Dabrafenib Plus Trametinib vs Vemurafenib Alone in Unresectable or Metastatic BRAF V600E/K Cutaneous Melanoma (COMBI-v)

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ClinicalTrials.gov Identifier: NCT01597908

Recruitment Status : Completed

First Posted : May 14, 2012

Results First Posted : December 4, 2014

Last Update Posted : February 24, 2021

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Sponsor:

Information provided by (Responsible Party):

Novartis ( Novartis Pharmaceuticals )

Study Type	Interventional
Study Design	Allocation: Randomized; Intervention Model: Parallel Assignment; Masking: None (Open Label); Primary Purpose: Treatment
Condition	Melanoma
Interventions	Drug: Dabrafenib Drug: Vemurafenib Drug: Trametinib
Enrollment	704

Participant Flow

Recruitment Details	This study was conducted at 207 centers in 28 countries worldwide (Argentina, Australia, Austria, Belgium, Brazil, Canada, Czech Republic, Denmark, Finland, France, Germany, Hungary, Ireland, Israel, Italy, South Korea, Netherlands, New Zealand, Norway, Poland, Russian Federation, Spain, Sweden,Switzerland, Taiwan, Ukraine, UK and USA).
Pre-assignment Details	694 subjects were planned and 704 subjects (352 each in combination therapy arm and vemurafenib monotherapy arm) were actually randomized and analyzed. Subjects were stratified by LDH level (> the ULN versus ≤ ULN) and BRAF mutation (V600E versus V600K).


Arm/Group Title	Dabrafenib Plus Trametinib	Vemurafenib	Crossover Dabrafenib Plus Trametinib
Arm/Group Description	Dabrafenib 150 milligrams (mg) oral...	Vemurafenib 960 mg orally BID until...	With Protocol Amendment 7, patients...
Arm/Group Description	Dabrafenib 150 milligrams (mg) orally twice daily (BID) and Trametinib 2 mg orally once daily until disease progression, death, unacceptable toxicity, or withdrawal of consent.	Vemurafenib 960 mg orally BID until disease progression, death, unacceptable toxicity, or withdrawal of consent.	With Protocol Amendment 7, patients still receiving study treatment on the Vemurafenib monotherapy arm were allowed to cross over to the Dabrafenib and Trametinib combination arm.
Period Title: Randomized Phase
Started ^[1]	352	352	0
Safety Set ^[2]	350	349	0
Completed ^[3]	1	0	0
Not Completed	351	352	0
Reason Not Completed
Death	217	238	0
Sponsor Decision	93	39	0
Lost to Follow-up	9	16	0
Physician Decision	6	3	0
Withdrawal by Subject	26	22	0
Crossover to Dabrafenib&Trametinib	0	34	0
[1] All randomized patients included into Intent-to-Treat (ITT) population. [2] All patients who received at least one dose of study treatment [3] ongoing status (incomplete end-of-study data and never received study treatment)
Period Title: Crossover Phase
Started ^[1]	0	0	34
Completed	0	0	0
Not Completed	0	0	34
Reason Not Completed
Death	0	0	11
Withdrawal by Subject	0	0	3
Sponsor Decision	0	0	20
[1] All crossover randomized patients included into ITT & Safety Sets

Baseline Characteristics

Arm/Group Title		Dabrafenib Plus Trametinib	Vemurafenib	Total
Arm/Group Description		Dabrafenib 150 milligrams (mg) oral...	Vemurafenib 960 mg orally BID until...	Total of all reporting groups
Arm/Group Description		Dabrafenib 150 milligrams (mg) orally twice daily (BID) and Trametinib 2 mg orally once daily until disease progression, death, unacceptable toxicity, or withdrawal of consent.	Vemurafenib 960 mg orally BID until disease progression, death, unacceptable toxicity, or withdrawal of consent.	Total of all reporting groups
Overall Number of Baseline Participants		352	352	704
Baseline Analysis Population Description		[Not Specified]
Baseline Analysis Population Description		[Not Specified]
Age, Continuous Mean (Standard Deviation) Unit of measure: Years
	Number Analyzed	352 participants	352 participants	704 participants
		54.1 (13.83)	54.3 (14.06)	54.2 (13.94)
Sex: Female, Male Measure Type: Count of Participants Unit of measure: Participants
	Number Analyzed	352 participants	352 participants	704 participants
	Female	144 40.9%	172 48.9%	316 44.9%
	Male	208 59.1%	180 51.1%	388 55.1%
Race/Ethnicity, Customized Measure Type: Number Unit of measure: Participants	Number Analyzed	352 participants	352 participants	704 participants
Asian - East Asian Heritage		8	8	16
White - Arabic/North African Heritage		4	2	6
White - White/Caucasian/European Heritage		339	339	678
White - Mixed Race		1	0	1
Mixed Race		0	1	1
African American/African Heritage		0	1	1
American Indian or Alaskan Native		0	1	1

Outcome Measures

1.Primary Outcome


Title	Overall Survival (OS)
Description	Overall Survival (OS) was defined as the interval of time between the ...
Description	Overall Survival (OS) was defined as the interval of time between the date of randomization and the date of death due to any cause. For patients who did not die, OS was censored at the date of last contact.
Time Frame	From the date of randomization until date of death due to any cause (up to approximately 6 years)

Outcome Measure Data

Analysis Population Description

Intent-to-Treat (ITT) Population.


Arm/Group Title	Dabrafenib Plus Trametinib	Vemurafenib
Arm/Group Description:	Dabrafenib 150 milligrams (mg) oral...	Vemurafenib 960 mg orally BID until...
Arm/Group Description:	Dabrafenib 150 milligrams (mg) orally twice daily (BID) and Trametinib 2 mg orally once daily until disease progression, death, unacceptable toxicity, or withdrawal of consent.	Vemurafenib 960 mg orally BID until disease progression, death, unacceptable toxicity, or withdrawal of consent.
Overall Number of Participants Analyzed	352	352
Median (95% Confidence Interval) Unit of Measure: Months
	26.0 (22.1 to 33.8)	17.8 (15.6 to 20.7)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Dabrafenib Plus Trametinib, Vemurafenib
	Comments	[Not Specified]
	Type of Statistical Test	Superiority or Other (legacy)
	Comments	[Not Specified]

Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.70
	Confidence Interval	(2-Sided) 95% 0.58 to 0.83
	Estimation Comments	Hazard ratios are estimated using a Pike estimator.

