ACP-196 (Acalabrutinib), a Novel Bruton Tyrosine Kinase (BTK) Inhibitor, for Treatment of Chronic Lymphocytic Leukemia, Richter's Syndrome or Prolymphocytic Leukemia

• ClinicalTrials.gov Identifier: NCT02029443
• Recruitment Status: Active, not recruiting
• First Posted: January 8, 2014
• Results First Posted: September 10, 2022
• Last Update Posted: April 24, 2024
• Sponsor: Acerta Pharma BV
• Information provided by (Responsible Party): Acerta Pharma BV

• Study Type: Interventional
• Study Design: Allocation: N/A; Intervention Model: Sequential Assignment; Masking: None (Open Label); Primary Purpose: Treatment
• Conditions: Chronic Lymphocytic Leukemia; Small Lymphocytic Lymphoma; Richter's Syndrome; Prolymphocytic Leukemia
• Intervention: Drug: Acalabrutinib
• Enrollment: 306

Participant Flow

Recruitment Details
Pre-assignment Details	Out of 306 enrolled participates, 5 participants were not treated with the study drug. The data of "All treated population" was collected and analyzed. The results data are reported per the primary completion date (data cut-off date of 15Jul2021). There will be no updated results for all outcome measures at the time of end of study.

Arm/Group Title	Relapsed/Refractory Cohort	Treatment-naive Cohort	Ibrutinib-intolerant Cohort	Richters Syndrome/Prolymphocytic Leukemia Transformation Cohort	Ibrutinib Relapsed/Refractory Cohort
Arm/Group Description	Phase 1 (dose-escalation) and Phase 2 (dose-expansion) were conducted for participants with relapsed/refractory chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL). In Phase 1, participants received oral once daily (QD) acalabrutinib at Dose 1 (Cohort 1), Dose 2 (Cohort 2a), Dose 3 (Cohort 3), and Dose 4 (Cohort 4a), and twice daily (BID) acalabrutinib at Dose 1 (Cohort 2b) and Dose 5 (Cohort 4b) for 28 days (1 cycle). In Phase 2, participants received oral acalabrutinib at Dose 1 BID (Cohort 2b) or Dose 5 QD (Cohort 2c, later switched to Dose 1 BID per protocol amendment 6) until disease progression or until the investigator considered the study treatment to be intolerable or no longer in the participant's best interest. Participants from Phase 1 continued to receive Dose 1 BID until disease progression or until the investigator considered the study treatment to be intolerable or no longer in the participant's best interest.	Treatment-naïve participants with confirmed CLL or SLL, received oral acalabrutinib Dose 5 QD (Cohort 7, later switched to Dose 1 BID per protocol amendment 6) or Dose 1 BID (Cohort 11) until disease progression or until the investigator considered the study treatment to be intolerable or no longer in the participant's best interest.	Participants with confirmed CLL or SLL and were not tolerating ibrutinib treatment, received oral acalabrutinib Dose 5 QD (Cohort 8a, later switched to Dose 1 BID per protocol amendment 4) or Dose 1 BID (Cohort 8b) until disease progression or until the investigator considered the study treatment to be intolerable or no longer in the participant's best interest.	Participants with diffuse large B-cell lymphoma (DLBCL) Richter's transformation (RS) or prolymphocytic leukemia transformation (PLL), received oral acalabrutinib Dose 5 BID (Cohort 9) until disease progression or until the investigator considered the study treatment to be intolerable or no longer in the participant's best interest.	Participants with confirmed CLL/SLL and had relapsed/refractory to ibrutinib treatment, received oral acalabrutinib Dose 5 QD (Cohort 10) until disease progression or until the investigator considered the study treatment to be intolerable or no longer in the participant's best interest.
Period Title: Overall Study
Started	134	99	33	29	6
Completed	41	70	6	3	0
Not Completed	93	29	27	26	6
Reason Not Completed
Completed 30-Day safety follow-up visit	53	16	12	2	1
Death	13	2	2	11	2
Lost to Follow-up	1	0	1	1	0
Started other anti-cancer therapy	17	4	7	9	3
Withdrawal by Subject	3	1	1	1	0
Other	6	6	4	2	0

Baseline Characteristics

Arm/Group Title		Relapsed/Refractory Cohort	Treatment-naive Cohort	Ibrutinib-intolerant Cohort	Richters Syndrome/Prolymphocytic Leukemia Transformation Cohort	Ibrutinib Relapsed/Refractory Cohort	Total
Arm/Group Description		Phase 1 (dose-escalation) and Phase 2 (dose-expansion) were conducted for participants with relapsed/refractory chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL). In Phase 1, participants received oral once daily (QD) acalabrutinib at Dose 1 (Cohort 1), Dose 2 (Cohort 2a), Dose 3 (Cohort 3), and Dose 4 (Cohort 4a), and twice daily (BID) acalabrutinib at Dose 1 (Cohort 2b) and Dose 5 (Cohort 4b) for 28 days (1 cycle). In Phase 2, participants received oral acalabrutinib at Dose 1 BID (Cohort 2b) or Dose 5 QD (Cohort 2c, later switched to Dose 1 BID per protocol amendment 6) until disease progression or until the investigator considered the study treatment to be intolerable or no longer in the participant's best interest. Participants from Phase 1 continued to receive Dose 1 BID until disease progression or until the investigator considered the study treatment to be intolerable or no longer in the participant's best interest.	Treatment-naïve participants with confirmed CLL or SLL, received oral acalabrutinib Dose 5 QD (Cohort 7, later switched to Dose 1 BID per protocol amendment 6) or Dose 1 BID (Cohort 11) until disease progression or until the investigator considered the study treatment to be intolerable or no longer in the participant's best interest.	Participants with confirmed CLL or SLL and were not tolerating ibrutinib treatment, received oral acalabrutinib Dose 5 QD (Cohort 8a, later switched to Dose 1 BID per protocol amendment 4) or Dose 1 BID (Cohort 8b) until disease progression or until the investigator considered the study treatment to be intolerable or no longer in the participant's best interest.	Participants with diffuse large B-cell lymphoma (DLBCL) Richter's transformation (RS) or prolymphocytic leukemia transformation (PLL), received oral acalabrutinib Dose 5 BID (Cohort 9) until disease progression or until the investigator considered the study treatment to be intolerable or no longer in the participant's best interest.	Participants with confirmed CLL/SLL and had relapsed/refractory to ibrutinib treatment, received oral acalabrutinib Dose 5 QD (Cohort 10) until disease progression or until the investigator considered the study treatment to be intolerable or no longer in the participant's best interest.	Total of all reporting groups
Overall Number of Baseline Participants		134	99	33	29	6	301
Baseline Analysis Population Description		All-treated population included all enrolled participants who received 1 or more doses of study drug.
Age, Continuous; Mean (Standard Deviation); Unit of measure: Years
	Number Analyzed	134 participants	99 participants	33 participants	29 participants	6 participants	301 participants
		65.6 (9.2)	63.5 (9.7)	63.9 (8.9)	65.0 (9.6)	62.5 (7.9)	64.6 (9.33)
Sex: Female, Male; Measure Type: Count of Participants; Unit of measure: Participants
	Number Analyzed	134 participants	99 participants	33 participants	29 participants	6 participants	301 participants
	Female	35 26.1%	33 33.3%	13 39.4%	14 48.3%	3 50.0%	98 32.6%
	Male	99 73.9%	66 66.7%	20 60.6%	15 51.7%	3 50.0%	203 67.4%
Ethnicity (NIH/OMB); Measure Type: Count of Participants; Unit of measure: Participants
	Number Analyzed	134 participants	99 participants	33 participants	29 participants	6 participants	301 participants
	Hispanic or Latino	2 1.5%	3 3.0%	0 0.0%	0 0.0%	0 0.0%	5 1.7%
	Not Hispanic or Latino	129 96.3%	94 94.9%	33 100.0%	28 96.6%	6 100.0%	290 96.3%
	Unknown or Not Reported	3 2.2%	2 2.0%	0 0.0%	1 3.4%	0 0.0%	6 2.0%
Race (NIH/OMB); Measure Type: Count of Participants; Unit of measure: Participants
	Number Analyzed	134 participants	99 participants	33 participants	29 participants	6 participants	301 participants
	American Indian or Alaska Native	1 0.7%	0 0.0%	0 0.0%	0 0.0%	0 0.0%	1 0.3%
	Asian	1 0.7%	2 2.0%	0 0.0%	0 0.0%	0 0.0%	3 1.0%
	Native Hawaiian or Other Pacific Islander	0 0.0%	0 0.0%	0 0.0%	0 0.0%	0 0.0%	0 0.0%
	Black or African American	6 4.5%	5 5.1%	2 6.1%	1 3.4%	1 16.7%	15 5.0%
	White	120 89.6%	88 88.9%	31 93.9%	27 93.1%	5 83.3%	271 90.0%
	More than one race	6 4.5%	4 4.0%	0 0.0%	1 3.4%	0 0.0%	11 3.7%
	Unknown or Not Reported	0 0.0%	0 0.0%	0 0.0%	0 0.0%	0 0.0%	0 0.0%

Outcome Measures

1. Primary Outcome

Title	Number of Participants With Dose Limiting Toxicities (DLTs) in Phase 1
Description	Participants with DLTs in Phase 1 are reported. The DLT was defined as any of the following events unless the adverse event is clearly related to disease progression or the participant's current medical history and associated comorbidities: (1) Any Grade 3 or greater nonhematologic toxicity with the exceptions of alopecia and Grade 3 nausea, vomiting, and diarrhea that respond to supportive therapy; (2) Hematologic toxicities including Grade 4 neutropenia lasting more than 5 days, Grade 4 or Grade 3 thrombocytopenia with bleeding or any requirement for platelets transfusion, Grade 3 or greater febrile neutropenia (body temperature of 38.5 degrees Celsius or more), or Grade 4 anemia, unexplained by underlying disease; or (3) Dosing delay due to toxicity for > 7 consecutive days.
Time Frame	From Day 1 to Day 28 after first dose of study drug

Outcome Measure Data

Analysis Population Description

All-treated population included all participants enrolled in Phase 1 (dose-escalation) of the study, received 1 or more doses of study drug, and observed from Day 1 to Day 28 after first dose of study drug.

Arm/Group Title	Cohort 1	Cohort 2a	Cohort 2b	Cohort 3	Cohort 4a	Cohort 4b
Arm/Group Description:	Participants with CLL/SLL received oral acalabrutinib Dose 1 QD for 28 days.	Participants with CLL/SLL received oral acalabrutinib Dose 2 QD for 28 days.	Participants with CLL/SLL received oral acalabrutinib Dose 2 BID for 28 days.	Participants with CLL/SLL received oral acalabrutinib Dose 3 QD for 28 days.	Participants with CLL/SLL received oral acalabrutinib Dose 4 QD for 28 days.	Participants with CLL/SLL received oral acalabrutinib Dose 4 QD for 28 days.
Overall Number of Participants Analyzed	9	8	29	7	6	6
Measure Type: Count of Participants; Unit of Measure: Participants
	0 0.0%	0 0.0%	0 0.0%	0 0.0%	0 0.0%	0 0.0%

2. Primary Outcome

Title	Number of Participants With Treatment Emergent Adverse Events (TEAEs) and Treatment Emergent Serious Adverse Events (TESAEs)
Description	An adverse event (AE) is any untoward medical occurrence in a participant who received study drug without regard to possibility of causal relationship. A serious adverse event (SAE) is 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. The TEAEs are defined as events present at baseline that worsened in intensity after administration of study drug or events absent at baseline that emerged after administration of study drug.
Time Frame	Day 1 through the final data cutoff date (approximately 7 years 6 months)

Outcome Measure Data

Analysis Population Description

All-treated population included all enrolled participants who received 1 or more doses of study drug.

Arm/Group Title	Relapsed/Refractory Cohort	Treatment-naive Cohort	Ibrutinib-intolerant Cohort	Richters Syndrome/Prolymphocytic Leukemia Transformation Cohort	Ibrutinib Relapsed/Refractory Cohort
Arm/Group Description:	Phase 1 (dose-escalation) and Phase 2 (dose-expansion) were conducted for participants with relapsed/refractory chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL). In Phase 1, participants received oral once daily (QD) acalabrutinib at Dose 1 (Cohort 1), Dose 2 (Cohort 2a), Dose 3 (Cohort 3), and Dose 4 (Cohort 4a), and twice daily (BID) acalabrutinib at Dose 1 (Cohort 2b) and Dose 5 (Cohort 4b) for 28 days (1 cycle). In Phase 2, participants received oral acalabrutinib at Dose 1 BID (Cohort 2b) or Dose 5 QD (Cohort 2c, later switched to Dose 1 BID per protocol amendment 6) until disease progression or until the investigator considered the study treatment to be intolerable or no longer in the participant's best interest. Participants from Phase 1 continued to receive Dose 1 BID until disease progression or until the investigator considered the study treatment to be intolerable or no longer in the participant's best interest.	Treatment-naïve participants with confirmed CLL or SLL, received oral acalabrutinib Dose 5 QD (Cohort 7, later switched to Dose 1 BID per protocol amendment 6) or Dose 1 BID (Cohort 11) until disease progression or until the investigator considered the study treatment to be intolerable or no longer in the participant's best interest.	Participants with confirmed CLL or SLL and were not tolerating ibrutinib treatment, received oral acalabrutinib Dose 5 QD (Cohort 8a, later switched to Dose 1 BID per protocol amendment 4) or Dose 1 BID (Cohort 8b) until disease progression or until the investigator considered the study treatment to be intolerable or no longer in the participant's best interest.	Participants with diffuse large B-cell lymphoma (DLBCL) Richter's transformation (RS) or prolymphocytic leukemia transformation (PLL), received oral acalabrutinib Dose 5 BID (Cohort 9) until disease progression or until the investigator considered the study treatment to be intolerable or no longer in the participant's best interest.	Participants with confirmed CLL/SLL and had relapsed/refractory to ibrutinib treatment, received oral acalabrutinib Dose 5 QD (Cohort 10) until disease progression or until the investigator considered the study treatment to be intolerable or no longer in the participant's best interest.
Overall Number of Participants Analyzed	134	99	33	29	6
Measure Type: Count of Participants; Unit of Measure: Participants
Any TEAEs	134 100.0%	99 100.0%	33 100.0%	28 96.6%	6 100.0%
Any TESAEs	86 64.2%	50 50.5%	20 60.6%	18 62.1%	3 50.0%

3. Primary Outcome

Title	Number of Participants With Treatment Emergent Events of Clinical Interest (ECI)
Description	The treatment emergent ECI included the events identified based on preclinical findings, emerging data from clinical studies relating to acalabrutinib, and pharmacological effects of approved Bruton's tyrosine kinase (BTK) inhibitors and reported after the first dose of the study drug.
Time Frame	Day 1 through the final data cutoff date (approximately 7 years 6 months)

Outcome Measure Data

Analysis Population Description

All-treated population included all enrolled participants who received 1 or more doses of study drug.

Arm/Group Title	Relapsed/Refractory Cohort	Treatment-naive Cohort	Ibrutinib-intolerant Cohort	Richters Syndrome/Prolymphocytic Leukemia Transformation Cohort	Ibrutinib Relapsed/Refractory Cohort
Arm/Group Description:	Phase 1 (dose-escalation) and Phase 2 (dose-expansion) were conducted for participants with relapsed/refractory chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL). In Phase 1, participants received oral once daily (QD) acalabrutinib at Dose 1 (Cohort 1), Dose 2 (Cohort 2a), Dose 3 (Cohort 3), and Dose 4 (Cohort 4a), and twice daily (BID) acalabrutinib at Dose 1 (Cohort 2b) and Dose 5 (Cohort 4b) for 28 days (1 cycle). In Phase 2, participants received oral acalabrutinib at Dose 1 BID (Cohort 2b) or Dose 5 QD (Cohort 2c, later switched to Dose 1 BID per protocol amendment 6) until disease progression or until the investigator considered the study treatment to be intolerable or no longer in the participant's best interest. Participants from Phase 1 continued to receive Dose 1 BID until disease progression or until the investigator considered the study treatment to be intolerable or no longer in the participant's best interest.	Treatment-naïve participants with confirmed CLL or SLL, received oral acalabrutinib Dose 5 QD (Cohort 7, later switched to Dose 1 BID per protocol amendment 6) or Dose 1 BID (Cohort 11) until disease progression or until the investigator considered the study treatment to be intolerable or no longer in the participant's best interest.	Participants with confirmed CLL or SLL and were not tolerating ibrutinib treatment, received oral acalabrutinib Dose 5 QD (Cohort 8a, later switched to Dose 1 BID per protocol amendment 4) or Dose 1 BID (Cohort 8b) until disease progression or until the investigator considered the study treatment to be intolerable or no longer in the participant's best interest.	Participants with diffuse large B-cell lymphoma (DLBCL) Richter's transformation (RS) or prolymphocytic leukemia transformation (PLL), received oral acalabrutinib Dose 5 BID (Cohort 9) until disease progression or until the investigator considered the study treatment to be intolerable or no longer in the participant's best interest.	Participants with confirmed CLL/SLL and had relapsed/refractory to ibrutinib treatment, received oral acalabrutinib Dose 5 QD (Cohort 10) until disease progression or until the investigator considered the study treatment to be intolerable or no longer in the participant's best interest.
Overall Number of Participants Analyzed	134	99	33	29	6
Measure Type: Count of Participants; Unit of Measure: Participants
Atrial fibrillation	12 9.0%	6 6.1%	4 12.1%	3 10.3%	0 0.0%
Ventricular tachyarrhythmias	2 1.5%	0 0.0%	0 0.0%	0 0.0%	0 0.0%
Anemia	22 16.4%	10 10.1%	4 12.1%	10 34.5%	1 16.7%
Neutropenia	26 19.4%	9 9.1%	5 15.2%	13 44.8%	1 16.7%
Other Leukopenia	2 1.5%	1 1.0%	1 3.0%	0 0.0%	0 0.0%
Thrombocytopenia	10 7.5%	1 1.0%	4 12.1%	4 13.8%	0 0.0%
Major hemorrhage	11 8.2%	8 8.1%	4 12.1%	0 0.0%	1 16.7%
Hepatotoxicity	4 3.0%	4 4.0%	1 3.0%	3 10.3%	0 0.0%
Hypertension	31 23.1%	29 29.3%	7 21.2%	2 6.9%	0 0.0%
Infections	118 88.1%	86 86.9%	25 75.8%	18 62.1%	4 66.7%
Interstitial lung disease/Pneumonitis	1 0.7%	3 3.0%	0 0.0%	0 0.0%	0 0.0%
Second primary malignancies, excluding non-melanoma skin	23 17.2%	14 14.1%	3 9.1%	1 3.4%	0 0.0%
Tumor lysis syndrome	1 0.7%	0 0.0%	0 0.0%	0 0.0%	0 0.0%

4. Primary Outcome

Title	Number of Participants With Clinically Important Laboratory Abnormalities With Common Terminology Criteria for Adverse Events (CTCAE) Grade 3 or More
Description	Participants with clinically important laboratory abnormalities with CTCAE Grade 3 or more are reported. Laboratory analysis included hematology, clinical chemistry, amylase, lipase, cardiac troponin I, hepatitis B and C testing, and urinalysis. The CTCAE version 4.03 is a descriptive terminology is used for AE reporting. The CTCAE v4.03 displays Grades 1 through 5 with unique clinical descriptions of severity for each AE based on this general guideline: Grade 3 as severe AE, Grade 4 as life-threatening or disabling AE, and Grade 5 as death related to AE.
Time Frame	Day 1 through the final data cutoff date (approximately 7 years 6 months)

Outcome Measure Data

Analysis Population Description

All-treated population included all enrolled participants who received 1 or more doses of study drug.

Arm/Group Title	Relapsed/Refractory Cohort	Treatment-naive Cohort	Ibrutinib-intolerant Cohort	Richters Syndrome/Prolymphocytic Leukemia Transformation Cohort	Ibrutinib Relapsed/Refractory Cohort
Arm/Group Description:	Phase 1 (dose-escalation) and Phase 2 (dose-expansion) were conducted for participants with relapsed/refractory chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL). In Phase 1, participants received oral once daily (QD) acalabrutinib at Dose 1 (Cohort 1), Dose 2 (Cohort 2a), Dose 3 (Cohort 3), and Dose 4 (Cohort 4a), and twice daily (BID) acalabrutinib at Dose 1 (Cohort 2b) and Dose 5 (Cohort 4b) for 28 days (1 cycle). In Phase 2, participants received oral acalabrutinib at Dose 1 BID (Cohort 2b) or Dose 5 QD (Cohort 2c, later switched to Dose 1 BID per protocol amendment 6) until disease progression or until the investigator considered the study treatment to be intolerable or no longer in the participant's best interest. Participants from Phase 1 continued to receive Dose 1 BID until disease progression or until the investigator considered the study treatment to be intolerable or no longer in the participant's best interest.	Treatment-naïve participants with confirmed CLL or SLL, received oral acalabrutinib Dose 5 QD (Cohort 7, later switched to Dose 1 BID per protocol amendment 6) or Dose 1 BID (Cohort 11) until disease progression or until the investigator considered the study treatment to be intolerable or no longer in the participant's best interest.	Participants with confirmed CLL or SLL and were not tolerating ibrutinib treatment, received oral acalabrutinib Dose 5 QD (Cohort 8a, later switched to Dose 1 BID per protocol amendment 4) or Dose 1 BID (Cohort 8b) until disease progression or until the investigator considered the study treatment to be intolerable or no longer in the participant's best interest.	Participants with diffuse large B-cell lymphoma (DLBCL) Richter's transformation (RS) or prolymphocytic leukemia transformation (PLL), received oral acalabrutinib Dose 5 BID (Cohort 9) until disease progression or until the investigator considered the study treatment to be intolerable or no longer in the participant's best interest.	Participants with confirmed CLL/SLL and had relapsed/refractory to ibrutinib treatment, received oral acalabrutinib Dose 5 QD (Cohort 10) until disease progression or until the investigator considered the study treatment to be intolerable or no longer in the participant's best interest.
Overall Number of Participants Analyzed	134	99	33	29	6
Measure Type: Count of Participants; Unit of Measure: Participants
Hemoglobin, platelets or neutrophils decreased	72 53.7%	30 30.3%	14 42.4%	19 65.5%	4 66.7%
Absolute neutrophil count (decreased)	57 42.5%	23 23.2%	11 33.3%	13 44.8%	3 50.0%
Hemoglobin (decreased)	17 12.7%	5 5.1%	3 9.1%	8 27.6%	3 50.0%
Platelets (decreased)	20 14.9%	3 3.0%	4 12.1%	5 17.2%	1 16.7%
Leukocytes (decreased)	12 9.0%	2 2.0%	3 9.1%	6 20.7%	0 0.0%
Leukocytes (increased)	29 21.6%	21 21.2%	7 21.2%	0 0.0%	2 33.3%
Absolute lymphocyte count (decreased)	20 14.9%	7 7.1%	2 6.1%	6 20.7%	0 0.0%
Absolute lymphocyte count (increased)	29 21.6%	8 8.1%	7 21.2%	3 10.3%	1 16.7%
Urate (increased)	24 17.9%	15 15.2%	8 24.2%	5 17.2%	2 33.3%
Sodium (decreased)	12 9.0%	5 5.1%	2 6.1%	3 10.3%	0 0.0%
Phosphate (decreased)	9 6.7%	1 1.0%	1 3.0%	1 3.4%	0 0.0%
Potassium (increased)	3 2.2%	5 5.1%	1 3.0%	0 0.0%	0 0.0%
Glucose (increased)	3 2.2%	1 1.0%	3 9.1%	0 0.0%	0 0.0%
Alanine aminotransferase (increased)	3 2.2%	1 1.0%	1 3.0%	1 3.4%	0 0.0%
Calcium (increased)	5 3.7%	0 0.0%	0 0.0%	1 3.4%	0 0.0%
Aspartate aminotransferase (increased)	2 1.5%	2 2.0%	0 0.0%	0 0.0%	0 0.0%
Magnesium (increased)	2 1.5%	2 2.0%	0 0.0%	0 0.0%	0 0.0%
Potassium (decreased)	2 1.5%	1 1.0%	0 0.0%	1 3.4%	0 0.0%
Albumin (decreased)	2 1.5%	1 1.0%	0 0.0%	0 0.0%	0 0.0%
Calcium (decreased)	2 1.5%	0 0.0%	0 0.0%	1 3.4%	0 0.0%
Alkaline phosphatase (increased)	1 0.7%	0 0.0%	0 0.0%	1 3.4%	0 0.0%
Amylase (increased)	2 1.5%	0 0.0%	0 0.0%	0 0.0%	0 0.0%
Bilirubin (increased)	2 1.5%	0 0.0%	0 0.0%	0 0.0%	0 0.0%
Creatinine (increased)	2 1.5%	0 0.0%	0 0.0%	0 0.0%	0 0.0%
Lipase (increased)	1 0.7%	1 1.0%	0 0.0%	0 0.0%	0 0.0%

5. Primary Outcome

Title	Number of Participants With Clinically Abnormal Vital Signs Reported as TEAEs
Description	Participants with clinically abnormal vital signs (blood pressure, respiratory rate, pulse rate, or body temperature) reported as TEAEs are reported.
Time Frame	Day 1 through the final data cutoff date (approximately 7 years 6 months)

Outcome Measure Data

Analysis Population Description

All-treated population included all enrolled participants who received 1 or more doses of study drug.

Arm/Group Title	Relapsed/Refractory Cohort	Treatment-naive Cohort	Ibrutinib-intolerant Cohort	Richters Syndrome/Prolymphocytic Leukemia Transformation Cohort	Ibrutinib Relapsed/Refractory Cohort
Arm/Group Description:	Phase 1 (dose-escalation) and Phase 2 (dose-expansion) were conducted for participants with relapsed/refractory chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL). In Phase 1, participants received oral once daily (QD) acalabrutinib at Dose 1 (Cohort 1), Dose 2 (Cohort 2a), Dose 3 (Cohort 3), and Dose 4 (Cohort 4a), and twice daily (BID) acalabrutinib at Dose 1 (Cohort 2b) and Dose 5 (Cohort 4b) for 28 days (1 cycle). In Phase 2, participants received oral acalabrutinib at Dose 1 BID (Cohort 2b) or Dose 5 QD (Cohort 2c, later switched to Dose 1 BID per protocol amendment 6) until disease progression or until the investigator considered the study treatment to be intolerable or no longer in the participant's best interest. Participants from Phase 1 continued to receive Dose 1 BID until disease progression or until the investigator considered the study treatment to be intolerable or no longer in the participant's best interest.	Treatment-naïve participants with confirmed CLL or SLL, received oral acalabrutinib Dose 5 QD (Cohort 7, later switched to Dose 1 BID per protocol amendment 6) or Dose 1 BID (Cohort 11) until disease progression or until the investigator considered the study treatment to be intolerable or no longer in the participant's best interest.	Participants with confirmed CLL or SLL and were not tolerating ibrutinib treatment, received oral acalabrutinib Dose 5 QD (Cohort 8a, later switched to Dose 1 BID per protocol amendment 4) or Dose 1 BID (Cohort 8b) until disease progression or until the investigator considered the study treatment to be intolerable or no longer in the participant's best interest.	Participants with diffuse large B-cell lymphoma (DLBCL) Richter's transformation (RS) or prolymphocytic leukemia transformation (PLL), received oral acalabrutinib Dose 5 BID (Cohort 9) until disease progression or until the investigator considered the study treatment to be intolerable or no longer in the participant's best interest.	Participants with confirmed CLL/SLL and had relapsed/refractory to ibrutinib treatment, received oral acalabrutinib Dose 5 QD (Cohort 10) until disease progression or until the investigator considered the study treatment to be intolerable or no longer in the participant's best interest.
Overall Number of Participants Analyzed	134	99	33	29	6
Measure Type: Count of Participants; Unit of Measure: Participants
Tachycardia	3 2.2%	8 8.1%	2 6.1%	3 10.3%	0 0.0%
Bradycardia	6 4.5%	1 1.0%	0 0.0%	0 0.0%	0 0.0%
Pyrexia	39 29.1%	14 14.1%	10 30.3%	6 20.7%	0 0.0%
Hyperpyrexia	0 0.0%	0 0.0%	0 0.0%	1 3.4%	0 0.0%
Hypothermia	0 0.0%	1 1.0%	0 0.0%	0 0.0%	0 0.0%
Procedural hypotension	0 0.0%	1 1.0%	0 0.0%	0 0.0%	0 0.0%
Blood pressure increased	0 0.0%	1 1.0%	0 0.0%	0 0.0%	0 0.0%
Dyspnoea	27 20.1%	18 18.2%	6 18.2%	3 10.3%	2 33.3%
Dyspnoea exertional	5 3.7%	5 5.1%	1 3.0%	0 0.0%	1 16.7%
Hypertension	30 22.4%	28 28.3%	6 18.2%	1 3.4%	0 0.0%
Hypotension	7 5.2%	12 12.1%	5 15.2%	1 3.4%	2 33.3%
Orthostatic hypotension	0 0.0%	5 5.1%	1 3.0%	0 0.0%	0 0.0%
Essential hypertension	0 0.0%	0 0.0%	1 3.0%	0 0.0%	0 0.0%
Hypertensive crisis	1 0.7%	0 0.0%	0 0.0%	0 0.0%	0 0.0%
Malignant hypertension	0 0.0%	0 0.0%	0 0.0%	1 3.4%	0 0.0%
Palpitations	13 9.7%	4 4.0%	0 0.0%	0 0.0%	0 0.0%

6. Primary Outcome

Title	Area Under the Plasma Concentration-time Curve From Time 0 to 6 Hours (AUC0-6) of Acalabrutinib
Description	The AUC0-6 of acalabrutinib is reported.
Time Frame	Predose and at 0.25, 0.5, 0.75, 1, 2, 4, and 6 hours postdose on Day 1 and Day 8

Outcome Measure Data

Analysis Population Description

Pharmacokinetic (PK) population included all participants who complied with the protocol sufficiently and displayed an evaluable PK profile (e.g. exposure to treatment, availability and integrity of measurements, and absence of major protocol violations). 'Number of participants analyzed' denotes the number of participants evaluated for this outcome measure. 'Number analyzed' denotes the number of participants evaluated for the specified time point.

Arm/Group Title		Cohort 1	Cohort 2a	Cohort 2b	Cohort 2c	Cohort 3	Cohort 4a	Cohort 4b	Cohort 7	Cohort 8a	Cohort 8b	Cohort 9	Cohort 10	Cohort 11
Arm/Group Description:		Participants with CLL/SLL received oral acalabrutinib Dose 1 QD for 28 days and later switched to acalabrutinib Dose 1 BID until disease progression or per the investigator considered the study treatment to be intolerable or no longer in the participant's best interest.	Participants with CLL/SLL received oral acalabrutinib Dose 2 QD for 28 days and later switched to acalabrutinib Dose 1 BID until disease progression or per the investigator considered the study treatment to be intolerable or no longer in the participant's best interest.	Participants with CLL received oral acalabrutinib Dose 1 BID until disease progression or per the investigator considered the study treatment to be intolerable or no longer in the participant's best interest.	Participants with CLL received oral acalabrutinib Dose 5 QD (later switched to Dose 1 BID per protocol amendment 6) until disease progression or per the investigator considered the study treatment to be intolerable or no longer in the participant's best interest.	Participants with CLL received oral acalabrutinib Dose 3 QD (later switched to Dose 1 BID per protocol amendment 6) until disease progression or per the investigator considered the study treatment to be intolerable or no longer in the participant's best interest.	Participants with CLL received oral acalabrutinib Dose 4 QD for 28 days and later switched to acalabrutinib Dose 1 BID until disease progression or per the investigator considered the study treatment to be intolerable or no longer in the participant's best interest.	Participants with CLL received oral acalabrutinib Dose 5 BID (later switched to Dose 1 BID per protocol amendment 6) until disease progression or per the investigator considered the study treatment to be intolerable or no longer in the participant's best interest.	Treatment-naïve participants with CLL or SLL received oral acalabrutinib Dose 5 QD (later switched to Dose 1 BID per protocol amendment 6) until disease progression or per the investigator considered the study treatment to be intolerable or no longer in the participant's best interest.	Participants with CLL or SLL and were not tolerating ibrutinib treatment, received oral acalabrutinib Dose 5 QD (which switched to Dose 1 BID per protocol amendment 4) until disease progression or per the investigator considered the study treatment to be intolerable or no longer in the participant's best interest.	Participants with CLL or SLL and were not tolerating ibrutinib treatment, received oral acalabrutinib Dose 1 BID until disease progression or per the investigator considered the study treatment to be intolerable or no longer in the participant's best interest.	Participants with DLBCLRS or PLL transformation, received oral acalabrutinib Dose 5 BID until disease progression or per the investigator considered the study treatment to be intolerable or no longer in the participant's best interest.	Participants with CLL/SLL and had relapsed/refractory ibrutinib treatment, received oral acalabrutinib Dose 5 BID until disease progression or per the investigator considered the study treatment to be intolerable or no longer in the participant's best interest.	Treatment-naïve participants with CLL/SLL, received oral acalabrutinib Dose 1 BID until disease progression or per the investigator considered the study treatment to be intolerable or no longer in the participant's best interest.
Overall Number of Participants Analyzed		8	7	24	12	6	6	6	33	3	7	6	5	16
Mean (Standard Deviation); Unit of Measure: hr*ng/mL
Day 1	Number Analyzed	8 participants	7 participants	24 participants	12 participants	6 participants	6 participants	6 participants	33 participants	3 participants	6 participants	5 participants	5 participants	16 participants
		971 (564)	1250 (836)	819 (493)	2170 (1180)	1880 (1810)	2960 (1570)	1950 (487)	1740 (1540)	362 (221)	670 (471)	1690 (849)	1100 (590)	789 (398)
Day 8	Number Analyzed	5 participants	7 participants	22 participants	12 participants	4 participants	5 participants	5 participants	29 participants	1 participants	7 participants	6 participants	5 participants	14 participants
		631 (193)	1180 (859)	858 (419)	1660 (554)	1750 (518)	1630 (1050)	1690 (1090)	1480 (986)	2080 [1] (NA)	834 (713)	1860 (786)	1250 (1050)	642 (310)

[1]

Standard deviation (SD) was not calculated as only one participant was evaluated at the time of the analysis.

7. Primary Outcome

Title	Area Under the Plasma Concentration-time Curve From Time 0 to Last Measurable Concentration (AUC0-last) of Acalabrutinib
Description	The AUC0-last of acalabrutinib is reported.
Time Frame	Predose and at 0.25, 0.5, 0.75, 1, 2, 4, 6, and 24 hours postdose on Day 1 and Day 8

Outcome Measure Data

Analysis Population Description

The PK population included all participants who complied with the protocol sufficiently and displayed an evaluable PK profile (e.g. exposure to treatment, availability and integrity of measurements, and absence of major protocol violations). 'Number of participants analyzed' denotes the number of participants evaluated for this outcome measure. 'Number analyzed' denotes the number of participants evaluated for the specified time point.

Arm/Group Title		Cohort 1	Cohort 2a	Cohort 2b	Cohort 2c	Cohort 3	Cohort 4a	Cohort 4b	Cohort 7	Cohort 8a	Cohort 8b	Cohort 9	Cohort 10	Cohort 11
Arm/Group Description:		Participants with CLL/SLL received oral acalabrutinib Dose 1 QD for 28 days and later switched to acalabrutinib Dose 1 BID until disease progression or per the investigator considered the study treatment to be intolerable or no longer in the participant's best interest.	Participants with CLL/SLL received oral acalabrutinib Dose 2 QD for 28 days and later switched to acalabrutinib Dose 1 BID until disease progression or per the investigator considered the study treatment to be intolerable or no longer in the participant's best interest.	Participants with CLL received oral acalabrutinib Dose 1 BID until disease progression or per the investigator considered the study treatment to be intolerable or no longer in the participant's best interest.	Participants with CLL received oral acalabrutinib Dose 5 QD (later switched to Dose 1 BID per protocol amendment 6) until disease progression or per the investigator considered the study treatment to be intolerable or no longer in the participant's best interest.	Participants with CLL received oral acalabrutinib Dose 3 QD (later switched to Dose 1 BID per protocol amendment 6) until disease progression or per the investigator considered the study treatment to be intolerable or no longer in the participant's best interest.	Participants with CLL received oral acalabrutinib Dose 4 QD for 28 days and later switched to acalabrutinib Dose 1 BID until disease progression or per the investigator considered the study treatment to be intolerable or no longer in the participant's best interest.	Participants with CLL received oral acalabrutinib Dose 5 BID (later switched to Dose 1 BID per protocol amendment 6) until disease progression or per the investigator considered the study treatment to be intolerable or no longer in the participant's best interest.	Treatment-naïve participants with CLL or SLL received oral acalabrutinib Dose 5 QD (later switched to Dose 1 BID per protocol amendment 6) until disease progression or per the investigator considered the study treatment to be intolerable or no longer in the participant's best interest.	Participants with CLL or SLL and were not tolerating ibrutinib treatment, received oral acalabrutinib Dose 5 QD (which switched to Dose 1 BID per protocol amendment 4) until disease progression or per the investigator considered the study treatment to be intolerable or no longer in the participant's best interest.	Participants with CLL or SLL and were not tolerating ibrutinib treatment, received oral acalabrutinib Dose 1 BID until disease progression or per the investigator considered the study treatment to be intolerable or no longer in the participant's best interest.	Participants with CLL/SLL received oral acalabrutinib Dose 5 BID until disease progression or per the investigator considered the study treatment to be intolerable or no longer in the participant's best interest.	Participants with CLL/SLL and had relapsed/refractory ibrutinib treatment, received oral acalabrutinib Dose 5 BID until disease progression or per the investigator considered the study treatment to be intolerable or no longer in the participant's best interest.	Treatment-naïve participants with CLL/SLL, received oral acalabrutinib Dose 1 BID until disease progression or per the investigator considered the study treatment to be intolerable or no longer in the participant's best interest.
Overall Number of Participants Analyzed		8	8	28	13	7	6	6	37	3	8	10	5	17
Mean (Standard Deviation); Unit of Measure: hr*ng/mL
Day 1	Number Analyzed	8 participants	8 participants	28 participants	13 participants	7 participants	6 participants	6 participants	37 participants	3 participants	8 participants	10 participants	5 participants	17 participants
		1030 (529)	1270 (775)	795 (502)	2280 (1060)	2030 (1670)	3430 (1640)	1950 (487)	1790 (1470)	539 (106)	570 (451)	1860 (1570)	1100 (590)	850 (462)
Day 8	Number Analyzed	7 participants	7 participants	28 participants	13 participants	7 participants	6 participants	6 participants	37 participants	2 participants	8 participants	9 participants	5 participants	16 participants
		729 (380)	1180 (861)	850 (660)	1850 (882)	2020 (1170)	1750 (979)	1560 (1020)	1400 (929)	1180 [1] (NA)	748 (701)	1710 (669)	1260 (1060)	660 (294)

[1]

The SD could not be derived due to insufficient number of participants were evaluated at the time of the analysis.

