Phase II Trial of Pimasertib Versus Dacarbazine in N-Ras Mutated Cutaneous Melanoma

• ClinicalTrials.gov Identifier: NCT01693068
• Recruitment Status: Completed
• First Posted: September 26, 2012
• Results First Posted: January 5, 2018
• Last Update Posted: January 5, 2018
• Sponsor: EMD Serono
• Collaborator: Merck KGaA, Darmstadt, Germany
• Information provided by (Responsible Party): EMD Serono

• Study Type: Interventional
• Study Design: Allocation: Randomized; Intervention Model: Parallel Assignment; Masking: None (Open Label); Primary Purpose: Treatment
• Condition: N-Ras Mutated Locally Advanced or Metastasis Malignant Cutaneous Melanoma
• Interventions: Drug: Pimasertib; Drug: Dacarbazine
• Enrollment: 194

Participant Flow

Recruitment Details	First/last subject (informed consent): 05 December 2012/04 June 2014. Cut-off date: 04 July 2015. Last subject last visit: 24 October 2016.
Pre-assignment Details	A total of 194 subjects were randomized in trial. Data presented based on the cut-off date of 04 July 2015.

Arm/Group Title	Dacarbazine	Pimasertib	Pimasertib (Crossover)
Arm/Group Description	Subjects received dacarbazine intravenously at dose of 1000 mg/m^2 of body surface area every 3 weeks on Day 1 of each 21-days cycle until progression of the disease, unacceptable toxicity, withdrawal of informed consent, or death, whichever occurred first. Eligible subjects with documented tumor progression on dacarbazine were offered to switch to pimasertib treatment.	Subjects received pimasertib orally as monotherapy at a dose of 60 milligram (mg) twice daily continuously. Treatment consisted of repeated 21-day cycles which was continued until progression of the disease, unacceptable toxicity, withdrawal of informed consent, or death, whichever occurred first.	Subjects who were randomized and received dacarbazine and were allowed to crossover to pimasertib treatment on progression of their disease.
Period Title: Randomization Period
Started	64	130	0
Treated	61	130	0
Completed	62	125	0
Not Completed	2	5	0
Reason Not Completed
On-study	2	5	0
Period Title: Cross-over (Dacarbazine To Pimasertib)
Started	0	0	41
Treated	0	0	41
Completed	0	0	40
Not Completed	0	0	1
Reason Not Completed
On-study	0	0	1

Baseline Characteristics

Arm/Group Title		Dacarbazine	Pimasertib	Total
Arm/Group Description		Subjects received dacarbazine intravenously at dose of 1000 mg/m^2 of body surface area every 3 weeks on Day 1 of each 21-days cycle until progression of the disease, unacceptable toxicity, withdrawal of informed consent, or death, whichever occurred first. Eligible subjects with documented tumor progression on dacarbazine were offered to switch to pimasertib treatment.	Subjects received pimasertib orally as monotherapy at a dose of 60 mg twice daily continuously. Treatment consisted of repeated 21-day cycles which was continued until progression of the disease, unacceptable toxicity, withdrawal of informed consent, or death, whichever occurred first.	Total of all reporting groups
Overall Number of Baseline Participants		64	130	194
Baseline Analysis Population Description		Intent-to-treat (ITT) analysis set included all subjects who were randomized to trial treatment.
Age, Categorical; Measure Type: Count of Participants; Unit of measure: Participants
	Number Analyzed	64 participants	130 participants	194 participants
	<=18 years	0 0.0%	0 0.0%	0 0.0%
	Between 18 and 65 years	36 56.3%	65 50.0%	101 52.1%
	>=65 years	28 43.8%	65 50.0%	93 47.9%
Sex: Female, Male; Measure Type: Count of Participants; Unit of measure: Participants
	Number Analyzed	64 participants	130 participants	194 participants
	Female	28 43.8%	62 47.7%	90 46.4%
	Male	36 56.3%	68 52.3%	104 53.6%

Outcome Measures

1. Primary Outcome

Title	Progression Free Survival (PFS)
Description	PFS was defined as the duration (in weeks) from randomization until the first progressive disease (PD) observation as assessed by the Investigator according to Response Evaluation Criteria for Solid Tumors (RECIST) version 1.1, or death due to any cause when death occurred within 12 weeks after the last tumor assessment (otherwise censored), whichever occurred first. PD was defined as at least a 20% increase in the sum of diameters of the target lesions, taking as reference the smallest sum since the treatment started (including baseline), or appearance of one or more new lesions, and/or unequivocal progression of existing non-target lesions.
Time Frame	From date of randomization until the date of first documented progression or date of death from any cause, whichever came first, assessed up to cut-off date (04-Jul-2015)

Outcome Measure Data

Analysis Population Description

ITT analysis set included all subjects who were randomized to trial treatment.

Arm/Group Title	Dacarbazine	Pimasertib
Arm/Group Description:	Subjects received dacarbazine intravenously at dose of 1000 mg/m^2 of body surface area every 3 weeks on Day 1 of each 21-days cycle until progression of the disease, unacceptable toxicity, withdrawal of informed consent, or death, whichever occurred first. Eligible subjects with documented tumor progression on dacarbazine were offered to switch to pimasertib treatment.	Subjects received pimasertib orally as monotherapy at a dose of 60 mg twice daily continuously. Treatment consisted of repeated 21-day cycles which was continued until progression of the disease, unacceptable toxicity, withdrawal of informed consent, or death, whichever occurred first.
Overall Number of Participants Analyzed	64	130
Median (95% Confidence Interval); Unit of Measure: weeks
	6.86; (6.00 to 12.14)	13.00; (12.29 to 17.71)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Dacarbazine, Pimasertib
	Comments	[Not Specified]
	Type of Statistical Test	Other
	Comments	A log-rank test stratified by baseline Eastern Cooperative Oncology Group performance status (ECOG PS) (using the interactive voice response system [IVRS] value) will tested the null hypothesis of no difference between the Pimasertib (first line) and the Dacarbazine treatment groups at the 5% level.
Statistical Test of Hypothesis	P-Value	0.0022
	Comments	[Not Specified]
	Method	Stratified Log Rank Test
	Comments	[Not Specified]
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.59
	Confidence Interval	(2-Sided) 95%; 0.42 to 0.83
	Estimation Comments	The Hazard Ratio is obtained from the Cox Proportional Hazards model based on dacarbazine and pimasertib only stratified by baseline ECOG Performance Status.

2. Secondary Outcome

Title	Objective Response Rate (ORR)
Description	ORR was defined as the percentage of subjects with complete response (CR) or partial response (PR) according to RECIST version 1.1 criteria. CR: defined as disappearance of all target and all non-target lesions. Any pathological lymph nodes (whether target or non-target) must have reduction in short axis to less than (<) 10 millimeter (mm). PR: defined as at least a 30% decrease in sum of diameters of target lesions, taking as reference the baseline sum diameters along with absence of new lesions and disease progression in non-target lesions.
Time Frame	From date of randomization until the date of first documented progression or date of death from any cause, whichever came first, assessed up to cut-off date (04-Jul-2015)

Outcome Measure Data

Analysis Population Description

ITT analysis set included all subjects who were randomized to trial treatment.

Arm/Group Title	Dacarbazine	Pimasertib
Arm/Group Description:	Subjects received dacarbazine intravenously at dose of 1000 mg/m^2 of body surface area every 3 weeks on Day 1 of each 21-days cycle until progression of the disease, unacceptable toxicity, withdrawal of informed consent, or death, whichever occurred first. Eligible subjects with documented tumor progression on dacarbazine were offered to switch to pimasertib treatment.	Subjects received pimasertib orally as monotherapy at a dose of 60 mg twice daily continuously. Treatment consisted of repeated 21-day cycles which was continued until progression of the disease, unacceptable toxicity, withdrawal of informed consent, or death, whichever occurred first.
Overall Number of Participants Analyzed	64	130
Measure Type: Number; Number (95% Confidence Interval); Unit of Measure: percentage of subjects
	14.1; (6.6 to 25.0)	26.9; (19.5 to 35.4)

3. Secondary Outcome

Title	Disease Control Rate (DCR)
Description	DCR was defined as the percentage of subjects with CR, PR, or stable disease (SD) for greater than (>) 3 months assessed by investigator according to RECIST version 1.1. CR: defined as disappearance of all target and all non-target lesions. Any pathological lymph nodes (whether target or non-target) must have reduction in short axis to less than <10 mm. PR: defined as at least a 30% decrease in sum of diameters of target lesions, taking as reference the baseline sum diameters along with absence of new lesions and disease progression in non-target lesions. SD: defined as neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD, taking as reference the smallest sum diameters while on study.
Time Frame	From date of randomization until the date of first documented progression or date of death from any cause, whichever came first, assessed up to cut-off date (04-Jul-2015)

Outcome Measure Data

Analysis Population Description

ITT analysis set included all subjects who were randomized to trial treatment.

Arm/Group Title	Dacarbazine	Pimasertib
Arm/Group Description:	Subjects received dacarbazine intravenously at dose of 1000 mg/m^2 of body surface area every 3 weeks on Day 1 of each 21-days cycle until progression of the disease, unacceptable toxicity, withdrawal of informed consent, or death, whichever occurred first. Eligible subjects with documented tumor progression on dacarbazine were offered to switch to pimasertib treatment.	Subjects received pimasertib orally as monotherapy at a dose of 60 mg twice daily continuously. Treatment consisted of repeated 21-day cycles which was continued until progression of the disease, unacceptable toxicity, withdrawal of informed consent, or death, whichever occurred first.
Overall Number of Participants Analyzed	64	130
Measure Type: Number; Number (95% Confidence Interval); Unit of Measure: percentage of subjects
	15.6; (7.8 to 26.9)	33.1; (25.1 to 41.9)

4. Secondary Outcome

Title	Percentage of Subjects With Progression-free Survival (PFS) at 6 Months
Description	PFS was defined as the duration (in weeks) from randomization until the first progressive disease (PD) observation as assessed by the Investigator according to Response Evaluation Criteria for Solid Tumors (RECIST) version 1.1, or death due to any cause when death occurred within 12 weeks after the last tumor assessment, whichever occurred first. PD was defined as at least a 20% increase in the sum of diameters of the target lesions, taking as reference the smallest sum since the treatment started (including baseline), or appearance of one or more new lesions, and/or unequivocal progression of existing non-target lesions. Percentage of Subjects with PFS at 6 Months were reported.
Time Frame	6 months

Outcome Measure Data

Analysis Population Description

ITT analysis set included all subjects who were randomized to trial treatment.

Arm/Group Title	Dacarbazine	Pimasertib
Arm/Group Description:	Subjects received dacarbazine intravenously at dose of 1000 mg/m^2 of body surface area every 3 weeks on Day 1 of each 21-days cycle until progression of the disease, unacceptable toxicity, withdrawal of informed consent, or death, whichever occurred first. Eligible subjects with documented tumor progression on dacarbazine were offered to switch to pimasertib treatment.	Subjects received pimasertib orally as monotherapy at a dose of 60 mg twice daily continuously. Treatment consisted of repeated 21-day cycles which was continued until progression of the disease, unacceptable toxicity, withdrawal of informed consent, or death, whichever occurred first.
Overall Number of Participants Analyzed	64	130
Measure Type: Number; Number (95% Confidence Interval); Unit of Measure: percentage of subjects
	9.4; (3.6 to 18.6)	17.3; (10.2 to 26.0)

5. Secondary Outcome

Title	Overall Survival (OS)
Description	OS was defined as the time (in months) from randomization to death due to any cause. Subjects without a death date were to be censored at the minimum of last known date alive, defined as the latest date available on the electronic case report form, and cut-off date.
Time Frame	From date of randomization until date of death from any cause, assessed up to cut-off date (04-Jul-2015)

Outcome Measure Data

Analysis Population Description

ITT analysis set included all subjects who were randomized to trial treatment.

Arm/Group Title	Dacarbazine	Pimasertib
Arm/Group Description:	Subjects received dacarbazine intravenously at dose of 1000 mg/m^2 of body surface area every 3 weeks on Day 1 of each 21-days cycle until progression of the disease, unacceptable toxicity, withdrawal of informed consent, or death, whichever occurred first. Eligible subjects with documented tumor progression on dacarbazine were offered to switch to pimasertib treatment.	Subjects received pimasertib orally as monotherapy at a dose of 60 mg twice daily continuously. Treatment consisted of repeated 21-day cycles which was continued until progression of the disease, unacceptable toxicity, withdrawal of informed consent, or death, whichever occurred first.
Overall Number of Participants Analyzed	64	130
Median (95% Confidence Interval); Unit of Measure: months
	10.61; (7.26 to 16.49)	8.87; (7.46 to 15.51)

6. Secondary Outcome

Title	Percentage of Subjects With Overall Survival (OS) at 12 Months
Description	OS was defined as the time (in months) from randomization to death due to any cause. Subjects without a death date were to be censored at the minimum of last known date alive, defined as the latest date available on the electronic case report form, and cut-off date. Percentage of Subjects with OS at 12 months were reported.
Time Frame	12 months

Outcome Measure Data

Analysis Population Description

ITT analysis set included all subjects who were randomized to trial treatment.