2.Secondary Outcome


Title	Progression-Free Survival (PFS), as Assessed by the Investigator
Description	Progression-free survival (PFS) was defined as the interval of time be...
Description	Progression-free survival (PFS) was defined as the interval of time between the date of randomization and the first documented occurrence of disease progression or death due to any cause. PFS for investigator-assessed response was summarized per Response Evaluation Criteria in Solid Tumors (RECIST), Version 1.1, which is a set of published rules defining when cancer patients improve (respond), stay the same (stabilize), or worsen (progress) during treatment. Disease progression was defined as at least a 20% increase in the sum of the diameters of target lesions with an absolute increase of at least 5 millimeters (mm) or the appearance of at least 1 new lesion, or the worsening of non-target lesions significant enough to require study treatment discontinuation.
Time Frame	From randomization until the earliest date of disease progression (PD) or death due to any cause (up to approximately 6 years)

Outcome Measure Data

Analysis Population Description

Intent-to-Treat (ITT) Population.


Arm/Group Title	Dabrafenib Plus Trametinib	Vemurafenib
Arm/Group Description:	Dabrafenib 150 milligrams (mg) oral...	Vemurafenib 960 mg orally BID until...
Arm/Group Description:	Dabrafenib 150 milligrams (mg) orally twice daily (BID) and Trametinib 2 mg orally once daily until disease progression, death, unacceptable toxicity, or withdrawal of consent.	Vemurafenib 960 mg orally BID until disease progression, death, unacceptable toxicity, or withdrawal of consent.
Overall Number of Participants Analyzed	352	352
Median (95% Confidence Interval) Unit of Measure: Months
	12.1 (9.7 to 14.7)	7.3 (6.0 to 8.1)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Dabrafenib Plus Trametinib, Vemurafenib
	Comments	[Not Specified]
	Type of Statistical Test	Superiority or Other (legacy)
	Comments	[Not Specified]

Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.62
	Confidence Interval	(2-Sided) 95% 0.52 to 0.73
	Estimation Comments	Hazard ratios are estimated using a Pike estimator.

3.Secondary Outcome


Title	Overall Response Rate (ORR) During Randomized Phase, as Assessed by the Investigator
Description	Overall response was defined as the percentage of confirmed responders...
Description	Overall response was defined as the percentage of confirmed responders (complete response [CR] + partial response [PR] per RECIST, Version 1.1) as summarized by Investigator assessment. CR was defined as the disappearance of all evidence of target lesions. PR was defined as at least a 30% reduction from Baseline in the sum of the longest diameter (LD) of all target lesions. Data were reported as those participants with measureable disease at Baseline.
Time Frame	From randomization until the first documented complete response or partial response (up to approximately 6 years)

Outcome Measure Data

Analysis Population Description

Intent-to-Treat (ITT) Population. Only participants with measurable disease at baseline were included.


Arm/Group Title	Dabrafenib Plus Trametinib	Vemurafenib
Arm/Group Description:	Dabrafenib 150 milligrams (mg) oral...	Vemurafenib 960 mg orally BID until...
Arm/Group Description:	Dabrafenib 150 milligrams (mg) orally twice daily (BID) and Trametinib 2 mg orally once daily until disease progression, death, unacceptable toxicity, or withdrawal of consent.	Vemurafenib 960 mg orally BID until disease progression, death, unacceptable toxicity, or withdrawal of consent.
Overall Number of Participants Analyzed	351	350
Measure Type: Number Number (95% Confidence Interval) Unit of Measure: Percentage of Participants
	68 (62.3 to 72.4)	53 (47.2 to 57.9)

4.Secondary Outcome


Title	Duration of Response (DOR), as Assessed by the Investigator
Description	Duration of Response (DOR) was defined as the time from the first docu...
Description	Duration of Response (DOR) was defined as the time from the first documented evidence of a CR (disappearance of all evidence of target lesions) or a PR (at least a 30% reduction from Baseline in the sum of the longest diameter of all target lesions) until disease progression or death due to any cause. PD was defined as at least a 20% increase in the sum of the diameters of target lesions with an absolute increase of at least 5 mm or the appearance of at least1 new lesion, or the worsening of non-target lesions significant enough to require study treatment discontinuation. Data were summarized per RECIST, Version 1.1.
Time Frame	From the time of the first documented response (CR or PR) until disease progression (up to approximately 6 years)

Outcome Measure Data

Analysis Population Description

Intent-to-Treat (ITT) Population. Only participants with confirmed response by RECIST version 1.1 were included.


Arm/Group Title	Dabrafenib Plus Trametinib	Vemurafenib
Arm/Group Description:	Dabrafenib 150 milligrams (mg) oral...	Vemurafenib 960 mg orally BID until...
Arm/Group Description:	Dabrafenib 150 milligrams (mg) orally twice daily (BID) and Trametinib 2 mg orally once daily until disease progression, death, unacceptable toxicity, or withdrawal of consent.	Vemurafenib 960 mg orally BID until disease progression, death, unacceptable toxicity, or withdrawal of consent.
Overall Number of Participants Analyzed	237	185
Median (95% Confidence Interval) Unit of Measure: Months
	13.8 (11.3 to 18.6)	8.5 (7.4 to 9.3)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Dabrafenib Plus Trametinib, Vemurafenib
	Comments	[Not Specified]
	Type of Statistical Test	Superiority or Other (legacy)
	Comments	[Not Specified]

Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.64
	Confidence Interval	(2-Sided) 95% 0.51 to 0.81
	Estimation Comments	[Not Specified]

5.Post-Hoc Outcome


Title	All Collected Deaths
Description	Pre-treatment deaths were collected from screening visit up to the fir...
Description	Pre-treatment deaths were collected from screening visit up to the first day of treatment, for a maximum duration of 28 days. Patients who died during the screening period are considered as screen failure. On treatment deaths were collected from FPFT up to 30 days after study drug discontinuation, for a maximum duration of 81.1 months (treatment duration ranged from 0.1 to 80.1 months). Deaths post treatment survival follow up were collected after the on- treatment period, up to approximately 6 years. Patients who didn't die during the on-treatment period and had not stopped study participation at the time of data cut-off (end of study) were censored.
Time Frame	up to 28 days before Day 1 (Screening), up to 81.1 months (on-treatment), up to approximately 6 years (study duration)

Outcome Measure Data

Analysis Population Description

Clinical database population; all treated patients and patients who died during screening.