8. Primary Outcome

Title	Area Under the Plasma Concentration-time Curve From Time 0 to Infinity (AUC0-inf) of Acalabrutinib
Description	The AUC0-inf of Acalabrutinib is reported.
Time Frame	Predose and at 0.25, 0.5, 0.75, 1, 2, 4, 6, and 24 hours postdose on Day 1 and Day 8

Outcome Measure Data

Analysis Population Description

The PK population included all participants who complied with the protocol sufficiently and displayed an evaluable PK profile (e.g. exposure to treatment, availability and integrity of measurements, and absence of major protocol violations). 'Number of participants analyzed' denotes the number of participants evaluated for this outcome measure. 'Number analyzed' denotes the number of participants evaluated for the specified time point.

Arm/Group Title		Cohort 1	Cohort 2a	Cohort 2b	Cohort 2c	Cohort 3	Cohort 4a	Cohort 4b	Cohort 7	Cohort 8a	Cohort 8b	Cohort 9	Cohort 10	Cohort 11
Arm/Group Description:		Participants with CLL/SLL received oral acalabrutinib Dose 1 QD for 28 days and later switched to acalabrutinib Dose 1 BID until disease progression or per the investigator considered the study treatment to be intolerable or no longer in the participant's best interest.	Participants with CLL/SLL received oral acalabrutinib Dose 2 QD for 28 days and later switched to acalabrutinib Dose 1 BID until disease progression or per the investigator considered the study treatment to be intolerable or no longer in the participant's best interest.	Participants with CLL received oral acalabrutinib Dose 1 BID until disease progression or per the investigator considered the study treatment to be intolerable or no longer in the participant's best interest.	Participants with CLL received oral acalabrutinib Dose 5 QD (later switched to Dose 1 BID per protocol amendment 6) until disease progression or per the investigator considered the study treatment to be intolerable or no longer in the participant's best interest.	Participants with CLL received oral acalabrutinib Dose 3 QD (later switched to Dose 1 BID per protocol amendment 6) until disease progression or per the investigator considered the study treatment to be intolerable or no longer in the participant's best interest.	Participants with CLL received oral acalabrutinib Dose 4 QD for 28 days and later switched to acalabrutinib Dose 1 BID until disease progression or per the investigator considered the study treatment to be intolerable or no longer in the participant's best interest.	Participants with CLL received oral acalabrutinib Dose 5 BID (later switched to Dose 1 BID per protocol amendment 6) until disease progression or per the investigator considered the study treatment to be intolerable or no longer in the participant's best interest.	Treatment-naïve participants with CLL or SLL received oral acalabrutinib Dose 5 QD (later switched to Dose 1 BID per protocol amendment 6) until disease progression or per the investigator considered the study treatment to be intolerable or no longer in the participant's best interest.	Participants with CLL or SLL and were not tolerating ibrutinib treatment, received oral acalabrutinib Dose 5 QD (which switched to Dose 1 BID per protocol amendment 4) until disease progression or per the investigator considered the study treatment to be intolerable or no longer in the participant's best interest.	Participants with CLL or SLL and were not tolerating ibrutinib treatment, received oral acalabrutinib Dose 1 BID until disease progression or per the investigator considered the study treatment to be intolerable or no longer in the participant's best interest.	Participants with DLBCLRS or PLL transformation, received oral acalabrutinib Dose 5 BID until disease progression or per the investigator considered the study treatment to be intolerable or no longer in the participant's best interest.	Participants with CLL/SLL and had relapsed/refractory ibrutinib treatment, received oral acalabrutinib Dose 5 BID until disease progression or per the investigator considered the study treatment to be intolerable or no longer in the participant's best interest.	Treatment-naïve participants with CLL/SLL, received oral acalabrutinib Dose 1 BID until disease progression or per the investigator considered the study treatment to be intolerable or no longer in the participant's best interest.
Overall Number of Participants Analyzed		8	7	24	11	7	5	6	32	3	6	8	4	15
Mean (Standard Deviation); Unit of Measure: hr*ng/mL
Day 1	Number Analyzed	8 participants	7 participants	22 participants	11 participants	7 participants	5 participants	6 participants	32 participants	3 participants	5 participants	6 participants	4 participants	15 participants
		1040 (534)	1320 (827)	855 (517)	2440 (1010)	2050 (1680)	3250 (1630)	1970 (495)	1910 (1530)	574 (76.3)	801 (410)	1770 (776)	1350 (373)	940 (430)
Day 8	Number Analyzed	6 participants	7 participants	24 participants	9 participants	5 participants	5 participants	4 participants	30 participants	1 participants	6 participants	8 participants	4 participants	15 participants
		621 (187)	1200 (865)	956 (665)	1990 (1020)	2360 (1210)	1750 (1140)	1780 (1230)	1540 (973)	2120 [1] (NA)	963 (728)	1750 (701)	1580 (1030)	652 (298)

[1]

The SD could not be calculated as only one participant was evaluated at the time of the analysis.

9. Primary Outcome

Title	Maximum Observed Plasma Concentration (Cmax) of Acalabrutinib
Description	The Cmax of Acalabrutinib is reported.
Time Frame	Predose and at 0.25, 0.5, 0.75, 1, 2, 4, 6, and 24 hours postdose on Day 1 and Day 8

Outcome Measure Data

Analysis Population Description

The PK population included all participants who complied with the protocol sufficiently and displayed an evaluable PK profile (e.g. exposure to treatment, availability and integrity of measurements, and absence of major protocol violations). 'Number of participants analyzed' denotes the number of participants evaluated for this outcome measure. 'Number analyzed' denotes the number of participants evaluated for the specified time point.

Arm/Group Title		Cohort 1	Cohort 2a	Cohort 2b	Cohort 2c	Cohort 3	Cohort 4a	Cohort 4b	Cohort 7	Cohort 8a	Cohort 8b	Cohort 9	Cohort 10	Cohort 11
Arm/Group Description:		Participants with CLL/SLL received oral acalabrutinib Dose 1 QD for 28 days and later switched to acalabrutinib Dose 1 BID until disease progression or per the investigator considered the study treatment to be intolerable or no longer in the participant's best interest.	Participants with CLL/SLL received oral acalabrutinib Dose 2 QD for 28 days and later switched to acalabrutinib Dose 1 BID until disease progression or per the investigator considered the study treatment to be intolerable or no longer in the participant's best interest.	Participants with CLL received oral acalabrutinib Dose 1 BID until disease progression or per the investigator considered the study treatment to be intolerable or no longer in the participant's best interest.	Participants with CLL received oral acalabrutinib Dose 5 QD (later switched to Dose 1 BID per protocol amendment 6) until disease progression or per the investigator considered the study treatment to be intolerable or no longer in the participant's best interest.	Participants with CLL received oral acalabrutinib Dose 3 QD (later switched to Dose 1 BID per protocol amendment 6) until disease progression or per the investigator considered the study treatment to be intolerable or no longer in the participant's best interest.	Participants with CLL received oral acalabrutinib Dose 4 QD for 28 days and later switched to acalabrutinib Dose 1 BID until disease progression or per the investigator considered the study treatment to be intolerable or no longer in the participant's best interest.	Participants with CLL received oral acalabrutinib Dose 5 BID (later switched to Dose 1 BID per protocol amendment 6) until disease progression or per the investigator considered the study treatment to be intolerable or no longer in the participant's best interest.	Treatment-naïve participants with CLL or SLL received oral acalabrutinib Dose 5 QD (later switched to Dose 1 BID per protocol amendment 6) until disease progression or per the investigator considered the study treatment to be intolerable or no longer in the participant's best interest.	Participants with CLL or SLL and were not tolerating ibrutinib treatment, received oral acalabrutinib Dose 5 QD (which switched to Dose 1 BID per protocol amendment 4) until disease progression or per the investigator considered the study treatment to be intolerable or no longer in the participant's best interest.	Participants with CLL or SLL and were not tolerating ibrutinib treatment, received oral acalabrutinib Dose 1 BID until disease progression or per the investigator considered the study treatment to be intolerable or no longer in the participant's best interest.	Participants with DLBCLRS or PLL transformation, received oral acalabrutinib Dose 5 BID until disease progression or per the investigator considered the study treatment to be intolerable or no longer in the participant's best interest.	Participants with CLL/SLL and had relapsed/refractory ibrutinib treatment, received oral acalabrutinib Dose 5 BID until disease progression or per the investigator considered the study treatment to be intolerable or no longer in the participant's best interest.	Treatment-naïve participants with CLL/SLL, received oral acalabrutinib Dose 1 BID until disease progression or per the investigator considered the study treatment to be intolerable or no longer in the participant's best interest.
Overall Number of Participants Analyzed		8	8	28	13	7	5	6	37	3	8	10	5	16
Mean (Standard Deviation); Unit of Measure: ng/mL
Day 1	Number Analyzed	8 participants	8 participants	28 participants	12 participants	7 participants	5 participants	6 participants	37 participants	3 participants	8 participants	10 participants	5 participants	16 participants
		685 (475)	754 (540)	706 (499)	1950 (1460)	1350 (1170)	1550 (1230)	1600 (291)	1390 (1260)	206 (240)	554 (500)	1190 (925)	727 (436)	930 (595)
Day 8	Number Analyzed	7 participants	6 participants	27 participants	13 participants	7 participants	5 participants	6 participants	36 participants	2 participants	8 participants	9 participants	4 participants	16 participants
		521 (308)	805 (757)	812 (829)	1350 (809)	1350 (933)	902 (638)	1320 (1540)	1020 (747)	939 [1] (NA)	616 (660)	1460 (913)	610 (751)	633 (449)

[1]

The SD was not calculated due to insufficient number of participants were evaluated at the time of the analysis.

10. Primary Outcome

Title	Time of Maximum Plasma Concentration (Tmax) of Acalabrutinib
Description	The Tmax of Acalabrutinib is reported.
Time Frame	Predose and at 0.25, 0.5, 0.75, 1, 2, 4, 6, and 24 hours postdose on Day 1 and Day 8

Outcome Measure Data

Analysis Population Description

The PK population included all participants who complied with the protocol sufficiently and displayed an evaluable PK profile (e.g. exposure to treatment, availability and integrity of measurements, and absence of major protocol violations). 'Number of participants analyzed' denotes the number of participants evaluated for this outcome measure. 'Number analyzed' denotes the number of participants evaluated for the specified time point.

Arm/Group Title		Cohort 1	Cohort 2a	Cohort 2b	Cohort 2c	Cohort 3	Cohort 4a	Cohort 4b	Cohort 7	Cohort 8a	Cohort 8b	Cohort 9	Cohort 10	Cohort 11
Arm/Group Description:		Participants with CLL/SLL received oral acalabrutinib Dose 1 QD for 28 days and later switched to acalabrutinib Dose 1 BID until disease progression or per the investigator considered the study treatment to be intolerable or no longer in the participant's best interest.	Participants with CLL/SLL received oral acalabrutinib Dose 2 QD for 28 days and later switched to acalabrutinib Dose 1 BID until disease progression or per the investigator considered the study treatment to be intolerable or no longer in the participant's best interest.	Participants with CLL received oral acalabrutinib Dose 1 BID until disease progression or per the investigator considered the study treatment to be intolerable or no longer in the participant's best interest.	Participants with CLL received oral acalabrutinib Dose 5 QD (later switched to Dose 1 BID per protocol amendment 6) until disease progression or per the investigator considered the study treatment to be intolerable or no longer in the participant's best interest.	Participants with CLL received oral acalabrutinib Dose 3 QD (later switched to Dose 1 BID per protocol amendment 6) until disease progression or per the investigator considered the study treatment to be intolerable or no longer in the participant's best interest.	Participants with CLL received oral acalabrutinib Dose 4 QD for 28 days and later switched to acalabrutinib Dose 1 BID until disease progression or per the investigator considered the study treatment to be intolerable or no longer in the participant's best interest.	Participants with CLL received oral acalabrutinib Dose 5 BID (later switched to Dose 1 BID per protocol amendment 6) until disease progression or per the investigator considered the study treatment to be intolerable or no longer in the participant's best interest.	Treatment-naïve participants with CLL or SLL received oral acalabrutinib Dose 5 QD (later switched to Dose 1 BID per protocol amendment 6) until disease progression or per the investigator considered the study treatment to be intolerable or no longer in the participant's best interest.	Participants with CLL or SLL and were not tolerating ibrutinib treatment, received oral acalabrutinib Dose 5 QD (which switched to Dose 1 BID per protocol amendment 4) until disease progression or per the investigator considered the study treatment to be intolerable or no longer in the participant's best interest.	Participants with CLL or SLL and were not tolerating ibrutinib treatment, received oral acalabrutinib Dose 1 BID until disease progression or per the investigator considered the study treatment to be intolerable or no longer in the participant's best interest.	Participants with DLBCLRS or PLL transformation, received oral acalabrutinib Dose 5 BID until disease progression or per the investigator considered the study treatment to be intolerable or no longer in the participant's best interest.	Participants with CLL/SLL and had relapsed/refractory ibrutinib treatment, received oral acalabrutinib Dose 5 BID until disease progression or per the investigator considered the study treatment to be intolerable or no longer in the participant's best interest.	Treatment-naïve participants with CLL/SLL, received oral acalabrutinib Dose 1 BID until disease progression or per the investigator considered the study treatment to be intolerable or no longer in the participant's best interest.
Overall Number of Participants Analyzed		8	8	28	13	7	5	6	37	3	8	10	5	16
Median (Full Range); Unit of Measure: Hours
Day 1	Number Analyzed	8 participants	8 participants	28 participants	12 participants	7 participants	5 participants	6 participants	37 participants	3 participants	8 participants	10 participants	5 participants	16 participants
		1.01; (0.417 to 2.00)	0.917; (0.500 to 3.83)	0.750; (0.500 to 2.30)	1.00; (0.250 to 5.92)	1.00; (0.500 to 1.83)	1.00; (0.750 to 4.00)	0.758; (0.250 to 1.08)	0.783; (0.250 to 2.10)	1.30; (0.750 to 2.20)	0.783; (0.500 to 5.83)	0.992; (0.500 to 4.05)	1.00; (0.500 to 1.08)	0.642; (0.483 to 2.00)
Day 8	Number Analyzed	7 participants	6 participants	27 participants	13 participants	7 participants	5 participants	6 participants	36 participants	2 participants	8 participants	9 participants	4 participants	16 participants
		1.05; (0.500 to 1.17)	0.517; (0.467 to 1.00)	0.750; (0.450 to 5.75)	1.03; (0.500 to 2.10)	1.00; (0.500 to 1.97)	0.700; (0.500 to 1.95)	0.758; (0.500 to 2.07)	0.750; (0.250 to 2.22)	1.49; (1.08 to 1.90)	0.908; (0.467 to 2.03)	1.00; (0.500 to 2.08)	1.58; (0.467 to 4.08)	0.533; (0.250 to 1.85)

11. Primary Outcome

Title	Terminal Elimination Half-life (t1/2) of Acalabrutinib
Description	The t1/2 of acalabrutinib is reported.
Time Frame	Predose and at 0.25, 0.5, 0.75, 1, 2, 4, 6, and 24 hours postdose on Day 1 and Day 8

Outcome Measure Data

Analysis Population Description

The PK population included all participants who complied with the protocol sufficiently and displayed an evaluable PK profile (e.g. exposure to treatment, availability and integrity of measurements, and absence of major protocol violations). 'Number of participants analyzed' denotes the number of participants evaluated for this outcome measure. 'Number analyzed' denotes the number of participants evaluated for the specified time point.

Arm/Group Title		Cohort 1	Cohort 2a	Cohort 2b	Cohort 2c	Cohort 3	Cohort 4a	Cohort 4b	Cohort 7	Cohort 8a	Cohort 8b	Cohort 9	Cohort 10	Cohort 11
Arm/Group Description:		Participants with CLL/SLL received oral acalabrutinib Dose 1 QD for 28 days and later switched to acalabrutinib Dose 1 BID until disease progression or per the investigator considered the study treatment to be intolerable or no longer in the participant's best interest.	Participants with CLL/SLL received oral acalabrutinib Dose 2 QD for 28 days and later switched to acalabrutinib Dose 1 BID until disease progression or per the investigator considered the study treatment to be intolerable or no longer in the participant's best interest.	Participants with CLL received oral acalabrutinib Dose 1 BID until disease progression or per the investigator considered the study treatment to be intolerable or no longer in the participant's best interest.	Participants with CLL received oral acalabrutinib Dose 5 QD (later switched to Dose 1 BID per protocol amendment 6) until disease progression or per the investigator considered the study treatment to be intolerable or no longer in the participant's best interest.	Participants with CLL received oral acalabrutinib Dose 3 QD (later switched to Dose 1 BID per protocol amendment 6) until disease progression or per the investigator considered the study treatment to be intolerable or no longer in the participant's best interest.	Participants with CLL received oral acalabrutinib Dose 4 QD for 28 days and later switched to acalabrutinib Dose 1 BID until disease progression or per the investigator considered the study treatment to be intolerable or no longer in the participant's best interest.	Participants with CLL received oral acalabrutinib Dose 5 BID (later switched to Dose 1 BID per protocol amendment 6) until disease progression or per the investigator considered the study treatment to be intolerable or no longer in the participant's best interest.	Treatment-naïve participants with CLL or SLL received oral acalabrutinib Dose 5 QD (later switched to Dose 1 BID per protocol amendment 6) until disease progression or per the investigator considered the study treatment to be intolerable or no longer in the participant's best interest.	Participants with CLL or SLL and were not tolerating ibrutinib treatment, received oral acalabrutinib Dose 5 QD (which switched to Dose 1 BID per protocol amendment 4) until disease progression or per the investigator considered the study treatment to be intolerable or no longer in the participant's best interest.	Participants with CLL or SLL and were not tolerating ibrutinib treatment, received oral acalabrutinib Dose 1 BID until disease progression or per the investigator considered the study treatment to be intolerable or no longer in the participant's best interest.	Participants with DLBCLRS or PLL transformation, received oral acalabrutinib Dose 5 BID until disease progression or per the investigator considered the study treatment to be intolerable or no longer in the participant's best interest.	Participants with CLL/SLL and had relapsed/refractory ibrutinib treatment, received oral acalabrutinib Dose 5 BID until disease progression or per the investigator considered the study treatment to be intolerable or no longer in the participant's best interest.	Treatment-naïve participants with CLL/SLL, received oral acalabrutinib Dose 1 BID until disease progression or per the investigator considered the study treatment to be intolerable or no longer in the participant's best interest.
Overall Number of Participants Analyzed		8	7	24	11	7	5	6	32	3	6	8	4	15
Mean (Standard Deviation); Unit of Measure: Hours
Day 1	Number Analyzed	8 participants	7 participants	22 participants	11 participants	7 participants	5 participants	6 participants	32 participants	3 participants	5 participants	6 participants	4 participants	15 participants
		1.48 (1.50)	1.44 (1.60)	0.914 (0.452)	0.993 (0.303)	2.89 (3.12)	3.52 (4.93)	0.869 (0.0811)	1.41 (1.73)	4.83 (3.69)	0.900 (0.140)	0.798 (0.0973)	1.01 (0.209)	0.781 (0.137)
Day 8	Number Analyzed	6 participants	7 participants	24 participants	9 participants	5 participants	5 participants	4 participants	30 participants	1 participants	6 participants	8 participants	4 participants	15 participants
		1.09 (0.216)	0.942 (0.107)	0.995 (0.621)	0.902 (0.187)	0.886 (0.131)	1.38 (0.546)	1.13 (0.408)	1.02 (0.454)	0.914 [1] (NA)	1.25 (0.494)	0.867 (0.289)	1.67 (1.41)	0.811 (0.174)

[1]

The SD was not calculated as only one participant was evaluated at the time of the analysis.

12. Primary Outcome

Title	Terminal Elimination Rate Constant (λz) of Acalabrutinib
Description	The λz of acalabrutinib is reported.
Time Frame	Predose and at 0.25, 0.5, 0.75, 1, 2, 4, 6, and 24 hours postdose on Day 1 and Day 8

Outcome Measure Data

Analysis Population Description

The PK population included all participants who complied with the protocol sufficiently and displayed an evaluable PK profile (e.g. exposure to treatment, availability and integrity of measurements, and absence of major protocol violations). 'Number of participants analyzed' denotes the number of participants evaluated for this outcome measure. 'Number analyzed' denotes the number of participants evaluated for the specified time point.

Arm/Group Title		Cohort 1	Cohort 2a	Cohort 2b	Cohort 2c	Cohort 3	Cohort 4a	Cohort 4b	Cohort 7	Cohort 8a	Cohort 8b	Cohort 9	Cohort 10	Cohort 11
Arm/Group Description:		Participants with CLL/SLL received oral acalabrutinib Dose 1 QD for 28 days and later switched to acalabrutinib Dose 1 BID until disease progression or per the investigator considered the study treatment to be intolerable or no longer in the participant's best interest.	Participants with CLL/SLL received oral acalabrutinib Dose 2 QD for 28 days and later switched to acalabrutinib Dose 1 BID until disease progression or per the investigator considered the study treatment to be intolerable or no longer in the participant's best interest.	Participants with CLL received oral acalabrutinib Dose 1 twice daily until disease progression or per the investigator considered the study treatment to be intolerable or no longer in the participant's best interest.	Participants with CLL received oral acalabrutinib Dose 5 QD (later switched to Dose 1 BID per protocol amendment 6) until disease progression or per the investigator considered the study treatment to be intolerable or no longer in the participant's best interest.	Participants with CLL received oral acalabrutinib Dose 3 QD (later switched to Dose 1 BID per protocol amendment 6) until disease progression or per the investigator considered the study treatment to be intolerable or no longer in the participant's best interest.	Participants with CLL received oral acalabrutinib Dose 4 QD for 28 days and later switched to acalabrutinib Dose 1 BID until disease progression or per the investigator considered the study treatment to be intolerable or no longer in the participant's best interest.	Participants with CLL received oral acalabrutinib Dose 5 BID (later switched to Dose 1 BID per protocol amendment 6) until disease progression or per the investigator considered the study treatment to be intolerable or no longer in the participant's best interest.	Treatment-naïve participants with CLL or SLL received oral acalabrutinib Dose 5 QD (later switched to Dose 1 BID per protocol amendment 6) until disease progression or per the investigator considered the study treatment to be intolerable or no longer in the participant's best interest.	Participants with CLL or SLL and were not tolerating ibrutinib treatment, received oral acalabrutinib Dose 5 QD (which switched to Dose 1 BID per protocol amendment 4) until disease progression or per the investigator considered the study treatment to be intolerable or no longer in the participant's best interest.	Participants with CLL or SLL and were not tolerating ibrutinib treatment, received oral acalabrutinib Dose 1 BID until disease progression or per the investigator considered the study treatment to be intolerable or no longer in the participant's best interest.	Participants with DLBCLRS or PLL transformation, received oral acalabrutinib Dose 5 BID until disease progression or per the investigator considered the study treatment to be intolerable or no longer in the participant's best interest.	Participants with CLL/SLL and had relapsed/refractory ibrutinib treatment, received oral acalabrutinib Dose 5 BID until disease progression or per the investigator considered the study treatment to be intolerable or no longer in the participant's best interest.	Treatment-naïve participants with CLL/SLL, received oral acalabrutinib Dose 1 BID until disease progression or per the investigator considered the study treatment to be intolerable or no longer in the participant's best interest.
Overall Number of Participants Analyzed		8	7	24	11	7	5	6	32	3	6	8	4	15
Mean (Standard Deviation); Unit of Measure: 1/hr
Day 1	Number Analyzed	8 participants	7 participants	22 participants	11 participants	7 participants	5 participants	6 participants	32 participants	3 participants	5 participants	6 participants	4 participants	15 participants
		0.679 (0.276)	0.750 (0.307)	0.848 (0.214)	0.755 (0.209)	0.502 (0.300)	0.557 (0.386)	0.804 (0.0793)	0.756 (0.292)	0.373 (0.468)	0.784 (0.112)	0.880 (0.114)	0.706 (0.144)	0.916 (0.177)
Day 8	Number Analyzed	6 participants	7 participants	24 participants	9 participants	5 participants	5 participants	4 participants	30 participants	1 participants	6 participants	8 participants	4 participants	15 participants
		0.655 (0.132)	0.744 (0.0866)	0.793 (0.191)	0.798 (0.161)	0.797 (0.128)	0.578 (0.243)	0.679 (0.251)	0.745 (0.174)	0.758 [1] (NA)	0.623 (0.218)	0.857 (0.209)	0.603 (0.324)	0.894 (0.204)

[1]

The SD was not calculated as only one participant was evaluated at the time of the analysis.

13. Primary Outcome

Title	Apparent Oral Clearance (CL/F) of Acalabrutinib
Description	The CL/F of acalabrutinib is reported.
Time Frame	Predose and at 0.25, 0.5, 0.75, 1, 2, 4, 6, and 24 hours postdose on Day 1 and Day 8

Outcome Measure Data

Analysis Population Description

The PK population included all participants who complied with the protocol sufficiently and displayed an evaluable PK profile (e.g. exposure to treatment, availability and integrity of measurements, and absence of major protocol violations). 'Number of participants analyzed' denotes the number of participants evaluated for this outcome measure. 'Number analyzed' denotes the number of participants evaluated for the specified time point.

Arm/Group Title		Cohort 1	Cohort 2a	Cohort 2b	Cohort 2c	Cohort 3	Cohort 4a	Cohort 4b	Cohort 7	Cohort 8a	Cohort 8b	Cohort 9	Cohort 10	Cohort 11
Arm/Group Description:		Participants with CLL/SLL received oral acalabrutinib Dose 1 QD for 28 days and later switched to acalabrutinib Dose 1 BID until disease progression or per the investigator considered the study treatment to be intolerable or no longer in the participant's best interest.	Participants with CLL/SLL received oral acalabrutinib Dose 2 QD for 28 days and later switched to acalabrutinib Dose 1 BID until disease progression or per the investigator considered the study treatment to be intolerable or no longer in the participant's best interest.	Participants with CLL received oral acalabrutinib Dose 1 BID until disease progression or per the investigator considered the study treatment to be intolerable or no longer in the participant's best interest.	Participants with CLL received oral acalabrutinib Dose 5 QD (later switched to Dose 1 BID per protocol amendment 6) until disease progression or per the investigator considered the study treatment to be intolerable or no longer in the participant's best interest.	Participants with CLL received oral acalabrutinib Dose 3 QD (later switched to Dose 1 BID per protocol amendment 6) until disease progression or per the investigator considered the study treatment to be intolerable or no longer in the participant's best interest.	Participants with CLL received oral acalabrutinib Dose 4 QD for 28 days and later switched to acalabrutinib Dose 1 BID until disease progression or per the investigator considered the study treatment to be intolerable or no longer in the participant's best interest.	Participants with CLL received oral acalabrutinib Dose 5 BID (later switched to Dose 1 BID per protocol amendment 6) until disease progression or per the investigator considered the study treatment to be intolerable or no longer in the participant's best interest.	Treatment-naïve participants with CLL or SLL received oral acalabrutinib Dose 5 QD (later switched to Dose 1 BID per protocol amendment 6) until disease progression or per the investigator considered the study treatment to be intolerable or no longer in the participant's best interest.	Participants with CLL or SLL and were not tolerating ibrutinib treatment, received oral acalabrutinib Dose 5 QD (which switched to Dose 1 BID per protocol amendment 4) until disease progression or per the investigator considered the study treatment to be intolerable or no longer in the participant's best interest.	Participants with CLL or SLL and were not tolerating ibrutinib treatment, received oral acalabrutinib Dose 1 BID until disease progression or per the investigator considered the study treatment to be intolerable or no longer in the participant's best interest.	Participants with DLBCLRS or PLL transformation, received oral acalabrutinib Dose 5 BID until disease progression or per the investigator considered the study treatment to be intolerable or no longer in the participant's best interest.	Participants with CLL/SLL and had relapsed/refractory ibrutinib treatment, received oral acalabrutinib Dose 5 BID until disease progression or per the investigator considered the study treatment to be intolerable or no longer in the participant's best interest.	Treatment-naïve participants with CLL/SLL, received oral acalabrutinib Dose 1 BID until disease progression or per the investigator considered the study treatment to be intolerable or no longer in the participant's best interest.
Overall Number of Participants Analyzed		8	7	24	11	7	5	6	32	3	6	8	4	15
Mean (Standard Deviation); Unit of Measure: L/hr
Day 1	Number Analyzed	8 participants	7 participants	22 participants	11 participants	7 participants	5 participants	6 participants	32 participants	3 participants	5 participants	6 participants	4 participants	15 participants
		114 (44.4)	193 (121)	212 (302)	112 (98.4)	265 (263)	169 (123)	108 (32.0)	315 (488)	352 (43.7)	311 (166)	142 (88.9)	156 (40.3)	137 (77.4)
Day 8	Number Analyzed	6 participants	7 participants	24 participants	9 participants	5 participants	5 participants	4 participants	30 participants	1 participants	6 participants	8 participants	4 participants	15 participants
		176 (62.1)	216 (154)	162 (141)	122 (55.5)	131 (70.3)	344 (242)	191 (180)	389 (1070)	94.5 [1] (NA)	336 (258)	132 (51.8)	167 (95.1)	188 (92.5)

[1]

The SD was not calculated as only one participant was evaluated at the time of the analysis.

14. Primary Outcome

Title	Apparent Volume of Distribution (Vz/F) of Acalabrutinib
Description	The Vz/F of acalabrutinib is reported.
Time Frame	Predose and at 0.25, 0.5, 0.75, 1, 2, 4, 6, and 24 hours postdose on Day 1 and Day 8

Outcome Measure Data

Analysis Population Description

The PK population included all participants who complied with the protocol sufficiently and displayed an evaluable PK profile (e.g. exposure to treatment, availability and integrity of measurements, and absence of major protocol violations). 'Number of participants analyzed' denotes the number of participants evaluated for this outcome measure. 'Number analyzed' denotes the number of participants evaluated for the specified time point.

Arm/Group Title		Cohort 1	Cohort 2a	Cohort 2b	Cohort 2c	Cohort 3	Cohort 4a	Cohort 4b	Cohort 7	Cohort 8a	Cohort 8b	Cohort 9	Cohort 10	Cohort 11
Arm/Group Description:		Participants with CLL/SLL received oral acalabrutinib Dose 1 QD for 28 days and later switched to acalabrutinib Dose 1 BID until disease progression or per the investigator considered the study treatment to be intolerable or no longer in the participant's best interest.	Participants with CLL/SLL received oral acalabrutinib Dose 2 QD for 28 days and later switched to acalabrutinib Dose 1 BID until disease progression or per the investigator considered the study treatment to be intolerable or no longer in the participant's best interest.	Participants with CLL received oral acalabrutinib Dose 1 twice daily until disease progression or per the investigator considered the study treatment to be intolerable or no longer in the participant's best interest.	Participants with CLL received oral acalabrutinib Dose 5 QD (later switched to Dose 1 BID per protocol amendment 6) until disease progression or per the investigator considered the study treatment to be intolerable or no longer in the participant's best interest.	Participants with CLL received oral acalabrutinib Dose 3 QD (later switched to Dose 1 BID per protocol amendment 6) until disease progression or per the investigator considered the study treatment to be intolerable or no longer in the participant's best interest.	Participants with CLL received oral acalabrutinib Dose 4 QD for 28 days and later switched to acalabrutinib Dose 1 BID until disease progression or per the investigator considered the study treatment to be intolerable or no longer in the participant's best interest.	Participants with CLL received oral acalabrutinib Dose 5 BID (later switched to Dose 1 BID per protocol amendment 6) until disease progression or per the investigator considered the study treatment to be intolerable or no longer in the participant's best interest.	Treatment-naïve participants with CLL or SLL received oral acalabrutinib Dose 5 QD (later switched to Dose 1 BID per protocol amendment 6) until disease progression or per the investigator considered the study treatment to be intolerable or no longer in the participant's best interest.	Participants with CLL or SLL and were not tolerating ibrutinib treatment, received oral acalabrutinib Dose 5 QD (which switched to Dose 1 BID per protocol amendment 4) until disease progression or per the investigator considered the study treatment to be intolerable or no longer in the participant's best interest.	Participants with CLL or SLL and were not tolerating ibrutinib treatment, received oral acalabrutinib Dose 1 BID until disease progression or per the investigator considered the study treatment to be intolerable or no longer in the participant's best interest.	Participants with DLBCLRS or PLL transformation, received oral acalabrutinib Dose 5 BID until disease progression or per the investigator considered the study treatment to be intolerable or no longer in the participant's best interest.	Participants with CLL/SLL and had relapsed/refractory ibrutinib treatment, received oral acalabrutinib Dose 5 BID until disease progression or per the investigator considered the study treatment to be intolerable or no longer in the participant's best interest.	Treatment-naïve participants with CLL/SLL, received oral acalabrutinib Dose 1 BID until disease progression or per the investigator considered the study treatment to be intolerable or no longer in the participant's best interest.
Overall Number of Participants Analyzed		8	7	24	11	7	5	6	32	3	6	8	4	15
Mean (Standard Deviation); Unit of Measure: L
Day 1	Number Analyzed	8 participants	7 participants	22 participants	11 participants	7 participants	5 participants	6 participants	32 participants	3 participants	5 participants	6 participants	4 participants	15 participants
		268 (332)	574 (992)	450 (1250)	182 (230)	2100 (3290)	1480 (2850)	133 (30.0)	930 (1750)	2600 (2030)	422 (290)	171 (125)	235 (105)	158 (102)
Day 8	Number Analyzed	6 participants	7 participants	24 participants	9 participants	5 participants	5 participants	4 participants	30 participants	1 participants	6 participants	8 participants	4 participants	15 participants
		286 (150)	302 (238)	333 (729)	165 (104)	172 (114)	739 (745)	384 (466)	1180 (4940)	125 [1] (NA)	726 (814)	179 (134)	533 (716)	234 (162)

[1]

The SD was not calculated as only one participant was evaluated at the time of the analysis.

15. Secondary Outcome

Title	Percentage of Participants With Objective Response (OR) as Assessed by the Investigator
Description	For CLL/SLL, OR is defined as complete remission (CR), CR with incomplete marrow recovery (CRi), or partial remission (PR). CR: lymphocytes (lympho) <4×10^9/L, normocellular bone marrow (BM), normal lymph nodes (NLN), liver and spleen (L/S), absolute neutrophil count (ANC) >1.5×10^9/L, platelets >100×10^9/L, hemoglobin (Hb) >11g/dL. Cri: lympho <4×10^9/L, hypocellular BM, NLN, L/S, persistent anemia, hrombocytopenia, or neutropenia. PR: >=50% reduction in lymphadenopathy and/or enlargement of L/S or lympho (<5×10^9/L or >=50% decrease from baseline) and criteria of ANC/platelets/Hb per CR or >=50% improvement over baseline. Hematology result were without exogenous growth factors/transfusion. For RS, OR as CR or PR by Cheson et al. 2014 based on PET/CT scans and bone marrow. CR: disappearance of all detectable clinical evidence of disease and disease-related symptoms and PR: >=50% decrease in sum of the product diameter of 6 largest nodal masses and no new sites of disease.
Time Frame	Day 1 through the final data cutoff date (approximately 7 years 6 months)

Outcome Measure Data

Analysis Population Description

Efficacy evaluable population included all enrolled participants who received 1 or more doses of study drug and had 1 or more response assessments after the first dose of study drug.