Arm/Group Title	Dacarbazine	Pimasertib
Arm/Group Description:	Subjects received dacarbazine intravenously at dose of 1000 mg/m^2 of body surface area every 3 weeks on Day 1 of each 21-days cycle until progression of the disease, unacceptable toxicity, withdrawal of informed consent, or death, whichever occurred first. Eligible subjects with documented tumor progression on dacarbazine were offered to switch to pimasertib treatment.	Subjects received pimasertib orally as monotherapy at a dose of 60 mg twice daily continuously. Treatment consisted of repeated 21-day cycles which was continued until progression of the disease, unacceptable toxicity, withdrawal of informed consent, or death, whichever occurred first.
Overall Number of Participants Analyzed	64	130
Measure Type: Number; Number (95% Confidence Interval); Unit of Measure: percentage of subjects
	44.5; (31.6 to 56.6)	43.3; (34.5 to 51.8)

7. Secondary Outcome

Title	Change From Baseline in Subject-reported Quality of Life Assessed by Functional Assessment Cancer Therapy - Melanoma Total Score (FACT-M TS) at Day 1 of Pre-Specified Cycles and End of Treatment (EOT)
Description	QoL assessed using Function Assessment Cancer Therapy-melanoma (FACT-M) assessment tool. This includes 27-item FACT-General (FACT-G) questionnaire which consists of 24 questions;7 relating to physical well-being (PWB),7 relating to social/family well-being (SWB),6 relating to emotional well-being (EWB) and 7 relating to functional well-being (FWB). Also, it includes melanoma-specific subscale consists of 16 questions for Melanoma Subscale (MS) and 8 questions for Melanoma Surgery Scale (MSS).Each of these questions could have a response of Not at all, a little bit, somewhat, quite a bit and very much. The responses were given a value between 0 and 4 with 4 being best response. The FACT-M Total Score (FACT-M TS) ranges from 0 to 172 and is derived as follows: FACT-M TS= PWB Score + SWB Score + EWB Score + FWB Score + MS Score. Higher scores represent a better quality of life.
Time Frame	Baseline, Day 1 of Cycle 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 30, 31, 32, 33, 35, 36, 37 and EOT (up to cut-off date [04-Jul-2015])

Outcome Measure Data

Analysis Population Description

ITT analysis set. Here "Number of Subjects Analyzed" = subjects evaluable for this outcome and "Number Analyzed" = subjects evaluable at specified time points for each arm, respectively. There were no subjects analyzed at certain time points (that is, Number Analyzed = 0) because there was no data collected for respective arms at those time points.

Arm/Group Title		Dacarbazine	Pimasertib
Arm/Group Description:		Subjects received dacarbazine intravenously at dose of 1000 mg/m^2 of body surface area every 3 weeks on Day 1 of each 21-days cycle until progression of the disease, unacceptable toxicity, withdrawal of informed consent, or death, whichever occurred first. Eligible subjects with documented tumor progression on dacarbazine were offered to switch to pimasertib treatment.	Subjects received pimasertib orally as monotherapy at a dose of 60 mg twice daily continuously. Treatment consisted of repeated 21-day cycles which was continued until progression of the disease, unacceptable toxicity, withdrawal of informed consent, or death, whichever occurred first.
Overall Number of Participants Analyzed		58	126
Mean (Standard Deviation); Unit of Measure: units on a scale
Baseline	Number Analyzed	58 participants	126 participants
		126.20 (23.828)	132.24 (22.179)
Change at Day 1 Cycle 2	Number Analyzed	45 participants	99 participants
		-3.05 (14.815)	-3.06 (18.492)
Change at Day 1 Cycle 3	Number Analyzed	24 participants	73 participants
		0.60 (19.965)	-6.77 (21.716)
Change at Day 1 Cycle 4	Number Analyzed	23 participants	63 participants
		4.11 (14.746)	-6.54 (19.919)
Change at Day 1 Cycle 5	Number Analyzed	10 participants	45 participants
		0.62 (11.810)	-2.81 (17.202)
Change at Day 1 Cycle 6	Number Analyzed	9 participants	33 participants
		-3.71 (15.674)	-8.45 (20.939)
Change at Day 1 Cycle 7	Number Analyzed	9 participants	29 participants
		-1.10 (13.318)	-8.84 (19.128)
Change at Day 1 Cycle 8	Number Analyzed	8 participants	18 participants
		1.28 (12.928)	-14.67 (18.508)
Change at Day 1 Cycle 9	Number Analyzed	6 participants	12 participants
		2.21 (16.224)	-13.67 (21.388)
Change at Day 1 Cycle 10	Number Analyzed	6 participants	10 participants
		4.40 (14.818)	-13.26 (20.716)
Change at Day 1 Cycle 11	Number Analyzed	4 participants	11 participants
		1.02 (19.161)	-14.10 (21.157)
Change at Day 1 Cycle 12	Number Analyzed	4 participants	11 participants
		1.56 (19.932)	-10.52 (18.895)
Change at Day 1 Cycle 13	Number Analyzed	4 participants	6 participants
		5.51 (20.191)	-13.38 (23.690)
Change at Day 1 Cycle 14	Number Analyzed	2 participants	8 participants
		11.50 (21.920)	-18.24 (22.998)
Change at Day 1 Cycle 15	Number Analyzed	3 participants	7 participants
		9.60 (15.345)	-11.33 (19.787)
Change at Day 1 Cycle 16	Number Analyzed	3 participants	7 participants
		10.56 (14.935)	-11.18 (23.680)
Change at Day 1 Cycle 17	Number Analyzed	2 participants	6 participants
		3.00 (5.657)	-9.18 (24.166)
Change at Day 1 Cycle 18	Number Analyzed	1 participants	5 participants
		27.00 [1] (NA)	-3.92 (9.640)
Change at Day 1 Cycle 19	Number Analyzed	2 participants	4 participants
		16.50 (14.849)	-1.15 (8.147)
Change at Day 1 Cycle 20	Number Analyzed	2 participants	3 participants
		16.00 (15.556)	1.17 (5.947)
Change at Day 1 Cycle 21	Number Analyzed	2 participants	3 participants
		17.00 (14.142)	4.17 (8.918)
Change at Day 1 Cycle 22	Number Analyzed	2 participants	3 participants
		18.00 (12.728)	1.32 (11.163)
Change at Day 1 Cycle 23	Number Analyzed	1 participants	2 participants
		27.00 [1] (NA)	-13.69 (15.354)
Change at Day 1 Cycle 24	Number Analyzed	2 participants	1 participants
		13.50 (19.092)	-3.83 [1] (NA)
Change at Day 1 Cycle 25	Number Analyzed	2 participants	1 participants
		14.50 (17.678)	-3.83 [1] (NA)
Change at Day 1 Cycle 26	Number Analyzed	1 participants	1 participants
		27.00 [1] (NA)	-2.83 [1] (NA)
Change at Day 1 Cycle 27	Number Analyzed	1 participants	0 participants
		27.00 [1] (NA)
Change at Day 1 Cycle 28	Number Analyzed	1 participants	1 participants
		27.00 [1] (NA)	-0.83 [1] (NA)
Change at Day 1 Cycle 30	Number Analyzed	0 participants	1 participants
			-1.83 [1] (NA)
Change at Day 1 Cycle 31	Number Analyzed	0 participants	1 participants
			-7.83 [1] (NA)
Change at Day 1 Cycle 32	Number Analyzed	0 participants	1 participants
			-7.83 [1] (NA)
Change at Day 1 Cycle 33	Number Analyzed	0 participants	1 participants
			-8.83 [1] (NA)
Change at Day 1 Cycle 35	Number Analyzed	0 participants	1 participants
			-1.83 [1] (NA)
Change at Day 1 Cycle 36	Number Analyzed	0 participants	1 participants
			-3.83 [1] (NA)
Change at Day 1 Cycle 37	Number Analyzed	0 participants	1 participants
			-4.83 [1] (NA)
Change at EOT	Number Analyzed	28 participants	75 participants
		-7.91 (23.119)	-9.98 (20.560)

[1]

Standard deviation could not be estimated as there was only 1 subject analyzed at the specified time point.

8. Secondary Outcome

Title	Change From Baseline in Subject-reported Quality of Life Assessed by Functional Assessment Cancer Therapy - Melanoma Trial Outcome Index (FACT-M TOI) at Day 1 of Pre-Specified Cycles and End of Treatment (EOT)
Description	QoL assessed using FACT-M assessment tool. This includes 27-item FACT-G questionnaire which consists of 24 questions; 7 relating to PWB, 7 relating to SWB, 6 relating to EWB and 7 relating to FWB. Also, it includes melanoma-specific subscale consists of 16 questions for MS and 8 questions for the MSS. Each of these questions could have a response of Not at all, a little bit, somewhat, quite a bit and very much. The responses were given a value between 0 and 4 with 4 being best response. The FACT-M Trial Outcome Index (FACT-M TOI) ranges from 0 to a high of 120 and is derived as: FACT-M TOI = PWB Score + FWB Score +MS Score. Higher scores represent a better quality of life.
Time Frame	Baseline, Day 1 of Cycle 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 30, 31, 32, 33, 35, 36, 37 and EOT (up to cut-off date [04-Jul-2015])

Outcome Measure Data

Analysis Population Description

ITT analysis set. Here "Number of Subjects Analyzed" = subjects evaluable for this outcome and "Number Analyzed" = subjects evaluable at specified time points for each arm, respectively. There were no subjects analyzed at certain time points (that is, Number Analyzed = 0) because there was no data collected for respective arms at those time points.

Arm/Group Title		Dacarbazine	Pimasertib
Arm/Group Description:		Subjects received dacarbazine intravenously at dose of 1000 mg/m^2 of body surface area every 3 weeks on Day 1 of each 21-days cycle until progression of the disease, unacceptable toxicity, withdrawal of informed consent, or death, whichever occurred first. Eligible subjects with documented tumor progression on dacarbazine were offered to switch to pimasertib treatment.	Subjects received pimasertib orally as monotherapy at a dose of 60 mg twice daily continuously. Treatment consisted of repeated 21-day cycles which was continued until progression of the disease, unacceptable toxicity, withdrawal of informed consent, or death, whichever occurred first.
Overall Number of Participants Analyzed		58	126
Mean (Standard Deviation); Unit of Measure: units on a scale
Baseline	Number Analyzed	58 participants	126 participants
		90.35 (19.348)	94.07 (17.534)
Change at Day 1 Cycle 2	Number Analyzed	45 participants	99 participants
		-3.33 (12.015)	-4.40 (14.286)
Change at Day 1 Cycle 3	Number Analyzed	24 participants	73 participants
		-0.69 (15.974)	-7.99 (17.089)
Change at Day 1 Cycle 4	Number Analyzed	23 participants	63 participants
		1.54 (10.304)	-7.97 (16.741)
Change at Day 1 Cycle 5	Number Analyzed	10 participants	45 participants
		-0.86 (5.405)	-4.37 (14.084)
Change at Day 1 Cycle 6	Number Analyzed	9 participants	33 participants
		-3.29 (7.752)	-9.15 (18.813)
Change at Day 1 Cycle 7	Number Analyzed	9 participants	29 participants
		-2.07 (6.859)	-8.99 (14.783)
Change at Day 1 Cycle 8	Number Analyzed	8 participants	18 participants
		0.83 (5.161)	-15.09 (14.458)
Change at Day 1 Cycle 9	Number Analyzed	6 participants	12 participants
		-1.93 (6.300)	-13.79 (17.198)
Change at Day 1 Cycle 10	Number Analyzed	6 participants	10 participants
		-1.10 (5.654)	-12.37 (17.058)
Change at Day 1 Cycle 11	Number Analyzed	4 participants	11 participants
		-2.90 (7.722)	-13.95 (17.006)
Change at Day 1 Cycle 12	Number Analyzed	4 participants	11 participants
		-2.40 (7.408)	-11.95 (17.311)
Change at Day 1 Cycle 13	Number Analyzed	4 participants	6 participants
		0.80 (7.697)	-13.57 (21.699)
Change at Day 1 Cycle 14	Number Analyzed	2 participants	8 participants
		0.00 (4.243)	-18.55 (19.880)
Change at Day 1 Cycle 15	Number Analyzed	3 participants	7 participants
		1.60 (4.084)	-13.59 (15.747)
Change at Day 1 Cycle 16	Number Analyzed	3 participants	7 participants
		0.61 (3.994)	-13.15 (19.130)
Change at Day 1 Cycle 17	Number Analyzed	2 participants	6 participants
		2.50 (0.707)	-10.66 (20.007)
Change at Day 1 Cycle 18	Number Analyzed	1 participants	5 participants
		3.00 [1] (NA)	-5.72 (4.614)
Change at Day 1 Cycle 19	Number Analyzed	2 participants	4 participants
		2.50 (0.707)	-4.94 (5.238)
Change at Day 1 Cycle 20	Number Analyzed	2 participants	3 participants
		4.00 (1.414)	-2.33 (1.155)
Change at Day 1 Cycle 21	Number Analyzed	2 participants	3 participants
		3.50 (0.707)	0.00 (2.000)
Change at Day 1 Cycle 22	Number Analyzed	2 participants	3 participants
		4.00 (1.414)	-1.40 (3.831)
Change at Day 1 Cycle 23	Number Analyzed	1 participants	2 participants
		3.00 [1] (NA)	-13.36 (16.061)
Change at Day 1 Cycle 24	Number Analyzed	2 participants	1 participants
		2.50 (0.707)	-2.00 [1] (NA)
Change at Day 1 Cycle 25	Number Analyzed	2 participants	1 participants
		3.50 (0.707)	-1.00 [1] (NA)
Change at Day 1 Cycle 26	Number Analyzed	1 participants	1 participants
		3.00 [1] (NA)	0.00 [1] (NA)
Change at Day 1 Cycle 27	Number Analyzed	1 participants	0 participants
		3.00 [1] (NA)
Change at Day 1 Cycle 28	Number Analyzed	1 participants	1 participants
		3.00 [1] (NA)	1.00 [1] (NA)
Change at Day 1 Cycle 30	Number Analyzed	0 participants	1 participants
			1.00 [1] (NA)
Change at Day 1 Cycle 31	Number Analyzed	0 participants	1 participants
			-3.00 [1] (NA)
Change at Day 1 Cycle 32	Number Analyzed	0 participants	1 participants
			-4.00 [1] (NA)
Change at Day 1 Cycle 33	Number Analyzed	0 participants	1 participants
			-3.00 [1] (NA)
Change at Day 1 Cycle 35	Number Analyzed	0 participants	1 participants
			0.00 [1] (NA)
Change at Day 1 Cycle 36	Number Analyzed	0 participants	1 participants
			0.00 [1] (NA)
Change at Day 1 Cycle 37	Number Analyzed	0 participants	1 participants
			-3.00 [1] (NA)
Change at EOT	Number Analyzed	28 participants	75 participants
		-8.18 (16.410)	-10.42 (16.256)

[1]

Standard deviation could not be estimated as there was only 1 subject analyzed at the specified time point.