Arm/Group Title	Dabrafenib Plus Trametinib	Vemurafenib	Crossover Dabrafenib + Trametinib
Arm/Group Description:	Dabrafenib 150 milligrams (mg) oral...	Vemurafenib 960 mg orally BID until...	With Protocol Amendment 7, patients...
Arm/Group Description:	Dabrafenib 150 milligrams (mg) orally twice daily (BID) and Trametinib 2 mg orally once daily until disease progression, death, unacceptable toxicity, or withdrawal of consent.	Vemurafenib 960 mg orally BID until disease progression, death, unacceptable toxicity, or withdrawal of consent.	With Protocol Amendment 7, patients still receiving study treatment on the Vemurafenib monotherapy arm were allowed to cross over to the Dabrafenib and Trametinib combination arm.
Overall Number of Participants Analyzed	351	349	34
Measure Type: Count of Participants Unit of Measure: Participants
Pre-treatment deaths	1 0.3%	0 0.0%	0 0.0%
On-treatment deaths	44 12.5%	47 13.5%	2 5.9%
Post-treatment deaths	172 49.0%	191 54.7%	9 26.5%
All deaths	216 61.5%	238 68.2%	11 32.4%

Adverse Events

Time Frame	Adverse events were collected from First Patient First Treatment (FPFT) up to 30 days after study drug discontinuation, for a maximum duration of 81.1 months (treatment duration ranged from 0.1 to 80.1 months). In addition, new malignancies and AEs possibly related to study treatment were collected up to approximately 6 years
Adverse Event Reporting Description	Any clinically significant sign or symptom that occurs during the study treatment and 30 days post treatment follow up. In addition, new malignancies and AEs possibly related to study treatment were collected even if they occurred more than 30 days post-treatment.