Arm/Group Title	Cohort 1	Cohort 2a	Cohort 2b	Cohort 2c	Cohort 3	Cohort 4a	Cohort 4b	Cohort 7	Cohort 11
Arm/Group Description:	Participants with CLL/SLL received oral acalabrutinib Dose 1 QD for 28 days and later switched to acalabrutinib Dose 1 BID until disease progression or per the investigator considered the study treatment to be intolerable or no longer in the participant's best interest.	Participants with CLL/SLL received oral acalabrutinib Dose 2 QD for 28 days and later switched to acalabrutinib Dose 1 BID until disease progression or per the investigator considered the study treatment to be intolerable or no longer in the participant's best interest.	Participants with CLL received oral acalabrutinib Dose 1 BID until disease progression or per the investigator considered the study treatment to be intolerable or no longer in the participant's best interest.	Participants with CLL received oral acalabrutinib Dose 5 QD (later switched to Dose 1 BID per protocol amendment 6) until disease progression or per the investigator considered the study treatment to be intolerable or no longer in the participant's best interest.	Participants with CLL received oral acalabrutinib Dose 3 QD (later switched to Dose 1 BID per protocol amendment 6) until disease progression or per the investigator considered the study treatment to be intolerable or no longer in the participant's best interest.	Participants with CLL received oral acalabrutinib Dose 4 QD for 28 days and later switched to acalabrutinib Dose 1 BID until disease progression or per the investigator considered the study treatment to be intolerable or no longer in the participant's best interest.	Participants with CLL received oral acalabrutinib Dose 5 BID (later switched to Dose 1 BID per protocol amendment 6) until disease progression or per the investigator considered the study treatment to be intolerable or no longer in the participant's best interest.	Treatment-naïve participants with CLL or SLL received oral acalabrutinib Dose 5 QD (later switched to Dose 1 BID per protocol amendment 6) until disease progression or per the investigator considered the study treatment to be intolerable or no longer in the participant's best interest.	Treatment-naïve participants with CLL/SLL, received oral acalabrutinib Dose 1 BID until disease progression or per the investigator considered the study treatment to be intolerable or no longer in the participant's best interest.
Overall Number of Participants Analyzed	8	8	63	32	7	6	6	37	60
Measure Type: Number; Number (95% Confidence Interval); Unit of Measure: Percentage of participants
	100.0; (63.1 to 100.0)	75; (34.9 to 96.8)	92.1; (82.4 to 97.4)	93.8; (79.2 to 99.2)	100.0; (59.0 to 100.0)	100.0; (54.1 to 100.0)	100.0; (54.1 to 100.0)	97.3; (85.8 to 99.9)	100.0; (94.0 to 100.0)

16. Secondary Outcome

Title	Duration of Response (DOR) as Assessed by the Investigator
Description	The DoR is defined as the time from the date of achieving the first CR, CRi, or PR to the date of progressive disease (PD) or death due to any cause, whichever occurred first. The CR, CRi, or PR are defined in the above outcome measure. For CLL/SLL, PD is defined as lympho >=50% increase from baseline with >= 5000 B lymphocytes/µL, progressive cytopenias by bone marrow biopsy, appearance of any new lesion or new appearance of hepatomegaly or splenomegaly or >= 50 % increase in lymphadenopathy/hepatomegaly/splenomegaly, platelets decrease of >=50% from baseline secondary to CLL or < 100,000/µL and worsening bone marrow or Hb decrease of > 2 g/dL from baseline secondary to CLL or decrease to less than 100 g/L and worsening bone marrow. For RS, PD is defined as an increase by 25 % in longest diameter, new lesion or assessable disease progression. The DoR was estimated using Kaplan-Meier method.
Time Frame	Day 1 through the final data cutoff date (approximately 7 years 6 months)

Outcome Measure Data

Analysis Population Description

Efficacy evaluable population included all enrolled participants who received 1 or more doses of study drug and had 1 or more response assessments after the first dose of study drug. The DoR was analyzed for participants who achieved OR.

Arm/Group Title	Cohort 1	Cohort 2a	Cohort 2b	Cohort 2c	Cohort 3	Cohort 4a	Cohort 4b	Cohort 7	Cohort 11
Arm/Group Description:	Participants with CLL/SLL received oral acalabrutinib Dose 1 QD for 28 days and later switched to acalabrutinib Dose 1 BID until disease progression or per the investigator considered the study treatment to be intolerable or no longer in the participant's best interest.	Participants with CLL/SLL received oral acalabrutinib Dose 2 QD for 28 days and later switched to acalabrutinib Dose 1 BID until disease progression or per the investigator considered the study treatment to be intolerable or no longer in the participant's best interest.	Participants with CLL received oral acalabrutinib Dose 1 BID until disease progression or per the investigator considered the study treatment to be intolerable or no longer in the participant's best interest.	Participants with CLL received oral acalabrutinib Dose 5 QD (later switched to Dose 1 BID per protocol amendment 6) until disease progression or per the investigator considered the study treatment to be intolerable or no longer in the participant's best interest.	Participants with CLL received oral acalabrutinib Dose 3 QD (later switched to Dose 1 BID per protocol amendment 6) until disease progression or per the investigator considered the study treatment to be intolerable or no longer in the participant's best interest.	Participants with CLL received oral acalabrutinib Dose 4 QD for 28 days and later switched to acalabrutinib Dose 1 BID until disease progression or per the investigator considered the study treatment to be intolerable or no longer in the participant's best interest.	Participants with CLL received oral acalabrutinib Dose 5 BID (later switched to Dose 1 BID per protocol amendment 6) until disease progression or per the investigator considered the study treatment to be intolerable or no longer in the participant's best interest.	Treatment-naïve participants with CLL or SLL received oral acalabrutinib Dose 5 QD (later switched to Dose 1 BID per protocol amendment 6) until disease progression or per the investigator considered the study treatment to be intolerable or no longer in the participant's best interest.	Treatment-naïve participants with CLL/SLL, received oral acalabrutinib Dose 1 BID until disease progression or per the investigator considered the study treatment to be intolerable or no longer in the participant's best interest.
Overall Number of Participants Analyzed	8	6	58	30	7	6	6	36	60
Median (95% Confidence Interval); Unit of Measure: Months
	33.3 [1]; (13.8 to NA)	26.7 [2]; (13.9 to NA)	77.3 [2]; (46.3 to NA)	43.0 [2]; (29.4 to NA)	NA [3]; (9.0 to NA)	64.1 [2]; (19.4 to NA)	NA [3]; (38.9 to NA)	NA [4]; (NA to NA)	NA [4]; (NA to NA)

[1]

Upper limit of 95% confidence interval (CI) was not calculated because insufficient number of participants had DoR.

[2]

Upper limit of 95% CI was not calculated because insufficient number of participants had DoR.

[3]

Median and upper limit of 95% CI were not calculated because insufficient number of participants had DoR.

[4]

Median and 95% CI were not calculated because insufficient number of participants had DoR.

17. Secondary Outcome

Title	Progression Free Survival (PFS) as Assessed by the Investigator
Description	The PFS is defined as the time from the date of first dose of study drug to the date of first PD or death due to any cause, whichever occurred first. For CLL/SLL, PD is defined as lympho >= 50 % increase from baseline with >= 5000 B lymphocytes/µL, progressive cytopenias by bone marrow biopsy, appearance of any new lesion or new appearance of hepatomegaly or splenomegaly or >= 50 % increase in lymphadenopathy/hepatomegaly/splenomegaly, platelets decrease of >= 50 % from baseline secondary to CLL or < 100,000/µL and worsening bone marrow or Hb decrease of > 2 g/dL from baseline secondary to CLL or decrease to less than 100 g/L and worsening bone marrow. For RS, PD is defined as an increase by 25 % in longest diameter, new lesion or assessable disease progression. The PFS was estimated using Kaplan-Meier method.
Time Frame	Day 1 through the final data cutoff date (approximately 7 years 6 months)

Outcome Measure Data

Analysis Population Description

Efficacy evaluable population included all enrolled participants who received 1 or more doses of study drug and had 1 or more response assessments after the first dose of study drug.

Arm/Group Title	Cohort 1	Cohort 2a	Cohort 2b	Cohort 2c	Cohort 3	Cohort 4a	Cohort 4b	Cohort 7	Cohort 11
Arm/Group Description:	Participants with CLL/SLL received oral acalabrutinib Dose 1 QD for 28 days and later switched to acalabrutinib Dose 1 BID until disease progression or per the investigator considered the study treatment to be intolerable or no longer in the participant's best interest.	Participants with CLL/SLL received oral acalabrutinib Dose 2 QD for 28 days and later switched to acalabrutinib Dose 1 BID until disease progression or per the investigator considered the study treatment to be intolerable or no longer in the participant's best interest.	Participants with CLL received oral acalabrutinib Dose 1 BID until disease progression or per the investigator considered the study treatment to be intolerable or no longer in the participant's best interest.	Participants with CLL received oral acalabrutinib Dose 5 QD (later switched to Dose 1 BID per protocol amendment 6) until disease progression or per the investigator considered the study treatment to be intolerable or no longer in the participant's best interest.	Participants with CLL received oral acalabrutinib Dose 3 QD (later switched to Dose 1 BID per protocol amendment 6) until disease progression or per the investigator considered the study treatment to be intolerable or no longer in the participant's best interest.	Participants with CLL received oral acalabrutinib Dose 4 QD for 28 days and later switched to acalabrutinib Dose 1 BID until disease progression or per the investigator considered the study treatment to be intolerable or no longer in the participant's best interest.	Participants with CLL received oral acalabrutinib Dose 5 BID (later switched to Dose 1 BID per protocol amendment 6) until disease progression or per the investigator considered the study treatment to be intolerable or no longer in the participant's best interest.	Treatment-naïve participants with CLL or SLL received oral acalabrutinib Dose 5 QD (later switched to Dose 1 BID per protocol amendment 6) until disease progression or per the investigator considered the study treatment to be intolerable or no longer in the participant's best interest.	Treatment-naïve participants with CLL/SLL, received oral acalabrutinib Dose 1 BID until disease progression or per the investigator considered the study treatment to be intolerable or no longer in the participant's best interest.
Overall Number of Participants Analyzed	9	8	65	33	7	6	6	37	62
Median (95% Confidence Interval); Unit of Measure: Months
	38.3 [1]; (15.5 to NA)	33.1 [1]; (15.8 to NA)	79.1 [1]; (49.8 to NA)	46.6 [1]; (33.9 to NA)	NA [2]; (12.7 to NA)	67.8 [1]; (33.2 to NA)	NA [2]; (40.7 to NA)	NA [3]; (NA to NA)	NA [3]; (NA to NA)

[1]

Upper limit of 95% CI was not calculated because insufficient number of participants had PFS.

[2]

Median and upper limit of 95% CI were not calculated because insufficient number of participants had PFS..

[3]

Median and 95% CI were not calculated because insufficient number of participants had PFS..

