/41 (0.00%)

0/48 (0.00%)

0/18 (0.00%)

0/154 (0.00%)

0/66 (0.00%)

1/18 (5.56%)

0/18 (0.00%)

0/12 (0.00%)

Skin hyperpigmentation * 1

0/3 (0.00%)

0/4 (0.00%)

0/8 (0.00%)

0/7 (0.00%)

0/8 (0.00%)

0/6 (0.00%)

0/6 (0.00%)

0/5 (0.00%)

0/3 (0.00%)

0/6 (0.00%)

0/9 (0.00%)

0/53 (0.00%)

1/85 (1.18%)

0/41 (0.00%)

0/48 (0.00%)

0/18 (0.00%)

0/154 (0.00%)

0/66 (0.00%)

1/18 (5.56%)

0/18 (0.00%)

0/12 (0.00%)

Skin mass * 1

0/3 (0.00%)

0/4 (0.00%)

0/8 (0.00%)

0/7 (0.00%)

0/8 (0.00%)

0/6 (0.00%)

0/6 (0.00%)

0/5 (0.00%)

0/3 (0.00%)

0/6 (0.00%)

0/9 (0.00%)

0/53 (0.00%)

0/85 (0.00%)

0/41 (0.00%)

0/48 (0.00%)

0/18 (0.00%)

1/154 (0.65%)

0/66 (0.00%)

1/18 (5.56%)

0/18 (0.00%)

0/12 (0.00%)

Surgical and medical procedures

Sinus operation * 1

0/3 (0.00%)

0/4 (0.00%)

0/8 (0.00%)

0/7 (0.00%)

0/8 (0.00%)

0/6 (0.00%)

0/6 (0.00%)

0/5 (0.00%)

0/3 (0.00%)

0/6 (0.00%)

1/9 (11.11%)

0/53 (0.00%)

0/85 (0.00%)

0/41 (0.00%)

0/48 (0.00%)

0/18 (0.00%)

1/154 (0.65%)

0/66 (0.00%)

0/18 (0.00%)

0/18 (0.00%)

0/12 (0.00%)

Vascular disorders

Deep vein thrombosis * 1

0/3 (0.00%)

0/4 (0.00%)

0/8 (0.00%)

0/7 (0.00%)

1/8 (12.50%)

0/6 (0.00%)

0/6 (0.00%)

0/5 (0.00%)

0/3 (0.00%)

0/6 (0.00%)

1/9 (11.11%)

3/53 (5.66%)

3/85 (3.53%)

6/41 (14.63%)

4/48 (8.33%)

2/18 (11.11%)

9/154 (5.84%)

1/66 (1.52%)

1/18 (5.56%)

0/18 (0.00%)

0/12 (0.00%)

Hypotension * 1

0/3 (0.00%)

0/4 (0.00%)

1/8 (12.50%)

0/7 (0.00%)

1/8 (12.50%)

0/6 (0.00%)

0/6 (0.00%)

0/5 (0.00%)

0/3 (0.00%)

0/6 (0.00%)

0/9 (0.00%)

5/53 (9.43%)

19/85 (22.35%)

7/41 (17.07%)

2/48 (4.17%)

0/18 (0.00%)

15/154 (9.74%)

5/66 (7.58%)

0/18 (0.00%)

2/18 (11.11%)

1/12 (8.33%)

Flushing * 1

0/3 (0.00%)

0/4 (0.00%)

1/8 (12.50%)

0/7 (0.00%)

0/8 (0.00%)

1/6 (16.67%)

0/6 (0.00%)

0/5 (0.00%)

0/3 (0.00%)

0/6 (0.00%)

0/9 (0.00%)

1/53 (1.89%)

1/85 (1.18%)

0/41 (0.00%)

0/48 (0.00%)

0/18 (0.00%)

2/154 (1.30%)

0/66 (0.00%)

2/18 (11.11%)

0/18 (0.00%)

0/12 (0.00%)

Hot flush * 1

0/3 (0.00%)

0/4 (0.00%)

1/8 (12.50%)

0/7 (0.00%)

0/8 (0.00%)

0/6 (0.00%)

0/6 (0.00%)

0/5 (0.00%)

0/3 (0.00%)

0/6 (0.00%)

0/9 (0.00%)

0/53 (0.00%)

1/85 (1.18%)

1/41 (2.44%)