Arm/Group Title	Dabrafenib Plus Trametinib	Vemurafenib	Crossover Dabrafenib Plus Trametinib	All Patients
Arm/Group Description	Dabrafenib 150 milligrams (mg) oral...	Vemurafenib 960 mg orally BID until...	With Protocol Amendment 7, patients...	All randomized patients who receive...
Arm/Group Description	Dabrafenib 150 milligrams (mg) orally twice daily (BID) and Trametinib 2 mg orally once daily until disease progression, death, unacceptable toxicity, or withdrawal of consent.	Vemurafenib 960 mg orally BID until disease progression, death, unacceptable toxicity, or withdrawal of consent.	With Protocol Amendment 7, patients still receiving study treatment on the Vemurafenib monotherapy arm were allowed to cross over to the Dabrafenib and Trametinib combination arm.	All randomized patients who received at least one dose of study treatment.
All-Cause Mortality
	Dabrafenib Plus Trametinib	Vemurafenib	Crossover Dabrafenib Plus Trametinib	All Patients
	Affected / at Risk (%)	Affected / at Risk (%)	Affected / at Risk (%)	Affected / at Risk (%)
Total	216/350 (61.71%)	238/349 (68.19%)	11/34 (32.35%)	465/699 (66.52%)
Serious Adverse Events Serious Adverse Events
	Dabrafenib Plus Trametinib	Vemurafenib	Crossover Dabrafenib Plus Trametinib	All Patients
	Affected / at Risk (%)	Affected / at Risk (%)	Affected / at Risk (%)	Affected / at Risk (%)
Total	172/350 (49.14%)	139/349 (39.83%)	15/34 (44.12%)	319/699 (45.64%)
Blood and lymphatic system disorders
Anaemia ^† 1	4/350 (1.14%)	2/349 (0.57%)	1/34 (2.94%)	7/699 (1.00%)
Febrile neutropenia ^† 1	1/350 (0.29%)	1/349 (0.29%)	0/34 (0.00%)	2/699 (0.29%)
Leukopenia ^† 1	2/350 (0.57%)	1/349 (0.29%)	0/34 (0.00%)	3/699 (0.43%)
Neutropenia ^† 1	2/350 (0.57%)	0/349 (0.00%)	0/34 (0.00%)	2/699 (0.29%)
Thrombocytopenia ^† 1	2/350 (0.57%)	0/349 (0.00%)	0/34 (0.00%)	2/699 (0.29%)
Cardiac disorders
Acute coronary syndrome ^† 1	0/350 (0.00%)	2/349 (0.57%)	0/34 (0.00%)	2/699 (0.29%)
Acute myocardial infarction ^† 1	1/350 (0.29%)	0/349 (0.00%)	0/34 (0.00%)	1/699 (0.14%)
Angina unstable ^† 1	0/350 (0.00%)	1/349 (0.29%)	0/34 (0.00%)	1/699 (0.14%)
Arrhythmia ^† 1	1/350 (0.29%)	0/349 (0.00%)	0/34 (0.00%)	1/699 (0.14%)
Arteriosclerosis coronary artery ^† 1	1/350 (0.29%)	0/349 (0.00%)	0/34 (0.00%)	1/699 (0.14%)
Atrial fibrillation ^† 1	3/350 (0.86%)	4/349 (1.15%)	0/34 (0.00%)	7/699 (1.00%)
Left ventricular dysfunction ^† 1	1/350 (0.29%)	0/349 (0.00%)	0/34 (0.00%)	1/699 (0.14%)
Myocardial infarction ^† 1	2/350 (0.57%)	2/349 (0.57%)	0/34 (0.00%)	4/699 (0.57%)
Pericardial effusion ^† 1	0/350 (0.00%)	1/349 (0.29%)	0/34 (0.00%)	1/699 (0.14%)
Pericarditis ^† 1	0/350 (0.00%)	5/349 (1.43%)	0/34 (0.00%)	5/699 (0.72%)
Sinus tachycardia ^† 1	1/350 (0.29%)	1/349 (0.29%)	0/34 (0.00%)	2/699 (0.29%)
Supraventricular tachycardia ^† 1	0/350 (0.00%)	1/349 (0.29%)	0/34 (0.00%)	1/699 (0.14%)
Tachyarrhythmia ^† 1	0/350 (0.00%)	0/349 (0.00%)	1/34 (2.94%)	1/699 (0.14%)
Tachycardia ^† 1	1/350 (0.29%)	0/349 (0.00%)	0/34 (0.00%)	1/699 (0.14%)
Ear and labyrinth disorders
Vertigo ^† 1	2/350 (0.57%)	0/349 (0.00%)	0/34 (0.00%)	2/699 (0.29%)
Eye disorders
Cataract ^† 1	1/350 (0.29%)	0/349 (0.00%)	0/34 (0.00%)	1/699 (0.14%)
Chorioretinopathy ^† 1	2/350 (0.57%)	1/349 (0.29%)	0/34 (0.00%)	3/699 (0.43%)
Eye haemorrhage ^† 1	0/350 (0.00%)	1/349 (0.29%)	0/34 (0.00%)	1/699 (0.14%)
Glaucoma ^† 1	0/350 (0.00%)	1/349 (0.29%)	0/34 (0.00%)	1/699 (0.14%)
Retinal degeneration ^† 1	0/350 (0.00%)	1/349 (0.29%)	0/34 (0.00%)	1/699 (0.14%)
Retinal tear ^† 1	1/350 (0.29%)	0/349 (0.00%)	0/34 (0.00%)	1/699 (0.14%)
Retinal vein occlusion ^† 1	0/350 (0.00%)	2/349 (0.57%)	0/34 (0.00%)	2/699 (0.29%)
Uveitis ^† 1	1/350 (0.29%)	1/349 (0.29%)	0/34 (0.00%)	2/699 (0.29%)
Vision blurred ^† 1	1/350 (0.29%)	0/349 (0.00%)	0/34 (0.00%)	1/699 (0.14%)
Vitreous detachment ^† 1	1/350 (0.29%)	0/349 (0.00%)	0/34 (0.00%)	1/699 (0.14%)
Gastrointestinal disorders
Abdominal pain ^† 1	0/350 (0.00%)	1/349 (0.29%)	1/34 (2.94%)	2/699 (0.29%)
Abdominal pain upper ^† 1	0/350 (0.00%)	1/349 (0.29%)	0/34 (0.00%)	1/699 (0.14%)
Constipation ^† 1	0/350 (0.00%)	1/349 (0.29%)	0/34 (0.00%)	1/699 (0.14%)
Diarrhoea ^† 1	3/350 (0.86%)	0/349 (0.00%)	0/34 (0.00%)	3/699 (0.43%)
Diverticulum intestinal haemorrhagic ^† 1	0/350 (0.00%)	0/349 (0.00%)	1/34 (2.94%)	1/699 (0.14%)
Duodenal perforation ^† 1	1/350 (0.29%)	0/349 (0.00%)	0/34 (0.00%)	1/699 (0.14%)
Duodenal ulcer ^† 1	2/350 (0.57%)	0/349 (0.00%)	0/34 (0.00%)	2/699 (0.29%)
Duodenal ulcer haemorrhage ^† 1	2/350 (0.57%)	0/349 (0.00%)	0/34 (0.00%)	2/699 (0.29%)