9. Secondary Outcome

Title	Number of Subjects With Treatment-Emergent Adverse Events (TEAEs), Serious TEAEs, TEAEs Leading to Discontinuation or TEAEs Leading to Death
Description	AE was defined as any untoward medical occurrence which does not necessarily have a causal relationship with this the study drug. An AE was defined as any unfavourable and unintended sign (including an abnormal laboratory finding), symptom, or disease temporally associated with the use of study drug, whether or not considered related to the study drug. A serious AE was an AE that resulted in any of the following outcomes: death; life threatening; persistent/significant disability/incapacity; initial or prolonged inpatient hospitalization; congenital anomaly/birth defect or was otherwise considered medically important. Treatment-emergent are events between first dose of study drug and up to 33 days after last dose that were absent before treatment or that worsened relative to pre-treatment state. TEAEs include both Serious TEAEs and non-serious TEAEs. TEAEs were to be reported separately for dacarbazine, pimasertib and pimasertib (crossover) reporting arms.
Time Frame	Baseline up to cut-off date (04-Jul-2015)

Outcome Measure Data

Analysis Population Description

Safety analysis set (SAF) consisted of all subjects who received at least 1 dose of any trial treatment.

Arm/Group Title	Dacarbazine	Pimasertib	Pimasertib (Crossover)
Arm/Group Description:	Subjects received dacarbazine intravenously at dose of 1000 mg/m^2 of body surface area every 3 weeks on Day 1 of each 21-days cycle until progression of the disease, unacceptable toxicity, withdrawal of informed consent, or death, whichever occurred first. Eligible subjects with documented tumor progression on dacarbazine were offered to switch to pimasertib treatment.	Subjects received pimasertib orally as monotherapy at a dose of 60 mg twice daily continuously. Treatment consisted of repeated 21-day cycles which was continued until progression of the disease, unacceptable toxicity, withdrawal of informed consent, or death, whichever occurred first.	Subjects who were randomized and received dacarbazine and were allowed to crossover to pimasertib treatment on progression of their disease.
Overall Number of Participants Analyzed	61	130	41
Measure Type: Number; Unit of Measure: subjects
TEAEs	60	130	41
Serious TEAEs	12	74	26
TEAEs Leading to Discontinuation	3	61	16
TEAEs Leading To Death	4	6	6

10. Secondary Outcome

Title	Number of Subjects With Adverse Events (AEs) of Special Interest
Description	Adverse events of special interest included ocular retinal vein occlusion, serious retinal detachment or similar retinal abnormality characterized by accumulation of serous fluid in the retina, creatine phosphokinase (CPK) elevation and isoenzyme TEAE of Special Interest (Grade >=2) and acute renal failure (Grade >=2). Subjects were presented under 3 reporting groups: Dacarbazine group: for subjects who received at least 1 dose of dacarbazine; Pimasertib group: for subjects who received at least 1 dose of pimasertib; Pimasertib (Crossover) group: for subjects who were initially randomized and received dacarbazine, but crossed over to pimasertib treatment on progression of their disease.
Time Frame	Baseline up to cut-off date (04-Jul-2015)

Outcome Measure Data

Analysis Population Description

Safety analysis set (SAF) consisted of all subjects who received at least 1 dose of any trial treatment.

Arm/Group Title	Dacarbazine	Pimasertib	Pimasertib (Crossover)
Arm/Group Description:	Subjects received dacarbazine intravenously at dose of 1000 mg/m^2 of body surface area every 3 weeks on Day 1 of each 21-days cycle until progression of the disease, unacceptable toxicity, withdrawal of informed consent, or death, whichever occurred first. Eligible subjects with documented tumor progression on dacarbazine were offered to switch to pimasertib treatment.	Subjects received pimasertib orally as monotherapy at a dose of 60 mg twice daily continuously. Treatment consisted of repeated 21-day cycles which was continued until progression of the disease, unacceptable toxicity, withdrawal of informed consent, or death, whichever occurred first.	Subjects who were randomized and received dacarbazine and were allowed to crossover to pimasertib treatment on progression of their disease.
Overall Number of Participants Analyzed	61	130	41
Measure Type: Number; Unit of Measure: subjects
Retinal vein occlusion	0	5	2
Serious retinal detachment	0	76	21
CPK/Isoenzyme TEAE of Special Interest (>=Grade 2)	0	74	24
Acute renal failure (Grade >= 2)	1	9	2

11. Secondary Outcome

Title	Number of Subjects With Clinically Significant Change From Baseline in Laboratory Parameter, Vital Signs, Electrocardiogram (ECG) and Ophthalmologic Findings
Description	Subjects were presented under 3 reporting groups: Dacarbazine group: for subjects who received at least 1 dose of dacarbazine; Pimasertib group: for subjects who received at least 1 dose of pimasertib; Pimasertib (Crossover) group: for subjects who were initially randomized and received dacarbazine, but crossed over to pimasertib treatment on progression of their disease.
Time Frame	Baseline up to cut-off date (04-Jul-2015)

Outcome Measure Data

Analysis Population Description

Safety analysis set (SAF) consisted of all subjects who received at least 1 dose of any trial treatment.

Arm/Group Title	Dacarbazine	Pimasertib	Pimasertib (Crossover)
Arm/Group Description:	Subjects received dacarbazine intravenously at dose of 1000 mg/m^2 of body surface area every 3 weeks on Day 1 of each 21-days cycle until progression of the disease, unacceptable toxicity, withdrawal of informed consent, or death, whichever occurred first. Eligible subjects with documented tumor progression on dacarbazine were offered to switch to pimasertib treatment.	Subjects received pimasertib orally as monotherapy at a dose of 60 mg twice daily continuously. Treatment consisted of repeated 21-day cycles which was continued until progression of the disease, unacceptable toxicity, withdrawal of informed consent, or death, whichever occurred first.	Subjects who were randomized and received dacarbazine and were allowed to crossover to pimasertib treatment on progression of their disease.
Overall Number of Participants Analyzed	61	130	41
Measure Type: Number; Unit of Measure: subjects
Laboratory Parameter	0	0	0
Vital Signs	0	0	0
ECG	0	0	0
Ophthalmologic Findings	0	0	0