Adverse Events

Time Frame	Day 1 through the final data cutoff date (approximately 7 years 6 months)
Adverse Event Reporting Description	[Not Specified]
Arm/Group Title	Relapsed/Refractory Cohort		Treatment-naive Cohort		Ibrutinib-intolerant Cohort		Richters Syndrome/Prolymphocytic Leukemia Transformation Cohort		Ibrutinib Relapsed/Refractory Cohort
Arm/Group Description	Phase 1 (dose-escalation) and Phase 2 (dose-expansion) were conducted for participants with relapsed/refractory chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL). In Phase 1, participants received oral once daily (QD) acalabrutinib at Dose 1 (Cohort 1), Dose 2 (Cohort 2a), Dose 3 (Cohort 3), and Dose 4 (Cohort 4a), and twice daily (BID) acalabrutinib at Dose 1 (Cohort 2b) and Dose 5 (Cohort 4b) for 28 days (1 cycle). In Phase 2, participants received oral acalabrutinib at Dose 1 BID (Cohort 2b) or Dose 5 QD (Cohort 2c, later switched to Dose 1 BID per protocol amendment 6) until disease progression or until the investigator considered the study treatment to be intolerable or no longer in the participant's best interest. Participants from Phase 1 continued to receive Dose 1 BID until disease progression or until the investigator considered the study treatment to be intolerable or no longer in the participant's best interest.		Treatment-naïve participants with confirmed CLL or SLL, received oral acalabrutinib Dose 5 QD (Cohort 7, later switched to Dose 1 BID per protocol amendment 6) or Dose 1 BID (Cohort 11) until disease progression or until the investigator considered the study treatment to be intolerable or no longer in the participant's best interest.		Participants with confirmed CLL or SLL and were not tolerating ibrutinib treatment, received oral acalabrutinib Dose 5 QD (Cohort 8a, later switched to Dose 1 BID per protocol amendment 4) or Dose 1 BID (Cohort 8b) until disease progression or until the investigator considered the study treatment to be intolerable or no longer in the participant's best interest.		Participants with diffuse large B-cell lymphoma (DLBCL) Richter's transformation (RS) or prolymphocytic leukemia transformation (PLL), received oral acalabrutinib Dose 5 BID (Cohort 9) until disease progression or until the investigator considered the study treatment to be intolerable or no longer in the participant's best interest.		Participants with confirmed CLL/SLL and had relapsed/refractory to ibrutinib treatment, received oral acalabrutinib Dose 5 QD (Cohort 10) until disease progression or until the investigator considered the study treatment to be intolerable or no longer in the participant's best interest.
All-Cause Mortality
	Relapsed/Refractory Cohort		Treatment-naive Cohort		Ibrutinib-intolerant Cohort		Richters Syndrome/Prolymphocytic Leukemia Transformation Cohort		Ibrutinib Relapsed/Refractory Cohort
	Affected / at Risk (%)		Affected / at Risk (%)		Affected / at Risk (%)		Affected / at Risk (%)		Affected / at Risk (%)
Total	13/134 (9.70%)		2/99 (2.02%)		2/33 (6.06%)		11/29 (37.93%)		2/6 (33.33%)
Serious Adverse Events
	Relapsed/Refractory Cohort		Treatment-naive Cohort		Ibrutinib-intolerant Cohort		Richters Syndrome/Prolymphocytic Leukemia Transformation Cohort		Ibrutinib Relapsed/Refractory Cohort
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	86/134 (64.18%)		50/99 (50.51%)		20/33 (60.61%)		18/29 (62.07%)		3/6 (50.00%)
Blood and lymphatic system disorders
Leukocytosis † 1	1/134 (0.75%)	1	0/99 (0.00%)	0	0/33 (0.00%)	0	0/29 (0.00%)	0	0/6 (0.00%)	0
Lymphadenitis † 1	1/134 (0.75%)	1	0/99 (0.00%)	0	0/33 (0.00%)	0	0/29 (0.00%)	0	0/6 (0.00%)	0
Methaemoglobinaemia † 1	1/134 (0.75%)	1	0/99 (0.00%)	0	0/33 (0.00%)	0	0/29 (0.00%)	0	0/6 (0.00%)	0
Splenic infarction † 1	0/134 (0.00%)	0	1/99 (1.01%)	1	0/33 (0.00%)	0	0/29 (0.00%)	0	0/6 (0.00%)	0
Anaemia † 1	4/134 (2.99%)	4	1/99 (1.01%)	1	1/33 (3.03%)	1	1/29 (3.45%)	1	0/6 (0.00%)	0
Thrombocytopenia † 1	2/134 (1.49%)	2	0/99 (0.00%)	0	0/33 (0.00%)	0	0/29 (0.00%)	0	0/6 (0.00%)	0
Autoimmune haemolytic anaemia † 1	2/134 (1.49%)	3	0/99 (0.00%)	0	0/33 (0.00%)	0	0/29 (0.00%)	0	0/6 (0.00%)	0
Febrile neutropenia † 1	3/134 (2.24%)	3	1/99 (1.01%)	2	1/33 (3.03%)	2	3/29 (10.34%)	3	0/6 (0.00%)	0
Haemolysis † 1	1/134 (0.75%)	1	0/99 (0.00%)	0	1/33 (3.03%)	1	0/29 (0.00%)	0	0/6 (0.00%)	0
Cardiac disorders
Acute coronary syndrome † 1	1/134 (0.75%)	1	0/99 (0.00%)	0	1/33 (3.03%)	1	0/29 (0.00%)	0	0/6 (0.00%)	0
Acute myocardial infarction † 1	0/134 (0.00%)	0	1/99 (1.01%)	1	0/33 (0.00%)	0	0/29 (0.00%)	0	0/6 (0.00%)	0
Angina pectoris † 1	1/134 (0.75%)	1	1/99 (1.01%)	1	0/33 (0.00%)	0	0/29 (0.00%)	0	0/6 (0.00%)	0
Atrial fibrillation † 1	4/134 (2.99%)	6	2/99 (2.02%)	2	1/33 (3.03%)	1	0/29 (0.00%)	0	0/6 (0.00%)	0
Atrial flutter † 1	0/134 (0.00%)	0	0/99 (0.00%)	0	1/33 (3.03%)	1	0/29 (0.00%)	0	0/6 (0.00%)	0
Atrioventricular block complete † 1	2/134 (1.49%)	2	0/99 (0.00%)	0	0/33 (0.00%)	0	0/29 (0.00%)	0	0/6 (0.00%)	0
Atrioventricular block second degree † 1	0/134 (0.00%)	0	1/99 (1.01%)	1	0/33 (0.00%)	0	0/29 (0.00%)	0	0/6 (0.00%)	0
Bradycardia † 1	1/134 (0.75%)	1	0/99 (0.00%)	0	0/33 (0.00%)	0	0/29 (0.00%)	0	0/6 (0.00%)	0
Cardiac arrest † 1	1/134 (0.75%)	1	0/99 (0.00%)	0	1/33 (3.03%)	1	0/29 (0.00%)	0	0/6 (0.00%)	0
Cardiac failure † 1	0/134 (0.00%)	0	1/99 (1.01%)	1	0/33 (0.00%)	0	0/29 (0.00%)	0	0/6 (0.00%)	0
Cardiac failure congestive † 1	1/134 (0.75%)	2	0/99 (0.00%)	0	0/33 (0.00%)	0	0/29 (0.00%)	0	0/6 (0.00%)	0
Cardiac tamponade † 1	1/134 (0.75%)	1	0/99 (0.00%)	0	0/33 (0.00%)	0	0/29 (0.00%)	0	0/6 (0.00%)	0
Coronary artery stenosis † 1	0/134 (0.00%)	0	1/99 (1.01%)	1	0/33 (0.00%)	0	0/29 (0.00%)	0	0/6 (0.00%)	0
Myocardial infarction † 1	1/134 (0.75%)	1	0/99 (0.00%)	0	0/33 (0.00%)	0	0/29 (0.00%)	0	0/6 (0.00%)	0
Stress cardiomyopathy † 1	0/134 (0.00%)	0	1/99 (1.01%)	1	0/33 (0.00%)	0	0/29 (0.00%)	0	0/6 (0.00%)	0
Supraventricular tachycardia † 1	0/134 (0.00%)	0	1/99 (1.01%)	1	1/33 (3.03%)	1	0/29 (0.00%)	0	0/6 (0.00%)	0
Ventricular fibrillation † 1	1/134 (0.75%)	1	0/99 (0.00%)	0	0/33 (0.00%)	0	0/29 (0.00%)	0	0/6 (0.00%)	0
Ear and labyrinth disorders
Vertigo † 1	0/134 (0.00%)	0	0/99 (0.00%)	0	1/33 (3.03%)	1	0/29 (0.00%)	0	0/6 (0.00%)	0
Gastrointestinal disorders
Abdominal pain † 1	3/134 (2.24%)	3	0/99 (0.00%)	0	1/33 (3.03%)	1	0/29 (0.00%)	0	1/6 (16.67%)	1
Colitis † 1	1/134 (0.75%)	1	0/99 (0.00%)	0	0/33 (0.00%)	0	0/29 (0.00%)	0	0/6 (0.00%)	0
Constipation † 1	0/134 (0.00%)	0	0/99 (0.00%)	0	0/33 (0.00%)	0	1/29 (3.45%)	1	0/6 (0.00%)	0
Diarrhoea † 1	4/134 (2.99%)	5	1/99 (1.01%)	1	0/33 (0.00%)	0	0/29 (0.00%)	0	1/6 (16.67%)	1
Epiploic appendagitis † 1	0/134 (0.00%)	0	1/99 (1.01%)	1	0/33 (0.00%)	0	0/29 (0.00%)	0	0/6 (0.00%)	0
Gastric haemorrhage † 1	1/134 (0.75%)	1	1/99 (1.01%)	1	0/33 (0.00%)	0	0/29 (0.00%)	0	0/6 (0.00%)	0
Inguinal hernia † 1	1/134 (0.75%)	1	0/99 (0.00%)	0	0/33 (0.00%)	0	1/29 (3.45%)	1	0/6 (0.00%)	0
Large intestinal haemorrhage † 1	0/134 (0.00%)	0	1/99 (1.01%)	1	0/33 (0.00%)	0	0/29 (0.00%)	0	0/6 (0.00%)	0
Lower gastrointestinal haemorrhage † 1	0/134 (0.00%)	0	1/99 (1.01%)	1	0/33 (0.00%)	0	0/29 (0.00%)	0	0/6 (0.00%)	0
Pancreatitis † 1	0/134 (0.00%)	0	2/99 (2.02%)	2	0/33 (0.00%)	0	0/29 (0.00%)	0	0/6 (0.00%)	0
Pancreatitis acute † 1	0/134 (0.00%)	0	1/99 (1.01%)	1	0/33 (0.00%)	0	0/29 (0.00%)	0	0/6 (0.00%)	0
Rectal haemorrhage † 1	2/134 (1.49%)	2	0/99 (0.00%)	0	0/33 (0.00%)	0	0/29 (0.00%)	0	0/6 (0.00%)	0
Small intestinal obstruction † 1	1/134 (0.75%)	1	1/99 (1.01%)	1	0/33 (0.00%)	0	0/29 (0.00%)	0	0/6 (0.00%)	0
Tongue haematoma † 1	1/134 (0.75%)	1	0/99 (0.00%)	0	0/33 (0.00%)	0	0/29 (0.00%)	0	0/6 (0.00%)	0
Upper gastrointestinal haemorrhage † 1	1/134 (0.75%)	1	0/99 (0.00%)	0	0/33 (0.00%)	0	0/29 (0.00%)	0	0/6 (0.00%)	0
General disorders
Asthenia † 1	0/134 (0.00%)	0	0/99 (0.00%)	0	1/33 (3.03%)	1	0/29 (0.00%)	0	0/6 (0.00%)	0
Chest pain † 1	1/134 (0.75%)	1	0/99 (0.00%)	0	1/33 (3.03%)	1	0/29 (0.00%)	0	0/6 (0.00%)	0
Fatigue † 1	0/134 (0.00%)	0	1/99 (1.01%)	1	0/33 (0.00%)	0	2/29 (6.90%)	2	0/6 (0.00%)	0
Infusion site injury † 1	0/134 (0.00%)	0	0/99 (0.00%)	0	1/33 (3.03%)	1	0/29 (0.00%)	0	0/6 (0.00%)	0
Malaise † 1	0/134 (0.00%)	0	0/99 (0.00%)	0	0/33 (0.00%)	0	1/29 (3.45%)	1	0/6 (0.00%)	0
Multiple organ dysfunction syndrome † 1	1/134 (0.75%)	1	1/99 (1.01%)	1	0/33 (0.00%)	0	0/29 (0.00%)	0	0/6 (0.00%)	0
Non-cardiac chest pain † 1	1/134 (0.75%)	1	1/99 (1.01%)	1	1/33 (3.03%)	1	0/29 (0.00%)	0	0/6 (0.00%)	0
Pain † 1	1/134 (0.75%)	1	0/99 (0.00%)	0	0/33 (0.00%)	0	1/29 (3.45%)	1	0/6 (0.00%)	0
Pyrexia † 1	2/134 (1.49%)	2	2/99 (2.02%)	2	2/33 (6.06%)	2	0/29 (0.00%)	0	0/6 (0.00%)	0
Hepatobiliary disorders
Bile duct stone † 1	0/134 (0.00%)	0	1/99 (1.01%)	1	0/33 (0.00%)	0	0/29 (0.00%)	0	0/6 (0.00%)	0
Cholecystitis † 1	0/134 (0.00%)	0	1/99 (1.01%)	1	1/33 (3.03%)	1	0/29 (0.00%)	0	0/6 (0.00%)	0
Cholelithiasis † 1	1/134 (0.75%)	1	0/99 (0.00%)	0	0/33 (0.00%)	0	0/29 (0.00%)	0	0/6 (0.00%)	0
Perforation bile duct † 1	0/134 (0.00%)	0	1/99 (1.01%)	1	0/33 (0.00%)	0	0/29 (0.00%)	0	0/6 (0.00%)	0
Immune system disorders
Anaphylactic reaction † 1	1/134 (0.75%)	1	0/99 (0.00%)	0	0/33 (0.00%)	0	0/29 (0.00%)	0	0/6 (0.00%)	0
Infections and infestations
Abscess limb † 1	0/134 (0.00%)	0	1/99 (1.01%)	1	0/33 (0.00%)	0	0/29 (0.00%)	0	0/6 (0.00%)	0
Acute sinusitis † 1	2/134 (1.49%)	2	1/99 (1.01%)	1	0/33 (0.00%)	0	0/29 (0.00%)	0	0/6 (0.00%)	0
Appendicitis † 1	1/134 (0.75%)	1	0/99 (0.00%)	0	0/33 (0.00%)	0	0/29 (0.00%)	0	0/6 (0.00%)	0
Aspergillus infection † 1	0/134 (0.00%)	0	0/99 (0.00%)	0	1/33 (3.03%)	1	0/29 (0.00%)	0	0/6 (0.00%)	0
Bacterial infection † 1	0/134 (0.00%)	0	0/99 (0.00%)	0	1/33 (3.03%)	1	0/29 (0.00%)	0	0/6 (0.00%)	0
Brain abscess † 1	0/134 (0.00%)	0	0/99 (0.00%)	0	0/33 (0.00%)	0	1/29 (3.45%)	1	0/6 (0.00%)	0
Bronchitis † 1	0/134 (0.00%)	0	0/99 (0.00%)	0	0/33 (0.00%)	0	1/29 (3.45%)	2	0/6 (0.00%)	0
Bronchitis bacterial † 1	0/134 (0.00%)	0	0/99 (0.00%)	0	1/33 (3.03%)	1	0/29 (0.00%)	0	0/6 (0.00%)	0
Covid-19 † 1	2/134 (1.49%)	2	1/99 (1.01%)	1	0/33 (0.00%)	0	0/29 (0.00%)	0	0/6 (0.00%)	0
Covid-19 pneumonia † 1	3/134 (2.24%)	4	0/99 (0.00%)	0	0/33 (0.00%)	0	0/29 (0.00%)	0	0/6 (0.00%)	0
Campylobacter gastroenteritis † 1	1/134 (0.75%)	1	0/99 (0.00%)	0	0/33 (0.00%)	0	0/29 (0.00%)	0	0/6 (0.00%)	0
Campylobacter infection † 1	1/134 (0.75%)	1	0/99 (0.00%)	0	0/33 (0.00%)	0	0/29 (0.00%)	0	0/6 (0.00%)	0
Candida sepsis † 1	1/134 (0.75%)	1	0/99 (0.00%)	0	0/33 (0.00%)	0	0/29 (0.00%)	0	0/6 (0.00%)	0
Cellulitis † 1	1/134 (0.75%)	1	1/99 (1.01%)	1	2/33 (6.06%)	2	0/29 (0.00%)	0	0/6 (0.00%)	0
Clostridium difficile colitis † 1	0/134 (0.00%)	0	0/99 (0.00%)	0	0/33 (0.00%)	0	1/29 (3.45%)	1	0/6 (0.00%)	0
Clostridium difficile infection † 1	0/134 (0.00%)	0	0/99 (0.00%)	0	0/33 (0.00%)	0	1/29 (3.45%)	1	0/6 (0.00%)	0
Cytomegalovirus infection reactivation † 1	0/134 (0.00%)	0	0/99 (0.00%)	0	0/33 (0.00%)	0	1/29 (3.45%)	1	0/6 (0.00%)	0
Diverticulitis † 1	0/134 (0.00%)	0	2/99 (2.02%)	2	0/33 (0.00%)	0	0/29 (0.00%)	0	0/6 (0.00%)	0
Escherichia sepsis † 1	1/134 (0.75%)	1	0/99 (0.00%)	0	0/33 (0.00%)	0	0/29 (0.00%)	0	0/6 (0.00%)	0
Gastroenteritis † 1	1/134 (0.75%)	1	0/99 (0.00%)	0	1/33 (3.03%)	1	0/29 (0.00%)	0	0/6 (0.00%)	0
Gastroenteritis rotavirus † 1	1/134 (0.75%)	1	0/99 (0.00%)	0	0/33 (0.00%)	0	0/29 (0.00%)	0	0/6 (0.00%)	0
Genital abscess † 1	1/134 (0.75%)	1	0/99 (0.00%)	0	0/33 (0.00%)	0	0/29 (0.00%)	0	0/6 (0.00%)	0
Genital infection fungal † 1	0/134 (0.00%)	0	1/99 (1.01%)	1	0/33 (0.00%)	0	0/29 (0.00%)	0	0/6 (0.00%)	0
Gingivitis † 1	1/134 (0.75%)	1	0/99 (0.00%)	0	0/33 (0.00%)	0	0/29 (0.00%)	0	0/6 (0.00%)	0
Groin abscess † 1	0/134 (0.00%)	0	0/99 (0.00%)	0	1/33 (3.03%)	1	0/29 (0.00%)	0	0/6 (0.00%)	0
Herpes simplex † 1	1/134 (0.75%)	1	0/99 (0.00%)	0	0/33 (0.00%)	0	0/29 (0.00%)	0	0/6 (0.00%)	0
Herpes virus infection † 1	0/134 (0.00%)	0	0/99 (0.00%)	0	1/33 (3.03%)	1	0/29 (0.00%)	0	0/6 (0.00%)	0
Herpes zoster † 1	0/134 (0.00%)	0	1/99 (1.01%)	1	1/33 (3.03%)	2	0/29 (0.00%)	0	0/6 (0.00%)	0
Infection † 1	0/134 (0.00%)	0	0/99 (0.00%)	0	0/33 (0.00%)	0	2/29 (6.90%)	2	0/6 (0.00%)	0
Influenza † 1	1/134 (0.75%)	1	3/99 (3.03%)	3	0/33 (0.00%)	0	0/29 (0.00%)	0	0/6 (0.00%)	0
Kidney infection † 1	0/134 (0.00%)	0	0/99 (0.00%)	0	0/33 (0.00%)	0	1/29 (3.45%)	1	0/6 (0.00%)	0
Klebsiella bacteraemia † 1	1/134 (0.75%)	1	1/99 (1.01%)	1	0/33 (0.00%)	0	0/29 (0.00%)	0	0/6 (0.00%)	0
Lower respiratory tract infection † 1	1/134 (0.75%)	1	0/99 (0.00%)	0	1/33 (3.03%)	1	0/29 (0.00%)	0	0/6 (0.00%)	0
Lymphangitis † 1	1/134 (0.75%)	1	0/99 (0.00%)	0	0/33 (0.00%)	0	0/29 (0.00%)	0	0/6 (0.00%)	0
Mycobacterium avium complex infection † 1	0/134 (0.00%)	0	0/99 (0.00%)	0	0/33 (0.00%)	0	1/29 (3.45%)	1	0/6 (0.00%)	0
Neutropenic sepsis † 1	1/134 (0.75%)	1	0/99 (0.00%)	0	0/33 (0.00%)	0	0/29 (0.00%)	0	0/6 (0.00%)	0
Parainfluenzae virus infection † 1	1/134 (0.75%)	1	0/99 (0.00%)	0	0/33 (0.00%)	0	0/29 (0.00%)	0	0/6 (0.00%)	0
Pelvic abscess † 1	0/134 (0.00%)	0	1/99 (1.01%)	1	0/33 (0.00%)	0	0/29 (0.00%)	0	0/6 (0.00%)	0
Pharyngitis † 1	1/134 (0.75%)	1	0/99 (0.00%)	0	0/33 (0.00%)	0	0/29 (0.00%)	0	0/6 (0.00%)	0
Pneumonia † 1	19/134 (14.18%)	24	6/99 (6.06%)	8	3/33 (9.09%)	8	1/29 (3.45%)	1	0/6 (0.00%)	0
Pneumonia fungal † 1	1/134 (0.75%)	1	0/99 (0.00%)	0	0/33 (0.00%)	0	0/29 (0.00%)	0	0/6 (0.00%)	0
Pneumonia parainfluenzae viral † 1	1/134 (0.75%)	1	0/99 (0.00%)	0	0/33 (0.00%)	0	0/29 (0.00%)	0	0/6 (0.00%)	0
Pneumonia pneumococcal † 1	1/134 (0.75%)	1	0/99 (0.00%)	0	0/33 (0.00%)	0	0/29 (0.00%)	0	0/6 (0.00%)	0
Pneumonia streptococcal † 1	1/134 (0.75%)	1	0/99 (0.00%)	0	0/33 (0.00%)	0	0/29 (0.00%)	0	0/6 (0.00%)	0
Pseudomonal sepsis † 1	1/134 (0.75%)	1	0/99 (0.00%)	0	0/33 (0.00%)	0	0/29 (0.00%)	0	0/6 (0.00%)	0
Pseudomonas infection † 1	0/134 (0.00%)	0	0/99 (0.00%)	0	1/33 (3.03%)	1	0/29 (0.00%)	0	0/6 (0.00%)	0
Pyelitis † 1	1/134 (0.75%)	1	0/99 (0.00%)	0	0/33 (0.00%)	0	0/29 (0.00%)	0	0/6 (0.00%)	0
Respiratory tract infection † 1	1/134 (0.75%)	1	0/99 (0.00%)	0	0/33 (0.00%)	0	1/29 (3.45%)	1	0/6 (0.00%)	0
Salmonellosis † 1	1/134 (0.75%)	1	0/99 (0.00%)	0	1/33 (3.03%)	1	0/29 (0.00%)	0	0/6 (0.00%)	0
Sepsis † 1	3/134 (2.24%)	6	2/99 (2.02%)	3	0/33 (0.00%)	0	2/29 (6.90%)	2	1/6 (16.67%)	1
Septic shock † 1	0/134 (0.00%)	0	0/99 (0.00%)	0	0/33 (0.00%)	0	0/29 (0.00%)	0	1/6 (16.67%)	1
Sinusitis † 1	0/134 (0.00%)	0	2/99 (2.02%)	3	0/33 (0.00%)	0	0/29 (0.00%)	0	0/6 (0.00%)	0
Skin infection † 1	0/134 (0.00%)	0	0/99 (0.00%)	0	1/33 (3.03%)	1	0/29 (0.00%)	0	0/6 (0.00%)	0
Subcutaneous abscess † 1	0/134 (0.00%)	0	1/99 (1.01%)	1	0/33 (0.00%)	0	0/29 (0.00%)	0	0/6 (0.00%)	0
Upper respiratory tract infection † 1	2/134 (1.49%)	2	0/99 (0.00%)	0	1/33 (3.03%)	2	0/29 (0.00%)	0	1/6 (16.67%)	1
Urinary tract infection † 1	3/134 (2.24%)	6	2/99 (2.02%)	6	2/33 (6.06%)	2	0/29 (0.00%)	0	0/6 (0.00%)	0
Viral myocarditis † 1	1/134 (0.75%)	1	0/99 (0.00%)	0	0/33 (0.00%)	0	0/29 (0.00%)	0	0/6 (0.00%)	0
Viral pharyngitis † 1	1/134 (0.75%)	1	0/99 (0.00%)	0	0/33 (0.00%)	0	0/29 (0.00%)	0	0/6 (0.00%)	0
Viral sepsis † 1	0/134 (0.00%)	0	1/99 (1.01%)	1	0/33 (0.00%)	0	0/29 (0.00%)	0	0/6 (0.00%)	0
Wound infection † 1	1/134 (0.75%)	1	0/99 (0.00%)	0	0/33 (0.00%)	0	0/29 (0.00%)	0	0/6 (0.00%)	0
Injury, poisoning and procedural complications
Fall † 1	1/134 (0.75%)	1	1/99 (1.01%)	1	0/33 (0.00%)	0	0/29 (0.00%)	0	0/6 (0.00%)	0
Femoral neck fracture † 1	1/134 (0.75%)	1	0/99 (0.00%)	0	0/33 (0.00%)	0	0/29 (0.00%)	0	0/6 (0.00%)	0
Fracture † 1	1/134 (0.75%)	1	0/99 (0.00%)	0	0/33 (0.00%)	0	0/29 (0.00%)	0	0/6 (0.00%)	0
Hip fracture † 1	2/134 (1.49%)	2	1/99 (1.01%)	1	0/33 (0.00%)	0	0/29 (0.00%)	0	0/6 (0.00%)	0
Post procedural haemorrhage † 1	0/134 (0.00%)	0	1/99 (1.01%)	1	0/33 (0.00%)	0	0/29 (0.00%)	0	0/6 (0.00%)	0
Rib fracture † 1	0/134 (0.00%)	0	1/99 (1.01%)	1	0/33 (0.00%)	0	0/29 (0.00%)	0	0/6 (0.00%)	0
Spinal compression fracture † 1	1/134 (0.75%)	1	0/99 (0.00%)	0	0/33 (0.00%)	0	0/29 (0.00%)	0	0/6 (0.00%)	0
Tibia fracture † 1	1/134 (0.75%)	1	0/99 (0.00%)	0	0/33 (0.00%)	0	0/29 (0.00%)	0	0/6 (0.00%)	0
Traumatic intracranial haemorrhage † 1	0/134 (0.00%)	0	1/99 (1.01%)	1	0/33 (0.00%)	0	0/29 (0.00%)	0	0/6 (0.00%)	0
Investigations
Alanine aminotransferase increased † 1	0/134 (0.00%)	0	0/99 (0.00%)	0	0/33 (0.00%)	0	1/29 (3.45%)	1	0/6 (0.00%)	0
Cytomegalovirus test positive † 1	0/134 (0.00%)	0	0/99 (0.00%)	0	0/33 (0.00%)	0	1/29 (3.45%)	1	0/6 (0.00%)	0
Immunosuppressant drug level increased † 1	0/134 (0.00%)	0	0/99 (0.00%)	0	0/33 (0.00%)	0	1/29 (3.45%)	1	0/6 (0.00%)	0
Troponin i increased † 1	0/134 (0.00%)	0	1/99 (1.01%)	1	0/33 (0.00%)	0	0/29 (0.00%)	0	0/6 (0.00%)	0
Metabolism and nutrition disorders
Decreased appetite † 1	0/134 (0.00%)	0	0/99 (0.00%)	0	1/33 (3.03%)	1	0/29 (0.00%)	0	0/6 (0.00%)	0
Dehydration † 1	0/134 (0.00%)	0	1/99 (1.01%)	1	0/33 (0.00%)	0	1/29 (3.45%)	1	0/6 (0.00%)	0
Hypercalcaemia † 1	4/134 (2.99%)	4	0/99 (0.00%)	0	0/33 (0.00%)	0	3/29 (10.34%)	5	0/6 (0.00%)	0
Hyperkalaemia † 1	1/134 (0.75%)	1	0/99 (0.00%)	0	0/33 (0.00%)	0	0/29 (0.00%)	0	0/6 (0.00%)	0
Hyponatraemia † 1	1/134 (0.75%)	1	1/99 (1.01%)	1	0/33 (0.00%)	0	0/29 (0.00%)	0	0/6 (0.00%)	0
Musculoskeletal and connective tissue disorders
Arthritis † 1	0/134 (0.00%)	0	1/99 (1.01%)	2	0/33 (0.00%)	0	0/29 (0.00%)	0	0/6 (0.00%)	0
Back pain † 1	0/134 (0.00%)	0	0/99 (0.00%)	0	1/33 (3.03%)	1	1/29 (3.45%)	1	0/6 (0.00%)	0
Flank pain † 1	1/134 (0.75%)	1	0/99 (0.00%)	0	0/33 (0.00%)	0	0/29 (0.00%)	0	0/6 (0.00%)	0
Joint effusion † 1	1/134 (0.75%)	1	0/99 (0.00%)	0	0/33 (0.00%)	0	0/29 (0.00%)	0	0/6 (0.00%)	0
Musculoskeletal chest pain † 1	0/134 (0.00%)	0	0/99 (0.00%)	0	1/33 (3.03%)	1	0/29 (0.00%)	0	0/6 (0.00%)	0
Vertebral column mass † 1	1/134 (0.75%)	1	0/99 (0.00%)	0	0/33 (0.00%)	0	0/29 (0.00%)	0	0/6 (0.00%)	0
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Adenocarcinoma of colon † 1	0/134 (0.00%)	0	1/99 (1.01%)	1	0/33 (0.00%)	0	0/29 (0.00%)	0	0/6 (0.00%)	0
Angiosarcoma † 1	0/134 (0.00%)	0	1/99 (1.01%)	1	0/33 (0.00%)	0	0/29 (0.00%)	0	0/6 (0.00%)	0
Basal cell carcinoma † 1	0/134 (0.00%)	0	2/99 (2.02%)	3	0/33 (0.00%)	0	0/29 (0.00%)	0	0/6 (0.00%)	0
Benign lung neoplasm † 1	0/134 (0.00%)	0	1/99 (1.01%)	1	0/33 (0.00%)	0	0/29 (0.00%)	0	0/6 (0.00%)	0
Bladder cancer recurrent † 1	1/134 (0.75%)	2	0/99 (0.00%)	0	0/33 (0.00%)	0	0/29 (0.00%)	0	0/6 (0.00%)	0
Central nervous system leukaemia † 1	0/134 (0.00%)	0	0/99 (0.00%)	0	1/33 (3.03%)	1	0/29 (0.00%)	0	0/6 (0.00%)	0
Chronic myeloid leukaemia † 1	1/134 (0.75%)	1	0/99 (0.00%)	0	0/33 (0.00%)	0	0/29 (0.00%)	0	0/6 (0.00%)	0
Colon cancer † 1	1/134 (0.75%)	1	0/99 (0.00%)	0	0/33 (0.00%)	0	0/29 (0.00%)	0	0/6 (0.00%)	0
Endometrial cancer metastatic † 1	0/134 (0.00%)	0	0/99 (0.00%)	0	1/33 (3.03%)	1	0/29 (0.00%)	0	0/6 (0.00%)	0
Glioblastoma multiforme † 1	0/134 (0.00%)	0	1/99 (1.01%)	1	0/33 (0.00%)	0	0/29 (0.00%)	0	0/6 (0.00%)	0
Lung adenocarcinoma † 1	1/134 (0.75%)	1	0/99 (0.00%)	0	0/33 (0.00%)	0	0/29 (0.00%)	0	0/6 (0.00%)	0
Lung adenocarcinoma stage 0 † 1	1/134 (0.75%)	1	0/99 (0.00%)	0	0/33 (0.00%)	0	0/29 (0.00%)	0	0/6 (0.00%)	0
Lung neoplasm † 1	1/134 (0.75%)	1	0/99 (0.00%)	0	0/33 (0.00%)	0	0/29 (0.00%)	0	0/6 (0.00%)	0
Lung neoplasm malignant † 1	0/134 (0.00%)	0	1/99 (1.01%)	1	0/33 (0.00%)	0	0/29 (0.00%)	0	0/6 (0.00%)	0
Metastases to meninges † 1	1/134 (0.75%)	1	0/99 (0.00%)	0	0/33 (0.00%)	0	0/29 (0.00%)	0	0/6 (0.00%)	0
Myelodysplastic syndrome † 1	1/134 (0.75%)	1	0/99 (0.00%)	0	0/33 (0.00%)	0	0/29 (0.00%)	0	0/6 (0.00%)	0
Neuroendocrine carcinoma of the skin † 1	0/134 (0.00%)	0	0/99 (0.00%)	0	1/33 (3.03%)	1	0/29 (0.00%)	0	0/6 (0.00%)	0
Papillary renal cell carcinoma † 1	1/134 (0.75%)	1	0/99 (0.00%)	0	0/33 (0.00%)	0	0/29 (0.00%)	0	0/6 (0.00%)	0
Plasmablastic lymphoma † 1	1/134 (0.75%)	1	0/99 (0.00%)	0	0/33 (0.00%)	0	0/29 (0.00%)	0	0/6 (0.00%)	0
Prostate cancer † 1	2/134 (1.49%)	2	2/99 (2.02%)	2	0/33 (0.00%)	0	0/29 (0.00%)	0	0/6 (0.00%)	0
Prostate cancer metastatic † 1	1/134 (0.75%)	1	0/99 (0.00%)	0	0/33 (0.00%)	0	0/29 (0.00%)	0	0/6 (0.00%)	0
Rectal adenocarcinoma † 1	1/134 (0.75%)	1	0/99 (0.00%)	0	0/33 (0.00%)	0	0/29 (0.00%)	0	0/6 (0.00%)	0
Renal cell carcinoma † 1	1/134 (0.75%)	1	1/99 (1.01%)	1	0/33 (0.00%)	0	0/29 (0.00%)	0	0/6 (0.00%)	0
Small cell lung cancer † 1	0/134 (0.00%)	0	1/99 (1.01%)	1	0/33 (0.00%)	0	0/29 (0.00%)	0	0/6 (0.00%)	0
Squamous cell carcinoma of skin † 1	1/134 (0.75%)	1	4/99 (4.04%)	4	0/33 (0.00%)	0	0/29 (0.00%)	0	0/6 (0.00%)	0
Tumour flare † 1	0/134 (0.00%)	0	1/99 (1.01%)	1	0/33 (0.00%)	0	0/29 (0.00%)	0	0/6 (0.00%)	0
Nervous system disorders
Amyotrophic lateral sclerosis † 1	0/134 (0.00%)	0	1/99 (1.01%)	1	0/33 (0.00%)	0	0/29 (0.00%)	0	0/6 (0.00%)	0
Cerebral haemorrhage † 1	0/134 (0.00%)	0	1/99 (1.01%)	1	0/33 (0.00%)	0	0/29 (0.00%)	0	0/6 (0.00%)	0
Cerebrovascular accident † 1	1/134 (0.75%)	2	0/99 (0.00%)	0	1/33 (3.03%)	1	0/29 (0.00%)	0	0/6 (0.00%)	0
Dizziness † 1	1/134 (0.75%)	1	0/99 (0.00%)	0	0/33 (0.00%)	0	0/29 (0.00%)	0	0/6 (0.00%)	0
Encephalopathy † 1	1/134 (0.75%)	1	0/99 (0.00%)	0	0/33 (0.00%)	0	0/29 (0.00%)	0	0/6 (0.00%)	0
Haemorrhage intracranial † 1	0/134 (0.00%)	0	0/99 (0.00%)	0	0/33 (0.00%)	0	0/29 (0.00%)	0	1/6 (16.67%)	1
Hemiparesis † 1	1/134 (0.75%)	1	0/99 (0.00%)	0	0/33 (0.00%)	0	0/29 (0.00%)	0	0/6 (0.00%)	0
Memory impairment † 1	0/134 (0.00%)	0	0/99 (0.00%)	0	1/33 (3.03%)	1	0/29 (0.00%)	0	0/6 (0.00%)	0
Multiple system atrophy † 1	0/134 (0.00%)	0	1/99 (1.01%)	1	0/33 (0.00%)	0	0/29 (0.00%)	0	0/6 (0.00%)	0
Seizure † 1	0/134 (0.00%)	0	1/99 (1.01%)	1	0/33 (0.00%)	0	0/29 (0.00%)	0	0/6 (0.00%)	0
Syncope † 1	3/134 (2.24%)	4	0/99 (0.00%)	0	1/33 (3.03%)	2	0/29 (0.00%)	0	0/6 (0.00%)	0
Transient ischaemic attack † 1	1/134 (0.75%)	1	0/99 (0.00%)	0	0/33 (0.00%)	0	0/29 (0.00%)	0	0/6 (0.00%)	0
Psychiatric disorders
Anxiety † 1	0/134 (0.00%)	0	1/99 (1.01%)	1	0/33 (0.00%)	0	0/29 (0.00%)	0	0/6 (0.00%)	0
Confusional state † 1	0/134 (0.00%)	0	0/99 (0.00%)	0	1/33 (3.03%)	1	0/29 (0.00%)	0	0/6 (0.00%)	0
Delirium † 1	2/134 (1.49%)	2	1/99 (1.01%)	1	0/33 (0.00%)	0	0/29 (0.00%)	0	0/6 (0.00%)	0
Suicidal ideation † 1	0/134 (0.00%)	0	1/99 (1.01%)	1	0/33 (0.00%)	0	0/29 (0.00%)	0	0/6 (0.00%)	0
Renal and urinary disorders
Acute kidney injury † 1	5/134 (3.73%)	5	1/99 (1.01%)	1	0/33 (0.00%)	0	2/29 (6.90%)	2	0/6 (0.00%)	0
Haematuria † 1	1/134 (0.75%)	1	0/99 (0.00%)	0	0/33 (0.00%)	0	0/29 (0.00%)	0	0/6 (0.00%)	0
Nephrolithiasis † 1	0/134 (0.00%)	0	1/99 (1.01%)	1	0/33 (0.00%)	0	0/29 (0.00%)	0	0/6 (0.00%)	0
Renal impairment † 1	1/134 (0.75%)	1	0/99 (0.00%)	0	0/33 (0.00%)	0	0/29 (0.00%)	0	0/6 (0.00%)	0
Subcapsular renal haematoma † 1	1/134 (0.75%)	2	0/99 (0.00%)	0	0/33 (0.00%)	0	0/29 (0.00%)	0	0/6 (0.00%)	0
Reproductive system and breast disorders
Pelvic pain † 1	1/134 (0.75%)	1	0/99 (0.00%)	0	0/33 (0.00%)	0	0/29 (0.00%)	0	0/6 (0.00%)	0
Respiratory, thoracic and mediastinal disorders
Acute respiratory failure † 1	1/134 (0.75%)	1	0/99 (0.00%)	0	0/33 (0.00%)	0	0/29 (0.00%)	0	0/6 (0.00%)	0
Dyspnoea † 1	2/134 (1.49%)	2	1/99 (1.01%)	1	0/33 (0.00%)	0	0/29 (0.00%)	0	0/6 (0.00%)	0
Pleural effusion † 1	0/134 (0.00%)	0	0/99 (0.00%)	0	0/33 (0.00%)	0	1/29 (3.45%)	1	0/6 (0.00%)	0
Pneumothorax † 1	0/134 (0.00%)	0	1/99 (1.01%)	1	0/33 (0.00%)	0	0/29 (0.00%)	0	0/6 (0.00%)	0
Respiratory alkalosis † 1	1/134 (0.75%)	1	0/99 (0.00%)	0	0/33 (0.00%)	0	0/29 (0.00%)	0	0/6 (0.00%)	0
Respiratory failure † 1	2/134 (1.49%)	6	0/99 (0.00%)	0	0/33 (0.00%)	0	1/29 (3.45%)	1	0/6 (0.00%)	0
Respiratory tract haemorrhage † 1	1/134 (0.75%)	1	0/99 (0.00%)	0	0/33 (0.00%)	0	0/29 (0.00%)	0	0/6 (0.00%)	0
Skin and subcutaneous tissue disorders
Rash † 1	0/134 (0.00%)	0	0/99 (0.00%)	0	0/33 (0.00%)	0	1/29 (3.45%)	1	0/6 (0.00%)	0
Vascular disorders
Hypertension † 1	2/134 (1.49%)	3	0/99 (0.00%)	0	0/33 (0.00%)	0	0/29 (0.00%)	0	0/6 (0.00%)	0
Hypotension † 1	0/134 (0.00%)	0	1/99 (1.01%)	1	0/33 (0.00%)	0	0/29 (0.00%)	0	0/6 (0.00%)	0
Malignant hypertension † 1	0/134 (0.00%)	0	0/99 (0.00%)	0	0/33 (0.00%)	0	1/29 (3.45%)	1	0/6 (0.00%)	0
Orthostatic hypotension † 1	0/134 (0.00%)	0	1/99 (1.01%)	1	0/33 (0.00%)	0	0/29 (0.00%)	0	0/6 (0.00%)	0
Phlebitis superficial † 1	0/134 (0.00%)	0	0/99 (0.00%)	0	1/33 (3.03%)	1	0/29 (0.00%)	0	0/6 (0.00%)	0
Aortic stenosis † 1	1/134 (0.75%)	1	0/99 (0.00%)	0	0/33 (0.00%)	0	0/29 (0.00%)	0	0/6 (0.00%)	0
Haematoma † 1	0/134 (0.00%)	0	0/99 (0.00%)	0	1/33 (3.03%)	1	0/29 (0.00%)	0	0/6 (0.00%)	0
1 Term from vocabulary, MedDRA 24.0; † Indicates events were collected by systematic assessment
Other (Not Including Serious) Adverse Events
Frequency Threshold for Reporting Other Adverse Events	0%
	Relapsed/Refractory Cohort		Treatment-naive Cohort		Ibrutinib-intolerant Cohort		Richters Syndrome/Prolymphocytic Leukemia Transformation Cohort		Ibrutinib Relapsed/Refractory Cohort
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	134/134 (100.00%)		99/99 (100.00%)		33/33 (100.00%)		28/29 (96.55%)		6/6 (100.00%)
Blood and lymphatic system disorders
Leukocytosis † 1	1/134 (0.75%)	1	1/99 (1.01%)	1	0/33 (0.00%)	0	0/29 (0.00%)	0	0/6 (0.00%)	0
Leukopenia † 1	0/134 (0.00%)	0	1/99 (1.01%)	1	0/33 (0.00%)	0	0/29 (0.00%)	0	0/6 (0.00%)	0
Lymph node pain † 1	7/134 (5.22%)	7	6/99 (6.06%)	6	3/33 (9.09%)	3	1/29 (3.45%)	1	0/6 (0.00%)	0
Lymphadenopathy † 1	4/134 (2.99%)	4	2/99 (2.02%)	2	1/33 (3.03%)	1	0/29 (0.00%)	0	0/6 (0.00%)	0
Lymphopenia † 1	1/134 (0.75%)	1	0/99 (0.00%)	0	0/33 (0.00%)	0	0/29 (0.00%)	0	0/6 (0.00%)	0
Microcytic anaemia † 1	1/134 (0.75%)	1	0/99 (0.00%)	0	0/33 (0.00%)	0	0/29 (0.00%)	0	0/6 (0.00%)	0
Neutropenia † 1	21/134 (15.67%)	42	8/99 (8.08%)	14	4/33 (12.12%)	8	7/29 (24.14%)	9	1/6 (16.67%)	1
Anaemia † 1	18/134 (13.43%)	27	9/99 (9.09%)	12	4/33 (12.12%)	7	9/29 (31.03%)	13	1/6 (16.67%)	2
Spontaneous haemorrhage † 1	0/134 (0.00%)	0	1/99 (1.01%)	1	0/33 (0.00%)	0	0/29 (0.00%)	0	0/6 (0.00%)	0
Thrombocytopenia † 1	5/134 (3.73%)	17	1/99 (1.01%)	1	3/33 (9.09%)	5	0/29 (0.00%)	0	0/6 (0.00%)	0
Febrile neutropenia † 1	3/134 (2.24%)	3	0/99 (0.00%)	0	0/33 (0.00%)	0	1/29 (3.45%)	1	0/6 (0.00%)	0
Haemolysis † 1	0/134 (0.00%)	0	0/99 (0.00%)	0	1/33 (3.03%)	1	0/29 (0.00%)	0	0/6 (0.00%)	0
Haemolytic anaemia † 1	0/134 (0.00%)	0	1/99 (1.01%)	1	0/33 (0.00%)	0	0/29 (0.00%)	0	0/6 (0.00%)	0
Increased tendency to bruise † 1	15/134 (11.19%)	15	10/99 (10.10%)	10	3/33 (9.09%)	3	1/29 (3.45%)	1	0/6 (0.00%)	0
Iron deficiency anaemia † 1	1/134 (0.75%)	1	3/99 (3.03%)	3	0/33 (0.00%)	0	0/29 (0.00%)	0	0/6 (0.00%)	0
Jaundice acholuric † 1	1/134 (0.75%)	1	0/99 (0.00%)	0	0/33 (0.00%)	0	0/29 (0.00%)	0	0/6 (0.00%)	0
Cardiac disorders
Acute coronary syndrome † 1	0/134 (0.00%)	0	1/99 (1.01%)	1	0/33 (0.00%)	0	0/29 (0.00%)	0	0/6 (0.00%)	0
Angina pectoris † 1	1/134 (0.75%)	1	2/99 (2.02%)	2	1/33 (3.03%)	1	0/29 (0.00%)	0	0/6 (0.00%)	0
Aortic valve disease † 1	1/134 (0.75%)	1	0/99 (0.00%)	0	0/33 (0.00%)	0	0/29 (0.00%)	0	0/6 (0.00%)	0
Aortic valve incompetence † 1	1/134 (0.75%)	1	1/99 (1.01%)	1	0/33 (0.00%)	0	0/29 (0.00%)	0	0/6 (0.00%)	0
Arteriosclerosis coronary artery † 1	1/134 (0.75%)	1	0/99 (0.00%)	0	0/33 (0.00%)	0	0/29 (0.00%)	0	0/6 (0.00%)	0
Atrial fibrillation † 1	10/134 (7.46%)	11	5/99 (5.05%)	8	2/33 (6.06%)	2	3/29 (10.34%)	6	0/6 (0.00%)	0
Atrial flutter † 1	1/134 (0.75%)	1	0/99 (0.00%)	0	0/33 (0.00%)	0	0/29 (0.00%)	0	0/6 (0.00%)	0
Bradycardia † 1	5/134 (3.73%)	8	1/99 (1.01%)	2	0/33 (0.00%)	0	0/29 (0.00%)	0	0/6 (0.00%)	0
Bundle branch block left † 1	1/134 (0.75%)	1	0/99 (0.00%)	0	0/33 (0.00%)	0	0/29 (0.00%)	0	0/6 (0.00%)	0
Bundle branch block right † 1	1/134 (0.75%)	1	0/99 (0.00%)	0	0/33 (0.00%)	0	0/29 (0.00%)	0	0/6 (0.00%)	0
Cardiac failure † 1	1/134 (0.75%)	1	0/99 (0.00%)	0	0/33 (0.00%)	0	0/29 (0.00%)	0	0/6 (0.00%)	0
Coronary artery disease † 1	0/134 (0.00%)	0	1/99 (1.01%)	1	0/33 (0.00%)	0	0/29 (0.00%)	0	0/6 (0.00%)	0
Coronary artery stenosis † 1	0/134 (0.00%)	0	1/99 (1.01%)	2	0/33 (0.00%)	0	0/29 (0.00%)	0	0/6 (0.00%)	0
Extrasystoles † 1	1/134 (0.75%)	1	0/99 (0.00%)	0	0/33 (0.00%)	0	0/29 (0.00%)	0	0/6 (0.00%)	0
Left ventricular failure † 1	1/134 (0.75%)	1	0/99 (0.00%)	0	0/33 (0.00%)	0	0/29 (0.00%)	0	0/6 (0.00%)	0
Mitral valve disease † 1	0/134 (0.00%)	0	2/99 (2.02%)	2	0/33 (0.00%)	0	0/29 (0.00%)	0	0/6 (0.00%)	0
Palpitations † 1	13/134 (9.70%)	15	4/99 (4.04%)	4	0/33 (0.00%)	0	0/29 (0.00%)	0	0/6 (0.00%)	0
Sinus bradycardia † 1	5/134 (3.73%)	6	2/99 (2.02%)	2	1/33 (3.03%)	1	0/29 (0.00%)	0	0/6 (0.00%)	0
Sinus tachycardia † 1	5/134 (3.73%)	6	10/99 (10.10%)	11	1/33 (3.03%)	1	0/29 (0.00%)	0	1/6 (16.67%)	1
Tachycardia † 1	3/134 (2.24%)	3	8/99 (8.08%)	9	2/33 (6.06%)	2	3/29 (10.34%)	3	0/6 (0.00%)	0
Tricuspid valve disease † 1	0/134 (0.00%)	0	1/99 (1.01%)	1	0/33 (0.00%)	0	0/29 (0.00%)	0	0/6 (0.00%)	0
Ventricular extrasystoles † 1	3/134 (2.24%)	3	0/99 (0.00%)	0	0/33 (0.00%)	0	0/29 (0.00%)	0	0/6 (0.00%)	0
Ventricular tachycardia † 1	1/134 (0.75%)	1	0/99 (0.00%)	0	0/33 (0.00%)	0	0/29 (0.00%)	0	0/6 (0.00%)	0
Congenital, familial and genetic disorders
Hypertrophic cardiomyopathy † 1	1/134 (0.75%)	1	1/99 (1.01%)	2	0/33 (0.00%)	0	0/29 (0.00%)	0	0/6 (0.00%)	0
Laryngocele † 1	0/134 (0.00%)	0	1/99 (1.01%)	1	0/33 (0.00%)	0	0/29 (0.00%)	0	0/6 (0.00%)	0
Porokeratosis † 1	0/134 (0.00%)	0	0/99 (0.00%)	0	1/33 (3.03%)	1	0/29 (0.00%)	0	0/6 (0.00%)	0
Ear and labyrinth disorders
Deafness † 1	2/134 (1.49%)	2	2/99 (2.02%)	2	0/33 (0.00%)	0	0/29 (0.00%)	0	0/6 (0.00%)	0