Gastric ulcer haemorrhage ^† 1	0/350 (0.00%)	1/349 (0.29%)	0/34 (0.00%)	1/699 (0.14%)
Gastrointestinal haemorrhage ^† 1	0/350 (0.00%)	0/349 (0.00%)	1/34 (2.94%)	1/699 (0.14%)
Gastrointestinal pain ^† 1	1/350 (0.29%)	0/349 (0.00%)	0/34 (0.00%)	1/699 (0.14%)
Haemorrhoidal haemorrhage ^† 1	0/350 (0.00%)	0/349 (0.00%)	1/34 (2.94%)	1/699 (0.14%)
Ileus ^† 1	0/350 (0.00%)	2/349 (0.57%)	0/34 (0.00%)	2/699 (0.29%)
Inguinal hernia ^† 1	2/350 (0.57%)	0/349 (0.00%)	0/34 (0.00%)	2/699 (0.29%)
Intestinal pseudo-obstruction ^† 1	1/350 (0.29%)	0/349 (0.00%)	0/34 (0.00%)	1/699 (0.14%)
Large intestine perforation ^† 1	0/350 (0.00%)	1/349 (0.29%)	0/34 (0.00%)	1/699 (0.14%)
Leukoplakia oral ^† 1	0/350 (0.00%)	1/349 (0.29%)	0/34 (0.00%)	1/699 (0.14%)
Nausea ^† 1	5/350 (1.43%)	1/349 (0.29%)	0/34 (0.00%)	6/699 (0.86%)
Pancreatitis ^† 1	0/350 (0.00%)	1/349 (0.29%)	0/34 (0.00%)	1/699 (0.14%)
Rectal polyp ^† 1	0/350 (0.00%)	0/349 (0.00%)	1/34 (2.94%)	1/699 (0.14%)
Umbilical hernia ^† 1	0/350 (0.00%)	0/349 (0.00%)	1/34 (2.94%)	1/699 (0.14%)
Vomiting ^† 1	8/350 (2.29%)	1/349 (0.29%)	0/34 (0.00%)	9/699 (1.29%)
General disorders
Asthenia ^† 1	3/350 (0.86%)	0/349 (0.00%)	0/34 (0.00%)	3/699 (0.43%)
Chest pain ^† 1	0/350 (0.00%)	1/349 (0.29%)	0/34 (0.00%)	1/699 (0.14%)
Chills ^† 1	14/350 (4.00%)	0/349 (0.00%)	0/34 (0.00%)	14/699 (2.00%)
Fatigue ^† 1	2/350 (0.57%)	1/349 (0.29%)	1/34 (2.94%)	4/699 (0.57%)
General physical health deterioration ^† 1	0/350 (0.00%)	1/349 (0.29%)	0/34 (0.00%)	1/699 (0.14%)
Inflammation ^† 1	0/350 (0.00%)	1/349 (0.29%)	0/34 (0.00%)	1/699 (0.14%)
Influenza like illness ^† 1	3/350 (0.86%)	0/349 (0.00%)	0/34 (0.00%)	3/699 (0.43%)
Malaise ^† 1	1/350 (0.29%)	0/349 (0.00%)	0/34 (0.00%)	1/699 (0.14%)
Non-cardiac chest pain ^† 1	0/350 (0.00%)	1/349 (0.29%)	0/34 (0.00%)	1/699 (0.14%)
Pyrexia ^† 1	55/350 (15.71%)	6/349 (1.72%)	0/34 (0.00%)	61/699 (8.73%)
Hepatobiliary disorders
Bile duct obstruction ^† 1	1/350 (0.29%)	0/349 (0.00%)	0/34 (0.00%)	1/699 (0.14%)
Cholecystitis ^† 1	4/350 (1.14%)	2/349 (0.57%)	0/34 (0.00%)	6/699 (0.86%)
Cholelithiasis ^† 1	0/350 (0.00%)	2/349 (0.57%)	0/34 (0.00%)	2/699 (0.29%)
Gallbladder polyp ^† 1	1/350 (0.29%)	0/349 (0.00%)	0/34 (0.00%)	1/699 (0.14%)
Hepatitis ^† 1	0/350 (0.00%)	1/349 (0.29%)	0/34 (0.00%)	1/699 (0.14%)
Hepatocellular injury ^† 1	1/350 (0.29%)	0/349 (0.00%)	0/34 (0.00%)	1/699 (0.14%)
Hepatotoxicity ^† 1	0/350 (0.00%)	2/349 (0.57%)	0/34 (0.00%)	2/699 (0.29%)
Hypertransaminasaemia ^† 1	1/350 (0.29%)	0/349 (0.00%)	0/34 (0.00%)	1/699 (0.14%)
Immune system disorders
Drug hypersensitivity ^† 1	0/350 (0.00%)	1/349 (0.29%)	0/34 (0.00%)	1/699 (0.14%)
Hypersensitivity ^† 1	0/350 (0.00%)	1/349 (0.29%)	0/34 (0.00%)	1/699 (0.14%)
Infections and infestations
Abdominal sepsis ^† 1	1/350 (0.29%)	0/349 (0.00%)	0/34 (0.00%)	1/699 (0.14%)
Abscess soft tissue ^† 1	1/350 (0.29%)	0/349 (0.00%)	0/34 (0.00%)	1/699 (0.14%)
Appendicitis ^† 1	0/350 (0.00%)	0/349 (0.00%)	1/34 (2.94%)	1/699 (0.14%)
Bacteraemia ^† 1	1/350 (0.29%)	0/349 (0.00%)	0/34 (0.00%)	1/699 (0.14%)
Biliary sepsis ^† 1	1/350 (0.29%)	0/349 (0.00%)	0/34 (0.00%)	1/699 (0.14%)
Bronchitis ^† 1	1/350 (0.29%)	0/349 (0.00%)	0/34 (0.00%)	1/699 (0.14%)
Cellulitis ^† 1	5/350 (1.43%)	1/349 (0.29%)	0/34 (0.00%)	6/699 (0.86%)
Clostridium difficile colitis ^† 1	0/350 (0.00%)	0/349 (0.00%)	1/34 (2.94%)	1/699 (0.14%)
Corneal abscess ^† 1	1/350 (0.29%)	0/349 (0.00%)	0/34 (0.00%)	1/699 (0.14%)
Diverticulitis ^† 1	1/350 (0.29%)	0/349 (0.00%)	0/34 (0.00%)	1/699 (0.14%)
Enterocolitis infectious ^† 1	1/350 (0.29%)	1/349 (0.29%)	0/34 (0.00%)	2/699 (0.29%)
Erysipelas ^† 1	4/350 (1.14%)	0/349 (0.00%)	0/34 (0.00%)	4/699 (0.57%)
Escherichia sepsis ^† 1	1/350 (0.29%)	0/349 (0.00%)	0/34 (0.00%)	1/699 (0.14%)
Gastroenteritis ^† 1	1/350 (0.29%)	0/349 (0.00%)	0/34 (0.00%)	1/699 (0.14%)
Gastroenteritis viral ^† 1	1/350 (0.29%)	0/349 (0.00%)	0/34 (0.00%)	1/699 (0.14%)
Gastrointestinal infection ^† 1	3/350 (0.86%)	2/349 (0.57%)	0/34 (0.00%)	5/699 (0.72%)
Haematoma infection ^† 1	1/350 (0.29%)	0/349 (0.00%)	0/34 (0.00%)	1/699 (0.14%)
Helicobacter infection ^† 1	1/350 (0.29%)	0/349 (0.00%)	0/34 (0.00%)	1/699 (0.14%)
Infection ^† 1	2/350 (0.57%)	1/349 (0.29%)	0/34 (0.00%)	3/699 (0.43%)
Influenza ^† 1	0/350 (0.00%)	0/349 (0.00%)	1/34 (2.94%)	1/699 (0.14%)
Kidney infection ^† 1	1/350 (0.29%)	0/349 (0.00%)	0/34 (0.00%)	1/699 (0.14%)
Lower respiratory tract infection ^† 1	1/350 (0.29%)	1/349 (0.29%)	0/34 (0.00%)	2/699 (0.29%)
Lung infection ^† 1	0/350 (0.00%)	1/349 (0.29%)	0/34 (0.00%)	1/699 (0.14%)
Meningitis ^† 1	0/350 (0.00%)	1/349 (0.29%)	0/34 (0.00%)	1/699 (0.14%)