Adverse Events

Time Frame	Baseline up to cut-off date (04-Jul-2015)
Adverse Event Reporting Description	Safety analysis set (SAF) consisted of all subjects who received at least 1 dose of any trial treatment. Subjects were presented under 3 reporting groups: Dacarbazine group: for subjects who received at least 1 dose of dacarbazine; Pimasertib group: for subjects who received at least 1 dose of pimasertib; Pimasertib (Crossover) group: for subjects who were initially randomized and received dacarbazine, but crossed over to pimasertib treatment on progression of their disease.
Arm/Group Title	Dacarbazine	Pimasertib	Pimasertib (Crossover)
Arm/Group Description	Subjects received dacarbazine intravenously at dose of 1000 mg/m^2 of body surface area every 3 weeks on Day 1 of each 21-days cycle until progression of the disease, unacceptable toxicity, withdrawal of informed consent, or death, whichever occurred first. Eligible subjects with documented tumor progression on dacarbazine were offered to switch to pimasertib treatment.	Subjects received pimasertib orally as monotherapy at a dose of 60 mg twice daily continuously. Treatment consisted of repeated 21-day cycles which was continued until progression of the disease, unacceptable toxicity, withdrawal of informed consent, or death, whichever occurred first.	Subjects who were randomized and received dacarbazine and were allowed to crossover to pimasertib treatment on progression of their disease.
All-Cause Mortality
	Dacarbazine	Pimasertib	Pimasertib (Crossover)
	Affected / at Risk (%)	Affected / at Risk (%)	Affected / at Risk (%)
Total	--/--	--/--	--/--
Serious Adverse Events
	Dacarbazine	Pimasertib	Pimasertib (Crossover)
	Affected / at Risk (%)	Affected / at Risk (%)	Affected / at Risk (%)
Total	12/61 (19.67%)	74/130 (56.92%)	26/41 (63.41%)
Blood and lymphatic system disorders
Anaemia * 1	1/61 (1.64%)	0/130 (0.00%)	2/41 (4.88%)
Iron deficiency anaemia * 1	0/61 (0.00%)	1/130 (0.77%)	0/41 (0.00%)
Leukocytosis * 1	0/61 (0.00%)	2/130 (1.54%)	0/41 (0.00%)
Lymphopenia * 1	0/61 (0.00%)	0/130 (0.00%)	1/41 (2.44%)
Thrombocytopenia * 1	3/61 (4.92%)	0/130 (0.00%)	0/41 (0.00%)
Cardiac disorders
Acute coronary syndrome * 1	0/61 (0.00%)	1/130 (0.77%)	0/41 (0.00%)
Acute myocardial infarction * 1	0/61 (0.00%)	1/130 (0.77%)	0/41 (0.00%)
Atrial fibrillation * 1	0/61 (0.00%)	2/130 (1.54%)	0/41 (0.00%)
Cardiac failure * 1	0/61 (0.00%)	3/130 (2.31%)	1/41 (2.44%)
Cor pulmonale acute * 1	0/61 (0.00%)	1/130 (0.77%)	0/41 (0.00%)
Left ventricular dysfunction * 1	0/61 (0.00%)	3/130 (2.31%)	0/41 (0.00%)
Myocardial ischaemia * 1	0/61 (0.00%)	1/130 (0.77%)	0/41 (0.00%)
Pericarditis * 1	1/61 (1.64%)	0/130 (0.00%)	0/41 (0.00%)
Eye disorders
Chorioretinopathy * 1	0/61 (0.00%)	1/130 (0.77%)	1/41 (2.44%)
Cystoid macular oedema * 1	0/61 (0.00%)	0/130 (0.00%)	1/41 (2.44%)
Macular detachment * 1	0/61 (0.00%)	0/130 (0.00%)	1/41 (2.44%)
Macular oedema * 1	0/61 (0.00%)	3/130 (2.31%)	0/41 (0.00%)
Retinal detachment * 1	0/61 (0.00%)	4/130 (3.08%)	1/41 (2.44%)
Retinal vein occlusion * 1	0/61 (0.00%)	4/130 (3.08%)	1/41 (2.44%)
Ulcerative keratitis * 1	0/61 (0.00%)	1/130 (0.77%)	0/41 (0.00%)
Gastrointestinal disorders
Abdominal pain * 1	1/61 (1.64%)	0/130 (0.00%)	0/41 (0.00%)
Constipation * 1	0/61 (0.00%)	1/130 (0.77%)	0/41 (0.00%)
Diarrhoea * 1	1/61 (1.64%)	6/130 (4.62%)	1/41 (2.44%)
Duodenal obstruction * 1	1/61 (1.64%)	0/130 (0.00%)	0/41 (0.00%)
Mouth ulceration * 1	0/61 (0.00%)	1/130 (0.77%)	0/41 (0.00%)
Nausea * 1	1/61 (1.64%)	3/130 (2.31%)	0/41 (0.00%)
Small intestinal obstruction * 1	0/61 (0.00%)	0/130 (0.00%)	2/41 (4.88%)
Vomiting * 1	1/61 (1.64%)	3/130 (2.31%)	1/41 (2.44%)
General disorders
Chest pain * 1	0/61 (0.00%)	1/130 (0.77%)	0/41 (0.00%)
Chills * 1	0/61 (0.00%)	1/130 (0.77%)	0/41 (0.00%)
Cyst rupture * 1	0/61 (0.00%)	1/130 (0.77%)	0/41 (0.00%)
Death * 1	0/61 (0.00%)	1/130 (0.77%)	0/41 (0.00%)
Disease progression * 1	1/61 (1.64%)	2/130 (1.54%)	1/41 (2.44%)
Fatigue * 1	0/61 (0.00%)	1/130 (0.77%)	0/41 (0.00%)
General physical health deterioration * 1	1/61 (1.64%)	2/130 (1.54%)	4/41 (9.76%)
Impaired healing * 1	0/61 (0.00%)	1/130 (0.77%)	0/41 (0.00%)
Malaise * 1	0/61 (0.00%)	1/130 (0.77%)	1/41 (2.44%)
Necrosis * 1	0/61 (0.00%)	1/130 (0.77%)	0/41 (0.00%)
Oedema peripheral * 1	0/61 (0.00%)	1/130 (0.77%)	0/41 (0.00%)
Pyrexia * 1	1/61 (1.64%)	4/130 (3.08%)	0/41 (0.00%)
Sudden death * 1	0/61 (0.00%)	2/130 (1.54%)	0/41 (0.00%)
Hepatobiliary disorders
Cholangitis * 1	0/61 (0.00%)	1/130 (0.77%)	0/41 (0.00%)
Hepatotoxicity * 1	0/61 (0.00%)	1/130 (0.77%)	0/41 (0.00%)
Infections and infestations
Bacteraemia * 1	0/61 (0.00%)	1/130 (0.77%)	0/41 (0.00%)
Candida infection * 1	0/61 (0.00%)	1/130 (0.77%)	0/41 (0.00%)
Catheter site infection * 1	0/61 (0.00%)	0/130 (0.00%)	1/41 (2.44%)
Cellulitis * 1	0/61 (0.00%)	3/130 (2.31%)	0/41 (0.00%)
Device related infection * 1	0/61 (0.00%)	1/130 (0.77%)	0/41 (0.00%)
Erysipelas * 1	0/61 (0.00%)	7/130 (5.38%)	1/41 (2.44%)
Infection * 1	0/61 (0.00%)	1/130 (0.77%)	0/41 (0.00%)
Localised infection * 1	0/61 (0.00%)	1/130 (0.77%)	0/41 (0.00%)
Lower respiratory tract infection * 1	0/61 (0.00%)	1/130 (0.77%)	0/41 (0.00%)
Pharyngitis * 1	0/61 (0.00%)	0/130 (0.00%)	1/41 (2.44%)
Pyelonephritis * 1	0/61 (0.00%)	0/130 (0.00%)	1/41 (2.44%)
Respiratory tract infection * 1	0/61 (0.00%)	1/130 (0.77%)	0/41 (0.00%)
Sepsis * 1	0/61 (0.00%)	2/130 (1.54%)	1/41 (2.44%)
Septic shock * 1	0/61 (0.00%)	1/130 (0.77%)	1/41 (2.44%)
Skin infection * 1	0/61 (0.00%)	1/130 (0.77%)	0/41 (0.00%)
Staphylococcal sepsis * 1	0/61 (0.00%)	1/130 (0.77%)	0/41 (0.00%)
Streptococcal sepsis * 1	1/61 (1.64%)	1/130 (0.77%)	0/41 (0.00%)
Urinary tract infection * 1	0/61 (0.00%)	2/130 (1.54%)	0/41 (0.00%)
Injury, poisoning and procedural complications
Subdural haematoma * 1	1/61 (1.64%)	0/130 (0.00%)	0/41 (0.00%)
Investigations
Alanine aminotransferase increased * 1	0/61 (0.00%)	1/130 (0.77%)	0/41 (0.00%)
Blood creatine phosphokinase increased * 1	0/61 (0.00%)	26/130 (20.00%)	8/41 (19.51%)
Blood creatinine increased * 1	1/61 (1.64%)	0/130 (0.00%)	0/41 (0.00%)
Ejection fraction decreased * 1	0/61 (0.00%)	5/130 (3.85%)	1/41 (2.44%)
Lipase increased * 1	0/61 (0.00%)	1/130 (0.77%)	0/41 (0.00%)
Troponin increased * 1	0/61 (0.00%)	1/130 (0.77%)	0/41 (0.00%)
Metabolism and nutrition disorders
Hypoglycaemia * 1	0/61 (0.00%)	0/130 (0.00%)	1/41 (2.44%)
Hypokalaemia * 1	0/61 (0.00%)	1/130 (0.77%)	0/41 (0.00%)
Hyponatraemia * 1	0/61 (0.00%)	1/130 (0.77%)	0/41 (0.00%)
Tumour lysis syndrome * 1	0/61 (0.00%)	1/130 (0.77%)	0/41 (0.00%)
Musculoskeletal and connective tissue disorders
Back pain * 1	0/61 (0.00%)	1/130 (0.77%)	1/41 (2.44%)
Inguinal mass * 1	0/61 (0.00%)	1/130 (0.77%)	0/41 (0.00%)
Muscular weakness * 1	0/61 (0.00%)	2/130 (1.54%)	0/41 (0.00%)
Pain in extremity * 1	0/61 (0.00%)	1/130 (0.77%)	0/41 (0.00%)
Pathological fracture * 1	1/61 (1.64%)	0/130 (0.00%)	0/41 (0.00%)
Spinal column stenosis * 1	0/61 (0.00%)	0/130 (0.00%)	1/41 (2.44%)
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Tumour associated fever * 1	0/61 (0.00%)	1/130 (0.77%)	0/41 (0.00%)
Nervous system disorders
Ataxia * 1	0/61 (0.00%)	1/130 (0.77%)	0/41 (0.00%)
Epilepsy * 1	0/61 (0.00%)	1/130 (0.77%)	0/41 (0.00%)
Headache * 1	0/61 (0.00%)	1/130 (0.77%)	0/41 (0.00%)
Metabolic encephalopathy * 1	0/61 (0.00%)	1/130 (0.77%)	0/41 (0.00%)
Neuralgia * 1	0/61 (0.00%)	1/130 (0.77%)	0/41 (0.00%)
Neuropathy peripheral * 1	0/61 (0.00%)	1/130 (0.77%)	0/41 (0.00%)
Presyncope * 1	0/61 (0.00%)	2/130 (1.54%)	0/41 (0.00%)
Transient ischaemic attack * 1	0/61 (0.00%)	0/130 (0.00%)	1/41 (2.44%)
Psychiatric disorders
Confusional state * 1	0/61 (0.00%)	1/130 (0.77%)	0/41 (0.00%)
Renal and urinary disorders
Urinary retention * 1	1/61 (1.64%)	1/130 (0.77%)	0/41 (0.00%)
Reproductive system and breast disorders
Breast haematoma * 1	1/61 (1.64%)	0/130 (0.00%)	0/41 (0.00%)
Respiratory, thoracic and mediastinal disorders
Dyspnoea * 1	0/61 (0.00%)	5/130 (3.85%)	0/41 (0.00%)
Haemoptysis * 1	0/61 (0.00%)	1/130 (0.77%)	0/41 (0.00%)
Pleural effusion * 1	0/61 (0.00%)	3/130 (2.31%)	0/41 (0.00%)
Pulmonary embolism * 1	1/61 (1.64%)	3/130 (2.31%)	2/41 (4.88%)
Respiratory distress * 1	1/61 (1.64%)	0/130 (0.00%)	0/41 (0.00%)
Skin and subcutaneous tissue disorders
Dermatitis acneiform * 1	0/61 (0.00%)	1/130 (0.77%)	1/41 (2.44%)
Drug eruption * 1	0/61 (0.00%)	0/130 (0.00%)	1/41 (2.44%)
Rash * 1	0/61 (0.00%)	1/130 (0.77%)	0/41 (0.00%)
Rash macular * 1	0/61 (0.00%)	1/130 (0.77%)	0/41 (0.00%)
Rash maculo-papular * 1	0/61 (0.00%)	0/130 (0.00%)	1/41 (2.44%)
Skin toxicity * 1	0/61 (0.00%)	1/130 (0.77%)	0/41 (0.00%)
Vascular disorders
Deep vein thrombosis * 1	1/61 (1.64%)	1/130 (0.77%)	0/41 (0.00%)
Hypertension * 1	0/61 (0.00%)	1/130 (0.77%)	0/41 (0.00%)
Hypotension * 1	0/61 (0.00%)	2/130 (1.54%)	0/41 (0.00%)
Venous thrombosis limb * 1	0/61 (0.00%)	0/130 (0.00%)	1/41 (2.44%)
* Indicates events were collected by non-systematic assessment; 1 Term from vocabulary, MedDRA 18.0
Other (Not Including Serious) Adverse Events
Frequency Threshold for Reporting Other Adverse Events	0%
	Dacarbazine	Pimasertib	Pimasertib (Crossover)
	Affected / at Risk (%)	Affected / at Risk (%)	Affected / at Risk (%)
Total	59/61 (96.72%)	130/130 (100.00%)	41/41 (100.00%)
Blood and lymphatic system disorders
Anaemia * 1	8/61 (13.11%)	13/130 (10.00%)	3/41 (7.32%)
Thrombocytopenia * 1	12/61 (19.67%)	8/130 (6.15%)	3/41 (7.32%)
Neutropenia * 1	13/61 (21.31%)	1/130 (0.77%)	0/41 (0.00%)
Lymphopenia * 1	1/61 (1.64%)	9/130 (6.92%)	2/41 (4.88%)
Leukopenia * 1	6/61 (9.84%)	1/130 (0.77%)	0/41 (0.00%)
Anaemia of chronic disease * 1	1/61 (1.64%)	0/130 (0.00%)	0/41 (0.00%)
Eosinophilia * 1	1/61 (1.64%)	0/130 (0.00%)	1/41 (2.44%)
Hypochromic anaemia * 1	0/61 (0.00%)	2/130 (1.54%)	0/41 (0.00%)
Increased tendency to bruise * 1	0/61 (0.00%)	1/130 (0.77%)	1/41 (2.44%)
Leukocytosis * 1	0/61 (0.00%)	2/130 (1.54%)	1/41 (2.44%)
Lymph node pain * 1	1/61 (1.64%)	0/130 (0.00%)	0/41 (0.00%)
Lymphadenitis * 1	0/61 (0.00%)	1/130 (0.77%)	0/41 (0.00%)
Lymphadenopathy * 1	1/61 (1.64%)	2/130 (1.54%)	0/41 (0.00%)
Lymphocytosis * 1	0/61 (0.00%)	1/130 (0.77%)	0/41 (0.00%)
Normochromic normocytic anaemia * 1	2/61 (3.28%)	2/130 (1.54%)	1/41 (2.44%)
Thrombocytosis * 1	0/61 (0.00%)	1/130 (0.77%)	0/41 (0.00%)
Cardiac disorders
Angina pectoris * 1	1/61 (1.64%)	2/130 (1.54%)	0/41 (0.00%)
Aortic valve disease * 1	0/61 (0.00%)	1/130 (0.77%)	0/41 (0.00%)
Aortic valve incompetence * 1	0/61 (0.00%)	3/130 (2.31%)	2/41 (4.88%)
Aortic valve stenosis * 1	0/61 (0.00%)	1/130 (0.77%)	0/41 (0.00%)
Atrial fibrillation * 1	2/61 (3.28%)	2/130 (1.54%)	0/41 (0.00%)
Atrioventricular block * 1	0/61 (0.00%)	3/130 (2.31%)	0/41 (0.00%)
Atrioventricular block first degree * 1	1/61 (1.64%)	0/130 (0.00%)	1/41 (2.44%)
Atrioventricular block second degree * 1	0/61 (0.00%)	1/130 (0.77%)	0/41 (0.00%)
Bradycardia * 1	0/61 (0.00%)	2/130 (1.54%)	1/41 (2.44%)
Bundle branch block * 1	0/61 (0.00%)	1/130 (0.77%)	0/41 (0.00%)
Bundle branch block right * 1	0/61 (0.00%)	2/130 (1.54%)	0/41 (0.00%)
Diastolic dysfunction * 1	0/61 (0.00%)	1/130 (0.77%)	0/41 (0.00%)
Left ventricular dysfunction * 1	0/61 (0.00%)	4/130 (3.08%)	0/41 (0.00%)
Left ventricular hypertrophy * 1	0/61 (0.00%)	1/130 (0.77%)	0/41 (0.00%)
Mitral valve incompetence * 1	0/61 (0.00%)	4/130 (3.08%)	2/41 (4.88%)
Mitral valve sclerosis * 1	0/61 (0.00%)	0/130 (0.00%)	1/41 (2.44%)
Palpitations * 1	2/61 (3.28%)	0/130 (0.00%)	0/41 (0.00%)
Pericardial effusion * 1	0/61 (0.00%)	0/130 (0.00%)	1/41 (2.44%)