Deafness unilateral † 1	0/134 (0.00%)	0	2/99 (2.02%)	2	0/33 (0.00%)	0	1/29 (3.45%)	1	0/6 (0.00%)	0
Ear congestion † 1	1/134 (0.75%)	1	0/99 (0.00%)	0	0/33 (0.00%)	0	0/29 (0.00%)	0	0/6 (0.00%)	0
Ear discomfort † 1	3/134 (2.24%)	3	2/99 (2.02%)	2	1/33 (3.03%)	2	0/29 (0.00%)	0	0/6 (0.00%)	0
Ear haemorrhage † 1	1/134 (0.75%)	1	1/99 (1.01%)	1	0/33 (0.00%)	0	0/29 (0.00%)	0	0/6 (0.00%)	0
Ear pain † 1	5/134 (3.73%)	5	6/99 (6.06%)	6	2/33 (6.06%)	2	0/29 (0.00%)	0	0/6 (0.00%)	0
Ear pruritus † 1	1/134 (0.75%)	1	1/99 (1.01%)	1	0/33 (0.00%)	0	0/29 (0.00%)	0	0/6 (0.00%)	0
Eustachian tube disorder † 1	0/134 (0.00%)	0	1/99 (1.01%)	1	0/33 (0.00%)	0	0/29 (0.00%)	0	0/6 (0.00%)	0
Eustachian tube dysfunction † 1	1/134 (0.75%)	1	0/99 (0.00%)	0	0/33 (0.00%)	0	0/29 (0.00%)	0	0/6 (0.00%)	0
External ear inflammation † 1	0/134 (0.00%)	0	1/99 (1.01%)	1	0/33 (0.00%)	0	0/29 (0.00%)	0	0/6 (0.00%)	0
External ear pain † 1	0/134 (0.00%)	0	1/99 (1.01%)	1	0/33 (0.00%)	0	0/29 (0.00%)	0	0/6 (0.00%)	0
Hyperacusis † 1	1/134 (0.75%)	1	0/99 (0.00%)	0	0/33 (0.00%)	0	0/29 (0.00%)	0	0/6 (0.00%)	0
Hypoacusis † 1	3/134 (2.24%)	3	6/99 (6.06%)	6	1/33 (3.03%)	1	1/29 (3.45%)	1	0/6 (0.00%)	0
Middle ear effusion † 1	0/134 (0.00%)	0	2/99 (2.02%)	2	0/33 (0.00%)	0	0/29 (0.00%)	0	0/6 (0.00%)	0
Motion sickness † 1	0/134 (0.00%)	0	1/99 (1.01%)	1	0/33 (0.00%)	0	0/29 (0.00%)	0	0/6 (0.00%)	0
Tinnitus † 1	4/134 (2.99%)	4	1/99 (1.01%)	1	3/33 (9.09%)	3	1/29 (3.45%)	1	0/6 (0.00%)	0
Tympanic membrane perforation † 1	2/134 (1.49%)	2	0/99 (0.00%)	0	0/33 (0.00%)	0	0/29 (0.00%)	0	0/6 (0.00%)	0
Vertigo † 1	8/134 (5.97%)	9	4/99 (4.04%)	4	5/33 (15.15%)	6	1/29 (3.45%)	1	0/6 (0.00%)	0
Vertigo positional † 1	2/134 (1.49%)	2	0/99 (0.00%)	0	0/33 (0.00%)	0	0/29 (0.00%)	0	0/6 (0.00%)	0
Vestibular disorder † 1	0/134 (0.00%)	0	1/99 (1.01%)	1	0/33 (0.00%)	0	0/29 (0.00%)	0	0/6 (0.00%)	0
Endocrine disorders
Goitre † 1	0/134 (0.00%)	0	1/99 (1.01%)	1	0/33 (0.00%)	0	0/29 (0.00%)	0	0/6 (0.00%)	0
Hypothyroidism † 1	3/134 (2.24%)	3	1/99 (1.01%)	1	0/33 (0.00%)	0	1/29 (3.45%)	1	0/6 (0.00%)	0
Thyroid calcification † 1	1/134 (0.75%)	1	0/99 (0.00%)	0	0/33 (0.00%)	0	0/29 (0.00%)	0	0/6 (0.00%)	0
Thyroid disorder † 1	0/134 (0.00%)	0	1/99 (1.01%)	1	0/33 (0.00%)	0	0/29 (0.00%)	0	0/6 (0.00%)	0
Thyroid mass † 1	2/134 (1.49%)	2	1/99 (1.01%)	1	1/33 (3.03%)	1	0/29 (0.00%)	0	0/6 (0.00%)	0
Eye disorders
Eyelid ptosis † 1	0/134 (0.00%)	0	1/99 (1.01%)	1	0/33 (0.00%)	0	0/29 (0.00%)	0	0/6 (0.00%)	0
Eyelid thickening † 1	1/134 (0.75%)	1	0/99 (0.00%)	0	0/33 (0.00%)	0	0/29 (0.00%)	0	0/6 (0.00%)	0
Lacrimation increased † 1	2/134 (1.49%)	2	2/99 (2.02%)	2	0/33 (0.00%)	0	0/29 (0.00%)	0	0/6 (0.00%)	0
Macular degeneration † 1	1/134 (0.75%)	1	3/99 (3.03%)	3	1/33 (3.03%)	2	0/29 (0.00%)	0	0/6 (0.00%)	0
Metamorphopsia † 1	1/134 (0.75%)	1	0/99 (0.00%)	0	0/33 (0.00%)	0	0/29 (0.00%)	0	0/6 (0.00%)	0
Night blindness † 1	0/134 (0.00%)	0	0/99 (0.00%)	0	1/33 (3.03%)	1	0/29 (0.00%)	0	0/6 (0.00%)	0
Ocular hyperaemia † 1	1/134 (0.75%)	1	1/99 (1.01%)	1	0/33 (0.00%)	0	0/29 (0.00%)	0	0/6 (0.00%)	0
Ocular hypertension † 1	1/134 (0.75%)	1	0/99 (0.00%)	0	0/33 (0.00%)	0	0/29 (0.00%)	0	0/6 (0.00%)	0
Photophobia † 1	1/134 (0.75%)	1	1/99 (1.01%)	1	0/33 (0.00%)	0	0/29 (0.00%)	0	0/6 (0.00%)	0
Photopsia † 1	2/134 (1.49%)	2	0/99 (0.00%)	0	1/33 (3.03%)	1	0/29 (0.00%)	0	0/6 (0.00%)	0
Posterior capsule opacification † 1	0/134 (0.00%)	0	0/99 (0.00%)	0	1/33 (3.03%)	1	0/29 (0.00%)	0	0/6 (0.00%)	0
Retinal artery occlusion † 1	1/134 (0.75%)	1	0/99 (0.00%)	0	0/33 (0.00%)	0	0/29 (0.00%)	0	0/6 (0.00%)	0
Retinal detachment † 1	0/134 (0.00%)	0	3/99 (3.03%)	4	0/33 (0.00%)	0	0/29 (0.00%)	0	0/6 (0.00%)	0
Retinal haemorrhage † 1	0/134 (0.00%)	0	1/99 (1.01%)	1	1/33 (3.03%)	1	0/29 (0.00%)	0	0/6 (0.00%)	0
Retinal tear † 1	1/134 (0.75%)	1	0/99 (0.00%)	0	0/33 (0.00%)	0	0/29 (0.00%)	0	0/6 (0.00%)	0
Scleral haemorrhage † 1	0/134 (0.00%)	0	1/99 (1.01%)	1	0/33 (0.00%)	0	0/29 (0.00%)	0	0/6 (0.00%)	0
Strabismus † 1	0/134 (0.00%)	0	1/99 (1.01%)	1	0/33 (0.00%)	0	0/29 (0.00%)	0	0/6 (0.00%)	0
Vision blurred † 1	5/134 (3.73%)	6	9/99 (9.09%)	9	0/33 (0.00%)	0	1/29 (3.45%)	1	0/6 (0.00%)	0
Visual acuity reduced † 1	2/134 (1.49%)	2	0/99 (0.00%)	0	0/33 (0.00%)	0	0/29 (0.00%)	0	0/6 (0.00%)	0
Visual impairment † 1	2/134 (1.49%)	2	0/99 (0.00%)	0	1/33 (3.03%)	1	0/29 (0.00%)	0	0/6 (0.00%)	0
Vitreous degeneration † 1	0/134 (0.00%)	0	1/99 (1.01%)	1	0/33 (0.00%)	0	0/29 (0.00%)	0	0/6 (0.00%)	0
Vitreous floaters † 1	2/134 (1.49%)	2	2/99 (2.02%)	2	1/33 (3.03%)	1	0/29 (0.00%)	0	0/6 (0.00%)	0
Vitreous haemorrhage † 1	1/134 (0.75%)	1	1/99 (1.01%)	1	0/33 (0.00%)	0	0/29 (0.00%)	0	0/6 (0.00%)	0
Cataract † 1	7/134 (5.22%)	9	6/99 (6.06%)	7	1/33 (3.03%)	1	0/29 (0.00%)	0	0/6 (0.00%)	0
Cataract nuclear † 1	0/134 (0.00%)	0	1/99 (1.01%)	1	0/33 (0.00%)	0	0/29 (0.00%)	0	0/6 (0.00%)	0
Chorioretinopathy † 1	0/134 (0.00%)	0	1/99 (1.01%)	1	0/33 (0.00%)	0	0/29 (0.00%)	0	0/6 (0.00%)	0
Conjunctival haemorrhage † 1	4/134 (2.99%)	4	1/99 (1.01%)	1	1/33 (3.03%)	1	0/29 (0.00%)	0	0/6 (0.00%)	0
Conjunctival hyperaemia † 1	1/134 (0.75%)	1	1/99 (1.01%)	1	0/33 (0.00%)	0	0/29 (0.00%)	0	0/6 (0.00%)	0
Dacryostenosis acquired † 1	0/134 (0.00%)	0	2/99 (2.02%)	2	0/33 (0.00%)	0	0/29 (0.00%)	0	0/6 (0.00%)	0
Dry eye † 1	5/134 (3.73%)	5	5/99 (5.05%)	5	0/33 (0.00%)	0	0/29 (0.00%)	0	0/6 (0.00%)	0
Episcleritis † 1	0/134 (0.00%)	0	1/99 (1.01%)	1	0/33 (0.00%)	0	0/29 (0.00%)	0	0/6 (0.00%)	0
Eye disorder † 1	1/134 (0.75%)	1	0/99 (0.00%)	0	0/33 (0.00%)	0	0/29 (0.00%)	0	0/6 (0.00%)	0
Eye haemorrhage † 1	0/134 (0.00%)	0	1/99 (1.01%)	1	1/33 (3.03%)	1	0/29 (0.00%)	0	0/6 (0.00%)	0
Eye inflammation † 1	1/134 (0.75%)	1	0/99 (0.00%)	0	1/33 (3.03%)	1	0/29 (0.00%)	0	0/6 (0.00%)	0
Eye irritation † 1	1/134 (0.75%)	1	0/99 (0.00%)	0	0/33 (0.00%)	0	0/29 (0.00%)	0	0/6 (0.00%)	0
Eye movement disorder † 1	1/134 (0.75%)	1	0/99 (0.00%)	0	0/33 (0.00%)	0	0/29 (0.00%)	0	0/6 (0.00%)	0
Eye pain † 1	1/134 (0.75%)	1	2/99 (2.02%)	2	0/33 (0.00%)	0	0/29 (0.00%)	0	0/6 (0.00%)	0
Eye pruritus † 1	0/134 (0.00%)	0	1/99 (1.01%)	1	0/33 (0.00%)	0	0/29 (0.00%)	0	0/6 (0.00%)	0
Eye swelling † 1	0/134 (0.00%)	0	1/99 (1.01%)	1	0/33 (0.00%)	0	0/29 (0.00%)	0	0/6 (0.00%)	0
Eyelid pain † 1	0/134 (0.00%)	0	1/99 (1.01%)	1	0/33 (0.00%)	0	0/29 (0.00%)	0	0/6 (0.00%)	0
Gastrointestinal disorders
Abdominal discomfort † 1	4/134 (2.99%)	4	5/99 (5.05%)	5	1/33 (3.03%)	1	0/29 (0.00%)	0	0/6 (0.00%)	0
Abdominal distension † 1	11/134 (8.21%)	12	8/99 (8.08%)	8	3/33 (9.09%)	3	2/29 (6.90%)	2	1/6 (16.67%)	1
Abdominal hernia † 1	2/134 (1.49%)	2	0/99 (0.00%)	0	0/33 (0.00%)	0	0/29 (0.00%)	0	0/6 (0.00%)	0
Abdominal pain † 1	16/134 (11.94%)	24	10/99 (10.10%)	17	3/33 (9.09%)	4	1/29 (3.45%)	1	1/6 (16.67%)	1
Abdominal pain lower † 1	0/134 (0.00%)	0	3/99 (3.03%)	4	1/33 (3.03%)	1	0/29 (0.00%)	0	0/6 (0.00%)	0
Abdominal pain upper † 1	11/134 (8.21%)	12	6/99 (6.06%)	6	1/33 (3.03%)	1	1/29 (3.45%)	1	0/6 (0.00%)	0
Abdominal tenderness † 1	0/134 (0.00%)	0	1/99 (1.01%)	1	0/33 (0.00%)	0	1/29 (3.45%)	1	0/6 (0.00%)	0
Anal fissure † 1	0/134 (0.00%)	0	1/99 (1.01%)	1	0/33 (0.00%)	0	0/29 (0.00%)	0	0/6 (0.00%)	0
Anal fissure haemorrhage † 1	0/134 (0.00%)	0	0/99 (0.00%)	0	1/33 (3.03%)	1	0/29 (0.00%)	0	0/6 (0.00%)	0
Anal haemorrhage † 1	1/134 (0.75%)	1	0/99 (0.00%)	0	0/33 (0.00%)	0	0/29 (0.00%)	0	0/6 (0.00%)	0
Anal pruritus † 1	0/134 (0.00%)	0	2/99 (2.02%)	2	0/33 (0.00%)	0	0/29 (0.00%)	0	0/6 (0.00%)	0
Anorectal discomfort † 1	1/134 (0.75%)	1	0/99 (0.00%)	0	0/33 (0.00%)	0	0/29 (0.00%)	0	0/6 (0.00%)	0
Aphthous ulcer † 1	3/134 (2.24%)	4	3/99 (3.03%)	3	0/33 (0.00%)	0	0/29 (0.00%)	0	0/6 (0.00%)	0
Barrett's oesophagus † 1	0/134 (0.00%)	0	1/99 (1.01%)	1	0/33 (0.00%)	0	0/29 (0.00%)	0	0/6 (0.00%)	0
Breath odour † 1	0/134 (0.00%)	0	0/99 (0.00%)	0	1/33 (3.03%)	1	0/29 (0.00%)	0	0/6 (0.00%)	0
Cheilitis † 1	0/134 (0.00%)	0	1/99 (1.01%)	1	0/33 (0.00%)	0	0/29 (0.00%)	0	0/6 (0.00%)	0
Coeliac disease † 1	0/134 (0.00%)	0	0/99 (0.00%)	0	1/33 (3.03%)	1	0/29 (0.00%)	0	0/6 (0.00%)	0
Colitis † 1	0/134 (0.00%)	0	1/99 (1.01%)	1	0/33 (0.00%)	0	0/29 (0.00%)	0	0/6 (0.00%)	0
Colitis ischaemic † 1	0/134 (0.00%)	0	1/99 (1.01%)	1	0/33 (0.00%)	0	0/29 (0.00%)	0	0/6 (0.00%)	0
Constipation † 1	35/134 (26.12%)	41	20/99 (20.20%)	22	7/33 (21.21%)	9	2/29 (6.90%)	2	1/6 (16.67%)	1
Dental caries † 1	11/134 (8.21%)	13	5/99 (5.05%)	6	2/33 (6.06%)	2	0/29 (0.00%)	0	0/6 (0.00%)	0
Diarrhoea † 1	71/134 (52.99%)	131	53/99 (53.54%)	93	20/33 (60.61%)	31	14/29 (48.28%)	19	0/6 (0.00%)	0
Diverticulum † 1	0/134 (0.00%)	0	2/99 (2.02%)	2	0/33 (0.00%)	0	0/29 (0.00%)	0	0/6 (0.00%)	0
Diverticulum intestinal † 1	1/134 (0.75%)	1	0/99 (0.00%)	0	0/33 (0.00%)	0	0/29 (0.00%)	0	0/6 (0.00%)	0
Dry mouth † 1	4/134 (2.99%)	4	6/99 (6.06%)	6	1/33 (3.03%)	1	0/29 (0.00%)	0	0/6 (0.00%)	0
Dumping syndrome † 1	0/134 (0.00%)	0	0/99 (0.00%)	0	1/33 (3.03%)	1	0/29 (0.00%)	0	0/6 (0.00%)	0
Duodenitis † 1	0/134 (0.00%)	0	1/99 (1.01%)	1	0/33 (0.00%)	0	0/29 (0.00%)	0	0/6 (0.00%)	0
Dyspepsia † 1	14/134 (10.45%)	14	10/99 (10.10%)	11	6/33 (18.18%)	6	1/29 (3.45%)	1	0/6 (0.00%)	0
Dysphagia † 1	9/134 (6.72%)	9	0/99 (0.00%)	0	1/33 (3.03%)	1	1/29 (3.45%)	1	0/6 (0.00%)	0
Enterocolitis † 1	1/134 (0.75%)	1	0/99 (0.00%)	0	0/33 (0.00%)	0	0/29 (0.00%)	0	0/6 (0.00%)	0
Eosinophilic oesophagitis † 1	0/134 (0.00%)	0	1/99 (1.01%)	1	0/33 (0.00%)	0	0/29 (0.00%)	0	0/6 (0.00%)	0
Flatulence † 1	7/134 (5.22%)	7	1/99 (1.01%)	1	0/33 (0.00%)	0	0/29 (0.00%)	0	0/6 (0.00%)	0
Food poisoning † 1	0/134 (0.00%)	0	3/99 (3.03%)	3	0/33 (0.00%)	0	0/29 (0.00%)	0	0/6 (0.00%)	0
Gastric haemorrhage † 1	0/134 (0.00%)	0	0/99 (0.00%)	0	1/33 (3.03%)	1	0/29 (0.00%)	0	0/6 (0.00%)	0
Gastric polyps † 1	0/134 (0.00%)	0	1/99 (1.01%)	1	0/33 (0.00%)	0	0/29 (0.00%)	0	0/6 (0.00%)	0
Gastritis † 1	2/134 (1.49%)	2	4/99 (4.04%)	4	0/33 (0.00%)	0	0/29 (0.00%)	0	0/6 (0.00%)	0
Gastrointestinal disorder † 1	1/134 (0.75%)	1	0/99 (0.00%)	0	0/33 (0.00%)	0	0/29 (0.00%)	0	0/6 (0.00%)	0
Gastrointestinal haemorrhage † 1	1/134 (0.75%)	1	0/99 (0.00%)	0	0/33 (0.00%)	0	0/29 (0.00%)	0	0/6 (0.00%)	0
Gastrointestinal pain † 1	3/134 (2.24%)	3	0/99 (0.00%)	0	1/33 (3.03%)	1	0/29 (0.00%)	0	0/6 (0.00%)	0
Gastrointestinal ulcer † 1	0/134 (0.00%)	0	1/99 (1.01%)	1	0/33 (0.00%)	0	0/29 (0.00%)	0	0/6 (0.00%)	0
Gastrooesophageal reflux disease † 1	12/134 (8.96%)	12	17/99 (17.17%)	20	2/33 (6.06%)	2	1/29 (3.45%)	1	0/6 (0.00%)	0
Gingival bleeding † 1	1/134 (0.75%)	1	1/99 (1.01%)	1	1/33 (3.03%)	1	0/29 (0.00%)	0	0/6 (0.00%)	0
Gingival blister † 1	1/134 (0.75%)	1	0/99 (0.00%)	0	0/33 (0.00%)	0	0/29 (0.00%)	0	0/6 (0.00%)	0
Gingival discolouration † 1	1/134 (0.75%)	1	0/99 (0.00%)	0	0/33 (0.00%)	0	0/29 (0.00%)	0	0/6 (0.00%)	0
Gingival disorder † 1	0/134 (0.00%)	0	1/99 (1.01%)	1	0/33 (0.00%)	0	0/29 (0.00%)	0	0/6 (0.00%)	0
Gingival pain † 1	0/134 (0.00%)	0	0/99 (0.00%)	0	1/33 (3.03%)	1	0/29 (0.00%)	0	0/6 (0.00%)	0
Haematemesis † 1	0/134 (0.00%)	0	1/99 (1.01%)	1	0/33 (0.00%)	0	0/29 (0.00%)	0	0/6 (0.00%)	0
Haematochezia † 1	1/134 (0.75%)	1	3/99 (3.03%)	3	0/33 (0.00%)	0	0/29 (0.00%)	0	0/6 (0.00%)	0
Haemorrhoids † 1	2/134 (1.49%)	2	4/99 (4.04%)	4	0/33 (0.00%)	0	0/29 (0.00%)	0	0/6 (0.00%)	0
Hiatus hernia † 1	2/134 (1.49%)	2	3/99 (3.03%)	3	0/33 (0.00%)	0	0/29 (0.00%)	0	0/6 (0.00%)	0
Hyperaesthesia teeth † 1	0/134 (0.00%)	0	0/99 (0.00%)	0	1/33 (3.03%)	1	0/29 (0.00%)	0	0/6 (0.00%)	0
Hypoaesthesia oral † 1	0/134 (0.00%)	0	0/99 (0.00%)	0	1/33 (3.03%)	1	0/29 (0.00%)	0	0/6 (0.00%)	0
Ileus † 1	1/134 (0.75%)	1	0/99 (0.00%)	0	0/33 (0.00%)	0	0/29 (0.00%)	0	0/6 (0.00%)	0
Impaired gastric emptying † 1	1/134 (0.75%)	1	0/99 (0.00%)	0	0/33 (0.00%)	0	0/29 (0.00%)	0	0/6 (0.00%)	0
Inguinal hernia † 1	1/134 (0.75%)	1	3/99 (3.03%)	3	0/33 (0.00%)	0	1/29 (3.45%)	1	0/6 (0.00%)	0
Irritable bowel syndrome † 1	1/134 (0.75%)	1	1/99 (1.01%)	1	0/33 (0.00%)	0	0/29 (0.00%)	0	0/6 (0.00%)	0
Large intestinal ulcer † 1	0/134 (0.00%)	0	1/99 (1.01%)	1	0/33 (0.00%)	0	0/29 (0.00%)	0	0/6 (0.00%)	0
Large intestine polyp † 1	3/134 (2.24%)	3	5/99 (5.05%)	5	0/33 (0.00%)	0	0/29 (0.00%)	0	0/6 (0.00%)	0
Lip blister † 1	0/134 (0.00%)	0	1/99 (1.01%)	1	0/33 (0.00%)	0	0/29 (0.00%)	0	0/6 (0.00%)	0
Lip dry † 1	0/134 (0.00%)	0	0/99 (0.00%)	0	0/33 (0.00%)	0	0/29 (0.00%)	0	1/6 (16.67%)	1
Lip erythema † 1	1/134 (0.75%)	1	0/99 (0.00%)	0	0/33 (0.00%)	0	0/29 (0.00%)	0	0/6 (0.00%)	0
Lip pain † 1	0/134 (0.00%)	0	1/99 (1.01%)	1	0/33 (0.00%)	0	0/29 (0.00%)	0	0/6 (0.00%)	0
Lip swelling † 1	0/134 (0.00%)	0	1/99 (1.01%)	1	0/33 (0.00%)	0	0/29 (0.00%)	0	0/6 (0.00%)	0
Lip ulceration † 1	0/134 (0.00%)	0	1/99 (1.01%)	1	0/33 (0.00%)	0	0/29 (0.00%)	0	0/6 (0.00%)	0
Melaena † 1	1/134 (0.75%)	1	1/99 (1.01%)	1	0/33 (0.00%)	0	0/29 (0.00%)	0	0/6 (0.00%)	0
Mouth haemorrhage † 1	3/134 (2.24%)	3	1/99 (1.01%)	1	1/33 (3.03%)	1	1/29 (3.45%)	1	0/6 (0.00%)	0
Mouth ulceration † 1	2/134 (1.49%)	3	1/99 (1.01%)	2	0/33 (0.00%)	0	1/29 (3.45%)	1	0/6 (0.00%)	0
Nausea † 1	47/134 (35.07%)	67	34/99 (34.34%)	53	11/33 (33.33%)	16	4/29 (13.79%)	4	2/6 (33.33%)	2
Odynophagia † 1	1/134 (0.75%)	1	0/99 (0.00%)	0	0/33 (0.00%)	0	0/29 (0.00%)	0	0/6 (0.00%)	0
Oesophageal obstruction † 1	0/134 (0.00%)	0	2/99 (2.02%)	2	0/33 (0.00%)	0	0/29 (0.00%)	0	0/6 (0.00%)	0
Oesophageal pain † 1	0/134 (0.00%)	0	1/99 (1.01%)	1	0/33 (0.00%)	0	0/29 (0.00%)	0	0/6 (0.00%)	0
Oesophageal spasm † 1	0/134 (0.00%)	0	1/99 (1.01%)	2	0/33 (0.00%)	0	0/29 (0.00%)	0	0/6 (0.00%)	0
Oesophagitis † 1	1/134 (0.75%)	1	1/99 (1.01%)	1	0/33 (0.00%)	0	0/29 (0.00%)	0	0/6 (0.00%)	0
Oesophagitis ulcerative † 1	1/134 (0.75%)	1	0/99 (0.00%)	0	0/33 (0.00%)	0	0/29 (0.00%)	0	0/6 (0.00%)	0
Oral blood blister † 1	5/134 (3.73%)	5	1/99 (1.01%)	1	1/33 (3.03%)	2	0/29 (0.00%)	0	0/6 (0.00%)	0
Oral disorder † 1	3/134 (2.24%)	3	2/99 (2.02%)	2	0/33 (0.00%)	0	0/29 (0.00%)	0	0/6 (0.00%)	0
Oral mucosa haematoma † 1	1/134 (0.75%)	1	0/99 (0.00%)	0	0/33 (0.00%)	0	0/29 (0.00%)	0	0/6 (0.00%)	0
Oral mucosal blistering † 1	0/134 (0.00%)	0	1/99 (1.01%)	1	0/33 (0.00%)	0	0/29 (0.00%)	0	0/6 (0.00%)	0
Oral pain † 1	5/134 (3.73%)	5	4/99 (4.04%)	4	1/33 (3.03%)	1	0/29 (0.00%)	0	0/6 (0.00%)	0
Peritoneal haematoma † 1	0/134 (0.00%)	0	1/99 (1.01%)	1	0/33 (0.00%)	0	0/29 (0.00%)	0	0/6 (0.00%)	0
Pharyngo-oesophageal diverticulum † 1	1/134 (0.75%)	1	0/99 (0.00%)	0	0/33 (0.00%)	0	0/29 (0.00%)	0	0/6 (0.00%)	0
Proctalgia † 1	2/134 (1.49%)	4	2/99 (2.02%)	2	0/33 (0.00%)	0	0/29 (0.00%)	0	0/6 (0.00%)	0
Pseudopolyposis † 1	1/134 (0.75%)	1	0/99 (0.00%)	0	0/33 (0.00%)	0	0/29 (0.00%)	0	0/6 (0.00%)	0
Rectal discharge † 1	1/134 (0.75%)	1	0/99 (0.00%)	0	0/33 (0.00%)	0	0/29 (0.00%)	0	0/6 (0.00%)	0
Rectal haemorrhage † 1	3/134 (2.24%)	4	6/99 (6.06%)	6	1/33 (3.03%)	1	1/29 (3.45%)	1	0/6 (0.00%)	0
Rectal polyp † 1	1/134 (0.75%)	1	0/99 (0.00%)	0	0/33 (0.00%)	0	0/29 (0.00%)	0	0/6 (0.00%)	0
Rectal prolapse † 1	1/134 (0.75%)	1	1/99 (1.01%)	1	0/33 (0.00%)	0	0/29 (0.00%)	0	0/6 (0.00%)	0
Retching † 1	1/134 (0.75%)	1	1/99 (1.01%)	1	0/33 (0.00%)	0	0/29 (0.00%)	0	0/6 (0.00%)	0
Salivary gland enlargement † 1	0/134 (0.00%)	0	1/99 (1.01%)	1	0/33 (0.00%)	0	0/29 (0.00%)	0	0/6 (0.00%)	0
Spigelian hernia † 1	0/134 (0.00%)	0	1/99 (1.01%)	1	0/33 (0.00%)	0	0/29 (0.00%)	0	0/6 (0.00%)	0
Stomatitis † 1	13/134 (9.70%)	16	14/99 (14.14%)	23	5/33 (15.15%)	6	1/29 (3.45%)	1	0/6 (0.00%)	0
Swollen tongue † 1	1/134 (0.75%)	1	0/99 (0.00%)	0	0/33 (0.00%)	0	0/29 (0.00%)	0	0/6 (0.00%)	0
Tongue geographic † 1	0/134 (0.00%)	0	1/99 (1.01%)	1	1/33 (3.03%)	1	0/29 (0.00%)	0	0/6 (0.00%)	0
Tongue haematoma † 1	1/134 (0.75%)	1	0/99 (0.00%)	0	0/33 (0.00%)	0	0/29 (0.00%)	0	0/6 (0.00%)	0
Tongue ulceration † 1	1/134 (0.75%)	1	0/99 (0.00%)	0	0/33 (0.00%)	0	0/29 (0.00%)	0	0/6 (0.00%)	0
Toothache † 1	6/134 (4.48%)	8	7/99 (7.07%)	8	1/33 (3.03%)	1	0/29 (0.00%)	0	0/6 (0.00%)	0
Umbilical hernia † 1	3/134 (2.24%)	3	4/99 (4.04%)	4	0/33 (0.00%)	0	0/29 (0.00%)	0	0/6 (0.00%)	0
Upper gastrointestinal haemorrhage † 1	0/134 (0.00%)	0	1/99 (1.01%)	1	0/33 (0.00%)	0	0/29 (0.00%)	0	0/6 (0.00%)	0
Vomiting † 1	33/134 (24.63%)	44	24/99 (24.24%)	30	9/33 (27.27%)	12	3/29 (10.34%)	3	1/6 (16.67%)	1
General disorders
Asthenia † 1	6/134 (4.48%)	7	1/99 (1.01%)	1	1/33 (3.03%)	1	2/29 (6.90%)	2	0/6 (0.00%)	0
Axillary pain † 1	2/134 (1.49%)	2	0/99 (0.00%)	0	1/33 (3.03%)	1	0/29 (0.00%)	0	0/6 (0.00%)	0
Catheter site haemorrhage † 1	0/134 (0.00%)	0	1/99 (1.01%)	1	0/33 (0.00%)	0	0/29 (0.00%)	0	0/6 (0.00%)	0
Chest discomfort † 1	4/134 (2.99%)	5	3/99 (3.03%)	4	0/33 (0.00%)	0	0/29 (0.00%)	0	1/6 (16.67%)	1
Chest pain † 1	3/134 (2.24%)	4	2/99 (2.02%)	2	0/33 (0.00%)	0	0/29 (0.00%)	0	1/6 (16.67%)	1
Chills † 1	16/134 (11.94%)	18	13/99 (13.13%)	14	3/33 (9.09%)	3	2/29 (6.90%)	3	1/6 (16.67%)	1
Complication associated with device † 1	0/134 (0.00%)	0	0/99 (0.00%)	0	1/33 (3.03%)	1	0/29 (0.00%)	0	0/6 (0.00%)	0
Crepitations † 1	0/134 (0.00%)	0	1/99 (1.01%)	1	0/33 (0.00%)	0	0/29 (0.00%)	0	0/6 (0.00%)	0
Cyst † 1	2/134 (1.49%)	2	3/99 (3.03%)	3	0/33 (0.00%)	0	0/29 (0.00%)	0	0/6 (0.00%)	0
Early satiety † 1	2/134 (1.49%)	3	1/99 (1.01%)	1	0/33 (0.00%)	0	0/29 (0.00%)	0	0/6 (0.00%)	0
Face oedema † 1	1/134 (0.75%)	1	1/99 (1.01%)	1	0/33 (0.00%)	0	0/29 (0.00%)	0	0/6 (0.00%)	0
Facial pain † 1	1/134 (0.75%)	1	4/99 (4.04%)	4	3/33 (9.09%)	3	0/29 (0.00%)	0	0/6 (0.00%)	0
Fat necrosis † 1	0/134 (0.00%)	0	1/99 (1.01%)	1	0/33 (0.00%)	0	0/29 (0.00%)	0	0/6 (0.00%)	0
Fatigue † 1	49/134 (36.57%)	58	22/99 (22.22%)	31	7/33 (21.21%)	10	6/29 (20.69%)	8	1/6 (16.67%)	1
Feeling cold † 1	1/134 (0.75%)	1	0/99 (0.00%)	0	0/33 (0.00%)	0	0/29 (0.00%)	0	0/6 (0.00%)	0
Feeling hot † 1	1/134 (0.75%)	1	0/99 (0.00%)	0	0/33 (0.00%)	0	0/29 (0.00%)	0	0/6 (0.00%)	0
Gait disturbance † 1	3/134 (2.24%)	3	3/99 (3.03%)	3	1/33 (3.03%)	1	0/29 (0.00%)	0	0/6 (0.00%)	0
General physical health deterioration † 1	1/134 (0.75%)	1	0/99 (0.00%)	0	0/33 (0.00%)	0	0/29 (0.00%)	0	0/6 (0.00%)	0
Granuloma † 1	1/134 (0.75%)	1	0/99 (0.00%)	0	0/33 (0.00%)	0	0/29 (0.00%)	0	0/6 (0.00%)	0
Hernia † 1	1/134 (0.75%)	1	0/99 (0.00%)	0	0/33 (0.00%)	0	0/29 (0.00%)	0	0/6 (0.00%)	0
Hyperpyrexia † 1	0/134 (0.00%)	0	0/99 (0.00%)	0	0/33 (0.00%)	0	1/29 (3.45%)	1	0/6 (0.00%)	0
Hypothermia † 1	0/134 (0.00%)	0	1/99 (1.01%)	1	0/33 (0.00%)	0	0/29 (0.00%)	0	0/6 (0.00%)	0
Influenza like illness † 1	12/134 (8.96%)	14	13/99 (13.13%)	14	2/33 (6.06%)	3	1/29 (3.45%)	1	0/6 (0.00%)	0
Infusion site rash † 1	1/134 (0.75%)	1	0/99 (0.00%)	0	0/33 (0.00%)	0	0/29 (0.00%)	0	0/6 (0.00%)	0
Injection site bruising † 1	1/134 (0.75%)	1	1/99 (1.01%)	1	0/33 (0.00%)	0	2/29 (6.90%)	2	0/6 (0.00%)	0
Injection site phlebitis † 1	0/134 (0.00%)	0	1/99 (1.01%)	1	0/33 (0.00%)	0	0/29 (0.00%)	0	0/6 (0.00%)	0
Injection site reaction † 1	0/134 (0.00%)	0	1/99 (1.01%)	1	0/33 (0.00%)	0	0/29 (0.00%)	0	0/6 (0.00%)	0
Injection site swelling † 1	0/134 (0.00%)	0	1/99 (1.01%)	1	0/33 (0.00%)	0	0/29 (0.00%)	0	0/6 (0.00%)	0
Localised oedema † 1	0/134 (0.00%)	0	1/99 (1.01%)	1	1/33 (3.03%)	1	0/29 (0.00%)	0	0/6 (0.00%)	0
Malaise † 1	6/134 (4.48%)	7	4/99 (4.04%)	5	2/33 (6.06%)	2	0/29 (0.00%)	0	0/6 (0.00%)	0
Mass † 1	0/134 (0.00%)	0	1/99 (1.01%)	1	0/33 (0.00%)	0	0/29 (0.00%)	0	0/6 (0.00%)	0
Medical device site bruise † 1	1/134 (0.75%)	1	0/99 (0.00%)	0	0/33 (0.00%)	0	0/29 (0.00%)	0	0/6 (0.00%)	0
Mucosal inflammation † 1	0/134 (0.00%)	0	0/99 (0.00%)	0	0/33 (0.00%)	0	1/29 (3.45%)	1	0/6 (0.00%)	0
Nodule † 1	0/134 (0.00%)	0	0/99 (0.00%)	0	1/33 (3.03%)	1	0/29 (0.00%)	0	0/6 (0.00%)	0
Non-cardiac chest pain † 1	8/134 (5.97%)	11	12/99 (12.12%)	16	8/33 (24.24%)	8	3/29 (10.34%)	3	0/6 (0.00%)	0
Oedema † 1	2/134 (1.49%)	2	2/99 (2.02%)	2	0/33 (0.00%)	0	0/29 (0.00%)	0	0/6 (0.00%)	0
Oedema peripheral † 1	28/134 (20.90%)	36	18/99 (18.18%)	25	7/33 (21.21%)	7	2/29 (6.90%)	2	0/6 (0.00%)	0
Pain † 1	3/134 (2.24%)	3	1/99 (1.01%)	1	0/33 (0.00%)	0	0/29 (0.00%)	0	0/6 (0.00%)	0
Peripheral swelling † 1	4/134 (2.99%)	4	2/99 (2.02%)	3	0/33 (0.00%)	0	0/29 (0.00%)	0	0/6 (0.00%)	0
Physical deconditioning † 1	0/134 (0.00%)	0	1/99 (1.01%)	1	0/33 (0.00%)	0	1/29 (3.45%)	1	0/6 (0.00%)	0
Polyp † 1	1/134 (0.75%)	1	1/99 (1.01%)	1	0/33 (0.00%)	0	0/29 (0.00%)	0	0/6 (0.00%)	0
Pyrexia † 1	39/134 (29.10%)	69	13/99 (13.13%)	19	10/33 (30.30%)	17	6/29 (20.69%)	12	0/6 (0.00%)	0
Suprapubic pain † 1	1/134 (0.75%)	1	0/99 (0.00%)	0	0/33 (0.00%)	0	0/29 (0.00%)	0	0/6 (0.00%)	0
Swelling † 1	0/134 (0.00%)	0	1/99 (1.01%)	1	1/33 (3.03%)	1	0/29 (0.00%)	0	0/6 (0.00%)	0
Swelling face † 1	3/134 (2.24%)	3	1/99 (1.01%)	1	0/33 (0.00%)	0	0/29 (0.00%)	0	0/6 (0.00%)	0
Systemic inflammatory response syndrome † 1	1/134 (0.75%)	1	0/99 (0.00%)	0	0/33 (0.00%)	0	0/29 (0.00%)	0	0/6 (0.00%)	0
Vaccination site mass † 1	1/134 (0.75%)	1	0/99 (0.00%)	0	0/33 (0.00%)	0	0/29 (0.00%)	0	0/6 (0.00%)	0
Vaccination site pain † 1	0/134 (0.00%)	0	2/99 (2.02%)	2	0/33 (0.00%)	0	0/29 (0.00%)	0	0/6 (0.00%)	0
Hepatobiliary disorders
Cholecystitis † 1	1/134 (0.75%)	3	0/99 (0.00%)	0	0/33 (0.00%)	0	0/29 (0.00%)	0	0/6 (0.00%)	0
Cholelithiasis † 1	2/134 (1.49%)	3	0/99 (0.00%)	0	0/33 (0.00%)	0	0/29 (0.00%)	0	0/6 (0.00%)	0
Hepatic mass † 1	0/134 (0.00%)	0	0/99 (0.00%)	0	1/33 (3.03%)	1	0/29 (0.00%)	0	0/6 (0.00%)	0
Hepatic steatosis † 1	0/134 (0.00%)	0	1/99 (1.01%)	1	0/33 (0.00%)	0	0/29 (0.00%)	0	0/6 (0.00%)	0
Immune system disorders
Allergy to arthropod bite † 1	7/134 (5.22%)	7	4/99 (4.04%)	4	0/33 (0.00%)	0	0/29 (0.00%)	0	0/6 (0.00%)	0
Allergy to arthropod sting † 1	0/134 (0.00%)	0	0/99 (0.00%)	0	0/33 (0.00%)	0	1/29 (3.45%)	1	0/6 (0.00%)	0
Contrast media allergy † 1	1/134 (0.75%)	1	2/99 (2.02%)	2	1/33 (3.03%)	1	0/29 (0.00%)	0	0/6 (0.00%)	0
Drug hypersensitivity † 1	3/134 (2.24%)	3	4/99 (4.04%)	4	0/33 (0.00%)	0	0/29 (0.00%)	0	0/6 (0.00%)	0
Food allergy † 1	0/134 (0.00%)	0	1/99 (1.01%)	1	1/33 (3.03%)	1	0/29 (0.00%)	0	0/6 (0.00%)	0
Graft versus host disease in gastrointestinal tract † 1	0/134 (0.00%)	0	0/99 (0.00%)	0	0/33 (0.00%)	0	1/29 (3.45%)	1	0/6 (0.00%)	0
Graft versus host disease in skin † 1	0/134 (0.00%)	0	0/99 (0.00%)	0	0/33 (0.00%)	0	1/29 (3.45%)	2	0/6 (0.00%)	0
Hypersensitivity † 1	1/134 (0.75%)	1	2/99 (2.02%)	2	0/33 (0.00%)	0	0/29 (0.00%)	0	0/6 (0.00%)	0
Hypogammaglobulinaemia † 1	3/134 (2.24%)	3	1/99 (1.01%)	1	0/33 (0.00%)	0	1/29 (3.45%)	1	0/6 (0.00%)	0
Immunodeficiency † 1	0/134 (0.00%)	0	2/99 (2.02%)	2	0/33 (0.00%)	0	0/29 (0.00%)	0	0/6 (0.00%)	0
Seasonal allergy † 1	2/134 (1.49%)	2	2/99 (2.02%)	2	1/33 (3.03%)	1	0/29 (0.00%)	0	0/6 (0.00%)	0
Infections and infestations
Abscess † 1	1/134 (0.75%)	1	0/99 (0.00%)	0	0/33 (0.00%)	0	0/29 (0.00%)	0	0/6 (0.00%)	0
Acute sinusitis † 1	1/134 (0.75%)	1	0/99 (0.00%)	0	0/33 (0.00%)	0	0/29 (0.00%)	0	0/6 (0.00%)	0
Appendicitis † 1	0/134 (0.00%)	0	1/99 (1.01%)	1	0/33 (0.00%)	0	0/29 (0.00%)	0	0/6 (0.00%)	0
Aspergillus infection † 1	0/134 (0.00%)	0	0/99 (0.00%)	0	1/33 (3.03%)	1	0/29 (0.00%)	0	0/6 (0.00%)	0
Bacteraemia † 1	1/134 (0.75%)	1	0/99 (0.00%)	0	1/33 (3.03%)	1	0/29 (0.00%)	0	0/6 (0.00%)	0
Bacteriuria † 1	0/134 (0.00%)	0	1/99 (1.01%)	1	0/33 (0.00%)	0	0/29 (0.00%)	0	0/6 (0.00%)	0
Body tinea † 1	1/134 (0.75%)	1	1/99 (1.01%)	1	0/33 (0.00%)	0	0/29 (0.00%)	0	0/6 (0.00%)	0
Breast abscess † 1	1/134 (0.75%)	1	0/99 (0.00%)	0	0/33 (0.00%)	0	0/29 (0.00%)	0	0/6 (0.00%)	0
Bronchitis † 1	14/134 (10.45%)	18	14/99 (14.14%)	16	6/33 (18.18%)	9	2/29 (6.90%)	3	0/6 (0.00%)	0
Bronchopulmonary aspergillosis † 1	0/134 (0.00%)	0	0/99 (0.00%)	0	0/33 (0.00%)	0	1/29 (3.45%)	2	0/6 (0.00%)	0
Burkholderia cepacia complex infection † 1	0/134 (0.00%)	0	1/99 (1.01%)	1	0/33 (0.00%)	0	0/29 (0.00%)	0	0/6 (0.00%)	0
Covid-19 † 1	4/134 (2.99%)	5	1/99 (1.01%)	1	0/33 (0.00%)	0	0/29 (0.00%)	0	0/6 (0.00%)	0
Campylobacter gastroenteritis † 1	0/134 (0.00%)	0	1/99 (1.01%)	1	0/33 (0.00%)	0	0/29 (0.00%)	0	0/6 (0.00%)	0
Campylobacter infection † 1	0/134 (0.00%)	0	0/99 (0.00%)	0	0/33 (0.00%)	0	1/29 (3.45%)	1	0/6 (0.00%)	0
Candida infection † 1	1/134 (0.75%)	1	0/99 (0.00%)	0	0/33 (0.00%)	0	0/29 (0.00%)	0	0/6 (0.00%)	0
Cellulitis † 1	12/134 (8.96%)	13	1/99 (1.01%)	1	3/33 (9.09%)	7	0/29 (0.00%)	0	0/6 (0.00%)	0
Chronic sinusitis † 1	1/134 (0.75%)	1	1/99 (1.01%)	1	0/33 (0.00%)	0	0/29 (0.00%)	0	0/6 (0.00%)	0
Clostridium difficile colitis † 1	0/134 (0.00%)	0	0/99 (0.00%)	0	1/33 (3.03%)	2	3/29 (10.34%)	3	0/6 (0.00%)	0
Clostridium difficile infection † 1	1/134 (0.75%)	1	0/99 (0.00%)	0	0/33 (0.00%)	0	0/29 (0.00%)	0	0/6 (0.00%)	0
Coccidioidomycosis † 1	1/134 (0.75%)	1	1/99 (1.01%)	1	0/33 (0.00%)	0	0/29 (0.00%)	0	0/6 (0.00%)	0
Conjunctivitis † 1	7/134 (5.22%)	7	5/99 (5.05%)	5	0/33 (0.00%)	0	1/29 (3.45%)	1	0/6 (0.00%)	0
Cystitis † 1	1/134 (0.75%)	1	0/99 (0.00%)	0	0/33 (0.00%)	0	0/29 (0.00%)	0	0/6 (0.00%)	0
Diverticulitis † 1	1/134 (0.75%)	1	3/99 (3.03%)	4	0/33 (0.00%)	0	0/29 (0.00%)	0	0/6 (0.00%)	0
Ear infection † 1	7/134 (5.22%)	8	3/99 (3.03%)	3	0/33 (0.00%)	0	0/29 (0.00%)	0	0/6 (0.00%)	0
Encephalitis † 1	0/134 (0.00%)	0	0/99 (0.00%)	0	1/33 (3.03%)	1	0/29 (0.00%)	0	0/6 (0.00%)	0
Enterocolitis infectious † 1	0/134 (0.00%)	0	1/99 (1.01%)	1	0/33 (0.00%)	0	0/29 (0.00%)	0	0/6 (0.00%)	0
Epididymitis † 1	0/134 (0.00%)	0	2/99 (2.02%)	2	1/33 (3.03%)	2	0/29 (0.00%)	0	0/6 (0.00%)	0
Epstein-barr virus infection reactivation † 1	1/134 (0.75%)	1	0/99 (0.00%)	0	0/33 (0.00%)	0	0/29 (0.00%)	0	0/6 (0.00%)	0
Escherichia bacteraemia † 1	1/134 (0.75%)	1	0/99 (0.00%)	0	0/33 (0.00%)	0	0/29 (0.00%)	0	0/6 (0.00%)	0
External ear cellulitis † 1	0/134 (0.00%)	0	0/99 (0.00%)	0	1/33 (3.03%)	1	0/29 (0.00%)	0	0/6 (0.00%)	0
Eye infection † 1	4/134 (2.99%)	5	1/99 (1.01%)	2	0/33 (0.00%)	0	0/29 (0.00%)	0	0/6 (0.00%)	0
Folliculitis † 1	2/134 (1.49%)	2	0/99 (0.00%)	0	0/33 (0.00%)	0	0/29 (0.00%)	0	0/6 (0.00%)	0
Fungal infection † 1	1/134 (0.75%)	2	1/99 (1.01%)	1	0/33 (0.00%)	0	0/29 (0.00%)	0	0/6 (0.00%)	0
Fungal skin infection † 1	2/134 (1.49%)	2	2/99 (2.02%)	2	0/33 (0.00%)	0	0/29 (0.00%)	0	0/6 (0.00%)	0
Furuncle † 1	1/134 (0.75%)	1	1/99 (1.01%)	1	0/33 (0.00%)	0	0/29 (0.00%)	0	0/6 (0.00%)	0
Gastroenteritis † 1	1/134 (0.75%)	1	2/99 (2.02%)	2	2/33 (6.06%)	2	0/29 (0.00%)	0	0/6 (0.00%)	0
Gastroenteritis viral † 1	5/134 (3.73%)	5	1/99 (1.01%)	1	0/33 (0.00%)	0	0/29 (0.00%)	0	0/6 (0.00%)	0
Gastrointestinal bacterial infection † 1	0/134 (0.00%)	0	0/99 (0.00%)	0	1/33 (3.03%)	1	0/29 (0.00%)	0	0/6 (0.00%)	0
Gastrointestinal viral infection † 1	0/134 (0.00%)	0	1/99 (1.01%)	1	0/33 (0.00%)	0	0/29 (0.00%)	0	0/6 (0.00%)	0
Genital infection fungal † 1	0/134 (0.00%)	0	1/99 (1.01%)	2	0/33 (0.00%)	0	0/29 (0.00%)	0	0/6 (0.00%)	0
Gingivitis † 1	2/134 (1.49%)	2	1/99 (1.01%)	1	0/33 (0.00%)	0	0/29 (0.00%)	0	0/6 (0.00%)	0
Groin abscess † 1	1/134 (0.75%)	1	0/99 (0.00%)	0	1/33 (3.03%)	1	0/29 (0.00%)	0	0/6 (0.00%)	0
Haemophilus infection † 1	0/134 (0.00%)	0	1/99 (1.01%)	1	1/33 (3.03%)	1	0/29 (0.00%)	0	0/6 (0.00%)	0
Hand-foot-and-mouth disease † 1	1/134 (0.75%)	1	0/99 (0.00%)	0	0/33 (0.00%)	0	0/29 (0.00%)	0	0/6 (0.00%)	0
Helicobacter infection † 1	1/134 (0.75%)	1	0/99 (0.00%)	0	0/33 (0.00%)	0	0/29 (0.00%)	0	0/6 (0.00%)	0
Hepatic infection † 1	0/134 (0.00%)	0	0/99 (0.00%)	0	1/33 (3.03%)	1	0/29 (0.00%)	0	0/6 (0.00%)	0
Herpes zoster † 1	6/134 (4.48%)	7	1/99 (1.01%)	1	2/33 (6.06%)	2	1/29 (3.45%)	1	1/6 (16.67%)	1
Infected bite † 1	1/134 (0.75%)	2	0/99 (0.00%)	0	0/33 (0.00%)	0	0/29 (0.00%)	0	0/6 (0.00%)	0
Infected dermal cyst † 1	1/134 (0.75%)	1	0/99 (0.00%)	0	0/33 (0.00%)	0	0/29 (0.00%)	0	0/6 (0.00%)	0
Influenza † 1	12/134 (8.96%)	13	6/99 (6.06%)	6	1/33 (3.03%)	1	1/29 (3.45%)	1	0/6 (0.00%)	0
Intervertebral discitis † 1	1/134 (0.75%)	1	0/99 (0.00%)	0	0/33 (0.00%)	0	0/29 (0.00%)	0	0/6 (0.00%)	0
Laryngitis † 1	1/134 (0.75%)	1	1/99 (1.01%)	2	1/33 (3.03%)	1	0/29 (0.00%)	0	0/6 (0.00%)	0
Localised infection † 1	0/134 (0.00%)	0	1/99 (1.01%)	1	1/33 (3.03%)	1	0/29 (0.00%)	0	0/6 (0.00%)	0
Lower respiratory tract infection † 1	9/134 (6.72%)	12	1/99 (1.01%)	1	3/33 (9.09%)	5	0/29 (0.00%)	0	0/6 (0.00%)	0
Lyme disease † 1	1/134 (0.75%)	2	0/99 (0.00%)	0	0/33 (0.00%)	0	0/29 (0.00%)	0	0/6 (0.00%)	0
Lymphangitis † 1	0/134 (0.00%)	0	0/99 (0.00%)	0	1/33 (3.03%)	1	0/29 (0.00%)	0	0/6 (0.00%)	0
Mastoiditis † 1	1/134 (0.75%)	1	0/99 (0.00%)	0	0/33 (0.00%)	0	0/29 (0.00%)	0	0/6 (0.00%)	0
Metapneumovirus infection † 1	0/134 (0.00%)	0	1/99 (1.01%)	1	0/33 (0.00%)	0	0/29 (0.00%)	0	0/6 (0.00%)	0
Moraxella infection † 1	1/134 (0.75%)	1	0/99 (0.00%)	0	0/33 (0.00%)	0	0/29 (0.00%)	0	0/6 (0.00%)	0
Mycobacterial infection † 1	0/134 (0.00%)	0	1/99 (1.01%)	1	0/33 (0.00%)	0	0/29 (0.00%)	0	0/6 (0.00%)	0
Myringitis † 1	0/134 (0.00%)	0	0/99 (0.00%)	0	0/33 (0.00%)	0	1/29 (3.45%)	1	0/6 (0.00%)	0
Nail infection † 1	3/134 (2.24%)	3	1/99 (1.01%)	1	0/33 (0.00%)	0	0/29 (0.00%)	0	0/6 (0.00%)	0
Nasopharyngitis † 1	11/134 (8.21%)	12	9/99 (9.09%)	11	3/33 (9.09%)	6	0/29 (0.00%)	0	0/6 (0.00%)	0
Onychomycosis † 1	0/134 (0.00%)	0	0/99 (0.00%)	0	0/33 (0.00%)	0	1/29 (3.45%)	1	0/6 (0.00%)	0
Oral candidiasis † 1	1/134 (0.75%)	1	0/99 (0.00%)	0	0/33 (0.00%)	0	2/29 (6.90%)	2	0/6 (0.00%)	0
Oral herpes † 1	5/134 (3.73%)	5	2/99 (2.02%)	2	3/33 (9.09%)	3	0/29 (0.00%)	0	0/6 (0.00%)	0
Oropharyngeal candidiasis † 1	0/134 (0.00%)	0	0/99 (0.00%)	0	0/33 (0.00%)	0	1/29 (3.45%)	1	0/6 (0.00%)	0
Otitis externa † 1	1/134 (0.75%)	1	3/99 (3.03%)	3	3/33 (9.09%)	3	0/29 (0.00%)	0	0/6 (0.00%)	0
Otitis media † 1	6/134 (4.48%)	6	1/99 (1.01%)	1	0/33 (0.00%)	0	0/29 (0.00%)	0	0/6 (0.00%)	0
Paronychia † 1	2/134 (1.49%)	3	0/99 (0.00%)	0	0/33 (0.00%)	0	0/29 (0.00%)	0	0/6 (0.00%)	0