Oesophageal candidiasis ^† 1	0/350 (0.00%)	1/349 (0.29%)	0/34 (0.00%)	1/699 (0.14%)
Peritonitis ^† 1	0/350 (0.00%)	1/349 (0.29%)	0/34 (0.00%)	1/699 (0.14%)
Pleural infection ^† 1	0/350 (0.00%)	1/349 (0.29%)	0/34 (0.00%)	1/699 (0.14%)
Pneumonia ^† 1	4/350 (1.14%)	6/349 (1.72%)	1/34 (2.94%)	10/699 (1.43%)
Post procedural infection ^† 1	1/350 (0.29%)	0/349 (0.00%)	0/34 (0.00%)	1/699 (0.14%)
Pyelonephritis ^† 1	0/350 (0.00%)	1/349 (0.29%)	0/34 (0.00%)	1/699 (0.14%)
Pyelonephritis acute ^† 1	1/350 (0.29%)	0/349 (0.00%)	0/34 (0.00%)	1/699 (0.14%)
Respiratory tract infection ^† 1	1/350 (0.29%)	0/349 (0.00%)	0/34 (0.00%)	1/699 (0.14%)
Sepsis ^† 1	3/350 (0.86%)	0/349 (0.00%)	1/34 (2.94%)	4/699 (0.57%)
Sinusitis ^† 1	0/350 (0.00%)	1/349 (0.29%)	0/34 (0.00%)	1/699 (0.14%)
Skin infection ^† 1	1/350 (0.29%)	0/349 (0.00%)	0/34 (0.00%)	1/699 (0.14%)
Streptococcal sepsis ^† 1	1/350 (0.29%)	0/349 (0.00%)	0/34 (0.00%)	1/699 (0.14%)
Tonsillitis ^† 1	0/350 (0.00%)	1/349 (0.29%)	0/34 (0.00%)	1/699 (0.14%)
Urinary tract infection ^† 1	10/350 (2.86%)	1/349 (0.29%)	1/34 (2.94%)	12/699 (1.72%)
Urosepsis ^† 1	1/350 (0.29%)	0/349 (0.00%)	0/34 (0.00%)	1/699 (0.14%)
Viral infection ^† 1	1/350 (0.29%)	0/349 (0.00%)	0/34 (0.00%)	1/699 (0.14%)
Injury, poisoning and procedural complications
Clavicle fracture ^† 1	1/350 (0.29%)	0/349 (0.00%)	0/34 (0.00%)	1/699 (0.14%)
Fall ^† 1	0/350 (0.00%)	0/349 (0.00%)	1/34 (2.94%)	1/699 (0.14%)
Femur fracture ^† 1	1/350 (0.29%)	1/349 (0.29%)	0/34 (0.00%)	2/699 (0.29%)
Pelvic fracture ^† 1	1/350 (0.29%)	0/349 (0.00%)	0/34 (0.00%)	1/699 (0.14%)
Post procedural complication ^† 1	1/350 (0.29%)	0/349 (0.00%)	0/34 (0.00%)	1/699 (0.14%)
Radiation necrosis ^† 1	0/350 (0.00%)	1/349 (0.29%)	0/34 (0.00%)	1/699 (0.14%)
Radius fracture ^† 1	2/350 (0.57%)	0/349 (0.00%)	0/34 (0.00%)	2/699 (0.29%)
Subdural haematoma ^† 1	1/350 (0.29%)	0/349 (0.00%)	0/34 (0.00%)	1/699 (0.14%)
Thoracic vertebral fracture ^† 1	0/350 (0.00%)	1/349 (0.29%)	0/34 (0.00%)	1/699 (0.14%)
Toxicity to various agents ^† 1	0/350 (0.00%)	1/349 (0.29%)	0/34 (0.00%)	1/699 (0.14%)
Vascular pseudoaneurysm ^† 1	1/350 (0.29%)	0/349 (0.00%)	0/34 (0.00%)	1/699 (0.14%)
Wound dehiscence ^† 1	1/350 (0.29%)	0/349 (0.00%)	0/34 (0.00%)	1/699 (0.14%)
Investigations
Alanine aminotransferase increased ^† 1	6/350 (1.71%)	9/349 (2.58%)	0/34 (0.00%)	15/699 (2.15%)
Aspartate aminotransferase increased ^† 1	3/350 (0.86%)	5/349 (1.43%)	0/34 (0.00%)	8/699 (1.14%)
Blood alkaline phosphatase increased ^† 1	0/350 (0.00%)	2/349 (0.57%)	0/34 (0.00%)	2/699 (0.29%)
Blood bilirubin increased ^† 1	2/350 (0.57%)	6/349 (1.72%)	0/34 (0.00%)	8/699 (1.14%)
Blood creatine phosphokinase increased ^† 1	3/350 (0.86%)	0/349 (0.00%)	0/34 (0.00%)	3/699 (0.43%)
Blood creatinine increased ^† 1	2/350 (0.57%)	1/349 (0.29%)	0/34 (0.00%)	3/699 (0.43%)
Ejection fraction decreased ^† 1	31/350 (8.86%)	1/349 (0.29%)	2/34 (5.88%)	34/699 (4.86%)
Hepatic enzyme increased ^† 1	4/350 (1.14%)	6/349 (1.72%)	0/34 (0.00%)	10/699 (1.43%)
International normalised ratio increased ^† 1	0/350 (0.00%)	1/349 (0.29%)	0/34 (0.00%)	1/699 (0.14%)
Transaminases increased ^† 1	1/350 (0.29%)	0/349 (0.00%)	0/34 (0.00%)	1/699 (0.14%)
Troponin I increased ^† 1	1/350 (0.29%)	0/349 (0.00%)	0/34 (0.00%)	1/699 (0.14%)
Metabolism and nutrition disorders
Dehydration ^† 1	8/350 (2.29%)	2/349 (0.57%)	0/34 (0.00%)	10/699 (1.43%)
Hypercalcaemia ^† 1	1/350 (0.29%)	0/349 (0.00%)	0/34 (0.00%)	1/699 (0.14%)
Hyperglycaemia ^† 1	1/350 (0.29%)	0/349 (0.00%)	0/34 (0.00%)	1/699 (0.14%)
Hyponatraemia ^† 1	5/350 (1.43%)	0/349 (0.00%)	0/34 (0.00%)	5/699 (0.72%)
Musculoskeletal and connective tissue disorders
Arthralgia ^† 1	0/350 (0.00%)	1/349 (0.29%)	0/34 (0.00%)	1/699 (0.14%)
Arthritis ^† 1	1/350 (0.29%)	1/349 (0.29%)	0/34 (0.00%)	2/699 (0.29%)
Chest wall haematoma ^† 1	1/350 (0.29%)	0/349 (0.00%)	0/34 (0.00%)	1/699 (0.14%)
Intervertebral disc protrusion ^† 1	1/350 (0.29%)	0/349 (0.00%)	0/34 (0.00%)	1/699 (0.14%)
Muscular weakness ^† 1	1/350 (0.29%)	0/349 (0.00%)	0/34 (0.00%)	1/699 (0.14%)
Musculoskeletal pain ^† 1	0/350 (0.00%)	1/349 (0.29%)	0/34 (0.00%)	1/699 (0.14%)
Osteoarthritis ^† 1	2/350 (0.57%)	0/349 (0.00%)	0/34 (0.00%)	2/699 (0.29%)
Pain in extremity ^† 1	1/350 (0.29%)	0/349 (0.00%)	0/34 (0.00%)	1/699 (0.14%)
Rhabdomyolysis ^† 1	2/350 (0.57%)	0/349 (0.00%)	0/34 (0.00%)	2/699 (0.29%)
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Acute myeloid leukaemia ^† 1	1/350 (0.29%)	0/349 (0.00%)	0/34 (0.00%)	1/699 (0.14%)
Astrocytoma ^† 1	0/350 (0.00%)	1/349 (0.29%)	0/34 (0.00%)	1/699 (0.14%)