Pulmonary valve incompetence * 1	0/61 (0.00%)	1/130 (0.77%)	0/41 (0.00%)
Sinus bradycardia * 1	0/61 (0.00%)	1/130 (0.77%)	0/41 (0.00%)
Sinus tachycardia * 1	0/61 (0.00%)	3/130 (2.31%)	0/41 (0.00%)
Supraventricular tachycardia * 1	0/61 (0.00%)	0/130 (0.00%)	2/41 (4.88%)
Tachycardia * 1	0/61 (0.00%)	1/130 (0.77%)	0/41 (0.00%)
Tricuspid valve incompetence * 1	0/61 (0.00%)	5/130 (3.85%)	4/41 (9.76%)
Ventricular hypokinesia * 1	0/61 (0.00%)	0/130 (0.00%)	1/41 (2.44%)
Congenital, familial and genetic disorders
Optic nerve hypoplasia * 1	0/61 (0.00%)	0/130 (0.00%)	1/41 (2.44%)
Ventricular septal defect * 1	0/61 (0.00%)	1/130 (0.77%)	0/41 (0.00%)
Ear and labyrinth disorders
Cerumen impaction * 1	0/61 (0.00%)	1/130 (0.77%)	0/41 (0.00%)
Ear congestion * 1	0/61 (0.00%)	1/130 (0.77%)	0/41 (0.00%)
Ear pain * 1	0/61 (0.00%)	3/130 (2.31%)	0/41 (0.00%)
Hypoacusis * 1	1/61 (1.64%)	0/130 (0.00%)	0/41 (0.00%)
Middle ear inflammation * 1	0/61 (0.00%)	1/130 (0.77%)	0/41 (0.00%)
Tinnitus * 1	0/61 (0.00%)	2/130 (1.54%)	1/41 (2.44%)
Vertigo * 1	2/61 (3.28%)	3/130 (2.31%)	0/41 (0.00%)
Endocrine disorders
Adrenal insufficiency * 1	0/61 (0.00%)	1/130 (0.77%)	0/41 (0.00%)
Hyperthyroidism * 1	1/61 (1.64%)	0/130 (0.00%)	0/41 (0.00%)
Eye disorders
Retinal detachment * 1	0/61 (0.00%)	56/130 (43.08%)	15/41 (36.59%)
Vision blurred * 1	0/61 (0.00%)	29/130 (22.31%)	9/41 (21.95%)
Eyelid oedema * 1	1/61 (1.64%)	18/130 (13.85%)	2/41 (4.88%)
Visual impairment * 1	0/61 (0.00%)	12/130 (9.23%)	2/41 (4.88%)
Periorbital oedema * 1	0/61 (0.00%)	12/130 (9.23%)	1/41 (2.44%)
Macular detachment * 1	0/61 (0.00%)	10/130 (7.69%)	2/41 (4.88%)
Blepharitis * 1	0/61 (0.00%)	1/130 (0.77%)	0/41 (0.00%)
Blindness * 1	0/61 (0.00%)	0/130 (0.00%)	1/41 (2.44%)
Cataract * 1	0/61 (0.00%)	1/130 (0.77%)	1/41 (2.44%)
Chalazion * 1	0/61 (0.00%)	1/130 (0.77%)	0/41 (0.00%)
Chorioretinopathy * 1	0/61 (0.00%)	3/130 (2.31%)	0/41 (0.00%)
Chromatopsia * 1	0/61 (0.00%)	2/130 (1.54%)	0/41 (0.00%)
Colour blindness acquired * 1	0/61 (0.00%)	1/130 (0.77%)	1/41 (2.44%)
Conjunctival haemorrhage * 1	0/61 (0.00%)	1/130 (0.77%)	0/41 (0.00%)
Conjunctival oedema * 1	0/61 (0.00%)	2/130 (1.54%)	0/41 (0.00%)
Cystoid macular oedema * 1	0/61 (0.00%)	1/130 (0.77%)	1/41 (2.44%)
Deposit eye * 1	0/61 (0.00%)	1/130 (0.77%)	0/41 (0.00%)
Detachment of retinal pigment epithelium * 1	0/61 (0.00%)	3/130 (2.31%)	2/41 (4.88%)
Diplopia * 1	0/61 (0.00%)	1/130 (0.77%)	0/41 (0.00%)
Dry eye * 1	1/61 (1.64%)	5/130 (3.85%)	0/41 (0.00%)
Erythema of eyelid * 1	0/61 (0.00%)	1/130 (0.77%)	0/41 (0.00%)
Eye discharge * 1	0/61 (0.00%)	1/130 (0.77%)	0/41 (0.00%)
Eye disorder * 1	0/61 (0.00%)	2/130 (1.54%)	0/41 (0.00%)
Eye haemorrhage * 1	0/61 (0.00%)	1/130 (0.77%)	0/41 (0.00%)
Eye inflammation * 1	0/61 (0.00%)	1/130 (0.77%)	0/41 (0.00%)
Eye oedema * 1	0/61 (0.00%)	1/130 (0.77%)	0/41 (0.00%)
Eye pain * 1	1/61 (1.64%)	3/130 (2.31%)	0/41 (0.00%)
Eye pruritus * 1	1/61 (1.64%)	0/130 (0.00%)	0/41 (0.00%)
Eye swelling * 1	0/61 (0.00%)	2/130 (1.54%)	0/41 (0.00%)
Eyelid haematoma * 1	0/61 (0.00%)	1/130 (0.77%)	0/41 (0.00%)
Eyelid ptosis * 1	0/61 (0.00%)	3/130 (2.31%)	0/41 (0.00%)
Glaucoma * 1	0/61 (0.00%)	1/130 (0.77%)	0/41 (0.00%)
Lacrimation increased * 1	0/61 (0.00%)	3/130 (2.31%)	0/41 (0.00%)
Macular cyst * 1	0/61 (0.00%)	0/130 (0.00%)	1/41 (2.44%)
Macular degeneration * 1	0/61 (0.00%)	2/130 (1.54%)	0/41 (0.00%)
Macular fibrosis * 1	0/61 (0.00%)	4/130 (3.08%)	0/41 (0.00%)
Macular oedema * 1	0/61 (0.00%)	6/130 (4.62%)	1/41 (2.44%)
Myopia * 1	0/61 (0.00%)	1/130 (0.77%)	0/41 (0.00%)
Ocular hyperaemia * 1	1/61 (1.64%)	1/130 (0.77%)	0/41 (0.00%)
Ocular hypertension * 1	0/61 (0.00%)	3/130 (2.31%)	2/41 (4.88%)
Optic disc haemorrhage * 1	0/61 (0.00%)	1/130 (0.77%)	0/41 (0.00%)
Photophobia * 1	0/61 (0.00%)	2/130 (1.54%)	0/41 (0.00%)
Photopsia * 1	0/61 (0.00%)	2/130 (1.54%)	0/41 (0.00%)
Presbyopia * 1	0/61 (0.00%)	1/130 (0.77%)	0/41 (0.00%)
Retinal deposits * 1	0/61 (0.00%)	1/130 (0.77%)	0/41 (0.00%)
Retinal disorder * 1	0/61 (0.00%)	0/130 (0.00%)	2/41 (4.88%)
Retinal haemorrhage * 1	0/61 (0.00%)	1/130 (0.77%)	0/41 (0.00%)
Retinal oedema * 1	0/61 (0.00%)	0/130 (0.00%)	1/41 (2.44%)
Retinal pigment epitheliopathy * 1	0/61 (0.00%)	2/130 (1.54%)	0/41 (0.00%)
Retinal vein occlusion * 1	0/61 (0.00%)	1/130 (0.77%)	1/41 (2.44%)
Retinopathy * 1	0/61 (0.00%)	1/130 (0.77%)	0/41 (0.00%)
Subretinal fluid * 1	0/61 (0.00%)	1/130 (0.77%)	1/41 (2.44%)
Visual acuity reduced * 1	0/61 (0.00%)	5/130 (3.85%)	0/41 (0.00%)
Vitreous detachment * 1	0/61 (0.00%)	1/130 (0.77%)	0/41 (0.00%)
Vitreous floaters * 1	0/61 (0.00%)	1/130 (0.77%)	0/41 (0.00%)
Xerophthalmia * 1	1/61 (1.64%)	0/130 (0.00%)	0/41 (0.00%)
Gastrointestinal disorders
Diarrhoea * 1	10/61 (16.39%)	106/130 (81.54%)	31/41 (75.61%)
Nausea * 1	25/61 (40.98%)	47/130 (36.15%)	17/41 (41.46%)
Vomiting * 1	14/61 (22.95%)	30/130 (23.08%)	16/41 (39.02%)
Constipation * 1	21/61 (34.43%)	24/130 (18.46%)	7/41 (17.07%)
Abdominal pain * 1	10/61 (16.39%)	31/130 (23.85%)	7/41 (17.07%)
Dry mouth * 1	2/61 (3.28%)	20/130 (15.38%)	8/41 (19.51%)
Stomatitis * 1	3/61 (4.92%)	21/130 (16.15%)	4/41 (9.76%)
Dyspepsia * 1	0/61 (0.00%)	11/130 (8.46%)	3/41 (7.32%)
Gastrooesophageal reflux disease * 1	2/61 (3.28%)	5/130 (3.85%)	2/41 (4.88%)
Rectal haemorrhage * 1	0/61 (0.00%)	8/130 (6.15%)	1/41 (2.44%)
Mouth ulceration * 1	0/61 (0.00%)	7/130 (5.38%)	1/41 (2.44%)
Abdominal distension * 1	1/61 (1.64%)	4/130 (3.08%)	2/41 (4.88%)
Abdominal pain lower * 1	0/61 (0.00%)	0/130 (0.00%)	1/41 (2.44%)
Abdominal pain upper * 1	0/61 (0.00%)	3/130 (2.31%)	2/41 (4.88%)
Anal polyp * 1	0/61 (0.00%)	1/130 (0.77%)	0/41 (0.00%)
Aphthous stomatitis * 1	0/61 (0.00%)	4/130 (3.08%)	2/41 (4.88%)
Aptyalism * 1	0/61 (0.00%)	1/130 (0.77%)	1/41 (2.44%)
Ascites * 1	0/61 (0.00%)	2/130 (1.54%)	0/41 (0.00%)
Cheilitis * 1	0/61 (0.00%)	4/130 (3.08%)	1/41 (2.44%)
Colitis * 1	0/61 (0.00%)	0/130 (0.00%)	1/41 (2.44%)
Duodenal ulcer * 1	0/61 (0.00%)	1/130 (0.77%)	0/41 (0.00%)
Dysphagia * 1	1/61 (1.64%)	5/130 (3.85%)	2/41 (4.88%)
Epigastric discomfort * 1	1/61 (1.64%)	0/130 (0.00%)	1/41 (2.44%)
Faeces discoloured * 1	0/61 (0.00%)	2/130 (1.54%)	0/41 (0.00%)
Flatulence * 1	0/61 (0.00%)	2/130 (1.54%)	1/41 (2.44%)
Gastric ulcer * 1	1/61 (1.64%)	1/130 (0.77%)	0/41 (0.00%)
Gastritis * 1	0/61 (0.00%)	2/130 (1.54%)	0/41 (0.00%)
Gastritis erosive * 1	0/61 (0.00%)	1/130 (0.77%)	0/41 (0.00%)
Glossitis * 1	0/61 (0.00%)	2/130 (1.54%)	1/41 (2.44%)
Glossodynia * 1	0/61 (0.00%)	2/130 (1.54%)	0/41 (0.00%)
Haematemesis * 1	0/61 (0.00%)	1/130 (0.77%)	0/41 (0.00%)
Haematochezia * 1	0/61 (0.00%)	1/130 (0.77%)	1/41 (2.44%)
Haemorrhoidal haemorrhage * 1	0/61 (0.00%)	2/130 (1.54%)	0/41 (0.00%)
Haemorrhoids * 1	1/61 (1.64%)	4/130 (3.08%)	1/41 (2.44%)
Hyperchlorhydria * 1	0/61 (0.00%)	0/130 (0.00%)	1/41 (2.44%)
Intestinal obstruction * 1	0/61 (0.00%)	1/130 (0.77%)	0/41 (0.00%)
Lip dry * 1	0/61 (0.00%)	1/130 (0.77%)	0/41 (0.00%)
Lip oedema * 1	0/61 (0.00%)	1/130 (0.77%)	1/41 (2.44%)
Lip pain * 1	1/61 (1.64%)	0/130 (0.00%)	0/41 (0.00%)
Melaena * 1	0/61 (0.00%)	0/130 (0.00%)	1/41 (2.44%)
Mesenteric vein thrombosis * 1	0/61 (0.00%)	1/130 (0.77%)	0/41 (0.00%)
Mouth swelling * 1	0/61 (0.00%)	0/130 (0.00%)	1/41 (2.44%)
Odynophagia * 1	0/61 (0.00%)	4/130 (3.08%)	0/41 (0.00%)
Oesophagitis * 1	0/61 (0.00%)	1/130 (0.77%)	0/41 (0.00%)
Oral discomfort * 1	0/61 (0.00%)	1/130 (0.77%)	0/41 (0.00%)
Oral dysaesthesia * 1	0/61 (0.00%)	1/130 (0.77%)	0/41 (0.00%)
Oral mucosal eruption * 1	0/61 (0.00%)	1/130 (0.77%)	0/41 (0.00%)
Oral mucosal erythema * 1	0/61 (0.00%)	1/130 (0.77%)	0/41 (0.00%)
Oral pain * 1	0/61 (0.00%)	1/130 (0.77%)	0/41 (0.00%)
Oral pruritus * 1	0/61 (0.00%)	1/130 (0.77%)	0/41 (0.00%)
Oral toxicity * 1	0/61 (0.00%)	1/130 (0.77%)	0/41 (0.00%)
Paraesthesia oral * 1	0/61 (0.00%)	1/130 (0.77%)	0/41 (0.00%)
Regurgitation * 1	1/61 (1.64%)	0/130 (0.00%)	0/41 (0.00%)
Salivary hypersecretion * 1	1/61 (1.64%)	0/130 (0.00%)	0/41 (0.00%)
Subileus * 1	0/61 (0.00%)	1/130 (0.77%)	0/41 (0.00%)
Tongue disorder * 1	0/61 (0.00%)	2/130 (1.54%)	0/41 (0.00%)
Tongue oedema * 1	0/61 (0.00%)	0/130 (0.00%)	1/41 (2.44%)
Tongue ulceration * 1	0/61 (0.00%)	2/130 (1.54%)	0/41 (0.00%)
Toothache * 1	0/61 (0.00%)	2/130 (1.54%)	0/41 (0.00%)
Umbilical hernia * 1	0/61 (0.00%)	0/130 (0.00%)	1/41 (2.44%)
General disorders
Oedema peripheral * 1	6/61 (9.84%)	59/130 (45.38%)	18/41 (43.90%)
Fatigue * 1	23/61 (37.70%)	39/130 (30.00%)	11/41 (26.83%)
Asthenia * 1	13/61 (21.31%)	39/130 (30.00%)	10/41 (24.39%)
Pyrexia * 1	5/61 (8.20%)	27/130 (20.77%)	10/41 (24.39%)
Chills * 1	3/61 (4.92%)	11/130 (8.46%)	3/41 (7.32%)
Axillary pain * 1	1/61 (1.64%)	1/130 (0.77%)	1/41 (2.44%)
Catheter site pain * 1	1/61 (1.64%)	0/130 (0.00%)	0/41 (0.00%)
Chest discomfort * 1	1/61 (1.64%)	0/130 (0.00%)	0/41 (0.00%)
Chest pain * 1	3/61 (4.92%)	2/130 (1.54%)	1/41 (2.44%)
Crying * 1	0/61 (0.00%)	1/130 (0.77%)	0/41 (0.00%)
Disease progression * 1	0/61 (0.00%)	0/130 (0.00%)	1/41 (2.44%)
Drug intolerance * 1	0/61 (0.00%)	1/130 (0.77%)	0/41 (0.00%)
Enanthema * 1	0/61 (0.00%)	1/130 (0.77%)	0/41 (0.00%)
Face oedema * 1	0/61 (0.00%)	12/130 (9.23%)	9/41 (21.95%)
Facial pain * 1	0/61 (0.00%)	0/130 (0.00%)	1/41 (2.44%)
Feeling cold * 1	0/61 (0.00%)	3/130 (2.31%)	0/41 (0.00%)
Gait disturbance * 1	0/61 (0.00%)	0/130 (0.00%)	1/41 (2.44%)
General physical health deterioration * 1	0/61 (0.00%)	2/130 (1.54%)	0/41 (0.00%)
Generalised oedema * 1	0/61 (0.00%)	1/130 (0.77%)	0/41 (0.00%)
Hyperpyrexia * 1	0/61 (0.00%)	1/130 (0.77%)	0/41 (0.00%)
Hyperthermia * 1	1/61 (1.64%)	0/130 (0.00%)	0/41 (0.00%)
Hypothermia * 1	0/61 (0.00%)	1/130 (0.77%)	1/41 (2.44%)
Inflammation * 1	0/61 (0.00%)	1/130 (0.77%)	0/41 (0.00%)
Influenza like illness * 1	1/61 (1.64%)	3/130 (2.31%)	0/41 (0.00%)
Injection site haematoma * 1	0/61 (0.00%)	0/130 (0.00%)	1/41 (2.44%)
Localised oedema * 1	0/61 (0.00%)	1/130 (0.77%)	0/41 (0.00%)
Malaise * 1	2/61 (3.28%)	5/130 (3.85%)	2/41 (4.88%)
Mucosal dryness * 1	0/61 (0.00%)	1/130 (0.77%)	0/41 (0.00%)
Non-cardiac chest pain * 1	1/61 (1.64%)	0/130 (0.00%)	1/41 (2.44%)
Oedema * 1	0/61 (0.00%)	2/130 (1.54%)	1/41 (2.44%)
Pain * 1	0/61 (0.00%)	1/130 (0.77%)	0/41 (0.00%)
Papillitis * 1	0/61 (0.00%)	1/130 (0.77%)	0/41 (0.00%)
Peripheral swelling * 1	0/61 (0.00%)	5/130 (3.85%)	2/41 (4.88%)
Secretion discharge * 1	1/61 (1.64%)	0/130 (0.00%)	0/41 (0.00%)
Sensation of foreign body * 1	0/61 (0.00%)	1/130 (0.77%)	0/41 (0.00%)
Temperature intolerance * 1	0/61 (0.00%)	0/130 (0.00%)	1/41 (2.44%)
Vessel puncture site haematoma * 1	1/61 (1.64%)	0/130 (0.00%)	0/41 (0.00%)
Vessel puncture site inflammation * 1	1/61 (1.64%)	0/130 (0.00%)	0/41 (0.00%)
Vessel puncture site pain * 1	1/61 (1.64%)	0/130 (0.00%)	0/41 (0.00%)
Xerosis * 1	0/61 (0.00%)	1/130 (0.77%)	2/41 (4.88%)
Hepatobiliary disorders
Cholestasis * 1	1/61 (1.64%)	4/130 (3.08%)	0/41 (0.00%)
Hepatic pain * 1	0/61 (0.00%)	1/130 (0.77%)	0/41 (0.00%)
Hepatocellular injury * 1	0/61 (0.00%)	7/130 (5.38%)	0/41 (0.00%)
Hepatomegaly * 1	0/61 (0.00%)	1/130 (0.77%)	0/41 (0.00%)
Immune system disorders
Sarcoidosis * 1	0/61 (0.00%)	1/130 (0.77%)	0/41 (0.00%)
Infections and infestations
Abdominal wall abscess * 1	0/61 (0.00%)	0/130 (0.00%)	1/41 (2.44%)
Abscess limb * 1	0/61 (0.00%)	0/130 (0.00%)	1/41 (2.44%)
Acute sinusitis * 1	1/61 (1.64%)	0/130 (0.00%)	0/41 (0.00%)
Acute tonsillitis * 1	0/61 (0.00%)	3/130 (2.31%)	1/41 (2.44%)
Bacterial infection * 1	1/61 (1.64%)	0/130 (0.00%)	0/41 (0.00%)
Bronchitis * 1	0/61 (0.00%)	0/130 (0.00%)	1/41 (2.44%)