Parotitis † 1	0/134 (0.00%)	0	1/99 (1.01%)	1	0/33 (0.00%)	0	0/29 (0.00%)	0	0/6 (0.00%)	0
Pelvic abscess † 1	0/134 (0.00%)	0	1/99 (1.01%)	1	0/33 (0.00%)	0	0/29 (0.00%)	0	0/6 (0.00%)	0
Perirectal abscess † 1	0/134 (0.00%)	0	1/99 (1.01%)	1	0/33 (0.00%)	0	0/29 (0.00%)	0	0/6 (0.00%)	0
Pharyngitis † 1	3/134 (2.24%)	3	3/99 (3.03%)	3	0/33 (0.00%)	0	0/29 (0.00%)	0	0/6 (0.00%)	0
Pharyngitis streptococcal † 1	2/134 (1.49%)	2	0/99 (0.00%)	0	0/33 (0.00%)	0	0/29 (0.00%)	0	0/6 (0.00%)	0
Pneumonia † 1	26/134 (19.40%)	29	12/99 (12.12%)	16	3/33 (9.09%)	9	3/29 (10.34%)	3	1/6 (16.67%)	1
Pneumonia bacterial † 1	1/134 (0.75%)	1	0/99 (0.00%)	0	0/33 (0.00%)	0	0/29 (0.00%)	0	0/6 (0.00%)	0
Pneumonia cryptococcal † 1	1/134 (0.75%)	1	0/99 (0.00%)	0	0/33 (0.00%)	0	0/29 (0.00%)	0	0/6 (0.00%)	0
Pneumonia pseudomonal † 1	0/134 (0.00%)	0	0/99 (0.00%)	0	1/33 (3.03%)	1	0/29 (0.00%)	0	0/6 (0.00%)	0
Pneumonia streptococcal † 1	1/134 (0.75%)	1	0/99 (0.00%)	0	0/33 (0.00%)	0	0/29 (0.00%)	0	0/6 (0.00%)	0
Post-acute covid-19 syndrome † 1	1/134 (0.75%)	1	0/99 (0.00%)	0	0/33 (0.00%)	0	0/29 (0.00%)	0	0/6 (0.00%)	0
Postoperative wound infection † 1	0/134 (0.00%)	0	1/99 (1.01%)	1	0/33 (0.00%)	0	0/29 (0.00%)	0	0/6 (0.00%)	0
Propionibacterium infection † 1	0/134 (0.00%)	0	1/99 (1.01%)	1	0/33 (0.00%)	0	0/29 (0.00%)	0	0/6 (0.00%)	0
Prostatic abscess † 1	1/134 (0.75%)	1	0/99 (0.00%)	0	0/33 (0.00%)	0	0/29 (0.00%)	0	0/6 (0.00%)	0
Pseudomonas infection † 1	0/134 (0.00%)	0	2/99 (2.02%)	2	0/33 (0.00%)	0	0/29 (0.00%)	0	0/6 (0.00%)	0
Rash pustular † 1	1/134 (0.75%)	1	1/99 (1.01%)	1	0/33 (0.00%)	0	0/29 (0.00%)	0	1/6 (16.67%)	1
Respiratory tract infection † 1	2/134 (1.49%)	2	0/99 (0.00%)	0	1/33 (3.03%)	1	1/29 (3.45%)	1	0/6 (0.00%)	0
Rhinitis † 1	4/134 (2.99%)	4	2/99 (2.02%)	2	1/33 (3.03%)	1	2/29 (6.90%)	2	0/6 (0.00%)	0
Rhinovirus infection † 1	0/134 (0.00%)	0	0/99 (0.00%)	0	1/33 (3.03%)	1	0/29 (0.00%)	0	1/6 (16.67%)	1
Salmonellosis † 1	1/134 (0.75%)	1	0/99 (0.00%)	0	0/33 (0.00%)	0	0/29 (0.00%)	0	0/6 (0.00%)	0
Scrotal infection † 1	0/134 (0.00%)	0	1/99 (1.01%)	1	0/33 (0.00%)	0	0/29 (0.00%)	0	0/6 (0.00%)	0
Sepsis † 1	0/134 (0.00%)	0	0/99 (0.00%)	0	0/33 (0.00%)	0	1/29 (3.45%)	1	0/6 (0.00%)	0
Sinusitis † 1	33/134 (24.63%)	44	22/99 (22.22%)	34	3/33 (9.09%)	6	2/29 (6.90%)	3	1/6 (16.67%)	1
Sinusitis bacterial † 1	0/134 (0.00%)	0	1/99 (1.01%)	1	1/33 (3.03%)	1	0/29 (0.00%)	0	0/6 (0.00%)	0
Skin bacterial infection † 1	1/134 (0.75%)	1	0/99 (0.00%)	0	0/33 (0.00%)	0	0/29 (0.00%)	0	0/6 (0.00%)	0
Skin infection † 1	2/134 (1.49%)	2	0/99 (0.00%)	0	3/33 (9.09%)	4	0/29 (0.00%)	0	0/6 (0.00%)	0
Staphylococcal infection † 1	3/134 (2.24%)	3	2/99 (2.02%)	2	0/33 (0.00%)	0	0/29 (0.00%)	0	0/6 (0.00%)	0
Subcutaneous abscess † 1	1/134 (0.75%)	1	0/99 (0.00%)	0	0/33 (0.00%)	0	0/29 (0.00%)	0	0/6 (0.00%)	0
Testicular abscess † 1	1/134 (0.75%)	1	0/99 (0.00%)	0	0/33 (0.00%)	0	0/29 (0.00%)	0	0/6 (0.00%)	0
Tinea cruris † 1	2/134 (1.49%)	2	0/99 (0.00%)	0	0/33 (0.00%)	0	0/29 (0.00%)	0	0/6 (0.00%)	0
Tinea infection † 1	1/134 (0.75%)	1	1/99 (1.01%)	1	0/33 (0.00%)	0	0/29 (0.00%)	0	0/6 (0.00%)	0
Tinea pedis † 1	0/134 (0.00%)	0	0/99 (0.00%)	0	1/33 (3.03%)	1	0/29 (0.00%)	0	0/6 (0.00%)	0
Tinea versicolour † 1	0/134 (0.00%)	0	1/99 (1.01%)	1	0/33 (0.00%)	0	0/29 (0.00%)	0	0/6 (0.00%)	0
Tonsillitis † 1	0/134 (0.00%)	0	1/99 (1.01%)	1	0/33 (0.00%)	0	0/29 (0.00%)	0	0/6 (0.00%)	0
Tooth abscess † 1	0/134 (0.00%)	0	1/99 (1.01%)	1	0/33 (0.00%)	0	0/29 (0.00%)	0	0/6 (0.00%)	0
Tooth infection † 1	3/134 (2.24%)	4	6/99 (6.06%)	6	2/33 (6.06%)	3	0/29 (0.00%)	0	0/6 (0.00%)	0
Tracheitis † 1	1/134 (0.75%)	1	0/99 (0.00%)	0	0/33 (0.00%)	0	0/29 (0.00%)	0	0/6 (0.00%)	0
Upper respiratory tract infection † 1	54/134 (40.30%)	88	49/99 (49.49%)	85	15/33 (45.45%)	25	3/29 (10.34%)	3	1/6 (16.67%)	1
Ureteritis † 1	1/134 (0.75%)	1	0/99 (0.00%)	0	0/33 (0.00%)	0	0/29 (0.00%)	0	0/6 (0.00%)	0
Urinary tract infection † 1	15/134 (11.19%)	32	13/99 (13.13%)	24	5/33 (15.15%)	11	2/29 (6.90%)	2	0/6 (0.00%)	0
Urinary tract infection bacterial † 1	0/134 (0.00%)	0	1/99 (1.01%)	1	0/33 (0.00%)	0	0/29 (0.00%)	0	0/6 (0.00%)	0
Urinary tract infection enterococcal † 1	0/134 (0.00%)	0	1/99 (1.01%)	1	0/33 (0.00%)	0	0/29 (0.00%)	0	0/6 (0.00%)	0
Vaginal infection † 1	2/134 (1.49%)	2	0/99 (0.00%)	0	1/33 (3.03%)	1	0/29 (0.00%)	0	0/6 (0.00%)	0
Vascular device infection † 1	1/134 (0.75%)	1	0/99 (0.00%)	0	0/33 (0.00%)	0	0/29 (0.00%)	0	0/6 (0.00%)	0
Viral pharyngitis † 1	0/134 (0.00%)	0	1/99 (1.01%)	1	0/33 (0.00%)	0	0/29 (0.00%)	0	0/6 (0.00%)	0
Viral upper respiratory tract infection † 1	3/134 (2.24%)	3	1/99 (1.01%)	1	0/33 (0.00%)	0	1/29 (3.45%)	1	0/6 (0.00%)	0
Vulvovaginal mycotic infection † 1	0/134 (0.00%)	0	0/99 (0.00%)	0	1/33 (3.03%)	1	0/29 (0.00%)	0	0/6 (0.00%)	0
Wound infection † 1	2/134 (1.49%)	3	2/99 (2.02%)	2	0/33 (0.00%)	0	0/29 (0.00%)	0	0/6 (0.00%)	0
Injury, poisoning and procedural complications
Anaemia postoperative † 1	1/134 (0.75%)	1	0/99 (0.00%)	0	0/33 (0.00%)	0	0/29 (0.00%)	0	0/6 (0.00%)	0
Animal bite † 1	5/134 (3.73%)	5	0/99 (0.00%)	0	1/33 (3.03%)	1	0/29 (0.00%)	0	0/6 (0.00%)	0
Arthropod bite † 1	10/134 (7.46%)	10	8/99 (8.08%)	13	1/33 (3.03%)	1	0/29 (0.00%)	0	0/6 (0.00%)	0
Axillary web syndrome † 1	0/134 (0.00%)	0	1/99 (1.01%)	1	0/33 (0.00%)	0	0/29 (0.00%)	0	0/6 (0.00%)	0
Bone contusion † 1	1/134 (0.75%)	1	1/99 (1.01%)	1	0/33 (0.00%)	0	0/29 (0.00%)	0	0/6 (0.00%)	0
Cartilage injury † 1	1/134 (0.75%)	1	1/99 (1.01%)	1	0/33 (0.00%)	0	0/29 (0.00%)	0	0/6 (0.00%)	0
Chest injury † 1	0/134 (0.00%)	0	1/99 (1.01%)	1	0/33 (0.00%)	0	0/29 (0.00%)	0	0/6 (0.00%)	0
Clavicle fracture † 1	0/134 (0.00%)	0	1/99 (1.01%)	1	0/33 (0.00%)	0	0/29 (0.00%)	0	0/6 (0.00%)	0
Concussion † 1	0/134 (0.00%)	0	1/99 (1.01%)	1	0/33 (0.00%)	0	0/29 (0.00%)	0	0/6 (0.00%)	0
Contusion † 1	42/134 (31.34%)	60	50/99 (50.51%)	62	11/33 (33.33%)	13	5/29 (17.24%)	6	0/6 (0.00%)	0
Dental restoration failure † 1	0/134 (0.00%)	0	1/99 (1.01%)	1	0/33 (0.00%)	0	0/29 (0.00%)	0	0/6 (0.00%)	0
Eye contusion † 1	2/134 (1.49%)	2	0/99 (0.00%)	0	0/33 (0.00%)	0	0/29 (0.00%)	0	0/6 (0.00%)	0
Face injury † 1	0/134 (0.00%)	0	1/99 (1.01%)	1	0/33 (0.00%)	0	0/29 (0.00%)	0	0/6 (0.00%)	0
Facial bones fracture † 1	1/134 (0.75%)	1	2/99 (2.02%)	2	0/33 (0.00%)	0	0/29 (0.00%)	0	0/6 (0.00%)	0
Fall † 1	21/134 (15.67%)	41	23/99 (23.23%)	34	6/33 (18.18%)	11	4/29 (13.79%)	4	1/6 (16.67%)	1
Foot fracture † 1	0/134 (0.00%)	0	1/99 (1.01%)	2	1/33 (3.03%)	2	0/29 (0.00%)	0	0/6 (0.00%)	0
Foreign body in eye † 1	0/134 (0.00%)	0	1/99 (1.01%)	1	1/33 (3.03%)	1	0/29 (0.00%)	0	0/6 (0.00%)	0
Fracture † 1	1/134 (0.75%)	1	0/99 (0.00%)	0	0/33 (0.00%)	0	0/29 (0.00%)	0	0/6 (0.00%)	0
Fractured coccyx † 1	1/134 (0.75%)	1	0/99 (0.00%)	0	0/33 (0.00%)	0	0/29 (0.00%)	0	0/6 (0.00%)	0
Hand fracture † 1	1/134 (0.75%)	1	0/99 (0.00%)	0	0/33 (0.00%)	0	0/29 (0.00%)	0	0/6 (0.00%)	0
Human bite † 1	1/134 (0.75%)	1	0/99 (0.00%)	0	0/33 (0.00%)	0	0/29 (0.00%)	0	0/6 (0.00%)	0
Humerus fracture † 1	1/134 (0.75%)	1	1/99 (1.01%)	1	0/33 (0.00%)	0	0/29 (0.00%)	0	0/6 (0.00%)	0
Infusion related reaction † 1	1/134 (0.75%)	1	1/99 (1.01%)	1	2/33 (6.06%)	2	1/29 (3.45%)	1	0/6 (0.00%)	0
Injury † 1	0/134 (0.00%)	0	1/99 (1.01%)	1	0/33 (0.00%)	0	0/29 (0.00%)	0	0/6 (0.00%)	0
Joint injury † 1	3/134 (2.24%)	3	2/99 (2.02%)	3	0/33 (0.00%)	0	0/29 (0.00%)	0	0/6 (0.00%)	0
Ligament injury † 1	1/134 (0.75%)	1	1/99 (1.01%)	1	0/33 (0.00%)	0	0/29 (0.00%)	0	0/6 (0.00%)	0
Ligament rupture † 1	1/134 (0.75%)	1	1/99 (1.01%)	1	0/33 (0.00%)	0	0/29 (0.00%)	0	0/6 (0.00%)	0
Ligament sprain † 1	3/134 (2.24%)	3	4/99 (4.04%)	4	0/33 (0.00%)	0	0/29 (0.00%)	0	0/6 (0.00%)	0
Limb injury † 1	4/134 (2.99%)	4	4/99 (4.04%)	5	1/33 (3.03%)	1	1/29 (3.45%)	1	0/6 (0.00%)	0
Meniscus injury † 1	2/134 (1.49%)	2	2/99 (2.02%)	2	1/33 (3.03%)	1	0/29 (0.00%)	0	0/6 (0.00%)	0
Muscle rupture † 1	0/134 (0.00%)	0	1/99 (1.01%)	1	1/33 (3.03%)	1	0/29 (0.00%)	0	0/6 (0.00%)	0
Muscle strain † 1	5/134 (3.73%)	5	5/99 (5.05%)	5	1/33 (3.03%)	1	0/29 (0.00%)	0	0/6 (0.00%)	0
Musculoskeletal injury † 1	1/134 (0.75%)	1	0/99 (0.00%)	0	0/33 (0.00%)	0	0/29 (0.00%)	0	0/6 (0.00%)	0
Nail injury † 1	1/134 (0.75%)	1	0/99 (0.00%)	0	0/33 (0.00%)	0	0/29 (0.00%)	0	0/6 (0.00%)	0
Patella fracture † 1	1/134 (0.75%)	1	0/99 (0.00%)	0	0/33 (0.00%)	0	0/29 (0.00%)	0	0/6 (0.00%)	0
Periorbital haemorrhage † 1	1/134 (0.75%)	1	1/99 (1.01%)	1	0/33 (0.00%)	0	0/29 (0.00%)	0	0/6 (0.00%)	0
Post procedural complication † 1	1/134 (0.75%)	1	1/99 (1.01%)	1	0/33 (0.00%)	0	0/29 (0.00%)	0	0/6 (0.00%)	0
Post procedural contusion † 1	0/134 (0.00%)	0	2/99 (2.02%)	2	0/33 (0.00%)	0	0/29 (0.00%)	0	0/6 (0.00%)	0
Post procedural haemorrhage † 1	2/134 (1.49%)	2	0/99 (0.00%)	0	0/33 (0.00%)	0	0/29 (0.00%)	0	0/6 (0.00%)	0
Post procedural inflammation † 1	0/134 (0.00%)	0	1/99 (1.01%)	1	0/33 (0.00%)	0	0/29 (0.00%)	0	0/6 (0.00%)	0
Post procedural swelling † 1	0/134 (0.00%)	0	1/99 (1.01%)	2	0/33 (0.00%)	0	0/29 (0.00%)	0	0/6 (0.00%)	0
Post-traumatic pain † 1	0/134 (0.00%)	0	1/99 (1.01%)	1	0/33 (0.00%)	0	0/29 (0.00%)	0	0/6 (0.00%)	0
Procedural hypotension † 1	0/134 (0.00%)	0	1/99 (1.01%)	1	0/33 (0.00%)	0	0/29 (0.00%)	0	0/6 (0.00%)	0
Procedural pain † 1	2/134 (1.49%)	2	3/99 (3.03%)	5	0/33 (0.00%)	0	0/29 (0.00%)	0	0/6 (0.00%)	0
Radiation pneumonitis † 1	1/134 (0.75%)	1	0/99 (0.00%)	0	0/33 (0.00%)	0	0/29 (0.00%)	0	0/6 (0.00%)	0
Radiation proctitis † 1	1/134 (0.75%)	1	0/99 (0.00%)	0	0/33 (0.00%)	0	0/29 (0.00%)	0	0/6 (0.00%)	0
Reactive gastropathy † 1	0/134 (0.00%)	0	1/99 (1.01%)	1	0/33 (0.00%)	0	0/29 (0.00%)	0	0/6 (0.00%)	0
Respiratory fume inhalation disorder † 1	1/134 (0.75%)	1	0/99 (0.00%)	0	0/33 (0.00%)	0	0/29 (0.00%)	0	0/6 (0.00%)	0
Rib fracture † 1	4/134 (2.99%)	4	3/99 (3.03%)	3	0/33 (0.00%)	0	0/29 (0.00%)	0	0/6 (0.00%)	0
Road traffic accident † 1	1/134 (0.75%)	1	1/99 (1.01%)	1	0/33 (0.00%)	0	0/29 (0.00%)	0	0/6 (0.00%)	0
Scar † 1	1/134 (0.75%)	1	1/99 (1.01%)	1	0/33 (0.00%)	0	0/29 (0.00%)	0	0/6 (0.00%)	0
Scratch † 1	2/134 (1.49%)	2	2/99 (2.02%)	2	0/33 (0.00%)	0	0/29 (0.00%)	0	0/6 (0.00%)	0
Scrotal haematoma † 1	1/134 (0.75%)	1	0/99 (0.00%)	0	0/33 (0.00%)	0	1/29 (3.45%)	2	0/6 (0.00%)	0
Skin abrasion † 1	2/134 (1.49%)	3	3/99 (3.03%)	3	0/33 (0.00%)	0	0/29 (0.00%)	0	0/6 (0.00%)	0
Skin laceration † 1	6/134 (4.48%)	7	5/99 (5.05%)	5	1/33 (3.03%)	1	0/29 (0.00%)	0	0/6 (0.00%)	0
Skin wound † 1	1/134 (0.75%)	1	0/99 (0.00%)	0	0/33 (0.00%)	0	0/29 (0.00%)	0	0/6 (0.00%)	0
Spinal compression fracture † 1	3/134 (2.24%)	3	2/99 (2.02%)	2	0/33 (0.00%)	0	0/29 (0.00%)	0	0/6 (0.00%)	0
Spinal fracture † 1	1/134 (0.75%)	1	0/99 (0.00%)	0	0/33 (0.00%)	0	0/29 (0.00%)	0	0/6 (0.00%)	0
Stoma site reaction † 1	1/134 (0.75%)	1	0/99 (0.00%)	0	0/33 (0.00%)	0	0/29 (0.00%)	0	0/6 (0.00%)	0
Stomal hernia † 1	1/134 (0.75%)	1	0/99 (0.00%)	0	0/33 (0.00%)	0	0/29 (0.00%)	0	0/6 (0.00%)	0
Tendon injury † 1	1/134 (0.75%)	1	2/99 (2.02%)	3	0/33 (0.00%)	0	0/29 (0.00%)	0	0/6 (0.00%)	0
Tendon rupture † 1	1/134 (0.75%)	1	3/99 (3.03%)	3	0/33 (0.00%)	0	0/29 (0.00%)	0	0/6 (0.00%)	0
Thermal burn † 1	1/134 (0.75%)	1	1/99 (1.01%)	1	1/33 (3.03%)	1	0/29 (0.00%)	0	0/6 (0.00%)	0
Thoracic vertebral fracture † 1	1/134 (0.75%)	1	0/99 (0.00%)	0	0/33 (0.00%)	0	0/29 (0.00%)	0	0/6 (0.00%)	0
Tooth fracture † 1	4/134 (2.99%)	4	2/99 (2.02%)	2	2/33 (6.06%)	2	0/29 (0.00%)	0	0/6 (0.00%)	0
Upper limb fracture † 1	0/134 (0.00%)	0	1/99 (1.01%)	1	0/33 (0.00%)	0	0/29 (0.00%)	0	0/6 (0.00%)	0
Vaccination complication † 1	6/134 (4.48%)	9	8/99 (8.08%)	12	0/33 (0.00%)	0	0/29 (0.00%)	0	0/6 (0.00%)	0
Vascular access complication † 1	1/134 (0.75%)	1	0/99 (0.00%)	0	0/33 (0.00%)	0	0/29 (0.00%)	0	0/6 (0.00%)	0
Venous injury † 1	1/134 (0.75%)	2	1/99 (1.01%)	1	0/33 (0.00%)	0	0/29 (0.00%)	0	0/6 (0.00%)	0
Wound † 1	3/134 (2.24%)	3	1/99 (1.01%)	1	0/33 (0.00%)	0	0/29 (0.00%)	0	0/6 (0.00%)	0
Wound dehiscence † 1	0/134 (0.00%)	0	1/99 (1.01%)	1	0/33 (0.00%)	0	0/29 (0.00%)	0	0/6 (0.00%)	0
Wound haemorrhage † 1	0/134 (0.00%)	0	0/99 (0.00%)	0	1/33 (3.03%)	1	0/29 (0.00%)	0	0/6 (0.00%)	0
Wrist fracture † 1	1/134 (0.75%)	1	0/99 (0.00%)	0	0/33 (0.00%)	0	0/29 (0.00%)	0	0/6 (0.00%)	0
Investigations
Activated partial thromboplastin time prolonged † 1	1/134 (0.75%)	1	1/99 (1.01%)	3	0/33 (0.00%)	0	0/29 (0.00%)	0	0/6 (0.00%)	0
Alanine aminotransferase increased † 1	3/134 (2.24%)	3	2/99 (2.02%)	4	0/33 (0.00%)	0	2/29 (6.90%)	2	0/6 (0.00%)	0
Amylase increased † 1	1/134 (0.75%)	1	1/99 (1.01%)	1	0/33 (0.00%)	0	0/29 (0.00%)	0	0/6 (0.00%)	0
Antinuclear antibody positive † 1	0/134 (0.00%)	0	1/99 (1.01%)	1	0/33 (0.00%)	0	0/29 (0.00%)	0	0/6 (0.00%)	0
Aspartate aminotransferase increased † 1	4/134 (2.99%)	4	2/99 (2.02%)	3	0/33 (0.00%)	0	1/29 (3.45%)	1	0/6 (0.00%)	0
Bk polyomavirus test positive † 1	1/134 (0.75%)	1	0/99 (0.00%)	0	0/33 (0.00%)	0	0/29 (0.00%)	0	0/6 (0.00%)	0
Blood albumin decreased † 1	0/134 (0.00%)	0	0/99 (0.00%)	0	1/33 (3.03%)	1	0/29 (0.00%)	0	0/6 (0.00%)	0
Blood alkaline phosphatase increased † 1	0/134 (0.00%)	0	1/99 (1.01%)	1	0/33 (0.00%)	0	0/29 (0.00%)	0	0/6 (0.00%)	0
Blood beta-d-glucan increased † 1	0/134 (0.00%)	0	0/99 (0.00%)	0	0/33 (0.00%)	0	1/29 (3.45%)	1	0/6 (0.00%)	0
Blood bilirubin increased † 1	1/134 (0.75%)	1	0/99 (0.00%)	0	0/33 (0.00%)	0	0/29 (0.00%)	0	0/6 (0.00%)	0
Blood cholesterol increased † 1	1/134 (0.75%)	1	0/99 (0.00%)	0	0/33 (0.00%)	0	0/29 (0.00%)	0	0/6 (0.00%)	0
Blood creatinine increased † 1	7/134 (5.22%)	9	2/99 (2.02%)	2	0/33 (0.00%)	0	0/29 (0.00%)	0	1/6 (16.67%)	1
Blood folate decreased † 1	1/134 (0.75%)	1	0/99 (0.00%)	0	0/33 (0.00%)	0	0/29 (0.00%)	0	0/6 (0.00%)	0
Blood immunoglobulin g decreased † 1	0/134 (0.00%)	0	0/99 (0.00%)	0	2/33 (6.06%)	2	0/29 (0.00%)	0	0/6 (0.00%)	0
Blood lactate dehydrogenase increased † 1	1/134 (0.75%)	1	0/99 (0.00%)	0	0/33 (0.00%)	0	0/29 (0.00%)	0	0/6 (0.00%)	0
Blood phosphorus decreased † 1	0/134 (0.00%)	0	0/99 (0.00%)	0	1/33 (3.03%)	1	0/29 (0.00%)	0	0/6 (0.00%)	0
Blood potassium decreased † 1	2/134 (1.49%)	2	0/99 (0.00%)	0	0/33 (0.00%)	0	0/29 (0.00%)	0	0/6 (0.00%)	0
Blood pressure increased † 1	0/134 (0.00%)	0	1/99 (1.01%)	1	0/33 (0.00%)	0	0/29 (0.00%)	0	0/6 (0.00%)	0
Blood sodium decreased † 1	1/134 (0.75%)	1	0/99 (0.00%)	0	0/33 (0.00%)	0	1/29 (3.45%)	1	0/6 (0.00%)	0
Blood testosterone decreased † 1	1/134 (0.75%)	1	0/99 (0.00%)	0	0/33 (0.00%)	0	0/29 (0.00%)	0	0/6 (0.00%)	0
Bone density decreased † 1	0/134 (0.00%)	0	1/99 (1.01%)	1	0/33 (0.00%)	0	0/29 (0.00%)	0	0/6 (0.00%)	0
Breath sounds abnormal † 1	1/134 (0.75%)	1	0/99 (0.00%)	0	0/33 (0.00%)	0	0/29 (0.00%)	0	0/6 (0.00%)	0
C-reactive protein increased † 1	0/134 (0.00%)	0	1/99 (1.01%)	1	0/33 (0.00%)	0	0/29 (0.00%)	0	0/6 (0.00%)	0
Cardiac murmur † 1	1/134 (0.75%)	1	5/99 (5.05%)	5	0/33 (0.00%)	0	0/29 (0.00%)	0	0/6 (0.00%)	0
Coagulation time prolonged † 1	1/134 (0.75%)	1	0/99 (0.00%)	0	0/33 (0.00%)	0	0/29 (0.00%)	0	0/6 (0.00%)	0
Computerised tomogram thorax abnormal † 1	1/134 (0.75%)	1	0/99 (0.00%)	0	0/33 (0.00%)	0	0/29 (0.00%)	0	0/6 (0.00%)	0
Eastern cooperative oncology group performance status worsened † 1	0/134 (0.00%)	0	1/99 (1.01%)	1	0/33 (0.00%)	0	0/29 (0.00%)	0	0/6 (0.00%)	0
Electrocardiogram qt prolonged † 1	1/134 (0.75%)	1	1/99 (1.01%)	3	0/33 (0.00%)	0	1/29 (3.45%)	1	0/6 (0.00%)	0
Haemoglobin decreased † 1	1/134 (0.75%)	1	0/99 (0.00%)	0	0/33 (0.00%)	0	1/29 (3.45%)	1	0/6 (0.00%)	0
Influenza a virus test positive † 1	1/134 (0.75%)	1	0/99 (0.00%)	0	0/33 (0.00%)	0	0/29 (0.00%)	0	0/6 (0.00%)	0
Influenza b virus test positive † 1	0/134 (0.00%)	0	0/99 (0.00%)	0	1/33 (3.03%)	1	0/29 (0.00%)	0	0/6 (0.00%)	0
Influenza virus test positive † 1	0/134 (0.00%)	0	0/99 (0.00%)	0	1/33 (3.03%)	1	0/29 (0.00%)	0	0/6 (0.00%)	0
International normalised ratio increased † 1	0/134 (0.00%)	0	1/99 (1.01%)	4	0/33 (0.00%)	0	0/29 (0.00%)	0	0/6 (0.00%)	0
Lipase increased † 1	1/134 (0.75%)	1	0/99 (0.00%)	0	0/33 (0.00%)	0	0/29 (0.00%)	0	0/6 (0.00%)	0
Lymphocyte count decreased † 1	1/134 (0.75%)	4	0/99 (0.00%)	0	0/33 (0.00%)	0	0/29 (0.00%)	0	0/6 (0.00%)	0
Lymphocyte count increased † 1	1/134 (0.75%)	1	0/99 (0.00%)	0	1/33 (3.03%)	1	0/29 (0.00%)	0	0/6 (0.00%)	0
Neutrophil count decreased † 1	1/134 (0.75%)	3	0/99 (0.00%)	0	0/33 (0.00%)	0	3/29 (10.34%)	6	0/6 (0.00%)	0
Neutrophil count increased † 1	1/134 (0.75%)	1	0/99 (0.00%)	0	0/33 (0.00%)	0	0/29 (0.00%)	0	0/6 (0.00%)	0
Norovirus test positive † 1	0/134 (0.00%)	0	0/99 (0.00%)	0	0/33 (0.00%)	0	0/29 (0.00%)	0	1/6 (16.67%)	1
Platelet count decreased † 1	4/134 (2.99%)	7	0/99 (0.00%)	0	1/33 (3.03%)	8	4/29 (13.79%)	4	0/6 (0.00%)	0
Prostatic specific antigen increased † 1	1/134 (0.75%)	2	0/99 (0.00%)	0	0/33 (0.00%)	0	0/29 (0.00%)	0	0/6 (0.00%)	0
Thyroid hormones increased † 1	0/134 (0.00%)	0	1/99 (1.01%)	1	0/33 (0.00%)	0	0/29 (0.00%)	0	0/6 (0.00%)	0
Transaminases increased † 1	0/134 (0.00%)	0	1/99 (1.01%)	1	0/33 (0.00%)	0	0/29 (0.00%)	0	0/6 (0.00%)	0
Troponin i increased † 1	1/134 (0.75%)	1	0/99 (0.00%)	0	0/33 (0.00%)	0	0/29 (0.00%)	0	0/6 (0.00%)	0
Troponin increased † 1	1/134 (0.75%)	2	1/99 (1.01%)	1	0/33 (0.00%)	0	0/29 (0.00%)	0	0/6 (0.00%)	0
Weight decreased † 1	27/134 (20.15%)	43	8/99 (8.08%)	13	3/33 (9.09%)	5	4/29 (13.79%)	6	0/6 (0.00%)	0
Weight increased † 1	34/134 (25.37%)	97	33/99 (33.33%)	105	10/33 (30.30%)	22	0/29 (0.00%)	0	0/6 (0.00%)	0
White blood cell count decreased † 1	1/134 (0.75%)	3	0/99 (0.00%)	0	1/33 (3.03%)	1	0/29 (0.00%)	0	0/6 (0.00%)	0
Metabolism and nutrition disorders
Decreased appetite † 1	22/134 (16.42%)	26	13/99 (13.13%)	19	2/33 (6.06%)	2	4/29 (13.79%)	4	0/6 (0.00%)	0
Dehydration † 1	4/134 (2.99%)	5	7/99 (7.07%)	7	2/33 (6.06%)	3	3/29 (10.34%)	3	0/6 (0.00%)	0
Failure to thrive † 1	1/134 (0.75%)	1	0/99 (0.00%)	0	0/33 (0.00%)	0	0/29 (0.00%)	0	0/6 (0.00%)	0
Fluid overload † 1	2/134 (1.49%)	2	0/99 (0.00%)	0	0/33 (0.00%)	0	0/29 (0.00%)	0	0/6 (0.00%)	0
Fluid retention † 1	1/134 (0.75%)	1	1/99 (1.01%)	1	0/33 (0.00%)	0	0/29 (0.00%)	0	0/6 (0.00%)	0
Gout † 1	0/134 (0.00%)	0	2/99 (2.02%)	2	1/33 (3.03%)	1	0/29 (0.00%)	0	0/6 (0.00%)	0
Hypercalcaemia † 1	3/134 (2.24%)	6	1/99 (1.01%)	1	0/33 (0.00%)	0	0/29 (0.00%)	0	0/6 (0.00%)	0
Hyperglycaemia † 1	1/134 (0.75%)	1	1/99 (1.01%)	1	0/33 (0.00%)	0	0/29 (0.00%)	0	0/6 (0.00%)	0
Hyperkalaemia † 1	4/134 (2.99%)	4	3/99 (3.03%)	4	0/33 (0.00%)	0	0/29 (0.00%)	0	0/6 (0.00%)	0
Hyperlipidaemia † 1	1/134 (0.75%)	1	1/99 (1.01%)	1	0/33 (0.00%)	0	0/29 (0.00%)	0	0/6 (0.00%)	0
Hypernatraemia † 1	0/134 (0.00%)	0	1/99 (1.01%)	1	0/33 (0.00%)	0	0/29 (0.00%)	0	0/6 (0.00%)	0
Hyperphagia † 1	1/134 (0.75%)	1	0/99 (0.00%)	0	0/33 (0.00%)	0	0/29 (0.00%)	0	0/6 (0.00%)	0
Hyperuricaemia † 1	4/134 (2.99%)	4	6/99 (6.06%)	6	1/33 (3.03%)	2	0/29 (0.00%)	0	0/6 (0.00%)	0
Hypoalbuminaemia † 1	1/134 (0.75%)	1	0/99 (0.00%)	0	0/33 (0.00%)	0	0/29 (0.00%)	0	0/6 (0.00%)	0
Hypocalcaemia † 1	1/134 (0.75%)	2	0/99 (0.00%)	0	1/33 (3.03%)	1	0/29 (0.00%)	0	0/6 (0.00%)	0
Hypoglycaemia † 1	1/134 (0.75%)	1	1/99 (1.01%)	2	2/33 (6.06%)	3	0/29 (0.00%)	0	0/6 (0.00%)	0
Hypokalaemia † 1	7/134 (5.22%)	8	4/99 (4.04%)	4	0/33 (0.00%)	0	4/29 (13.79%)	5	1/6 (16.67%)	1
Hypomagnesaemia † 1	2/134 (1.49%)	2	2/99 (2.02%)	2	0/33 (0.00%)	0	2/29 (6.90%)	2	0/6 (0.00%)	0
Hyponatraemia † 1	2/134 (1.49%)	2	2/99 (2.02%)	2	1/33 (3.03%)	1	0/29 (0.00%)	0	0/6 (0.00%)	0
Hypophosphataemia † 1	4/134 (2.99%)	5	0/99 (0.00%)	0	1/33 (3.03%)	1	0/29 (0.00%)	0	0/6 (0.00%)	0
Iron deficiency † 1	1/134 (0.75%)	1	4/99 (4.04%)	4	0/33 (0.00%)	0	0/29 (0.00%)	0	0/6 (0.00%)	0
Polydipsia † 1	1/134 (0.75%)	1	0/99 (0.00%)	0	0/33 (0.00%)	0	0/29 (0.00%)	0	0/6 (0.00%)	0
Tumour lysis syndrome † 1	1/134 (0.75%)	1	0/99 (0.00%)	0	0/33 (0.00%)	0	0/29 (0.00%)	0	0/6 (0.00%)	0
Type 2 diabetes mellitus † 1	2/134 (1.49%)	2	0/99 (0.00%)	0	0/33 (0.00%)	0	0/29 (0.00%)	0	0/6 (0.00%)	0
Vitamin b complex deficiency † 1	1/134 (0.75%)	1	0/99 (0.00%)	0	0/33 (0.00%)	0	0/29 (0.00%)	0	0/6 (0.00%)	0
Vitamin b12 deficiency † 1	0/134 (0.00%)	0	1/99 (1.01%)	1	0/33 (0.00%)	0	0/29 (0.00%)	0	0/6 (0.00%)	0
Vitamin d deficiency † 1	1/134 (0.75%)	1	1/99 (1.01%)	1	1/33 (3.03%)	1	0/29 (0.00%)	0	0/6 (0.00%)	0
Musculoskeletal and connective tissue disorders
Arthralgia † 1	47/134 (35.07%)	78	55/99 (55.56%)	83	9/33 (27.27%)	13	6/29 (20.69%)	8	0/6 (0.00%)	0
Arthritis † 1	7/134 (5.22%)	8	10/99 (10.10%)	10	2/33 (6.06%)	2	0/29 (0.00%)	0	0/6 (0.00%)	0
Back pain † 1	19/134 (14.18%)	21	22/99 (22.22%)	26	3/33 (9.09%)	3	4/29 (13.79%)	5	0/6 (0.00%)	0
Bone pain † 1	4/134 (2.99%)	4	1/99 (1.01%)	1	3/33 (9.09%)	4	2/29 (6.90%)	2	0/6 (0.00%)	0
Bursa disorder † 1	0/134 (0.00%)	0	0/99 (0.00%)	0	1/33 (3.03%)	1	0/29 (0.00%)	0	0/6 (0.00%)	0
Bursitis † 1	2/134 (1.49%)	2	1/99 (1.01%)	1	0/33 (0.00%)	0	0/29 (0.00%)	0	0/6 (0.00%)	0
Cervical spinal stenosis † 1	0/134 (0.00%)	0	1/99 (1.01%)	1	0/33 (0.00%)	0	0/29 (0.00%)	0	0/6 (0.00%)	0
Chondrocalcinosis pyrophosphate † 1	1/134 (0.75%)	1	1/99 (1.01%)	1	0/33 (0.00%)	0	0/29 (0.00%)	0	0/6 (0.00%)	0
Dupuytren's contracture † 1	1/134 (0.75%)	1	1/99 (1.01%)	1	0/33 (0.00%)	0	0/29 (0.00%)	0	0/6 (0.00%)	0
Exostosis † 1	0/134 (0.00%)	0	1/99 (1.01%)	1	0/33 (0.00%)	0	0/29 (0.00%)	0	0/6 (0.00%)	0
Flank pain † 1	3/134 (2.24%)	3	6/99 (6.06%)	6	1/33 (3.03%)	1	0/29 (0.00%)	0	0/6 (0.00%)	0
Groin pain † 1	5/134 (3.73%)	5	3/99 (3.03%)	3	0/33 (0.00%)	0	0/29 (0.00%)	0	0/6 (0.00%)	0
Haemarthrosis † 1	0/134 (0.00%)	0	0/99 (0.00%)	0	0/33 (0.00%)	0	1/29 (3.45%)	1	0/6 (0.00%)	0
Intervertebral disc degeneration † 1	2/134 (1.49%)	2	0/99 (0.00%)	0	0/33 (0.00%)	0	0/29 (0.00%)	0	0/6 (0.00%)	0
Intervertebral disc protrusion † 1	1/134 (0.75%)	1	0/99 (0.00%)	0	0/33 (0.00%)	0	0/29 (0.00%)	0	0/6 (0.00%)	0
Joint effusion † 1	2/134 (1.49%)	2	0/99 (0.00%)	0	0/33 (0.00%)	0	0/29 (0.00%)	0	0/6 (0.00%)	0
Joint hyperextension † 1	1/134 (0.75%)	1	0/99 (0.00%)	0	0/33 (0.00%)	0	0/29 (0.00%)	0	0/6 (0.00%)	0
Joint stiffness † 1	2/134 (1.49%)	2	0/99 (0.00%)	0	0/33 (0.00%)	0	1/29 (3.45%)	1	0/6 (0.00%)	0
Joint swelling † 1	3/134 (2.24%)	3	2/99 (2.02%)	2	0/33 (0.00%)	0	1/29 (3.45%)	1	0/6 (0.00%)	0
Limb discomfort † 1	0/134 (0.00%)	0	1/99 (1.01%)	1	0/33 (0.00%)	0	0/29 (0.00%)	0	0/6 (0.00%)	0
Limb mass † 1	4/134 (2.99%)	4	0/99 (0.00%)	0	0/33 (0.00%)	0	0/29 (0.00%)	0	0/6 (0.00%)	0
Medial tibial stress syndrome † 1	0/134 (0.00%)	0	1/99 (1.01%)	1	0/33 (0.00%)	0	0/29 (0.00%)	0	0/6 (0.00%)	0
Muscle atrophy † 1	0/134 (0.00%)	0	1/99 (1.01%)	1	0/33 (0.00%)	0	0/29 (0.00%)	0	1/6 (16.67%)	1
Muscle spasms † 1	11/134 (8.21%)	14	14/99 (14.14%)	20	3/33 (9.09%)	4	0/29 (0.00%)	0	0/6 (0.00%)	0
Muscular weakness † 1	4/134 (2.99%)	6	7/99 (7.07%)	7	1/33 (3.03%)	1	0/29 (0.00%)	0	0/6 (0.00%)	0
Musculoskeletal chest pain † 1	2/134 (1.49%)	2	2/99 (2.02%)	2	2/33 (6.06%)	2	0/29 (0.00%)	0	0/6 (0.00%)	0
Musculoskeletal deformity † 1	0/134 (0.00%)	0	1/99 (1.01%)	1	0/33 (0.00%)	0	0/29 (0.00%)	0	0/6 (0.00%)	0
Musculoskeletal discomfort † 1	3/134 (2.24%)	3	0/99 (0.00%)	0	0/33 (0.00%)	0	1/29 (3.45%)	1	0/6 (0.00%)	0
Musculoskeletal disorder † 1	0/134 (0.00%)	0	1/99 (1.01%)	1	0/33 (0.00%)	0	0/29 (0.00%)	0	0/6 (0.00%)	0
Musculoskeletal pain † 1	1/134 (0.75%)	1	2/99 (2.02%)	2	0/33 (0.00%)	0	0/29 (0.00%)	0	0/6 (0.00%)	0
Musculoskeletal stiffness † 1	0/134 (0.00%)	0	2/99 (2.02%)	2	0/33 (0.00%)	0	1/29 (3.45%)	2	0/6 (0.00%)	0
Myalgia † 1	18/134 (13.43%)	22	14/99 (14.14%)	17	8/33 (24.24%)	10	3/29 (10.34%)	3	1/6 (16.67%)	1
Neck pain † 1	5/134 (3.73%)	5	4/99 (4.04%)	4	1/33 (3.03%)	1	0/29 (0.00%)	0	1/6 (16.67%)	1
Osteoarthritis † 1	2/134 (1.49%)	3	1/99 (1.01%)	1	0/33 (0.00%)	0	1/29 (3.45%)	1	0/6 (0.00%)	0
Osteonecrosis † 1	2/134 (1.49%)	2	0/99 (0.00%)	0	0/33 (0.00%)	0	0/29 (0.00%)	0	0/6 (0.00%)	0
Osteopenia † 1	2/134 (1.49%)	2	1/99 (1.01%)	1	0/33 (0.00%)	0	0/29 (0.00%)	0	0/6 (0.00%)	0
Osteoporosis † 1	5/134 (3.73%)	5	3/99 (3.03%)	3	0/33 (0.00%)	0	0/29 (0.00%)	0	0/6 (0.00%)	0
Pain in extremity † 1	24/134 (17.91%)	32	11/99 (11.11%)	14	5/33 (15.15%)	7	4/29 (13.79%)	4	1/6 (16.67%)	1
Pain in jaw † 1	2/134 (1.49%)	2	0/99 (0.00%)	0	0/33 (0.00%)	0	1/29 (3.45%)	1	0/6 (0.00%)	0
Plantar fasciitis † 1	2/134 (1.49%)	2	1/99 (1.01%)	1	0/33 (0.00%)	0	0/29 (0.00%)	0	0/6 (0.00%)	0
Polymyalgia rheumatica † 1	1/134 (0.75%)	1	0/99 (0.00%)	0	0/33 (0.00%)	0	0/29 (0.00%)	0	0/6 (0.00%)	0
Rheumatoid arthritis † 1	0/134 (0.00%)	0	1/99 (1.01%)	1	0/33 (0.00%)	0	0/29 (0.00%)	0	0/6 (0.00%)	0
Rotator cuff syndrome † 1	1/134 (0.75%)	1	1/99 (1.01%)	1	1/33 (3.03%)	1	1/29 (3.45%)	1	0/6 (0.00%)	0
Scoliosis † 1	0/134 (0.00%)	0	1/99 (1.01%)	1	0/33 (0.00%)	0	0/29 (0.00%)	0	0/6 (0.00%)	0
Sinus tarsi syndrome † 1	0/134 (0.00%)	0	0/99 (0.00%)	0	1/33 (3.03%)	1	0/29 (0.00%)	0	0/6 (0.00%)	0
Spinal osteoarthritis † 1	1/134 (0.75%)	2	0/99 (0.00%)	0	0/33 (0.00%)	0	0/29 (0.00%)	0	0/6 (0.00%)	0
Spinal pain † 1	0/134 (0.00%)	0	0/99 (0.00%)	0	0/33 (0.00%)	0	1/29 (3.45%)	1	0/6 (0.00%)	0
Spinal stenosis † 1	1/134 (0.75%)	1	0/99 (0.00%)	0	0/33 (0.00%)	0	0/29 (0.00%)	0	0/6 (0.00%)	0
Spondylolisthesis † 1	1/134 (0.75%)	1	0/99 (0.00%)	0	0/33 (0.00%)	0	0/29 (0.00%)	0	0/6 (0.00%)	0
Synovial cyst † 1	0/134 (0.00%)	0	1/99 (1.01%)	1	0/33 (0.00%)	0	0/29 (0.00%)	0	0/6 (0.00%)	0
Temporomandibular joint syndrome † 1	1/134 (0.75%)	1	0/99 (0.00%)	0	0/33 (0.00%)	0	0/29 (0.00%)	0	0/6 (0.00%)	0
Tendon pain † 1	1/134 (0.75%)	1	1/99 (1.01%)	1	0/33 (0.00%)	0	0/29 (0.00%)	0	0/6 (0.00%)	0
Tendonitis † 1	0/134 (0.00%)	0	4/99 (4.04%)	4	0/33 (0.00%)	0	0/29 (0.00%)	0	0/6 (0.00%)	0
Trigger finger † 1	2/134 (1.49%)	2	2/99 (2.02%)	2	0/33 (0.00%)	0	0/29 (0.00%)	0	0/6 (0.00%)	0
Vertebral column mass † 1	1/134 (0.75%)	1	0/99 (0.00%)	0	0/33 (0.00%)	0	0/29 (0.00%)	0	0/6 (0.00%)	0
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Basal cell carcinoma † 1	11/134 (8.21%)	12	11/99 (11.11%)	17	4/33 (12.12%)	4	0/29 (0.00%)	0	0/6 (0.00%)	0
Basosquamous carcinoma of skin † 1	1/134 (0.75%)	1	0/99 (0.00%)	0	0/33 (0.00%)	0	0/29 (0.00%)	0	0/6 (0.00%)	0
Benign neoplasm † 1	0/134 (0.00%)	0	1/99 (1.01%)	1	0/33 (0.00%)	0	0/29 (0.00%)	0	0/6 (0.00%)	0
Benign neoplasm of urethra † 1	1/134 (0.75%)	1	0/99 (0.00%)	0	0/33 (0.00%)	0	0/29 (0.00%)	0	0/6 (0.00%)	0
Bladder cancer † 1	1/134 (0.75%)	1	0/99 (0.00%)	0	0/33 (0.00%)	0	0/29 (0.00%)	0	0/6 (0.00%)	0
Bladder cancer recurrent † 1	1/134 (0.75%)	1	0/99 (0.00%)	0	0/33 (0.00%)	0	0/29 (0.00%)	0	0/6 (0.00%)	0
Bowen's disease † 1	1/134 (0.75%)	1	0/99 (0.00%)	0	0/33 (0.00%)	0	0/29 (0.00%)	0	0/6 (0.00%)	0
Clear cell renal cell carcinoma † 1	1/134 (0.75%)	1	0/99 (0.00%)	0	0/33 (0.00%)	0	0/29 (0.00%)	0	0/6 (0.00%)	0
Colon adenoma † 1	1/134 (0.75%)	1	2/99 (2.02%)	2	0/33 (0.00%)	0	0/29 (0.00%)	0	0/6 (0.00%)	0
Dysplastic naevus † 1	1/134 (0.75%)	1	0/99 (0.00%)	0	0/33 (0.00%)	0	1/29 (3.45%)	1	0/6 (0.00%)	0
Eye naevus † 1	1/134 (0.75%)	1	0/99 (0.00%)	0	0/33 (0.00%)	0	0/29 (0.00%)	0	0/6 (0.00%)	0
Fibroma † 1	1/134 (0.75%)	2	0/99 (0.00%)	0	0/33 (0.00%)	0	0/29 (0.00%)	0	0/6 (0.00%)	0
Fibrous histiocytoma † 1	1/134 (0.75%)	1	0/99 (0.00%)	0	0/33 (0.00%)	0	0/29 (0.00%)	0	0/6 (0.00%)	0
Haemangioma of skin † 1	0/134 (0.00%)	0	1/99 (1.01%)	1	0/33 (0.00%)	0	0/29 (0.00%)	0	0/6 (0.00%)	0
Large intestine benign neoplasm † 1	1/134 (0.75%)	1	0/99 (0.00%)	0	0/33 (0.00%)	0	0/29 (0.00%)	0	0/6 (0.00%)	0
Leukaemia cutis † 1	1/134 (0.75%)	2	0/99 (0.00%)	0	0/33 (0.00%)	0	0/29 (0.00%)	0	0/6 (0.00%)	0
Lip neoplasm † 1	1/134 (0.75%)	1	0/99 (0.00%)	0	0/33 (0.00%)	0	0/29 (0.00%)	0	0/6 (0.00%)	0
Lip squamous cell carcinoma † 1	1/134 (0.75%)	1	0/99 (0.00%)	0	0/33 (0.00%)	0	0/29 (0.00%)	0	0/6 (0.00%)	0
Lipoma † 1	2/134 (1.49%)	2	2/99 (2.02%)	2	0/33 (0.00%)	0	0/29 (0.00%)	0	0/6 (0.00%)	0
Lung adenocarcinoma † 1	1/134 (0.75%)	1	0/99 (0.00%)	0	0/33 (0.00%)	0	0/29 (0.00%)	0	0/6 (0.00%)	0
Lung neoplasm malignant † 1	1/134 (0.75%)	1	0/99 (0.00%)	0	0/33 (0.00%)	0	0/29 (0.00%)	0	0/6 (0.00%)	0
Malignant melanoma † 1	2/134 (1.49%)	3	1/99 (1.01%)	1	1/33 (3.03%)	1	0/29 (0.00%)	0	0/6 (0.00%)	0
Malignant melanoma in situ † 1	1/134 (0.75%)	1	1/99 (1.01%)	1	0/33 (0.00%)	0	0/29 (0.00%)	0	0/6 (0.00%)	0
Melanocytic naevus † 1	2/134 (1.49%)	2	3/99 (3.03%)	3	0/33 (0.00%)	0	0/29 (0.00%)	0	0/6 (0.00%)	0
Metastases to spine † 1	1/134 (0.75%)	1	0/99 (0.00%)	0	0/33 (0.00%)	0	0/29 (0.00%)	0	0/6 (0.00%)	0
Nasal neoplasm † 1	1/134 (0.75%)	1	0/99 (0.00%)	0	0/33 (0.00%)	0	0/29 (0.00%)	0	0/6 (0.00%)	0
Neoplasm † 1	1/134 (0.75%)	1	0/99 (0.00%)	0	0/33 (0.00%)	0	0/29 (0.00%)	0	0/6 (0.00%)	0
Neoplasm skin † 1	1/134 (0.75%)	1	0/99 (0.00%)	0	0/33 (0.00%)	0	0/29 (0.00%)	0	0/6 (0.00%)	0
Ovarian neoplasm † 1	0/134 (0.00%)	0	1/99 (1.01%)	1	0/33 (0.00%)	0	0/29 (0.00%)	0	0/6 (0.00%)	0
Pancreatic neoplasm † 1	1/134 (0.75%)	1	0/99 (0.00%)	0	0/33 (0.00%)	0	0/29 (0.00%)	0	0/6 (0.00%)	0
Paraneoplastic syndrome † 1	0/134 (0.00%)	0	1/99 (1.01%)	1	0/33 (0.00%)	0	0/29 (0.00%)	0	0/6 (0.00%)	0
Prostate cancer † 1	2/134 (1.49%)	2	1/99 (1.01%)	1	0/33 (0.00%)	0	0/29 (0.00%)	0	0/6 (0.00%)	0
Renal cell carcinoma † 1	1/134 (0.75%)	1	0/99 (0.00%)	0	0/33 (0.00%)	0	0/29 (0.00%)	0	0/6 (0.00%)	0
Renal neoplasm † 1	3/134 (2.24%)	3	0/99 (0.00%)	0	0/33 (0.00%)	0	0/29 (0.00%)	0	0/6 (0.00%)	0
Sebaceous adenoma † 1	1/134 (0.75%)	1	0/99 (0.00%)	0	0/33 (0.00%)	0	0/29 (0.00%)	0	0/6 (0.00%)	0
Seborrhoeic keratosis † 1	6/134 (4.48%)	6	5/99 (5.05%)	5	0/33 (0.00%)	0	0/29 (0.00%)	0	0/6 (0.00%)	0
Sinonasal papilloma † 1	0/134 (0.00%)	0	1/99 (1.01%)	1	0/33 (0.00%)	0	0/29 (0.00%)	0	0/6 (0.00%)	0
Skin cancer † 1	1/134 (0.75%)	1	2/99 (2.02%)	2	0/33 (0.00%)	0	0/29 (0.00%)	0	0/6 (0.00%)	0