Basal cell carcinoma ^† 1	13/350 (3.71%)	5/349 (1.43%)	2/34 (5.88%)	20/699 (2.86%)
Benign neoplasm of adrenal gland ^† 1	1/350 (0.29%)	0/349 (0.00%)	0/34 (0.00%)	1/699 (0.14%)
Bowen's disease ^† 1	2/350 (0.57%)	3/349 (0.86%)	0/34 (0.00%)	5/699 (0.72%)
Carcinoma in situ ^† 1	0/350 (0.00%)	1/349 (0.29%)	0/34 (0.00%)	1/699 (0.14%)
Carcinoma in situ of skin ^† 1	1/350 (0.29%)	0/349 (0.00%)	0/34 (0.00%)	1/699 (0.14%)
Colon adenoma ^† 1	0/350 (0.00%)	0/349 (0.00%)	1/34 (2.94%)	1/699 (0.14%)
Intracranial tumour haemorrhage ^† 1	1/350 (0.29%)	0/349 (0.00%)	0/34 (0.00%)	1/699 (0.14%)
Keratoacanthoma ^† 1	3/350 (0.86%)	23/349 (6.59%)	1/34 (2.94%)	26/699 (3.72%)
Lentigo maligna ^† 1	0/350 (0.00%)	1/349 (0.29%)	0/34 (0.00%)	1/699 (0.14%)
Lip squamous cell carcinoma ^† 1	0/350 (0.00%)	1/349 (0.29%)	0/34 (0.00%)	1/699 (0.14%)
Lung adenocarcinoma ^† 1	1/350 (0.29%)	0/349 (0.00%)	0/34 (0.00%)	1/699 (0.14%)
Lung neoplasm malignant ^† 1	2/350 (0.57%)	1/349 (0.29%)	0/34 (0.00%)	3/699 (0.43%)
Lymphoma ^† 1	1/350 (0.29%)	0/349 (0.00%)	0/34 (0.00%)	1/699 (0.14%)
Malignant melanoma ^† 1	2/350 (0.57%)	7/349 (2.01%)	0/34 (0.00%)	9/699 (1.29%)
Malignant melanoma in situ ^† 1	0/350 (0.00%)	2/349 (0.57%)	0/34 (0.00%)	2/699 (0.29%)
Meningioma ^† 1	1/350 (0.29%)	0/349 (0.00%)	0/34 (0.00%)	1/699 (0.14%)
Metastases to central nervous system ^† 1	1/350 (0.29%)	1/349 (0.29%)	0/34 (0.00%)	2/699 (0.29%)
Metastatic malignant melanoma ^† 1	0/350 (0.00%)	1/349 (0.29%)	0/34 (0.00%)	1/699 (0.14%)
Neoplasm ^† 1	0/350 (0.00%)	1/349 (0.29%)	0/34 (0.00%)	1/699 (0.14%)
Neoplasm malignant ^† 1	0/350 (0.00%)	1/349 (0.29%)	0/34 (0.00%)	1/699 (0.14%)
Prostatic adenoma ^† 1	1/350 (0.29%)	0/349 (0.00%)	0/34 (0.00%)	1/699 (0.14%)
Rectal adenocarcinoma ^† 1	0/350 (0.00%)	1/349 (0.29%)	0/34 (0.00%)	1/699 (0.14%)
Renal cell carcinoma ^† 1	1/350 (0.29%)	0/349 (0.00%)	0/34 (0.00%)	1/699 (0.14%)
Skin papilloma ^† 1	0/350 (0.00%)	1/349 (0.29%)	0/34 (0.00%)	1/699 (0.14%)
Squamous cell carcinoma ^† 1	3/350 (0.86%)	27/349 (7.74%)	0/34 (0.00%)	30/699 (4.29%)
Squamous cell carcinoma of skin ^† 1	3/350 (0.86%)	30/349 (8.60%)	0/34 (0.00%)	33/699 (4.72%)
Superficial spreading melanoma stage unspecified ^† 1	1/350 (0.29%)	0/349 (0.00%)	0/34 (0.00%)	1/699 (0.14%)
Transitional cell carcinoma ^† 1	0/350 (0.00%)	1/349 (0.29%)	0/34 (0.00%)	1/699 (0.14%)
Nervous system disorders
Ataxia ^† 1	1/350 (0.29%)	0/349 (0.00%)	0/34 (0.00%)	1/699 (0.14%)
Brain stem haemorrhage ^† 1	1/350 (0.29%)	0/349 (0.00%)	0/34 (0.00%)	1/699 (0.14%)
Cerebral haemorrhage ^† 1	3/350 (0.86%)	1/349 (0.29%)	0/34 (0.00%)	4/699 (0.57%)
Cerebral ischaemia ^† 1	0/350 (0.00%)	1/349 (0.29%)	0/34 (0.00%)	1/699 (0.14%)
Cerebrovascular accident ^† 1	1/350 (0.29%)	1/349 (0.29%)	0/34 (0.00%)	2/699 (0.29%)
Dizziness ^† 1	1/350 (0.29%)	1/349 (0.29%)	0/34 (0.00%)	2/699 (0.29%)
Epilepsy ^† 1	1/350 (0.29%)	1/349 (0.29%)	1/34 (2.94%)	2/699 (0.29%)
Generalised tonic-clonic seizure ^† 1	1/350 (0.29%)	0/349 (0.00%)	0/34 (0.00%)	1/699 (0.14%)
Haemorrhage intracranial ^† 1	2/350 (0.57%)	0/349 (0.00%)	0/34 (0.00%)	2/699 (0.29%)
Haemorrhagic stroke ^† 1	0/350 (0.00%)	0/349 (0.00%)	1/34 (2.94%)	1/699 (0.14%)
Headache ^† 1	2/350 (0.57%)	1/349 (0.29%)	0/34 (0.00%)	3/699 (0.43%)
Hepatic encephalopathy ^† 1	1/350 (0.29%)	0/349 (0.00%)	0/34 (0.00%)	1/699 (0.14%)
Hypoaesthesia ^† 1	1/350 (0.29%)	0/349 (0.00%)	0/34 (0.00%)	1/699 (0.14%)
Loss of consciousness ^† 1	1/350 (0.29%)	0/349 (0.00%)	0/34 (0.00%)	1/699 (0.14%)
Lumbar radiculopathy ^† 1	1/350 (0.29%)	0/349 (0.00%)	0/34 (0.00%)	1/699 (0.14%)
Migraine ^† 1	0/350 (0.00%)	1/349 (0.29%)	0/34 (0.00%)	1/699 (0.14%)
Partial seizures ^† 1	1/350 (0.29%)	0/349 (0.00%)	0/34 (0.00%)	1/699 (0.14%)
Seizure ^† 1	1/350 (0.29%)	0/349 (0.00%)	0/34 (0.00%)	1/699 (0.14%)
Syncope ^† 1	1/350 (0.29%)	0/349 (0.00%)	1/34 (2.94%)	2/699 (0.29%)
Transient ischaemic attack ^† 1	0/350 (0.00%)	1/349 (0.29%)	0/34 (0.00%)	1/699 (0.14%)
Tremor ^† 1	1/350 (0.29%)	0/349 (0.00%)	0/34 (0.00%)	1/699 (0.14%)
Psychiatric disorders
Confusional state ^† 1	0/350 (0.00%)	1/349 (0.29%)	0/34 (0.00%)	1/699 (0.14%)
Mental status changes ^† 1	1/350 (0.29%)	0/349 (0.00%)	0/34 (0.00%)	1/699 (0.14%)
Renal and urinary disorders
Acute kidney injury ^† 1	2/350 (0.57%)	1/349 (0.29%)	0/34 (0.00%)	3/699 (0.43%)
Calculus urinary ^† 1	1/350 (0.29%)	0/349 (0.00%)	0/34 (0.00%)	1/699 (0.14%)
Nephrolithiasis ^† 1	1/350 (0.29%)	0/349 (0.00%)	0/34 (0.00%)	1/699 (0.14%)
Nephropathy toxic ^† 1	1/350 (0.29%)	0/349 (0.00%)	0/34 (0.00%)	1/699 (0.14%)
Prerenal failure ^† 1	0/350 (0.00%)	1/349 (0.29%)	0/34 (0.00%)	1/699 (0.14%)