Cellulitis * 1	0/61 (0.00%)	2/130 (1.54%)	2/41 (4.88%)
Cholangitis infective * 1	0/61 (0.00%)	1/130 (0.77%)	0/41 (0.00%)
Conjunctivitis * 1	0/61 (0.00%)	8/130 (6.15%)	0/41 (0.00%)
Conjunctivitis viral * 1	0/61 (0.00%)	1/130 (0.77%)	0/41 (0.00%)
Cystitis * 1	0/61 (0.00%)	2/130 (1.54%)	0/41 (0.00%)
Enterobacter infection * 1	0/61 (0.00%)	1/130 (0.77%)	0/41 (0.00%)
Erysipelas * 1	0/61 (0.00%)	2/130 (1.54%)	0/41 (0.00%)
Folliculitis * 1	1/61 (1.64%)	17/130 (13.08%)	7/41 (17.07%)
Fungal oesophagitis * 1	0/61 (0.00%)	1/130 (0.77%)	0/41 (0.00%)
Fungal skin infection * 1	0/61 (0.00%)	1/130 (0.77%)	0/41 (0.00%)
Furuncle * 1	0/61 (0.00%)	0/130 (0.00%)	1/41 (2.44%)
Gastroenteritis * 1	0/61 (0.00%)	1/130 (0.77%)	1/41 (2.44%)
Helicobacter infection * 1	0/61 (0.00%)	1/130 (0.77%)	0/41 (0.00%)
Herpes simplex * 1	0/61 (0.00%)	2/130 (1.54%)	0/41 (0.00%)
Herpes virus infection * 1	1/61 (1.64%)	0/130 (0.00%)	0/41 (0.00%)
Herpes zoster * 1	0/61 (0.00%)	2/130 (1.54%)	0/41 (0.00%)
Impetigo * 1	0/61 (0.00%)	2/130 (1.54%)	0/41 (0.00%)
Infected bites * 1	0/61 (0.00%)	1/130 (0.77%)	0/41 (0.00%)
Infection * 1	0/61 (0.00%)	1/130 (0.77%)	0/41 (0.00%)
Influenza * 1	1/61 (1.64%)	2/130 (1.54%)	0/41 (0.00%)
Klebsiella infection * 1	0/61 (0.00%)	1/130 (0.77%)	0/41 (0.00%)
Laryngitis * 1	0/61 (0.00%)	0/130 (0.00%)	1/41 (2.44%)
Localised infection * 1	0/61 (0.00%)	2/130 (1.54%)	1/41 (2.44%)
Lower respiratory tract infection * 1	1/61 (1.64%)	0/130 (0.00%)	0/41 (0.00%)
Lung infection * 1	0/61 (0.00%)	1/130 (0.77%)	0/41 (0.00%)
Lymph gland infection * 1	1/61 (1.64%)	0/130 (0.00%)	0/41 (0.00%)
Nasopharyngitis * 1	3/61 (4.92%)	8/130 (6.15%)	2/41 (4.88%)
Oral candidiasis * 1	0/61 (0.00%)	5/130 (3.85%)	1/41 (2.44%)
Oral fungal infection * 1	0/61 (0.00%)	0/130 (0.00%)	1/41 (2.44%)
Oral herpes * 1	0/61 (0.00%)	2/130 (1.54%)	0/41 (0.00%)
Paronychia * 1	0/61 (0.00%)	9/130 (6.92%)	3/41 (7.32%)
Pharyngitis * 1	0/61 (0.00%)	2/130 (1.54%)	0/41 (0.00%)
Pneumonia escherichia * 1	0/61 (0.00%)	1/130 (0.77%)	0/41 (0.00%)
Pseudomonas infection * 1	0/61 (0.00%)	1/130 (0.77%)	1/41 (2.44%)
Pulpitis dental * 1	0/61 (0.00%)	1/130 (0.77%)	0/41 (0.00%)
Rash pustular * 1	1/61 (1.64%)	16/130 (12.31%)	3/41 (7.32%)
Rhinitis * 1	1/61 (1.64%)	1/130 (0.77%)	2/41 (4.88%)
Sinusitis * 1	1/61 (1.64%)	0/130 (0.00%)	0/41 (0.00%)
Skin candida * 1	0/61 (0.00%)	2/130 (1.54%)	0/41 (0.00%)
Skin infection * 1	0/61 (0.00%)	4/130 (3.08%)	1/41 (2.44%)
Staphylococcal bacteraemia * 1	0/61 (0.00%)	1/130 (0.77%)	0/41 (0.00%)
Staphylococcal skin infection * 1	0/61 (0.00%)	1/130 (0.77%)	0/41 (0.00%)
Superinfection viral * 1	0/61 (0.00%)	1/130 (0.77%)	0/41 (0.00%)
Tinea cruris * 1	0/61 (0.00%)	2/130 (1.54%)	0/41 (0.00%)
Tinea pedis * 1	0/61 (0.00%)	1/130 (0.77%)	0/41 (0.00%)
Tinea versicolour * 1	0/61 (0.00%)	1/130 (0.77%)	0/41 (0.00%)
Tonsillitis * 1	1/61 (1.64%)	0/130 (0.00%)	0/41 (0.00%)
Tooth abscess * 1	1/61 (1.64%)	0/130 (0.00%)	0/41 (0.00%)
Trichophytosis * 1	1/61 (1.64%)	0/130 (0.00%)	0/41 (0.00%)
Upper respiratory tract infection * 1	0/61 (0.00%)	0/130 (0.00%)	1/41 (2.44%)
Urinary tract infection * 1	1/61 (1.64%)	7/130 (5.38%)	0/41 (0.00%)
Vaginal infection * 1	0/61 (0.00%)	2/130 (1.54%)	0/41 (0.00%)
Viral infection * 1	1/61 (1.64%)	0/130 (0.00%)	0/41 (0.00%)
Vulvovaginal mycotic infection * 1	0/61 (0.00%)	0/130 (0.00%)	1/41 (2.44%)
Wound infection * 1	1/61 (1.64%)	0/130 (0.00%)	0/41 (0.00%)
Injury, poisoning and procedural complications
Chest injury * 1	1/61 (1.64%)	0/130 (0.00%)	0/41 (0.00%)
Clavicle fracture * 1	1/61 (1.64%)	0/130 (0.00%)	0/41 (0.00%)
Concussion * 1	1/61 (1.64%)	0/130 (0.00%)	0/41 (0.00%)
Excoriation * 1	0/61 (0.00%)	1/130 (0.77%)	0/41 (0.00%)
Fall * 1	0/61 (0.00%)	3/130 (2.31%)	0/41 (0.00%)
Lip injury * 1	0/61 (0.00%)	1/130 (0.77%)	1/41 (2.44%)
Muscle strain * 1	0/61 (0.00%)	1/130 (0.77%)	0/41 (0.00%)
Optic nerve injury * 1	0/61 (0.00%)	1/130 (0.77%)	0/41 (0.00%)
Procedural pain * 1	2/61 (3.28%)	0/130 (0.00%)	0/41 (0.00%)
Rib fracture * 1	1/61 (1.64%)	1/130 (0.77%)	0/41 (0.00%)
Scratch * 1	0/61 (0.00%)	1/130 (0.77%)	0/41 (0.00%)
Spinal compression fracture * 1	1/61 (1.64%)	0/130 (0.00%)	0/41 (0.00%)
Sunburn * 1	0/61 (0.00%)	0/130 (0.00%)	1/41 (2.44%)
Tendon rupture * 1	1/61 (1.64%)	0/130 (0.00%)	0/41 (0.00%)
Traumatic shock * 1	1/61 (1.64%)	0/130 (0.00%)	0/41 (0.00%)
Wound * 1	0/61 (0.00%)	3/130 (2.31%)	0/41 (0.00%)
Wound complication * 1	0/61 (0.00%)	1/130 (0.77%)	0/41 (0.00%)
Investigations
Blood creatine phosphokinase increased * 1	3/61 (4.92%)	86/130 (66.15%)	28/41 (68.29%)
Aspartate aminotransferase increased * 1	3/61 (4.92%)	17/130 (13.08%)	4/41 (9.76%)
Ejection fraction decreased * 1	0/61 (0.00%)	13/130 (10.00%)	3/41 (7.32%)
Weight decreased * 1	2/61 (3.28%)	8/130 (6.15%)	3/41 (7.32%)
Alanine aminotransferase increased * 1	4/61 (6.56%)	6/130 (4.62%)	1/41 (2.44%)
Weight increased * 1	0/61 (0.00%)	9/130 (6.92%)	2/41 (4.88%)
Blood alkaline phosphatase increased * 1	2/61 (3.28%)	5/130 (3.85%)	3/41 (7.32%)
Gamma-glutamyltransferase increased * 1	2/61 (3.28%)	4/130 (3.08%)	3/41 (7.32%)
Amylase increased * 1	0/61 (0.00%)	1/130 (0.77%)	1/41 (2.44%)
Blood albumin decreased * 1	0/61 (0.00%)	3/130 (2.31%)	0/41 (0.00%)
Blood bicarbonate decreased * 1	0/61 (0.00%)	0/130 (0.00%)	1/41 (2.44%)
Blood bilirubin increased * 1	1/61 (1.64%)	1/130 (0.77%)	0/41 (0.00%)
Blood creatinine increased * 1	2/61 (3.28%)	2/130 (1.54%)	1/41 (2.44%)
Blood fibrinogen decreased * 1	0/61 (0.00%)	1/130 (0.77%)	0/41 (0.00%)
Blood lactate dehydrogenase increased * 1	1/61 (1.64%)	3/130 (2.31%)	1/41 (2.44%)
Blood phosphorus increased * 1	0/61 (0.00%)	1/130 (0.77%)	0/41 (0.00%)
Blood potassium increased * 1	0/61 (0.00%)	1/130 (0.77%)	0/41 (0.00%)
Blood pressure increased * 1	2/61 (3.28%)	0/130 (0.00%)	0/41 (0.00%)
Blood urea increased * 1	0/61 (0.00%)	1/130 (0.77%)	0/41 (0.00%)
Body temperature increased * 1	1/61 (1.64%)	0/130 (0.00%)	0/41 (0.00%)
Breath sounds abnormal * 1	0/61 (0.00%)	1/130 (0.77%)	0/41 (0.00%)
C-reactive protein increased * 1	0/61 (0.00%)	2/130 (1.54%)	0/41 (0.00%)
Creatinine renal clearance decreased * 1	0/61 (0.00%)	1/130 (0.77%)	0/41 (0.00%)
Electrocardiogram PR prolongation * 1	0/61 (0.00%)	1/130 (0.77%)	0/41 (0.00%)
Electrocardiogram QRS complex prolonged * 1	0/61 (0.00%)	1/130 (0.77%)	0/41 (0.00%)
Electrocardiogram QT prolonged * 1	0/61 (0.00%)	4/130 (3.08%)	1/41 (2.44%)
Electrocardiogram repolarisation abnormality * 1	0/61 (0.00%)	1/130 (0.77%)	0/41 (0.00%)
Glomerular filtration rate decreased * 1	0/61 (0.00%)	1/130 (0.77%)	0/41 (0.00%)
Haemoglobin decreased * 1	0/61 (0.00%)	2/130 (1.54%)	0/41 (0.00%)
Hepatic enzyme increased * 1	1/61 (1.64%)	1/130 (0.77%)	0/41 (0.00%)
International normalised ratio increased * 1	0/61 (0.00%)	0/130 (0.00%)	1/41 (2.44%)
Intraocular pressure increased * 1	0/61 (0.00%)	3/130 (2.31%)	1/41 (2.44%)
Lipase increased * 1	1/61 (1.64%)	2/130 (1.54%)	2/41 (4.88%)
Lymphocyte count decreased * 1	0/61 (0.00%)	5/130 (3.85%)	0/41 (0.00%)
Neutrophil count decreased * 1	1/61 (1.64%)	3/130 (2.31%)	0/41 (0.00%)
Oxygen saturation decreased * 1	1/61 (1.64%)	0/130 (0.00%)	0/41 (0.00%)
Platelet count decreased * 1	1/61 (1.64%)	6/130 (4.62%)	1/41 (2.44%)
Protein total decreased * 1	0/61 (0.00%)	0/130 (0.00%)	1/41 (2.44%)
Protein total increased * 1	0/61 (0.00%)	1/130 (0.77%)	0/41 (0.00%)
Pupillary light reflex tests abnormal * 1	0/61 (0.00%)	1/130 (0.77%)	0/41 (0.00%)
Troponin increased * 1	0/61 (0.00%)	1/130 (0.77%)	0/41 (0.00%)
White blood cell count decreased * 1	2/61 (3.28%)	2/130 (1.54%)	0/41 (0.00%)
White blood cell count increased * 1	0/61 (0.00%)	1/130 (0.77%)	0/41 (0.00%)
Metabolism and nutrition disorders
Decreased appetite * 1	8/61 (13.11%)	22/130 (16.92%)	7/41 (17.07%)
Hypokalaemia * 1	3/61 (4.92%)	13/130 (10.00%)	5/41 (12.20%)
Hypoalbuminaemia * 1	0/61 (0.00%)	10/130 (7.69%)	2/41 (4.88%)
Hypomagnesaemia * 1	0/61 (0.00%)	4/130 (3.08%)	3/41 (7.32%)
Hyponatraemia * 1	0/61 (0.00%)	7/130 (5.38%)	0/41 (0.00%)
Cell death * 1	0/61 (0.00%)	1/130 (0.77%)	0/41 (0.00%)
Dehydration * 1	0/61 (0.00%)	4/130 (3.08%)	1/41 (2.44%)
Diabetes mellitus * 1	0/61 (0.00%)	2/130 (1.54%)	0/41 (0.00%)
Electrolyte imbalance * 1	0/61 (0.00%)	1/130 (0.77%)	0/41 (0.00%)
Fluid retention * 1	0/61 (0.00%)	2/130 (1.54%)	1/41 (2.44%)
Gout * 1	1/61 (1.64%)	1/130 (0.77%)	0/41 (0.00%)
Hyperamylasaemia * 1	0/61 (0.00%)	1/130 (0.77%)	0/41 (0.00%)
Hyperglycaemia * 1	1/61 (1.64%)	3/130 (2.31%)	0/41 (0.00%)
Hyperkalaemia * 1	0/61 (0.00%)	5/130 (3.85%)	0/41 (0.00%)
Hyperlipasaemia * 1	0/61 (0.00%)	1/130 (0.77%)	0/41 (0.00%)
Hyperphosphataemia * 1	0/61 (0.00%)	1/130 (0.77%)	0/41 (0.00%)
Hypertriglyceridaemia * 1	0/61 (0.00%)	1/130 (0.77%)	0/41 (0.00%)
Hypocalcaemia * 1	0/61 (0.00%)	3/130 (2.31%)	2/41 (4.88%)
Hypoglycaemia * 1	0/61 (0.00%)	1/130 (0.77%)	1/41 (2.44%)
Hypophosphataemia * 1	1/61 (1.64%)	3/130 (2.31%)	2/41 (4.88%)
Hypoproteinaemia * 1	0/61 (0.00%)	1/130 (0.77%)	0/41 (0.00%)
Increased appetite * 1	0/61 (0.00%)	1/130 (0.77%)	0/41 (0.00%)
Iron deficiency * 1	0/61 (0.00%)	1/130 (0.77%)	0/41 (0.00%)
Malnutrition * 1	0/61 (0.00%)	1/130 (0.77%)	1/41 (2.44%)
Oligodipsia * 1	0/61 (0.00%)	1/130 (0.77%)	0/41 (0.00%)
Musculoskeletal and connective tissue disorders
Myalgia * 1	4/61 (6.56%)	18/130 (13.85%)	4/41 (9.76%)
Arthralgia * 1	3/61 (4.92%)	9/130 (6.92%)	7/41 (17.07%)
Back pain * 1	3/61 (4.92%)	8/130 (6.15%)	8/41 (19.51%)
Pain in extremity * 1	3/61 (4.92%)	9/130 (6.92%)	6/41 (14.63%)
Muscular weakness * 1	1/61 (1.64%)	8/130 (6.15%)	1/41 (2.44%)
Groin pain * 1	3/61 (4.92%)	3/130 (2.31%)	1/41 (2.44%)
Musculoskeletal pain * 1	2/61 (3.28%)	2/130 (1.54%)	4/41 (9.76%)
Arthritis * 1	0/61 (0.00%)	1/130 (0.77%)	0/41 (0.00%)
Bone pain * 1	0/61 (0.00%)	0/130 (0.00%)	2/41 (4.88%)
Chondrocalcinosis * 1	0/61 (0.00%)	1/130 (0.77%)	0/41 (0.00%)
Haemarthrosis * 1	0/61 (0.00%)	1/130 (0.77%)	0/41 (0.00%)
Joint swelling * 1	0/61 (0.00%)	2/130 (1.54%)	0/41 (0.00%)
Mobility decreased * 1	0/61 (0.00%)	0/130 (0.00%)	1/41 (2.44%)
Muscle contracture * 1	0/61 (0.00%)	1/130 (0.77%)	0/41 (0.00%)
Muscle spasms * 1	1/61 (1.64%)	1/130 (0.77%)	1/41 (2.44%)
Muscle twitching * 1	0/61 (0.00%)	1/130 (0.77%)	0/41 (0.00%)
Musculoskeletal chest pain * 1	1/61 (1.64%)	1/130 (0.77%)	1/41 (2.44%)
Musculoskeletal discomfort * 1	0/61 (0.00%)	1/130 (0.77%)	1/41 (2.44%)
Musculoskeletal disorder * 1	0/61 (0.00%)	1/130 (0.77%)	0/41 (0.00%)
Musculoskeletal stiffness * 1	1/61 (1.64%)	0/130 (0.00%)	0/41 (0.00%)
Neck mass * 1	0/61 (0.00%)	0/130 (0.00%)	1/41 (2.44%)
Neck pain * 1	2/61 (3.28%)	5/130 (3.85%)	1/41 (2.44%)
Pain in jaw * 1	2/61 (3.28%)	1/130 (0.77%)	0/41 (0.00%)
Rhabdomyolysis * 1	0/61 (0.00%)	0/130 (0.00%)	1/41 (2.44%)
Spinal osteoarthritis * 1	0/61 (0.00%)	2/130 (1.54%)	0/41 (0.00%)
Spinal pain * 1	2/61 (3.28%)	0/130 (0.00%)	1/41 (2.44%)
Tendonitis * 1	1/61 (1.64%)	0/130 (0.00%)	1/41 (2.44%)
Trismus * 1	0/61 (0.00%)	2/130 (1.54%)	0/41 (0.00%)
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Basal cell carcinoma * 1	0/61 (0.00%)	2/130 (1.54%)	0/41 (0.00%)
Blepharal papilloma * 1	0/61 (0.00%)	1/130 (0.77%)	0/41 (0.00%)
Breast neoplasm * 1	1/61 (1.64%)	0/130 (0.00%)	0/41 (0.00%)
Cancer pain * 1	1/61 (1.64%)	0/130 (0.00%)	0/41 (0.00%)
Malignant melanoma * 1	2/61 (3.28%)	0/130 (0.00%)	1/41 (2.44%)
Metastatic pain * 1	0/61 (0.00%)	1/130 (0.77%)	1/41 (2.44%)
Monoclonal gammopathy * 1	0/61 (0.00%)	1/130 (0.77%)	0/41 (0.00%)
Pyogenic granuloma * 1	0/61 (0.00%)	1/130 (0.77%)	0/41 (0.00%)
Skin cancer * 1	1/61 (1.64%)	0/130 (0.00%)	0/41 (0.00%)
Skin papilloma * 1	1/61 (1.64%)	0/130 (0.00%)	0/41 (0.00%)