1/48 (2.08%)

0/18 (0.00%)

4/154 (2.60%)

0/66 (0.00%)

2/18 (11.11%)

0/18 (0.00%)

0/12 (0.00%)

Hypertension * 1

0/3 (0.00%)

0/4 (0.00%)

0/8 (0.00%)

0/7 (0.00%)

0/8 (0.00%)

0/6 (0.00%)

0/6 (0.00%)

0/5 (0.00%)

0/3 (0.00%)

0/6 (0.00%)

1/9 (11.11%)

1/53 (1.89%)

8/85 (9.41%)

2/41 (4.88%)

2/48 (4.17%)

0/18 (0.00%)

7/154 (4.55%)

1/66 (1.52%)

0/18 (0.00%)

1/18 (5.56%)

1/12 (8.33%)

Jugular vein thrombosis * 1

0/3 (0.00%)

0/4 (0.00%)

0/8 (0.00%)

0/7 (0.00%)

0/8 (0.00%)

0/6 (0.00%)

0/6 (0.00%)

0/5 (0.00%)

0/3 (0.00%)

0/6 (0.00%)

0/9 (0.00%)

0/53 (0.00%)

0/85 (0.00%)

0/41 (0.00%)

0/48 (0.00%)

1/18 (5.56%)

0/154 (0.00%)

0/66 (0.00%)

0/18 (0.00%)

0/18 (0.00%)

0/12 (0.00%)

Thrombophlebitis superficial * 1

0/3 (0.00%)

0/4 (0.00%)

0/8 (0.00%)

1/7 (14.29%)

0/8 (0.00%)

0/6 (0.00%)

0/6 (0.00%)

0/5 (0.00%)

0/3 (0.00%)

0/6 (0.00%)

0/9 (0.00%)

0/53 (0.00%)

0/85 (0.00%)

0/41 (0.00%)

0/48 (0.00%)

0/18 (0.00%)

0/154 (0.00%)

0/66 (0.00%)

0/18 (0.00%)

0/18 (0.00%)

0/12 (0.00%)

Thrombosis * 1

0/3 (0.00%)

0/4 (0.00%)

0/8 (0.00%)

1/7 (14.29%)

0/8 (0.00%)

0/6 (0.00%)

0/6 (0.00%)

0/5 (0.00%)

0/3 (0.00%)

0/6 (0.00%)

0/9 (0.00%)

0/53 (0.00%)

0/85 (0.00%)

0/41 (0.00%)

0/48 (0.00%)

0/18 (0.00%)

0/154 (0.00%)

0/66 (0.00%)

0/18 (0.00%)

0/18 (0.00%)

0/12 (0.00%)

1 Term from vocabulary, MedDRA 23.0; * Indicates events were collected by non-systematic assessment; [1] MedDRA v24.1 was used for RP2D Cohort: MET Exon 14 Alterations NSCLC: Crizotinib 250 mg group.

Limitations and Caveats

[Not Specified]

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

There IS an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.

Pfizer has the right to review disclosures, requesting a delay of less than 60 days. Investigator will postpone single center publications until after disclosure of pooled data (all sites), less than 12 months from study completion/termination at all participating sites. Investigator may not disclose previously undisclosed confidential information other than study results.

Results Point of Contact

• Name/Title: Pfizer ClinicalTrials.gov Call Center
• Organization: Pfizer Inc.
• Phone: 1-800-718-1021
• EMail: ClinicalTrials.gov_Inquiries@pfizer.com

Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):

Ng TL, Tsui DCC, Wang S, Usari T, Patil T, Wilner K, Camidge DR. Association of anticoagulant use with clinical outcomes from crizotinib in ALK- and ROS1-rearranged advanced non-small cell lung cancers: A retrospective analysis of PROFILE 1001. Cancer Med. 2022 Dec;11(23):4422-4429. doi: 10.1002/cam4.4789. Epub 2022 May 5.

Camidge DR, Otterson GA, Clark JW, Ignatius Ou SH, Weiss J, Ades S, Shapiro GI, Socinski MA, Murphy DA, Conte U, Tang Y, Wang SC, Wilner KD, Villaruz LC. Crizotinib in Patients With MET-Amplified NSCLC. J Thorac Oncol. 2021 Jun;16(6):1017-1029. doi: 10.1016/j.jtho.2021.02.010. Epub 2021 Mar 4.