Skin neoplasm bleeding † 1	0/134 (0.00%)	0	1/99 (1.01%)	1	0/33 (0.00%)	0	0/29 (0.00%)	0	0/6 (0.00%)	0
Skin papilloma † 1	4/134 (2.99%)	4	2/99 (2.02%)	3	0/33 (0.00%)	0	1/29 (3.45%)	1	0/6 (0.00%)	0
Squamous cell carcinoma † 1	2/134 (1.49%)	2	4/99 (4.04%)	5	0/33 (0.00%)	0	0/29 (0.00%)	0	0/6 (0.00%)	0
Squamous cell carcinoma of skin † 1	8/134 (5.97%)	9	7/99 (7.07%)	7	1/33 (3.03%)	1	0/29 (0.00%)	0	0/6 (0.00%)	0
Tongue neoplasm benign † 1	1/134 (0.75%)	1	0/99 (0.00%)	0	0/33 (0.00%)	0	0/29 (0.00%)	0	0/6 (0.00%)	0
Transitional cell carcinoma † 1	1/134 (0.75%)	1	0/99 (0.00%)	0	0/33 (0.00%)	0	0/29 (0.00%)	0	0/6 (0.00%)	0
Uterine leiomyoma † 1	1/134 (0.75%)	1	0/99 (0.00%)	0	0/33 (0.00%)	0	0/29 (0.00%)	0	0/6 (0.00%)	0
Nervous system disorders
Amnesia † 1	0/134 (0.00%)	0	2/99 (2.02%)	2	0/33 (0.00%)	0	0/29 (0.00%)	0	0/6 (0.00%)	0
Aphasia † 1	1/134 (0.75%)	1	0/99 (0.00%)	0	0/33 (0.00%)	0	0/29 (0.00%)	0	0/6 (0.00%)	0
Balance disorder † 1	2/134 (1.49%)	2	0/99 (0.00%)	0	0/33 (0.00%)	0	0/29 (0.00%)	0	0/6 (0.00%)	0
Burning sensation † 1	0/134 (0.00%)	0	1/99 (1.01%)	1	1/33 (3.03%)	1	0/29 (0.00%)	0	0/6 (0.00%)	0
Carotid arteriosclerosis † 1	0/134 (0.00%)	0	1/99 (1.01%)	1	0/33 (0.00%)	0	0/29 (0.00%)	0	0/6 (0.00%)	0
Carotid artery aneurysm † 1	1/134 (0.75%)	1	0/99 (0.00%)	0	0/33 (0.00%)	0	0/29 (0.00%)	0	0/6 (0.00%)	0
Carpal tunnel syndrome † 1	5/134 (3.73%)	6	0/99 (0.00%)	0	0/33 (0.00%)	0	0/29 (0.00%)	0	0/6 (0.00%)	0
Cerebral microhaemorrhage † 1	0/134 (0.00%)	0	0/99 (0.00%)	0	1/33 (3.03%)	1	0/29 (0.00%)	0	0/6 (0.00%)	0
Cerebrovascular accident † 1	1/134 (0.75%)	1	0/99 (0.00%)	0	0/33 (0.00%)	0	0/29 (0.00%)	0	0/6 (0.00%)	0
Cervical radiculopathy † 1	0/134 (0.00%)	0	1/99 (1.01%)	1	0/33 (0.00%)	0	0/29 (0.00%)	0	0/6 (0.00%)	0
Cognitive disorder † 1	1/134 (0.75%)	1	0/99 (0.00%)	0	0/33 (0.00%)	0	0/29 (0.00%)	0	0/6 (0.00%)	0
Dementia alzheimer's type † 1	0/134 (0.00%)	0	1/99 (1.01%)	1	0/33 (0.00%)	0	0/29 (0.00%)	0	0/6 (0.00%)	0
Depressed level of consciousness † 1	0/134 (0.00%)	0	0/99 (0.00%)	0	0/33 (0.00%)	0	1/29 (3.45%)	1	0/6 (0.00%)	0
Disturbance in attention † 1	1/134 (0.75%)	1	0/99 (0.00%)	0	0/33 (0.00%)	0	0/29 (0.00%)	0	0/6 (0.00%)	0
Dizziness † 1	24/134 (17.91%)	27	20/99 (20.20%)	22	6/33 (18.18%)	7	4/29 (13.79%)	6	1/6 (16.67%)	1
Dizziness postural † 1	3/134 (2.24%)	3	0/99 (0.00%)	0	0/33 (0.00%)	0	0/29 (0.00%)	0	0/6 (0.00%)	0
Dysarthria † 1	0/134 (0.00%)	0	0/99 (0.00%)	0	1/33 (3.03%)	1	0/29 (0.00%)	0	0/6 (0.00%)	0
Dysgeusia † 1	4/134 (2.99%)	4	2/99 (2.02%)	2	1/33 (3.03%)	1	0/29 (0.00%)	0	0/6 (0.00%)	0
Encephalopathy † 1	0/134 (0.00%)	0	0/99 (0.00%)	0	0/33 (0.00%)	0	1/29 (3.45%)	1	0/6 (0.00%)	0
Facial paralysis † 1	1/134 (0.75%)	1	0/99 (0.00%)	0	0/33 (0.00%)	0	0/29 (0.00%)	0	0/6 (0.00%)	0
Headache † 1	68/134 (50.75%)	98	48/99 (48.48%)	79	14/33 (42.42%)	18	12/29 (41.38%)	16	1/6 (16.67%)	3
Hemianopia † 1	1/134 (0.75%)	1	0/99 (0.00%)	0	0/33 (0.00%)	0	0/29 (0.00%)	0	0/6 (0.00%)	0
Hemiparesis † 1	1/134 (0.75%)	1	2/99 (2.02%)	2	0/33 (0.00%)	0	0/29 (0.00%)	0	0/6 (0.00%)	0
Hypersomnia † 1	2/134 (1.49%)	3	0/99 (0.00%)	0	0/33 (0.00%)	0	0/29 (0.00%)	0	0/6 (0.00%)	0
Hypoaesthesia † 1	1/134 (0.75%)	1	3/99 (3.03%)	3	0/33 (0.00%)	0	0/29 (0.00%)	0	0/6 (0.00%)	0
Hypogeusia † 1	1/134 (0.75%)	1	0/99 (0.00%)	0	0/33 (0.00%)	0	0/29 (0.00%)	0	0/6 (0.00%)	0
Idiopathic partial epilepsy † 1	1/134 (0.75%)	1	0/99 (0.00%)	0	0/33 (0.00%)	0	0/29 (0.00%)	0	0/6 (0.00%)	0
Intracranial pressure increased † 1	0/134 (0.00%)	0	0/99 (0.00%)	0	0/33 (0.00%)	0	1/29 (3.45%)	1	0/6 (0.00%)	0
Lethargy † 1	2/134 (1.49%)	2	2/99 (2.02%)	2	1/33 (3.03%)	1	1/29 (3.45%)	1	0/6 (0.00%)	0
Memory impairment † 1	5/134 (3.73%)	6	5/99 (5.05%)	6	2/33 (6.06%)	3	0/29 (0.00%)	0	0/6 (0.00%)	0
Mental impairment † 1	2/134 (1.49%)	2	1/99 (1.01%)	1	1/33 (3.03%)	1	0/29 (0.00%)	0	0/6 (0.00%)	0
Migraine † 1	1/134 (0.75%)	1	2/99 (2.02%)	2	0/33 (0.00%)	0	0/29 (0.00%)	0	0/6 (0.00%)	0
Neuralgia † 1	3/134 (2.24%)	3	1/99 (1.01%)	1	1/33 (3.03%)	1	1/29 (3.45%)	1	0/6 (0.00%)	0
Neuropathy peripheral † 1	4/134 (2.99%)	4	1/99 (1.01%)	1	1/33 (3.03%)	1	1/29 (3.45%)	1	0/6 (0.00%)	0
Nystagmus † 1	0/134 (0.00%)	0	0/99 (0.00%)	0	1/33 (3.03%)	1	0/29 (0.00%)	0	0/6 (0.00%)	0
Paraesthesia † 1	19/134 (14.18%)	19	14/99 (14.14%)	15	5/33 (15.15%)	5	1/29 (3.45%)	2	0/6 (0.00%)	0
Parosmia † 1	0/134 (0.00%)	0	0/99 (0.00%)	0	1/33 (3.03%)	1	0/29 (0.00%)	0	0/6 (0.00%)	0
Peripheral motor neuropathy † 1	1/134 (0.75%)	1	0/99 (0.00%)	0	1/33 (3.03%)	1	0/29 (0.00%)	0	0/6 (0.00%)	0
Peripheral sensory neuropathy † 1	4/134 (2.99%)	5	5/99 (5.05%)	5	2/33 (6.06%)	2	2/29 (6.90%)	2	0/6 (0.00%)	0
Post herpetic neuralgia † 1	2/134 (1.49%)	2	1/99 (1.01%)	1	1/33 (3.03%)	2	0/29 (0.00%)	0	0/6 (0.00%)	0
Presyncope † 1	6/134 (4.48%)	7	4/99 (4.04%)	4	1/33 (3.03%)	1	0/29 (0.00%)	0	0/6 (0.00%)	0
Radiculopathy † 1	0/134 (0.00%)	0	1/99 (1.01%)	1	0/33 (0.00%)	0	0/29 (0.00%)	0	0/6 (0.00%)	0
Resting tremor † 1	1/134 (0.75%)	1	0/99 (0.00%)	0	0/33 (0.00%)	0	0/29 (0.00%)	0	0/6 (0.00%)	0
Restless legs syndrome † 1	1/134 (0.75%)	1	2/99 (2.02%)	2	1/33 (3.03%)	1	1/29 (3.45%)	1	0/6 (0.00%)	0
Retinal migraine † 1	1/134 (0.75%)	1	0/99 (0.00%)	0	0/33 (0.00%)	0	0/29 (0.00%)	0	0/6 (0.00%)	0
Sciatica † 1	1/134 (0.75%)	1	6/99 (6.06%)	7	1/33 (3.03%)	1	0/29 (0.00%)	0	0/6 (0.00%)	0
Seizure † 1	0/134 (0.00%)	0	1/99 (1.01%)	1	0/33 (0.00%)	0	1/29 (3.45%)	1	0/6 (0.00%)	0
Sinus headache † 1	3/134 (2.24%)	3	1/99 (1.01%)	1	0/33 (0.00%)	0	0/29 (0.00%)	0	0/6 (0.00%)	0
Somnolence † 1	2/134 (1.49%)	2	2/99 (2.02%)	2	0/33 (0.00%)	0	1/29 (3.45%)	1	0/6 (0.00%)	0
Spinal cord disorder † 1	0/134 (0.00%)	0	1/99 (1.01%)	1	0/33 (0.00%)	0	0/29 (0.00%)	0	0/6 (0.00%)	0
Subarachnoid haemorrhage † 1	1/134 (0.75%)	1	0/99 (0.00%)	0	0/33 (0.00%)	0	0/29 (0.00%)	0	0/6 (0.00%)	0
Syncope † 1	6/134 (4.48%)	6	7/99 (7.07%)	9	2/33 (6.06%)	2	0/29 (0.00%)	0	0/6 (0.00%)	0
Taste disorder † 1	2/134 (1.49%)	2	0/99 (0.00%)	0	1/33 (3.03%)	1	1/29 (3.45%)	1	0/6 (0.00%)	0
Tremor † 1	0/134 (0.00%)	0	2/99 (2.02%)	2	0/33 (0.00%)	0	0/29 (0.00%)	0	0/6 (0.00%)	0
Product Issues
Device dislocation † 1	1/134 (0.75%)	2	0/99 (0.00%)	0	0/33 (0.00%)	0	0/29 (0.00%)	0	0/6 (0.00%)	0
Psychiatric disorders
Abnormal dreams † 1	0/134 (0.00%)	0	1/99 (1.01%)	1	0/33 (0.00%)	0	0/29 (0.00%)	0	0/6 (0.00%)	0
Affect lability † 1	0/134 (0.00%)	0	2/99 (2.02%)	2	0/33 (0.00%)	0	0/29 (0.00%)	0	0/6 (0.00%)	0
Anger † 1	1/134 (0.75%)	1	0/99 (0.00%)	0	0/33 (0.00%)	0	0/29 (0.00%)	0	0/6 (0.00%)	0
Anxiety † 1	14/134 (10.45%)	15	9/99 (9.09%)	12	2/33 (6.06%)	2	0/29 (0.00%)	0	0/6 (0.00%)	0
Confusional state † 1	2/134 (1.49%)	4	3/99 (3.03%)	3	0/33 (0.00%)	0	2/29 (6.90%)	2	0/6 (0.00%)	0
Depressed mood † 1	2/134 (1.49%)	2	0/99 (0.00%)	0	0/33 (0.00%)	0	0/29 (0.00%)	0	0/6 (0.00%)	0
Depression † 1	10/134 (7.46%)	10	5/99 (5.05%)	5	1/33 (3.03%)	1	2/29 (6.90%)	2	0/6 (0.00%)	0
Emotional distress † 1	0/134 (0.00%)	0	1/99 (1.01%)	1	0/33 (0.00%)	0	0/29 (0.00%)	0	0/6 (0.00%)	0
Homicidal ideation † 1	1/134 (0.75%)	1	0/99 (0.00%)	0	0/33 (0.00%)	0	0/29 (0.00%)	0	0/6 (0.00%)	0
Insomnia † 1	18/134 (13.43%)	20	19/99 (19.19%)	20	5/33 (15.15%)	5	4/29 (13.79%)	4	0/6 (0.00%)	0
Libido decreased † 1	3/134 (2.24%)	3	0/99 (0.00%)	0	0/33 (0.00%)	0	0/29 (0.00%)	0	0/6 (0.00%)	0
Mental status changes † 1	1/134 (0.75%)	1	0/99 (0.00%)	0	0/33 (0.00%)	0	0/29 (0.00%)	0	0/6 (0.00%)	0
Panic attack † 1	0/134 (0.00%)	0	1/99 (1.01%)	1	0/33 (0.00%)	0	0/29 (0.00%)	0	0/6 (0.00%)	0
Phonophobia † 1	0/134 (0.00%)	0	1/99 (1.01%)	1	0/33 (0.00%)	0	0/29 (0.00%)	0	0/6 (0.00%)	0
Premature ejaculation † 1	1/134 (0.75%)	1	0/99 (0.00%)	0	0/33 (0.00%)	0	0/29 (0.00%)	0	0/6 (0.00%)	0
Sleep disorder † 1	1/134 (0.75%)	1	0/99 (0.00%)	0	0/33 (0.00%)	0	0/29 (0.00%)	0	0/6 (0.00%)	0
Stress † 1	1/134 (0.75%)	1	1/99 (1.01%)	1	0/33 (0.00%)	0	0/29 (0.00%)	0	0/6 (0.00%)	0
Suicidal ideation † 1	0/134 (0.00%)	0	1/99 (1.01%)	1	0/33 (0.00%)	0	0/29 (0.00%)	0	0/6 (0.00%)	0
Renal and urinary disorders
Acute kidney injury † 1	7/134 (5.22%)	9	1/99 (1.01%)	1	1/33 (3.03%)	1	0/29 (0.00%)	0	2/6 (33.33%)	2
Bladder hypertrophy † 1	1/134 (0.75%)	1	0/99 (0.00%)	0	0/33 (0.00%)	0	0/29 (0.00%)	0	0/6 (0.00%)	0
Chronic kidney disease † 1	3/134 (2.24%)	6	1/99 (1.01%)	1	1/33 (3.03%)	1	0/29 (0.00%)	0	0/6 (0.00%)	0
Dysuria † 1	6/134 (4.48%)	8	2/99 (2.02%)	2	1/33 (3.03%)	1	0/29 (0.00%)	0	0/6 (0.00%)	0
Haematuria † 1	7/134 (5.22%)	8	10/99 (10.10%)	13	3/33 (9.09%)	3	1/29 (3.45%)	1	0/6 (0.00%)	0
Lower urinary tract symptoms † 1	0/134 (0.00%)	0	1/99 (1.01%)	1	0/33 (0.00%)	0	0/29 (0.00%)	0	0/6 (0.00%)	0
Micturition urgency † 1	6/134 (4.48%)	6	2/99 (2.02%)	2	2/33 (6.06%)	2	1/29 (3.45%)	1	0/6 (0.00%)	0
Nephrolithiasis † 1	7/134 (5.22%)	9	1/99 (1.01%)	1	0/33 (0.00%)	0	0/29 (0.00%)	0	0/6 (0.00%)	0
Nocturia † 1	9/134 (6.72%)	9	5/99 (5.05%)	5	0/33 (0.00%)	0	0/29 (0.00%)	0	0/6 (0.00%)	0
Pollakiuria † 1	18/134 (13.43%)	20	8/99 (8.08%)	8	3/33 (9.09%)	4	1/29 (3.45%)	1	0/6 (0.00%)	0
Proteinuria † 1	0/134 (0.00%)	0	0/99 (0.00%)	0	1/33 (3.03%)	1	0/29 (0.00%)	0	0/6 (0.00%)	0
Renal colic † 1	1/134 (0.75%)	1	1/99 (1.01%)	1	0/33 (0.00%)	0	0/29 (0.00%)	0	0/6 (0.00%)	0
Renal failure † 1	1/134 (0.75%)	1	2/99 (2.02%)	2	0/33 (0.00%)	0	0/29 (0.00%)	0	0/6 (0.00%)	0
Renal impairment † 1	1/134 (0.75%)	1	0/99 (0.00%)	0	0/33 (0.00%)	0	0/29 (0.00%)	0	0/6 (0.00%)	0
Renal mass † 1	0/134 (0.00%)	0	1/99 (1.01%)	1	0/33 (0.00%)	0	0/29 (0.00%)	0	0/6 (0.00%)	0
Renal pain † 1	1/134 (0.75%)	1	0/99 (0.00%)	0	0/33 (0.00%)	0	0/29 (0.00%)	0	0/6 (0.00%)	0
Subcapsular renal haematoma † 1	1/134 (0.75%)	1	0/99 (0.00%)	0	0/33 (0.00%)	0	0/29 (0.00%)	0	0/6 (0.00%)	0
Urge incontinence † 1	1/134 (0.75%)	1	0/99 (0.00%)	0	0/33 (0.00%)	0	0/29 (0.00%)	0	0/6 (0.00%)	0
Urinary hesitation † 1	1/134 (0.75%)	1	0/99 (0.00%)	0	0/33 (0.00%)	0	0/29 (0.00%)	0	0/6 (0.00%)	0
Urinary incontinence † 1	5/134 (3.73%)	5	4/99 (4.04%)	4	0/33 (0.00%)	0	0/29 (0.00%)	0	0/6 (0.00%)	0
Urinary retention † 1	4/134 (2.99%)	4	4/99 (4.04%)	4	0/33 (0.00%)	0	0/29 (0.00%)	0	0/6 (0.00%)	0
Urinary tract obstruction † 1	1/134 (0.75%)	1	0/99 (0.00%)	0	0/33 (0.00%)	0	0/29 (0.00%)	0	0/6 (0.00%)	0
Urinary tract pain † 1	2/134 (1.49%)	2	0/99 (0.00%)	0	0/33 (0.00%)	0	1/29 (3.45%)	1	0/6 (0.00%)	0
Reproductive system and breast disorders
Benign prostatic hyperplasia † 1	4/134 (2.99%)	4	3/99 (3.03%)	3	0/33 (0.00%)	0	0/29 (0.00%)	0	0/6 (0.00%)	0
Breast mass † 1	0/134 (0.00%)	0	1/99 (1.01%)	1	0/33 (0.00%)	0	0/29 (0.00%)	0	0/6 (0.00%)	0
Breast pain † 1	0/134 (0.00%)	0	1/99 (1.01%)	1	0/33 (0.00%)	0	0/29 (0.00%)	0	0/6 (0.00%)	0
Erectile dysfunction † 1	5/134 (3.73%)	6	3/99 (3.03%)	3	0/33 (0.00%)	0	0/29 (0.00%)	0	0/6 (0.00%)	0
Genital haemorrhage † 1	0/134 (0.00%)	0	1/99 (1.01%)	1	0/33 (0.00%)	0	0/29 (0.00%)	0	0/6 (0.00%)	0
Gynaecomastia † 1	2/134 (1.49%)	2	0/99 (0.00%)	0	0/33 (0.00%)	0	0/29 (0.00%)	0	0/6 (0.00%)	0
Haematospermia † 1	1/134 (0.75%)	1	0/99 (0.00%)	0	0/33 (0.00%)	0	0/29 (0.00%)	0	0/6 (0.00%)	0
Oedema genital † 1	0/134 (0.00%)	0	1/99 (1.01%)	1	0/33 (0.00%)	0	0/29 (0.00%)	0	0/6 (0.00%)	0
Ovarian cyst † 1	1/134 (0.75%)	1	0/99 (0.00%)	0	0/33 (0.00%)	0	0/29 (0.00%)	0	0/6 (0.00%)	0
Pelvic pain † 1	1/134 (0.75%)	1	2/99 (2.02%)	3	1/33 (3.03%)	1	0/29 (0.00%)	0	0/6 (0.00%)	0
Penile oedema † 1	1/134 (0.75%)	1	0/99 (0.00%)	0	0/33 (0.00%)	0	0/29 (0.00%)	0	0/6 (0.00%)	0
Peyronie's disease † 1	1/134 (0.75%)	1	1/99 (1.01%)	1	0/33 (0.00%)	0	0/29 (0.00%)	0	0/6 (0.00%)	0
Postmenopausal haemorrhage † 1	1/134 (0.75%)	1	0/99 (0.00%)	0	0/33 (0.00%)	0	0/29 (0.00%)	0	0/6 (0.00%)	0
Prostatic obstruction † 1	0/134 (0.00%)	0	1/99 (1.01%)	1	0/33 (0.00%)	0	0/29 (0.00%)	0	0/6 (0.00%)	0
Prostatitis † 1	1/134 (0.75%)	1	1/99 (1.01%)	1	0/33 (0.00%)	0	0/29 (0.00%)	0	0/6 (0.00%)	0
Scrotal haemorrhage † 1	2/134 (1.49%)	2	0/99 (0.00%)	0	0/33 (0.00%)	0	0/29 (0.00%)	0	0/6 (0.00%)	0
Testicular cyst † 1	1/134 (0.75%)	1	0/99 (0.00%)	0	0/33 (0.00%)	0	0/29 (0.00%)	0	0/6 (0.00%)	0
Testicular mass † 1	0/134 (0.00%)	0	1/99 (1.01%)	1	0/33 (0.00%)	0	0/29 (0.00%)	0	0/6 (0.00%)	0
Testicular pain † 1	0/134 (0.00%)	0	1/99 (1.01%)	1	0/33 (0.00%)	0	0/29 (0.00%)	0	0/6 (0.00%)	0
Vaginal discharge † 1	0/134 (0.00%)	0	1/99 (1.01%)	1	0/33 (0.00%)	0	0/29 (0.00%)	0	0/6 (0.00%)	0
Vaginal haemorrhage † 1	2/134 (1.49%)	3	1/99 (1.01%)	1	0/33 (0.00%)	0	0/29 (0.00%)	0	0/6 (0.00%)	0
Vulvovaginal dryness † 1	0/134 (0.00%)	0	0/99 (0.00%)	0	1/33 (3.03%)	1	0/29 (0.00%)	0	0/6 (0.00%)	0
Vulvovaginal pruritus † 1	0/134 (0.00%)	0	1/99 (1.01%)	1	0/33 (0.00%)	0	0/29 (0.00%)	0	0/6 (0.00%)	0
Respiratory, thoracic and mediastinal disorders
Acquired diaphragmatic eventration † 1	0/134 (0.00%)	0	1/99 (1.01%)	1	0/33 (0.00%)	0	0/29 (0.00%)	0	0/6 (0.00%)	0
Asthma † 1	1/134 (0.75%)	1	1/99 (1.01%)	1	1/33 (3.03%)	1	0/29 (0.00%)	0	0/6 (0.00%)	0
Asthma exercise induced † 1	1/134 (0.75%)	1	0/99 (0.00%)	0	0/33 (0.00%)	0	0/29 (0.00%)	0	0/6 (0.00%)	0
Atelectasis † 1	1/134 (0.75%)	1	0/99 (0.00%)	0	0/33 (0.00%)	0	0/29 (0.00%)	0	0/6 (0.00%)	0
Bronchitis chronic † 1	0/134 (0.00%)	0	1/99 (1.01%)	1	0/33 (0.00%)	0	0/29 (0.00%)	0	0/6 (0.00%)	0
Catarrh † 1	1/134 (0.75%)	1	0/99 (0.00%)	0	0/33 (0.00%)	0	0/29 (0.00%)	0	0/6 (0.00%)	0
Chronic obstructive pulmonary disease † 1	1/134 (0.75%)	2	0/99 (0.00%)	0	0/33 (0.00%)	0	0/29 (0.00%)	0	0/6 (0.00%)	0
Cough † 1	47/134 (35.07%)	63	32/99 (32.32%)	41	13/33 (39.39%)	19	4/29 (13.79%)	12	1/6 (16.67%)	1
Dysphonia † 1	5/134 (3.73%)	7	4/99 (4.04%)	4	0/33 (0.00%)	0	0/29 (0.00%)	0	0/6 (0.00%)	0
Dyspnoea † 1	27/134 (20.15%)	36	17/99 (17.17%)	18	6/33 (18.18%)	6	3/29 (10.34%)	3	2/6 (33.33%)	2
Dyspnoea exertional † 1	5/134 (3.73%)	5	5/99 (5.05%)	5	1/33 (3.03%)	1	0/29 (0.00%)	0	1/6 (16.67%)	1
Emphysema † 1	0/134 (0.00%)	0	1/99 (1.01%)	1	0/33 (0.00%)	0	0/29 (0.00%)	0	0/6 (0.00%)	0
Epistaxis † 1	16/134 (11.94%)	25	12/99 (12.12%)	19	4/33 (12.12%)	7	3/29 (10.34%)	3	0/6 (0.00%)	0
Haemoptysis † 1	0/134 (0.00%)	0	1/99 (1.01%)	1	1/33 (3.03%)	1	0/29 (0.00%)	0	0/6 (0.00%)	0
Haemothorax † 1	0/134 (0.00%)	0	1/99 (1.01%)	1	0/33 (0.00%)	0	0/29 (0.00%)	0	0/6 (0.00%)	0
Hiccups † 1	0/134 (0.00%)	0	1/99 (1.01%)	1	0/33 (0.00%)	0	1/29 (3.45%)	1	0/6 (0.00%)	0
Hypoxia † 1	2/134 (1.49%)	6	1/99 (1.01%)	1	0/33 (0.00%)	0	2/29 (6.90%)	2	0/6 (0.00%)	0
Interstitial lung disease † 1	0/134 (0.00%)	0	1/99 (1.01%)	1	0/33 (0.00%)	0	0/29 (0.00%)	0	0/6 (0.00%)	0
Laryngeal haemorrhage † 1	1/134 (0.75%)	1	0/99 (0.00%)	0	0/33 (0.00%)	0	0/29 (0.00%)	0	0/6 (0.00%)	0
Laryngeal inflammation † 1	1/134 (0.75%)	1	1/99 (1.01%)	1	1/33 (3.03%)	1	0/29 (0.00%)	0	0/6 (0.00%)	0
Lung infiltration † 1	0/134 (0.00%)	0	1/99 (1.01%)	1	0/33 (0.00%)	0	0/29 (0.00%)	0	0/6 (0.00%)	0
Lung opacity † 1	0/134 (0.00%)	0	1/99 (1.01%)	1	0/33 (0.00%)	0	0/29 (0.00%)	0	0/6 (0.00%)	0
Nasal congestion † 1	20/134 (14.93%)	30	28/99 (28.28%)	30	6/33 (18.18%)	7	1/29 (3.45%)	1	0/6 (0.00%)	0
Nasal discomfort † 1	0/134 (0.00%)	0	1/99 (1.01%)	1	0/33 (0.00%)	0	0/29 (0.00%)	0	0/6 (0.00%)	0
Nasal septum deviation † 1	1/134 (0.75%)	1	0/99 (0.00%)	0	0/33 (0.00%)	0	0/29 (0.00%)	0	0/6 (0.00%)	0
Oropharyngeal pain † 1	23/134 (17.16%)	26	17/99 (17.17%)	22	4/33 (12.12%)	4	0/29 (0.00%)	0	0/6 (0.00%)	0
Orthopnoea † 1	1/134 (0.75%)	1	0/99 (0.00%)	0	0/33 (0.00%)	0	0/29 (0.00%)	0	0/6 (0.00%)	0
Paranasal sinus hypersecretion † 1	0/134 (0.00%)	0	1/99 (1.01%)	1	0/33 (0.00%)	0	0/29 (0.00%)	0	0/6 (0.00%)	0
Pharyngeal disorder † 1	1/134 (0.75%)	1	0/99 (0.00%)	0	0/33 (0.00%)	0	0/29 (0.00%)	0	0/6 (0.00%)	0
Pleural effusion † 1	3/134 (2.24%)	3	4/99 (4.04%)	6	1/33 (3.03%)	1	5/29 (17.24%)	6	0/6 (0.00%)	0
Pleurisy † 1	1/134 (0.75%)	1	0/99 (0.00%)	0	0/33 (0.00%)	0	0/29 (0.00%)	0	0/6 (0.00%)	0
Pleuritic pain † 1	1/134 (0.75%)	1	1/99 (1.01%)	2	0/33 (0.00%)	0	0/29 (0.00%)	0	0/6 (0.00%)	0
Pneumonia aspiration † 1	0/134 (0.00%)	0	2/99 (2.02%)	2	0/33 (0.00%)	0	0/29 (0.00%)	0	0/6 (0.00%)	0
Pneumothorax † 1	0/134 (0.00%)	0	1/99 (1.01%)	1	0/33 (0.00%)	0	0/29 (0.00%)	0	0/6 (0.00%)	0
Productive cough † 1	20/134 (14.93%)	28	8/99 (8.08%)	9	3/33 (9.09%)	5	2/29 (6.90%)	2	0/6 (0.00%)	0
Pulmonary hypertension † 1	2/134 (1.49%)	2	0/99 (0.00%)	0	0/33 (0.00%)	0	0/29 (0.00%)	0	0/6 (0.00%)	0
Pulmonary mass † 1	4/134 (2.99%)	4	6/99 (6.06%)	6	1/33 (3.03%)	1	0/29 (0.00%)	0	0/6 (0.00%)	0
Pulmonary oedema † 1	2/134 (1.49%)	2	0/99 (0.00%)	0	0/33 (0.00%)	0	1/29 (3.45%)	1	0/6 (0.00%)	0
Pulmonary pain † 1	0/134 (0.00%)	0	1/99 (1.01%)	1	0/33 (0.00%)	0	0/29 (0.00%)	0	0/6 (0.00%)	0
Rales † 1	0/134 (0.00%)	0	1/99 (1.01%)	1	0/33 (0.00%)	0	0/29 (0.00%)	0	0/6 (0.00%)	0
Reflux laryngitis † 1	1/134 (0.75%)	1	0/99 (0.00%)	0	1/33 (3.03%)	1	1/29 (3.45%)	1	0/6 (0.00%)	0
Respiratory acidosis † 1	0/134 (0.00%)	0	1/99 (1.01%)	1	0/33 (0.00%)	0	0/29 (0.00%)	0	0/6 (0.00%)	0
Respiratory disorder † 1	0/134 (0.00%)	0	1/99 (1.01%)	1	0/33 (0.00%)	0	0/29 (0.00%)	0	0/6 (0.00%)	0
Respiratory symptom † 1	0/134 (0.00%)	0	3/99 (3.03%)	3	0/33 (0.00%)	0	0/29 (0.00%)	0	0/6 (0.00%)	0
Respiratory tract congestion † 1	3/134 (2.24%)	3	2/99 (2.02%)	2	0/33 (0.00%)	0	1/29 (3.45%)	1	0/6 (0.00%)	0
Rhinalgia † 1	0/134 (0.00%)	0	0/99 (0.00%)	0	1/33 (3.03%)	1	0/29 (0.00%)	0	0/6 (0.00%)	0
Rhinitis allergic † 1	13/134 (9.70%)	15	14/99 (14.14%)	14	1/33 (3.03%)	1	0/29 (0.00%)	0	0/6 (0.00%)	0
Rhinorrhoea † 1	16/134 (11.94%)	17	9/99 (9.09%)	10	1/33 (3.03%)	2	1/29 (3.45%)	1	0/6 (0.00%)	0
Sinus congestion † 1	6/134 (4.48%)	7	6/99 (6.06%)	6	0/33 (0.00%)	0	0/29 (0.00%)	0	0/6 (0.00%)	0
Sinus disorder † 1	1/134 (0.75%)	1	1/99 (1.01%)	1	0/33 (0.00%)	0	0/29 (0.00%)	0	0/6 (0.00%)	0
Sinus pain † 1	0/134 (0.00%)	0	3/99 (3.03%)	3	0/33 (0.00%)	0	0/29 (0.00%)	0	0/6 (0.00%)	0
Sleep apnoea syndrome † 1	7/134 (5.22%)	7	5/99 (5.05%)	5	1/33 (3.03%)	1	0/29 (0.00%)	0	0/6 (0.00%)	0
Sneezing † 1	2/134 (1.49%)	2	3/99 (3.03%)	3	0/33 (0.00%)	0	0/29 (0.00%)	0	0/6 (0.00%)	0
Sputum increased † 1	1/134 (0.75%)	1	0/99 (0.00%)	0	0/33 (0.00%)	0	0/29 (0.00%)	0	0/6 (0.00%)	0
Stridor † 1	1/134 (0.75%)	1	0/99 (0.00%)	0	0/33 (0.00%)	0	0/29 (0.00%)	0	0/6 (0.00%)	0
Tachypnoea † 1	1/134 (0.75%)	1	1/99 (1.01%)	1	0/33 (0.00%)	0	1/29 (3.45%)	1	0/6 (0.00%)	0
Throat irritation † 1	1/134 (0.75%)	1	1/99 (1.01%)	1	1/33 (3.03%)	1	0/29 (0.00%)	0	0/6 (0.00%)	0
Tonsillolith † 1	0/134 (0.00%)	0	1/99 (1.01%)	1	0/33 (0.00%)	0	0/29 (0.00%)	0	0/6 (0.00%)	0
Upper respiratory tract congestion † 1	1/134 (0.75%)	1	0/99 (0.00%)	0	0/33 (0.00%)	0	0/29 (0.00%)	0	0/6 (0.00%)	0
Upper-airway cough syndrome † 1	16/134 (11.94%)	16	11/99 (11.11%)	16	5/33 (15.15%)	5	0/29 (0.00%)	0	0/6 (0.00%)	0
Vocal cord polyp † 1	1/134 (0.75%)	1	0/99 (0.00%)	0	0/33 (0.00%)	0	0/29 (0.00%)	0	0/6 (0.00%)	0
Wheezing † 1	2/134 (1.49%)	2	3/99 (3.03%)	3	0/33 (0.00%)	0	0/29 (0.00%)	0	0/6 (0.00%)	0
Skin and subcutaneous tissue disorders
Acne † 1	0/134 (0.00%)	0	1/99 (1.01%)	1	0/33 (0.00%)	0	0/29 (0.00%)	0	0/6 (0.00%)	0
Actinic keratosis † 1	10/134 (7.46%)	11	5/99 (5.05%)	5	2/33 (6.06%)	4	0/29 (0.00%)	0	0/6 (0.00%)	0
Alopecia † 1	8/134 (5.97%)	9	8/99 (8.08%)	8	1/33 (3.03%)	1	1/29 (3.45%)	1	0/6 (0.00%)	0
Blister † 1	0/134 (0.00%)	0	1/99 (1.01%)	1	1/33 (3.03%)	1	0/29 (0.00%)	0	0/6 (0.00%)	0
Blood blister † 1	3/134 (2.24%)	3	2/99 (2.02%)	3	1/33 (3.03%)	1	0/29 (0.00%)	0	0/6 (0.00%)	0
Brachioradial pruritus † 1	1/134 (0.75%)	1	0/99 (0.00%)	0	0/33 (0.00%)	0	0/29 (0.00%)	0	0/6 (0.00%)	0
Cold sweat † 1	1/134 (0.75%)	1	0/99 (0.00%)	0	1/33 (3.03%)	1	0/29 (0.00%)	0	0/6 (0.00%)	0
Decubitus ulcer † 1	1/134 (0.75%)	1	0/99 (0.00%)	0	0/33 (0.00%)	0	0/29 (0.00%)	0	0/6 (0.00%)	0
Dermal cyst † 1	3/134 (2.24%)	3	1/99 (1.01%)	1	0/33 (0.00%)	0	0/29 (0.00%)	0	0/6 (0.00%)	0
Dermatitis † 1	3/134 (2.24%)	3	0/99 (0.00%)	0	0/33 (0.00%)	0	0/29 (0.00%)	0	0/6 (0.00%)	0
Dermatitis acneiform † 1	1/134 (0.75%)	1	4/99 (4.04%)	4	0/33 (0.00%)	0	0/29 (0.00%)	0	0/6 (0.00%)	0
Dermatitis allergic † 1	0/134 (0.00%)	0	1/99 (1.01%)	1	0/33 (0.00%)	0	0/29 (0.00%)	0	0/6 (0.00%)	0
Dermatitis bullous † 1	1/134 (0.75%)	1	0/99 (0.00%)	0	1/33 (3.03%)	1	0/29 (0.00%)	0	0/6 (0.00%)	0
Dermatitis contact † 1	5/134 (3.73%)	5	5/99 (5.05%)	5	2/33 (6.06%)	2	0/29 (0.00%)	0	0/6 (0.00%)	0
Dermatitis exfoliative generalised † 1	1/134 (0.75%)	1	0/99 (0.00%)	0	0/33 (0.00%)	0	0/29 (0.00%)	0	0/6 (0.00%)	0
Dermatitis psoriasiform † 1	0/134 (0.00%)	0	1/99 (1.01%)	1	0/33 (0.00%)	0	0/29 (0.00%)	0	0/6 (0.00%)	0
Dermatosis † 1	1/134 (0.75%)	1	0/99 (0.00%)	0	0/33 (0.00%)	0	0/29 (0.00%)	0	0/6 (0.00%)	0
Drug eruption † 1	0/134 (0.00%)	0	0/99 (0.00%)	0	3/33 (9.09%)	4	0/29 (0.00%)	0	0/6 (0.00%)	0
Dry skin † 1	13/134 (9.70%)	14	6/99 (6.06%)	7	6/33 (18.18%)	7	0/29 (0.00%)	0	1/6 (16.67%)	1
Ecchymosis † 1	17/134 (12.69%)	18	16/99 (16.16%)	17	5/33 (15.15%)	5	0/29 (0.00%)	0	1/6 (16.67%)	1
Eczema † 1	5/134 (3.73%)	5	5/99 (5.05%)	5	3/33 (9.09%)	3	0/29 (0.00%)	0	0/6 (0.00%)	0
Eczema nummular † 1	1/134 (0.75%)	1	0/99 (0.00%)	0	0/33 (0.00%)	0	0/29 (0.00%)	0	0/6 (0.00%)	0
Erythema † 1	12/134 (8.96%)	12	3/99 (3.03%)	3	0/33 (0.00%)	0	0/29 (0.00%)	0	0/6 (0.00%)	0
Erythema annulare † 1	0/134 (0.00%)	0	2/99 (2.02%)	2	0/33 (0.00%)	0	0/29 (0.00%)	0	0/6 (0.00%)	0
Erythema nodosum † 1	1/134 (0.75%)	1	0/99 (0.00%)	0	1/33 (3.03%)	1	0/29 (0.00%)	0	0/6 (0.00%)	0
Follicular mucinosis † 1	0/134 (0.00%)	0	1/99 (1.01%)	1	0/33 (0.00%)	0	0/29 (0.00%)	0	0/6 (0.00%)	0
Granulomatous dermatitis † 1	1/134 (0.75%)	1	0/99 (0.00%)	0	0/33 (0.00%)	0	0/29 (0.00%)	0	0/6 (0.00%)	0
Hair texture abnormal † 1	1/134 (0.75%)	1	1/99 (1.01%)	1	0/33 (0.00%)	0	0/29 (0.00%)	0	0/6 (0.00%)	0
Hand dermatitis † 1	0/134 (0.00%)	0	1/99 (1.01%)	1	0/33 (0.00%)	0	0/29 (0.00%)	0	0/6 (0.00%)	0
Hyperhidrosis † 1	12/134 (8.96%)	14	11/99 (11.11%)	14	2/33 (6.06%)	2	2/29 (6.90%)	2	0/6 (0.00%)	0
Hypertrichosis † 1	0/134 (0.00%)	0	1/99 (1.01%)	1	0/33 (0.00%)	0	0/29 (0.00%)	0	0/6 (0.00%)	0
Ingrowing nail † 1	0/134 (0.00%)	0	2/99 (2.02%)	2	0/33 (0.00%)	0	0/29 (0.00%)	0	0/6 (0.00%)	0
Ingrown hair † 1	0/134 (0.00%)	0	0/99 (0.00%)	0	1/33 (3.03%)	1	0/29 (0.00%)	0	0/6 (0.00%)	0
Keratosis pilaris † 1	1/134 (0.75%)	1	0/99 (0.00%)	0	0/33 (0.00%)	0	0/29 (0.00%)	0	0/6 (0.00%)	0
Lichenoid keratosis † 1	0/134 (0.00%)	0	0/99 (0.00%)	0	0/33 (0.00%)	0	1/29 (3.45%)	1	0/6 (0.00%)	0
Macule † 1	0/134 (0.00%)	0	2/99 (2.02%)	2	0/33 (0.00%)	0	0/29 (0.00%)	0	0/6 (0.00%)	0
Madarosis † 1	0/134 (0.00%)	0	1/99 (1.01%)	1	0/33 (0.00%)	0	0/29 (0.00%)	0	0/6 (0.00%)	0
Miliaria † 1	0/134 (0.00%)	0	1/99 (1.01%)	1	0/33 (0.00%)	0	0/29 (0.00%)	0	0/6 (0.00%)	0
Nail bed bleeding † 1	1/134 (0.75%)	1	0/99 (0.00%)	0	0/33 (0.00%)	0	0/29 (0.00%)	0	0/6 (0.00%)	0
Nail bed inflammation † 1	1/134 (0.75%)	1	0/99 (0.00%)	0	0/33 (0.00%)	0	0/29 (0.00%)	0	0/6 (0.00%)	0
Nail discolouration † 1	3/134 (2.24%)	3	1/99 (1.01%)	1	1/33 (3.03%)	1	0/29 (0.00%)	0	0/6 (0.00%)	0
Nail disorder † 1	0/134 (0.00%)	0	0/99 (0.00%)	0	1/33 (3.03%)	1	0/29 (0.00%)	0	0/6 (0.00%)	0
Nail ridging † 1	0/134 (0.00%)	0	1/99 (1.01%)	1	0/33 (0.00%)	0	0/29 (0.00%)	0	0/6 (0.00%)	0
Necrobiosis lipoidica diabeticorum † 1	1/134 (0.75%)	1	0/99 (0.00%)	0	0/33 (0.00%)	0	0/29 (0.00%)	0	0/6 (0.00%)	0
Neurodermatitis † 1	0/134 (0.00%)	0	1/99 (1.01%)	1	0/33 (0.00%)	0	0/29 (0.00%)	0	0/6 (0.00%)	0
Night sweats † 1	21/134 (15.67%)	24	15/99 (15.15%)	19	2/33 (6.06%)	3	2/29 (6.90%)	2	0/6 (0.00%)	0
Nodular rash † 1	1/134 (0.75%)	1	0/99 (0.00%)	0	0/33 (0.00%)	0	0/29 (0.00%)	0	0/6 (0.00%)	0
Onychoclasis † 1	0/134 (0.00%)	0	2/99 (2.02%)	2	2/33 (6.06%)	2	1/29 (3.45%)	1	0/6 (0.00%)	0
Pain of skin † 1	1/134 (0.75%)	1	1/99 (1.01%)	1	0/33 (0.00%)	0	0/29 (0.00%)	0	0/6 (0.00%)	0
Panniculitis † 1	0/134 (0.00%)	0	0/99 (0.00%)	0	1/33 (3.03%)	1	0/29 (0.00%)	0	0/6 (0.00%)	0
Papule † 1	1/134 (0.75%)	1	0/99 (0.00%)	0	0/33 (0.00%)	0	0/29 (0.00%)	0	0/6 (0.00%)	0
Petechiae † 1	28/134 (20.90%)	34	18/99 (18.18%)	24	3/33 (9.09%)	3	2/29 (6.90%)	2	0/6 (0.00%)	0
Photosensitivity reaction † 1	0/134 (0.00%)	0	1/99 (1.01%)	1	0/33 (0.00%)	0	0/29 (0.00%)	0	0/6 (0.00%)	0
Pigmentation disorder † 1	0/134 (0.00%)	0	1/99 (1.01%)	1	0/33 (0.00%)	0	0/29 (0.00%)	0	0/6 (0.00%)	0
Pityriasis rosea † 1	0/134 (0.00%)	0	1/99 (1.01%)	1	0/33 (0.00%)	0	0/29 (0.00%)	0	0/6 (0.00%)	0
Poikiloderma † 1	0/134 (0.00%)	0	1/99 (1.01%)	1	0/33 (0.00%)	0	0/29 (0.00%)	0	0/6 (0.00%)	0
Precancerous skin lesion † 1	3/134 (2.24%)	3	3/99 (3.03%)	4	1/33 (3.03%)	1	0/29 (0.00%)	0	0/6 (0.00%)	0
Pruritus † 1	12/134 (8.96%)	15	8/99 (8.08%)	10	2/33 (6.06%)	2	2/29 (6.90%)	3	0/6 (0.00%)	0
Pruritus allergic † 1	1/134 (0.75%)	1	0/99 (0.00%)	0	0/33 (0.00%)	0	0/29 (0.00%)	0	0/6 (0.00%)	0
Psoriasis † 1	2/134 (1.49%)	4	0/99 (0.00%)	0	0/33 (0.00%)	0	0/29 (0.00%)	0	0/6 (0.00%)	0
Purpura † 1	0/134 (0.00%)	0	2/99 (2.02%)	2	0/33 (0.00%)	0	0/29 (0.00%)	0	0/6 (0.00%)	0
Purpura senile † 1	0/134 (0.00%)	0	3/99 (3.03%)	3	0/33 (0.00%)	0	0/29 (0.00%)	0	0/6 (0.00%)	0
Rash † 1	21/134 (15.67%)	23	18/99 (18.18%)	23	6/33 (18.18%)	6	2/29 (6.90%)	2	1/6 (16.67%)	1
Rash erythematous † 1	6/134 (4.48%)	6	4/99 (4.04%)	5	1/33 (3.03%)	1	0/29 (0.00%)	0	0/6 (0.00%)	0
Rash macular † 1	3/134 (2.24%)	3	2/99 (2.02%)	2	0/33 (0.00%)	0	0/29 (0.00%)	0	0/6 (0.00%)	0
Rash maculo-papular † 1	17/134 (12.69%)	18	12/99 (12.12%)	13	3/33 (9.09%)	4	0/29 (0.00%)	0	0/6 (0.00%)	0
Rash papular † 1	1/134 (0.75%)	1	1/99 (1.01%)	1	0/33 (0.00%)	0	0/29 (0.00%)	0	0/6 (0.00%)	0
Rash pruritic † 1	2/134 (1.49%)	2	3/99 (3.03%)	3	0/33 (0.00%)	0	0/29 (0.00%)	0	0/6 (0.00%)	0
Rash vesicular † 1	0/134 (0.00%)	0	0/99 (0.00%)	0	1/33 (3.03%)	2	0/29 (0.00%)	0	0/6 (0.00%)	0
Rosacea † 1	2/134 (1.49%)	2	3/99 (3.03%)	3	0/33 (0.00%)	0	0/29 (0.00%)	0	0/6 (0.00%)	0
Scab † 1	4/134 (2.99%)	4	1/99 (1.01%)	1	0/33 (0.00%)	0	0/29 (0.00%)	0	0/6 (0.00%)	0
Skin discolouration † 1	0/134 (0.00%)	0	1/99 (1.01%)	1	0/33 (0.00%)	0	0/29 (0.00%)	0	0/6 (0.00%)	0
Skin exfoliation † 1	1/134 (0.75%)	1	0/99 (0.00%)	0	0/33 (0.00%)	0	0/29 (0.00%)	0	0/6 (0.00%)	0
Skin fragility † 1	1/134 (0.75%)	1	0/99 (0.00%)	0	0/33 (0.00%)	0	0/29 (0.00%)	0	0/6 (0.00%)	0
Skin haemorrhage † 1	1/134 (0.75%)	1	0/99 (0.00%)	0	0/33 (0.00%)	0	1/29 (3.45%)	2	0/6 (0.00%)	0
Skin hyperpigmentation † 1	2/134 (1.49%)	2	3/99 (3.03%)	3	0/33 (0.00%)	0	0/29 (0.00%)	0	0/6 (0.00%)	0
Skin lesion † 1	18/134 (13.43%)	22	5/99 (5.05%)	5	5/33 (15.15%)	5	0/29 (0.00%)	0	0/6 (0.00%)	0
Skin mass † 1	2/134 (1.49%)	2	3/99 (3.03%)	5	3/33 (9.09%)	3	0/29 (0.00%)	0	0/6 (0.00%)	0
Skin plaque † 1	1/134 (0.75%)	1	0/99 (0.00%)	0	0/33 (0.00%)	0	0/29 (0.00%)	0	0/6 (0.00%)	0
Solar lentigo † 1	1/134 (0.75%)	1	0/99 (0.00%)	0	0/33 (0.00%)	0	0/29 (0.00%)	0	0/6 (0.00%)	0
Stasis dermatitis † 1	1/134 (0.75%)	1	0/99 (0.00%)	0	0/33 (0.00%)	0	0/29 (0.00%)	0	0/6 (0.00%)	0
Transient acantholytic dermatosis † 1	1/134 (0.75%)	1	0/99 (0.00%)	0	0/33 (0.00%)	0	0/29 (0.00%)	0	0/6 (0.00%)	0
Urticaria † 1	4/134 (2.99%)	6	3/99 (3.03%)	3	1/33 (3.03%)	1	0/29 (0.00%)	0	1/6 (16.67%)	1
Social circumstances
Excessive exercise † 1	1/134 (0.75%)	1	0/99 (0.00%)	0	0/33 (0.00%)	0	0/29 (0.00%)	0	0/6 (0.00%)	0
Vascular disorders
Haemorrhage † 1	0/134 (0.00%)	0	1/99 (1.01%)	1	0/33 (0.00%)	0	0/29 (0.00%)	0	0/6 (0.00%)	0
Hot flush † 1	5/134 (3.73%)	6	5/99 (5.05%)	6	1/33 (3.03%)	1	0/29 (0.00%)	0	0/6 (0.00%)	0
Hypertension † 1	29/134 (21.64%)	39	28/99 (28.28%)	60	6/33 (18.18%)	8	1/29 (3.45%)	1	0/6 (0.00%)	0
Hypertensive crisis † 1	1/134 (0.75%)	1	0/99 (0.00%)	0	0/33 (0.00%)	0	0/29 (0.00%)	0	0/6 (0.00%)	0
Hypotension † 1	7/134 (5.22%)	7	11/99 (11.11%)	11	5/33 (15.15%)	6	1/29 (3.45%)	1	2/6 (33.33%)	2
Lymphoedema † 1	1/134 (0.75%)	2	1/99 (1.01%)	1	1/33 (3.03%)	1	0/29 (0.00%)	0	0/6 (0.00%)	0
Orthostatic hypotension † 1	0/134 (0.00%)	0	5/99 (5.05%)	7	1/33 (3.03%)	1	0/29 (0.00%)	0	0/6 (0.00%)	0
Peripheral coldness † 1	0/134 (0.00%)	0	1/99 (1.01%)	2	0/33 (0.00%)	0	0/29 (0.00%)	0	0/6 (0.00%)	0
Plethoric face † 1	0/134 (0.00%)	0	1/99 (1.01%)	1	0/33 (0.00%)	0	0/29 (0.00%)	0	0/6 (0.00%)	0
Poor peripheral circulation † 1	0/134 (0.00%)	0	1/99 (1.01%)	1	0/33 (0.00%)	0	0/29 (0.00%)	0	0/6 (0.00%)	0
Thrombophlebitis superficial † 1	0/134 (0.00%)	0	0/99 (0.00%)	0	1/33 (3.03%)	1	0/29 (0.00%)	0	0/6 (0.00%)	0
Varicose vein † 1	1/134 (0.75%)	1	1/99 (1.01%)	1	0/33 (0.00%)	0	0/29 (0.00%)	0	0/6 (0.00%)	0
Vasculitis † 1	0/134 (0.00%)	0	1/99 (1.01%)	1	0/33 (0.00%)	0	0/29 (0.00%)	0	0/6 (0.00%)	0
Aortic aneurysm † 1	2/134 (1.49%)	2	2/99 (2.02%)	2	0/33 (0.00%)	0	0/29 (0.00%)	0	0/6 (0.00%)	0
Arterial thrombosis † 1	0/134 (0.00%)	0	0/99 (0.00%)	0	0/33 (0.00%)	0	0/29 (0.00%)	0	1/6 (16.67%)	1
Arteriosclerosis † 1	0/134 (0.00%)	0	1/99 (1.01%)	1	0/33 (0.00%)	0	0/29 (0.00%)	0	0/6 (0.00%)	0
Brachiocephalic vein thrombosis † 1	0/134 (0.00%)	0	0/99 (0.00%)	0	1/33 (3.03%)	1	0/29 (0.00%)	0	0/6 (0.00%)	0
Capillary disorder † 1	0/134 (0.00%)	0	1/99 (1.01%)	1	0/33 (0.00%)	0	0/29 (0.00%)	0	0/6 (0.00%)	0
Capillary leak syndrome † 1	1/134 (0.75%)	1	0/99 (0.00%)	0	0/33 (0.00%)	0	0/29 (0.00%)	0	0/6 (0.00%)	0
Deep vein thrombosis † 1	1/134 (0.75%)	1	0/99 (0.00%)	0	1/33 (3.03%)	1	0/29 (0.00%)	0	0/6 (0.00%)	0
Essential hypertension † 1	0/134 (0.00%)	0	0/99 (0.00%)	0	1/33 (3.03%)	1	0/29 (0.00%)	0	0/6 (0.00%)	0
Extravasation blood † 1	2/134 (1.49%)	2	0/99 (0.00%)	0	0/33 (0.00%)	0	0/29 (0.00%)	0	0/6 (0.00%)	0
Flushing † 1	3/134 (2.24%)	3	1/99 (1.01%)	1	0/33 (0.00%)	0	0/29 (0.00%)	0	0/6 (0.00%)	0
Haematoma † 1	6/134 (4.48%)	6	5/99 (5.05%)	6	0/33 (0.00%)	0	1/29 (3.45%)	1	0/6 (0.00%)	0
1 Term from vocabulary, MedDRA 24.0; † Indicates events were collected by systematic assessment