Squamous cell carcinoma * 1	1/61 (1.64%)	0/130 (0.00%)	0/41 (0.00%)
Tumour haemorrhage * 1	2/61 (3.28%)	0/130 (0.00%)	0/41 (0.00%)
Tumour pain * 1	2/61 (3.28%)	0/130 (0.00%)	0/41 (0.00%)
Nervous system disorders
Dizziness * 1	3/61 (4.92%)	17/130 (13.08%)	5/41 (12.20%)
Headache * 1	8/61 (13.11%)	16/130 (12.31%)	0/41 (0.00%)
Dysgeusia * 1	6/61 (9.84%)	11/130 (8.46%)	4/41 (9.76%)
Paraesthesia * 1	9/61 (14.75%)	4/130 (3.08%)	2/41 (4.88%)
Sciatica * 1	3/61 (4.92%)	5/130 (3.85%)	3/41 (7.32%)
Dysaesthesia * 1	4/61 (6.56%)	1/130 (0.77%)	0/41 (0.00%)
Ageusia * 1	0/61 (0.00%)	1/130 (0.77%)	0/41 (0.00%)
Altered state of consciousness * 1	1/61 (1.64%)	0/130 (0.00%)	0/41 (0.00%)
Amnesia * 1	0/61 (0.00%)	2/130 (1.54%)	0/41 (0.00%)
Aphasia * 1	1/61 (1.64%)	1/130 (0.77%)	0/41 (0.00%)
Ataxia * 1	0/61 (0.00%)	1/130 (0.77%)	0/41 (0.00%)
Autonomic nervous system imbalance * 1	1/61 (1.64%)	0/130 (0.00%)	0/41 (0.00%)
Balance disorder * 1	0/61 (0.00%)	1/130 (0.77%)	0/41 (0.00%)
Cervicobrachial syndrome * 1	0/61 (0.00%)	1/130 (0.77%)	0/41 (0.00%)
Cognitive disorder * 1	0/61 (0.00%)	1/130 (0.77%)	0/41 (0.00%)
Depressed level of consciousness * 1	0/61 (0.00%)	1/130 (0.77%)	0/41 (0.00%)
Dizziness postural * 1	0/61 (0.00%)	0/130 (0.00%)	1/41 (2.44%)
Dysarthria * 1	1/61 (1.64%)	2/130 (1.54%)	0/41 (0.00%)
Hyperaesthesia * 1	0/61 (0.00%)	1/130 (0.77%)	0/41 (0.00%)
Hypoaesthesia * 1	1/61 (1.64%)	1/130 (0.77%)	2/41 (4.88%)
Lethargy * 1	0/61 (0.00%)	2/130 (1.54%)	0/41 (0.00%)
Loss of consciousness * 1	0/61 (0.00%)	2/130 (1.54%)	0/41 (0.00%)
Memory impairment * 1	0/61 (0.00%)	5/130 (3.85%)	1/41 (2.44%)
Migraine * 1	0/61 (0.00%)	0/130 (0.00%)	1/41 (2.44%)
Motor dysfunction * 1	1/61 (1.64%)	0/130 (0.00%)	1/41 (2.44%)
Muscle contractions involuntary * 1	0/61 (0.00%)	1/130 (0.77%)	0/41 (0.00%)
Myasthenic syndrome * 1	0/61 (0.00%)	1/130 (0.77%)	0/41 (0.00%)
Neuropathy peripheral * 1	0/61 (0.00%)	1/130 (0.77%)	1/41 (2.44%)
Neurotoxicity * 1	0/61 (0.00%)	1/130 (0.77%)	0/41 (0.00%)
Peripheral motor neuropathy * 1	0/61 (0.00%)	1/130 (0.77%)	0/41 (0.00%)
Peripheral sensory neuropathy * 1	0/61 (0.00%)	2/130 (1.54%)	0/41 (0.00%)
Presyncope * 1	0/61 (0.00%)	3/130 (2.31%)	2/41 (4.88%)
Sensorimotor disorder * 1	1/61 (1.64%)	0/130 (0.00%)	0/41 (0.00%)
Sensory disturbance * 1	0/61 (0.00%)	2/130 (1.54%)	1/41 (2.44%)
Somnolence * 1	0/61 (0.00%)	6/130 (4.62%)	1/41 (2.44%)
Syncope * 1	0/61 (0.00%)	4/130 (3.08%)	1/41 (2.44%)
Tremor * 1	1/61 (1.64%)	2/130 (1.54%)	0/41 (0.00%)
Visual field defect * 1	0/61 (0.00%)	2/130 (1.54%)	0/41 (0.00%)
Psychiatric disorders
Agitation * 1	0/61 (0.00%)	1/130 (0.77%)	0/41 (0.00%)
Anxiety * 1	6/61 (9.84%)	3/130 (2.31%)	2/41 (4.88%)
Confusional state * 1	0/61 (0.00%)	3/130 (2.31%)	0/41 (0.00%)
Depressed mood * 1	1/61 (1.64%)	0/130 (0.00%)	0/41 (0.00%)
Depression * 1	1/61 (1.64%)	1/130 (0.77%)	0/41 (0.00%)
Dyssomnia * 1	0/61 (0.00%)	1/130 (0.77%)	0/41 (0.00%)
Euphoric mood * 1	0/61 (0.00%)	1/130 (0.77%)	0/41 (0.00%)
Hallucination * 1	0/61 (0.00%)	1/130 (0.77%)	0/41 (0.00%)
Hallucination, visual * 1	0/61 (0.00%)	0/130 (0.00%)	1/41 (2.44%)
Insomnia * 1	4/61 (6.56%)	7/130 (5.38%)	1/41 (2.44%)
Irritability * 1	1/61 (1.64%)	0/130 (0.00%)	0/41 (0.00%)
Mood altered * 1	1/61 (1.64%)	0/130 (0.00%)	0/41 (0.00%)
Nervousness * 1	0/61 (0.00%)	0/130 (0.00%)	1/41 (2.44%)
Nightmare * 1	0/61 (0.00%)	1/130 (0.77%)	0/41 (0.00%)
Persecutory delusion * 1	0/61 (0.00%)	1/130 (0.77%)	0/41 (0.00%)
Psychomotor retardation * 1	0/61 (0.00%)	0/130 (0.00%)	2/41 (4.88%)
Renal and urinary disorders
Acute kidney injury * 1	0/61 (0.00%)	4/130 (3.08%)	1/41 (2.44%)
Cystitis noninfective * 1	0/61 (0.00%)	0/130 (0.00%)	1/41 (2.44%)
Dysuria * 1	0/61 (0.00%)	8/130 (6.15%)	1/41 (2.44%)
Haematuria * 1	0/61 (0.00%)	2/130 (1.54%)	0/41 (0.00%)
Micturition urgency * 1	0/61 (0.00%)	1/130 (0.77%)	0/41 (0.00%)
Oliguria * 1	0/61 (0.00%)	2/130 (1.54%)	0/41 (0.00%)
Proteinuria * 1	0/61 (0.00%)	4/130 (3.08%)	0/41 (0.00%)
Renal injury * 1	0/61 (0.00%)	1/130 (0.77%)	0/41 (0.00%)
Renal vein occlusion * 1	0/61 (0.00%)	1/130 (0.77%)	0/41 (0.00%)
Urinary incontinence * 1	0/61 (0.00%)	1/130 (0.77%)	0/41 (0.00%)
Urinary retention * 1	1/61 (1.64%)	2/130 (1.54%)	0/41 (0.00%)
Reproductive system and breast disorders
Amenorrhoea * 1	0/61 (0.00%)	1/130 (0.77%)	0/41 (0.00%)
Breast pain * 1	0/61 (0.00%)	1/130 (0.77%)	0/41 (0.00%)
Genital discomfort * 1	0/61 (0.00%)	0/130 (0.00%)	1/41 (2.44%)
Genital erythema * 1	1/61 (1.64%)	0/130 (0.00%)	1/41 (2.44%)
Haematospermia * 1	0/61 (0.00%)	1/130 (0.77%)	0/41 (0.00%)
Pelvic pain * 1	0/61 (0.00%)	1/130 (0.77%)	0/41 (0.00%)
Scrotal haematocoele * 1	0/61 (0.00%)	0/130 (0.00%)	1/41 (2.44%)
Scrotal oedema * 1	0/61 (0.00%)	1/130 (0.77%)	0/41 (0.00%)
Respiratory, thoracic and mediastinal disorders
Acute respiratory distress syndrome * 1	0/61 (0.00%)	1/130 (0.77%)	0/41 (0.00%)
Asthma * 1	0/61 (0.00%)	1/130 (0.77%)	0/41 (0.00%)
Atelectasis * 1	1/61 (1.64%)	0/130 (0.00%)	0/41 (0.00%)
Bronchospasm * 1	0/61 (0.00%)	1/130 (0.77%)	0/41 (0.00%)
Cough * 1	5/61 (8.20%)	9/130 (6.92%)	3/41 (7.32%)
Dry throat * 1	0/61 (0.00%)	1/130 (0.77%)	1/41 (2.44%)
Dysphonia * 1	1/61 (1.64%)	5/130 (3.85%)	1/41 (2.44%)
Dyspnoea * 1	4/61 (6.56%)	26/130 (20.00%)	6/41 (14.63%)
Dyspnoea exertional * 1	1/61 (1.64%)	4/130 (3.08%)	1/41 (2.44%)
Epistaxis * 1	2/61 (3.28%)	8/130 (6.15%)	2/41 (4.88%)
Hiccups * 1	0/61 (0.00%)	1/130 (0.77%)	0/41 (0.00%)
Hypoventilation * 1	0/61 (0.00%)	1/130 (0.77%)	0/41 (0.00%)
Hypoxia * 1	0/61 (0.00%)	2/130 (1.54%)	0/41 (0.00%)
Lung disorder * 1	0/61 (0.00%)	1/130 (0.77%)	0/41 (0.00%)
Nasal disorder * 1	0/61 (0.00%)	2/130 (1.54%)	0/41 (0.00%)
Nasal oedema * 1	0/61 (0.00%)	0/130 (0.00%)	1/41 (2.44%)
Nocturnal dyspnoea * 1	0/61 (0.00%)	0/130 (0.00%)	1/41 (2.44%)
Oropharyngeal pain * 1	1/61 (1.64%)	4/130 (3.08%)	3/41 (7.32%)
Orthopnoea * 1	0/61 (0.00%)	1/130 (0.77%)	0/41 (0.00%)
Pharyngeal inflammation * 1	0/61 (0.00%)	1/130 (0.77%)	0/41 (0.00%)
Pharyngeal ulceration * 1	0/61 (0.00%)	1/130 (0.77%)	0/41 (0.00%)
Pleural effusion * 1	1/61 (1.64%)	4/130 (3.08%)	0/41 (0.00%)
Pneumonitis * 1	0/61 (0.00%)	2/130 (1.54%)	1/41 (2.44%)
Productive cough * 1	0/61 (0.00%)	1/130 (0.77%)	0/41 (0.00%)
Pulmonary embolism * 1	1/61 (1.64%)	2/130 (1.54%)	2/41 (4.88%)
Rales * 1	1/61 (1.64%)	1/130 (0.77%)	0/41 (0.00%)
Respiratory disorder * 1	1/61 (1.64%)	0/130 (0.00%)	0/41 (0.00%)
Respiratory failure * 1	0/61 (0.00%)	3/130 (2.31%)	0/41 (0.00%)
Rhinalgia * 1	0/61 (0.00%)	1/130 (0.77%)	0/41 (0.00%)
Rhinitis allergic * 1	0/61 (0.00%)	0/130 (0.00%)	1/41 (2.44%)
Rhinorrhoea * 1	2/61 (3.28%)	0/130 (0.00%)	0/41 (0.00%)
Throat irritation * 1	1/61 (1.64%)	1/130 (0.77%)	0/41 (0.00%)
Wheezing * 1	0/61 (0.00%)	2/130 (1.54%)	0/41 (0.00%)
Skin and subcutaneous tissue disorders
Rash * 1	5/61 (8.20%)	46/130 (35.38%)	18/41 (43.90%)
Dermatitis acneiform * 1	0/61 (0.00%)	47/130 (36.15%)	9/41 (21.95%)
Pruritus * 1	1/61 (1.64%)	17/130 (13.08%)	7/41 (17.07%)
Erythema * 1	2/61 (3.28%)	14/130 (10.77%)	4/41 (9.76%)
Skin fissures * 1	0/61 (0.00%)	17/130 (13.08%)	2/41 (4.88%)
Alopecia * 1	2/61 (3.28%)	13/130 (10.00%)	4/41 (9.76%)
Rash maculo-papular * 1	0/61 (0.00%)	12/130 (9.23%)	6/41 (14.63%)
Dry skin * 1	1/61 (1.64%)	11/130 (8.46%)	3/41 (7.32%)
Eczema * 1	0/61 (0.00%)	8/130 (6.15%)	1/41 (2.44%)
Acne * 1	0/61 (0.00%)	4/130 (3.08%)	3/41 (7.32%)
Decubitus ulcer * 1	0/61 (0.00%)	1/130 (0.77%)	0/41 (0.00%)
Dermatitis * 1	0/61 (0.00%)	3/130 (2.31%)	1/41 (2.44%)
Dermatitis exfoliative * 1	0/61 (0.00%)	2/130 (1.54%)	2/41 (4.88%)
Diffuse alopecia * 1	1/61 (1.64%)	0/130 (0.00%)	0/41 (0.00%)
Drug eruption * 1	0/61 (0.00%)	0/130 (0.00%)	1/41 (2.44%)
Erythrosis * 1	1/61 (1.64%)	0/130 (0.00%)	0/41 (0.00%)
Haemorrhage subcutaneous * 1	0/61 (0.00%)	0/130 (0.00%)	1/41 (2.44%)
Hair growth abnormal * 1	0/61 (0.00%)	1/130 (0.77%)	0/41 (0.00%)
Hirsutism * 1	0/61 (0.00%)	1/130 (0.77%)	0/41 (0.00%)
Hyperhidrosis * 1	2/61 (3.28%)	2/130 (1.54%)	0/41 (0.00%)
Hyperkeratosis * 1	1/61 (1.64%)	0/130 (0.00%)	0/41 (0.00%)
Ingrowing nail * 1	0/61 (0.00%)	2/130 (1.54%)	1/41 (2.44%)
Intertrigo * 1	1/61 (1.64%)	4/130 (3.08%)	0/41 (0.00%)
Nail bed inflammation * 1	0/61 (0.00%)	1/130 (0.77%)	0/41 (0.00%)
Nail discolouration * 1	0/61 (0.00%)	1/130 (0.77%)	0/41 (0.00%)
Nail disorder * 1	0/61 (0.00%)	1/130 (0.77%)	0/41 (0.00%)
Night sweats * 1	2/61 (3.28%)	0/130 (0.00%)	0/41 (0.00%)
Onycholysis * 1	0/61 (0.00%)	1/130 (0.77%)	0/41 (0.00%)
Pain of skin * 1	0/61 (0.00%)	4/130 (3.08%)	0/41 (0.00%)
Palmar-plantar erythrodysaesthesia syndrome * 1	0/61 (0.00%)	6/130 (4.62%)	0/41 (0.00%)
Papule * 1	0/61 (0.00%)	3/130 (2.31%)	0/41 (0.00%)
Petechiae * 1	1/61 (1.64%)	0/130 (0.00%)	0/41 (0.00%)
Photosensitivity reaction * 1	2/61 (3.28%)	3/130 (2.31%)	0/41 (0.00%)
Pigmentation disorder * 1	0/61 (0.00%)	1/130 (0.77%)	1/41 (2.44%)
Prurigo * 1	0/61 (0.00%)	1/130 (0.77%)	0/41 (0.00%)
Pruritus generalised * 1	0/61 (0.00%)	1/130 (0.77%)	0/41 (0.00%)
Psoriasis * 1	0/61 (0.00%)	1/130 (0.77%)	0/41 (0.00%)
Rash erythematous * 1	0/61 (0.00%)	4/130 (3.08%)	2/41 (4.88%)
Rash generalised * 1	0/61 (0.00%)	5/130 (3.85%)	1/41 (2.44%)
Rash macular * 1	0/61 (0.00%)	2/130 (1.54%)	1/41 (2.44%)
Rash morbilliform * 1	0/61 (0.00%)	1/130 (0.77%)	0/41 (0.00%)
Rash papular * 1	0/61 (0.00%)	4/130 (3.08%)	0/41 (0.00%)
Rash pruritic * 1	0/61 (0.00%)	1/130 (0.77%)	0/41 (0.00%)
Rosacea * 1	1/61 (1.64%)	2/130 (1.54%)	1/41 (2.44%)
Scab * 1	1/61 (1.64%)	2/130 (1.54%)	0/41 (0.00%)
Seborrhoeic dermatitis * 1	0/61 (0.00%)	1/130 (0.77%)	0/41 (0.00%)
Skin burning sensation * 1	0/61 (0.00%)	2/130 (1.54%)	0/41 (0.00%)
Skin erosion * 1	0/61 (0.00%)	1/130 (0.77%)	0/41 (0.00%)
Skin exfoliation * 1	1/61 (1.64%)	4/130 (3.08%)	1/41 (2.44%)
Skin irritation * 1	0/61 (0.00%)	1/130 (0.77%)	0/41 (0.00%)
Skin lesion * 1	0/61 (0.00%)	1/130 (0.77%)	0/41 (0.00%)
Skin mass * 1	1/61 (1.64%)	0/130 (0.00%)	0/41 (0.00%)
Skin reaction * 1	0/61 (0.00%)	0/130 (0.00%)	1/41 (2.44%)
Skin ulcer * 1	0/61 (0.00%)	1/130 (0.77%)	0/41 (0.00%)
Solar dermatitis * 1	0/61 (0.00%)	1/130 (0.77%)	0/41 (0.00%)
Stasis dermatitis * 1	0/61 (0.00%)	2/130 (1.54%)	0/41 (0.00%)
Swelling face * 1	0/61 (0.00%)	4/130 (3.08%)	0/41 (0.00%)
Toxic skin eruption * 1	0/61 (0.00%)	1/130 (0.77%)	0/41 (0.00%)
Urticaria * 1	0/61 (0.00%)	2/130 (1.54%)	0/41 (0.00%)
Vascular disorders
Capillary leak syndrome * 1	0/61 (0.00%)	1/130 (0.77%)	0/41 (0.00%)
Deep vein thrombosis * 1	0/61 (0.00%)	1/130 (0.77%)	0/41 (0.00%)
Diastolic hypertension * 1	0/61 (0.00%)	1/130 (0.77%)	0/41 (0.00%)
Flushing * 1	2/61 (3.28%)	1/130 (0.77%)	1/41 (2.44%)
Haematoma * 1	2/61 (3.28%)	1/130 (0.77%)	0/41 (0.00%)
Hot flush * 1	1/61 (1.64%)	0/130 (0.00%)	0/41 (0.00%)
Hypertension * 1	2/61 (3.28%)	21/130 (16.15%)	6/41 (14.63%)
Hypotension * 1	3/61 (4.92%)	4/130 (3.08%)	2/41 (4.88%)
Lymphoedema * 1	2/61 (3.28%)	11/130 (8.46%)	3/41 (7.32%)
Pelvic venous thrombosis * 1	0/61 (0.00%)	1/130 (0.77%)	0/41 (0.00%)
Peripheral coldness * 1	0/61 (0.00%)	1/130 (0.77%)	0/41 (0.00%)
Peripheral ischaemia * 1	0/61 (0.00%)	0/130 (0.00%)	1/41 (2.44%)
Peripheral venous disease * 1	1/61 (1.64%)	0/130 (0.00%)	0/41 (0.00%)
Phlebitis * 1	0/61 (0.00%)	0/130 (0.00%)	1/41 (2.44%)
Thrombophlebitis * 1	0/61 (0.00%)	1/130 (0.77%)	0/41 (0.00%)
Vascular compression * 1	1/61 (1.64%)	0/130 (0.00%)	0/41 (0.00%)
Vena cava thrombosis * 1	1/61 (1.64%)	0/130 (0.00%)	0/41 (0.00%)
Venous thrombosis limb * 1	0/61 (0.00%)	1/130 (0.77%)	0/41 (0.00%)
* Indicates events were collected by non-systematic assessment; 1 Term from vocabulary, MedDRA 18.0