Solomon BJ, Kim EE, Winter M, Monti K, Tang Y, Wilner KD, Wang S, Ou SI. Ophthalmological assessment of crizotinib in advanced non-small-cell lung cancer. Lung Cancer. 2020 Jul;145:167-172. doi: 10.1016/j.lungcan.2020.04.010. Epub 2020 Apr 28.

Clark JW, Camidge DR, Kwak EL, Maki RG, Shapiro GI, Chen I, Tan W, Randolph S, Christensen JG, Ozeck M, Tang Y, Wilner KD, Salgia R. Dose-escalation trial of the ALK, MET & ROS1 inhibitor, crizotinib, in patients with advanced cancer. Future Oncol. 2020 Jan;16(1):4289-4301. doi: 10.2217/fon-2019-0653. Epub 2019 Nov 28.

Shaw AT, Riely GJ, Bang YJ, Kim DW, Camidge DR, Solomon BJ, Varella-Garcia M, Iafrate AJ, Shapiro GI, Usari T, Wang SC, Wilner KD, Clark JW, Ou SI. Crizotinib in ROS1-rearranged advanced non-small-cell lung cancer (NSCLC): updated results, including overall survival, from PROFILE 1001. Ann Oncol. 2019 Jul 1;30(7):1121-1126. doi: 10.1093/annonc/mdz131.

Camidge DR, Kim EE, Usari T, Polli A, Lewis I, Wilner KD. Renal Effects of Crizotinib in Patients With ALK-Positive Advanced NSCLC. J Thorac Oncol. 2019 Jun;14(6):1077-1085. doi: 10.1016/j.jtho.2019.02.015. Epub 2019 Feb 26.

Yoneda KY, Scranton JR, Cadogan MA, Tassell V, Nadanaciva S, Wilner KD, Stollenwerk NS. Interstitial Lung Disease Associated With Crizotinib in Patients With Advanced Non-Small Cell Lung Cancer: Independent Review of Four PROFILE Trials. Clin Lung Cancer. 2017 Sep;18(5):472-479. doi: 10.1016/j.cllc.2017.03.004. Epub 2017 Mar 14.

Shaw AT, Ou SH, Bang YJ, Camidge DR, Solomon BJ, Salgia R, Riely GJ, Varella-Garcia M, Shapiro GI, Costa DB, Doebele RC, Le LP, Zheng Z, Tan W, Stephenson P, Shreeve SM, Tye LM, Christensen JG, Wilner KD, Clark JW, Iafrate AJ. Crizotinib in ROS1-rearranged non-small-cell lung cancer. N Engl J Med. 2014 Nov 20;371(21):1963-71. doi: 10.1056/NEJMoa1406766. Epub 2014 Sep 27.

Go H, Kim DW, Kim D, Keam B, Kim TM, Lee SH, Heo DS, Bang YJ, Chung DH. Clinicopathologic analysis of ROS1-rearranged non-small-cell lung cancer and proposal of a diagnostic algorithm. J Thorac Oncol. 2013 Nov;8(11):1445-50. doi: 10.1097/JTO.0b013e3182a4dd6e.

Awad MM, Katayama R, McTigue M, Liu W, Deng YL, Brooun A, Friboulet L, Huang D, Falk MD, Timofeevski S, Wilner KD, Lockerman EL, Khan TM, Mahmood S, Gainor JF, Digumarthy SR, Stone JR, Mino-Kenudson M, Christensen JG, Iafrate AJ, Engelman JA, Shaw AT. Acquired resistance to crizotinib from a mutation in CD74-ROS1. N Engl J Med. 2013 Jun 20;368(25):2395-401. doi: 10.1056/NEJMoa1215530. Epub 2013 Jun 1.

Camidge DR, Bang YJ, Kwak EL, Iafrate AJ, Varella-Garcia M, Fox SB, Riely GJ, Solomon B, Ou SH, Kim DW, Salgia R, Fidias P, Engelman JA, Gandhi L, Janne PA, Costa DB, Shapiro GI, Lorusso P, Ruffner K, Stephenson P, Tang Y, Wilner K, Clark JW, Shaw AT. Activity and safety of crizotinib in patients with ALK-positive non-small-cell lung cancer: updated results from a phase 1 study. Lancet Oncol. 2012 Oct;13(10):1011-9. doi: 10.1016/S1470-2045(12)70344-3. Epub 2012 Sep 4.