Limitations and Caveats

The Phase 2 dose was chosen on the basis of the pharmacodynamics data.

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.

MedImmune has 60 days to review results communications prior to public release and may delete information that compromises ongoing studies or is considered proprietary. This restriction is not intended to compromise the objective scientific integrity of the manuscript, it being understood that results shall be published regardless of outcome.

Results Point of Contact

• Name/Title: Global Clinical Lead
• Organization: Acerta Pharma BV
• Phone: 1-877-240-9479
• EMail: information.center@astrazeneca.com

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

Eyre TA, Schuh A, Wierda WG, Brown JR, Ghia P, Pagel JM, Furman RR, Cheung J, Hamdy A, Izumi R, Patel P, Wang MH, Xu Y, Byrd JC, Hillmen P. Acalabrutinib monotherapy for treatment of chronic lymphocytic leukaemia (ACE-CL-001): analysis of the Richter transformation cohort of an open-label, single-arm, phase 1-2 study. Lancet Haematol. 2021 Dec;8(12):e912-e921. doi: 10.1016/S2352-3026(21)00305-7. Epub 2021 Nov 1.

Byrd JC, Wierda WG, Schuh A, Devereux S, Chaves JM, Brown JR, Hillmen P, Martin P, Awan FT, Stephens DM, Ghia P, Barrientos J, Pagel JM, Woyach JA, Burke K, Covey T, Gulrajani M, Hamdy A, Izumi R, Frigault MM, Patel P, Rothbaum W, Wang MH, O'Brien S, Furman RR. Acalabrutinib monotherapy in patients with relapsed/refractory chronic lymphocytic leukemia: updated phase 2 results. Blood. 2020 Apr 9;135(15):1204-1213. doi: 10.1182/blood.2018884940.

Awan FT, Schuh A, Brown JR, Furman RR, Pagel JM, Hillmen P, Stephens DM, Woyach J, Bibikova E, Charuworn P, Frigault MM, Hamdy A, Izumi R, Linghu B, Patel P, Wang MH, Byrd JC. Acalabrutinib monotherapy in patients with chronic lymphocytic leukemia who are intolerant to ibrutinib. Blood Adv. 2019 May 14;3(9):1553-1562. doi: 10.1182/bloodadvances.2018030007.

Long M, Beckwith K, Do P, Mundy BL, Gordon A, Lehman AM, Maddocks KJ, Cheney C, Jones JA, Flynn JM, Andritsos LA, Awan F, Fraietta JA, June CH, Maus MV, Woyach JA, Caligiuri MA, Johnson AJ, Muthusamy N, Byrd JC. Ibrutinib treatment improves T cell number and function in CLL patients. J Clin Invest. 2017 Aug 1;127(8):3052-3064. doi: 10.1172/JCI89756. Epub 2017 Jul 17.

Byrd JC, Harrington B, O'Brien S, Jones JA, Schuh A, Devereux S, Chaves J, Wierda WG, Awan FT, Brown JR, Hillmen P, Stephens DM, Ghia P, Barrientos JC, Pagel JM, Woyach J, Johnson D, Huang J, Wang X, Kaptein A, Lannutti BJ, Covey T, Fardis M, McGreivy J, Hamdy A, Rothbaum W, Izumi R, Diacovo TG, Johnson AJ, Furman RR. Acalabrutinib (ACP-196) in Relapsed Chronic Lymphocytic Leukemia. N Engl J Med. 2016 Jan 28;374(4):323-32. doi: 10.1056/NEJMoa1509981. Epub 2015 Dec 7.

• Responsible Party: Acerta Pharma BV
• ClinicalTrials.gov Identifier: NCT02029443
• Other Study ID Numbers: ACE-CL-001; 2014-000440-15 ( EudraCT Number )
• First Submitted: January 6, 2014
• First Posted: January 8, 2014
• Results First Submitted: June 27, 2022
• Results First Posted: September 10, 2022
• Last Update Posted: April 24, 2024