Limitations and Caveats

[Not Specified]

More Information

Certain Agreements

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

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

 

Results Point of Contact

• Name/Title: Merck KGaA Communication Center
• Organization: Merck Healthcare, a business of Merck KGaA, Darmstadt, Germany
• Phone: +49-6151-72-5200
• EMail: service@merckgroup.com

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

Lebbe C, Dutriaux C, Lesimple T, Kruit W, Kerger J, Thomas L, Guillot B, Braud F, Garbe C, Grob JJ, Loquai C, Ferraresi V, Robert C, Vasey P, Conry R, Isaacs R, Espinosa E, Schueler A, Massimini G, Dreno B. Pimasertib Versus Dacarbazine in Patients With Unresectable NRAS-Mutated Cutaneous Melanoma: Phase II, Randomized, Controlled Trial with Crossover. Cancers (Basel). 2020 Jun 29;12(7):1727. doi: 10.3390/cancers12071727.

• Responsible Party: EMD Serono
• ClinicalTrials.gov Identifier: NCT01693068
• Other Study ID Numbers: EMR 200066-007; 2012-002669-37 ( EudraCT Number )
• First Submitted: September 14, 2012
• First Posted: September 26, 2012
• Results First Submitted: October 23, 2017
• Results First Posted: January 5, 2018
• Last Update Posted: January 5, 2018