Ou SH, Azada M, Dy J, Stiber JA. Asymptomatic profound sinus bradycardia (heart rate </=45) in non-small cell lung cancer patients treated with crizotinib. J Thorac Oncol. 2011 Dec;6(12):2135-7. doi: 10.1097/JTO.0b013e3182307e06.

Shaw AT, Yeap BY, Solomon BJ, Riely GJ, Gainor J, Engelman JA, Shapiro GI, Costa DB, Ou SH, Butaney M, Salgia R, Maki RG, Varella-Garcia M, Doebele RC, Bang YJ, Kulig K, Selaru P, Tang Y, Wilner KD, Kwak EL, Clark JW, Iafrate AJ, Camidge DR. Effect of crizotinib on overall survival in patients with advanced non-small-cell lung cancer harbouring ALK gene rearrangement: a retrospective analysis. Lancet Oncol. 2011 Oct;12(11):1004-12. doi: 10.1016/S1470-2045(11)70232-7. Epub 2011 Sep 18.

Kijima T, Takeuchi K, Tetsumoto S, Shimada K, Takahashi R, Hirata H, Nagatomo I, Hoshino S, Takeda Y, Kida H, Goya S, Tachibana I, Kawase I. Favorable response to crizotinib in three patients with echinoderm microtubule-associated protein-like 4-anaplastic lymphoma kinase fusion-type oncogene-positive non-small cell lung cancer. Cancer Sci. 2011 Aug;102(8):1602-4. doi: 10.1111/j.1349-7006.2011.01970.x.

Ou SH, Kwak EL, Siwak-Tapp C, Dy J, Bergethon K, Clark JW, Camidge DR, Solomon BJ, Maki RG, Bang YJ, Kim DW, Christensen J, Tan W, Wilner KD, Salgia R, Iafrate AJ. Activity of crizotinib (PF02341066), a dual mesenchymal-epithelial transition (MET) and anaplastic lymphoma kinase (ALK) inhibitor, in a non-small cell lung cancer patient with de novo MET amplification. J Thorac Oncol. 2011 May;6(5):942-6. doi: 10.1097/JTO.0b013e31821528d3.

Costa DB, Kobayashi S, Pandya SS, Yeo WL, Shen Z, Tan W, Wilner KD. CSF concentration of the anaplastic lymphoma kinase inhibitor crizotinib. J Clin Oncol. 2011 May 20;29(15):e443-5. doi: 10.1200/JCO.2010.34.1313. Epub 2011 Mar 21. No abstract available.

Butrynski JE, D'Adamo DR, Hornick JL, Dal Cin P, Antonescu CR, Jhanwar SC, Ladanyi M, Capelletti M, Rodig SJ, Ramaiya N, Kwak EL, Clark JW, Wilner KD, Christensen JG, Janne PA, Maki RG, Demetri GD, Shapiro GI. Crizotinib in ALK-rearranged inflammatory myofibroblastic tumor. N Engl J Med. 2010 Oct 28;363(18):1727-33. doi: 10.1056/NEJMoa1007056.

Kwak EL, Bang YJ, Camidge DR, Shaw AT, Solomon B, Maki RG, Ou SH, Dezube BJ, Janne PA, Costa DB, Varella-Garcia M, Kim WH, Lynch TJ, Fidias P, Stubbs H, Engelman JA, Sequist LV, Tan W, Gandhi L, Mino-Kenudson M, Wei GC, Shreeve SM, Ratain MJ, Settleman J, Christensen JG, Haber DA, Wilner K, Salgia R, Shapiro GI, Clark JW, Iafrate AJ. Anaplastic lymphoma kinase inhibition in non-small-cell lung cancer. N Engl J Med. 2010 Oct 28;363(18):1693-703. doi: 10.1056/NEJMoa1006448. Erratum In: N Engl J Med. 2011 Feb 10;364(6):588.

• Responsible Party: Pfizer
• ClinicalTrials.gov Identifier: NCT00585195
• Other Study ID Numbers: A8081001; PROFILE 1001 ( Other Identifier: Alias Study Number )
• First Submitted: December 29, 2007
• First Posted: January 3, 2008
• Results First Submitted: July 30, 2021
• Results First Posted: October 14, 2021
• Last Update Posted: February 8, 2023