Renal failure ^† 1	4/350 (1.14%)	0/349 (0.00%)	0/34 (0.00%)	4/699 (0.57%)
Urethral stenosis ^† 1	1/350 (0.29%)	0/349 (0.00%)	0/34 (0.00%)	1/699 (0.14%)
Reproductive system and breast disorders
Ovarian cyst ^† 1	1/350 (0.29%)	0/349 (0.00%)	0/34 (0.00%)	1/699 (0.14%)
Uterine haemorrhage ^† 1	0/350 (0.00%)	1/349 (0.29%)	0/34 (0.00%)	1/699 (0.14%)
Respiratory, thoracic and mediastinal disorders
Asthma ^† 1	0/350 (0.00%)	1/349 (0.29%)	0/34 (0.00%)	1/699 (0.14%)
Cough ^† 1	1/350 (0.29%)	0/349 (0.00%)	0/34 (0.00%)	1/699 (0.14%)
Dyspnoea ^† 1	2/350 (0.57%)	2/349 (0.57%)	0/34 (0.00%)	4/699 (0.57%)
Dyspnoea exertional ^† 1	0/350 (0.00%)	0/349 (0.00%)	1/34 (2.94%)	1/699 (0.14%)
Haemoptysis ^† 1	1/350 (0.29%)	0/349 (0.00%)	0/34 (0.00%)	1/699 (0.14%)
Haemothorax ^† 1	0/350 (0.00%)	1/349 (0.29%)	0/34 (0.00%)	1/699 (0.14%)
Interstitial lung disease ^† 1	0/350 (0.00%)	1/349 (0.29%)	0/34 (0.00%)	1/699 (0.14%)
Pleural effusion ^† 1	0/350 (0.00%)	3/349 (0.86%)	0/34 (0.00%)	3/699 (0.43%)
Pneumonia aspiration ^† 1	1/350 (0.29%)	0/349 (0.00%)	0/34 (0.00%)	1/699 (0.14%)
Pneumonitis ^† 1	2/350 (0.57%)	0/349 (0.00%)	1/34 (2.94%)	3/699 (0.43%)
Pulmonary embolism ^† 1	6/350 (1.71%)	0/349 (0.00%)	1/34 (2.94%)	7/699 (1.00%)
Pulmonary oedema ^† 1	0/350 (0.00%)	1/349 (0.29%)	0/34 (0.00%)	1/699 (0.14%)
Skin and subcutaneous tissue disorders
Actinic keratosis ^† 1	0/350 (0.00%)	2/349 (0.57%)	1/34 (2.94%)	3/699 (0.43%)
Chronic cutaneous lupus erythematosus ^† 1	1/350 (0.29%)	0/349 (0.00%)	0/34 (0.00%)	1/699 (0.14%)
Dermatitis ^† 1	1/350 (0.29%)	0/349 (0.00%)	0/34 (0.00%)	1/699 (0.14%)
Dermatitis bullous ^† 1	0/350 (0.00%)	1/349 (0.29%)	0/34 (0.00%)	1/699 (0.14%)
Erythema ^† 1	0/350 (0.00%)	1/349 (0.29%)	0/34 (0.00%)	1/699 (0.14%)
Erythema nodosum ^† 1	1/350 (0.29%)	0/349 (0.00%)	0/34 (0.00%)	1/699 (0.14%)
Purpura ^† 1	2/350 (0.57%)	0/349 (0.00%)	0/34 (0.00%)	2/699 (0.29%)
Rash ^† 1	3/350 (0.86%)	3/349 (0.86%)	0/34 (0.00%)	6/699 (0.86%)
Rash erythematous ^† 1	0/350 (0.00%)	1/349 (0.29%)	0/34 (0.00%)	1/699 (0.14%)
Rash maculo-papular ^† 1	1/350 (0.29%)	2/349 (0.57%)	0/34 (0.00%)	3/699 (0.43%)
Skin lesion ^† 1	0/350 (0.00%)	1/349 (0.29%)	0/34 (0.00%)	1/699 (0.14%)
Vascular disorders
Aortic aneurysm ^† 1	1/350 (0.29%)	0/349 (0.00%)	0/34 (0.00%)	1/699 (0.14%)
Deep vein thrombosis ^† 1	1/350 (0.29%)	0/349 (0.00%)	0/34 (0.00%)	1/699 (0.14%)
Embolism ^† 1	0/350 (0.00%)	1/349 (0.29%)	0/34 (0.00%)	1/699 (0.14%)
Haemorrhage ^† 1	1/350 (0.29%)	0/349 (0.00%)	0/34 (0.00%)	1/699 (0.14%)
Hypertension ^† 1	1/350 (0.29%)	1/349 (0.29%)	0/34 (0.00%)	2/699 (0.29%)
Hypotension ^† 1	5/350 (1.43%)	0/349 (0.00%)	0/34 (0.00%)	5/699 (0.72%)
Lymphocele ^† 1	0/350 (0.00%)	1/349 (0.29%)	0/34 (0.00%)	1/699 (0.14%)
Lymphoedema ^† 1	0/350 (0.00%)	0/349 (0.00%)	1/34 (2.94%)	1/699 (0.14%)
Varicose vein ^† 1	1/350 (0.29%)	0/349 (0.00%)	0/34 (0.00%)	1/699 (0.14%)
1 Term from vocabulary, MedDRA (19.0) † Indicates events were collected by systematic assessment
Other (Not Including Serious) Adverse Events
Frequency Threshold for Reporting Other Adverse Events	5%
	Dabrafenib Plus Trametinib	Vemurafenib	Crossover Dabrafenib Plus Trametinib	All Patients
	Affected / at Risk (%)	Affected / at Risk (%)	Affected / at Risk (%)	Affected / at Risk (%)
Total	338/350 (96.57%)	341/349 (97.71%)	32/34 (94.12%)	679/699 (97.14%)
Blood and lymphatic system disorders
Anaemia ^† 1	29/350 (8.29%)	20/349 (5.73%)	3/34 (8.82%)	52/699 (7.44%)
Leukopenia ^† 1	17/350 (4.86%)	7/349 (2.01%)	6/34 (17.65%)	29/699 (4.15%)
Lymphopenia ^† 1	9/350 (2.57%)	9/349 (2.58%)	2/34 (5.88%)	20/699 (2.86%)
Neutropenia ^† 1	37/350 (10.57%)	6/349 (1.72%)	9/34 (26.47%)	51/699 (7.30%)
Thrombocytopenia ^† 1	11/350 (3.14%)	2/349 (0.57%)	3/34 (8.82%)	16/699 (2.29%)
Ear and labyrinth disorders
Tinnitus ^† 1	5/350 (1.43%)	3/349 (0.86%)	2/34 (5.88%)	10/699 (1.43%)
Eye disorders
Vision blurred ^† 1	23/350 (6.57%)	18/349 (5.16%)	1/34 (2.94%)	42/699 (6.01%)
Gastrointestinal disorders
Abdominal pain ^† 1	41/350 (11.71%)	33/349 (9.46%)	3/34 (8.82%)	75/699 (10.73%)
Abdominal pain upper ^† 1	38/350 (10.86%)	36/349 (10.32%)	4/34 (11.76%)	78/699 (11.16%)
Constipation ^† 1	58/350 (16.57%)	25/349 (7.16%)	7/34 (20.59%)	89/699 (12.73%)
Diarrhoea ^† 1	131/350 (37.43%)	137/349 (39.26%)	5/34 (14.71%)	268/699 (38.34%)
Dry mouth ^† 1	27/350 (7.71%)	8/349 (2.29%)	1/34 (2.94%)	36/699 (5.15%)
Dyspepsia ^† 1	20/350 (5.71%)	15/349 (4.30%)	3/34 (8.82%)	37/699 (5.29%)
Haemorrhoids ^† 1	4/350 (1.14%)	7/349 (2.01%)	3/34 (8.82%)	14/699 (2.00%)
Nausea ^† 1	125/350 (35.71%)	131/349 (37.54%)	8/34 (23.53%)	261/699 (37.34%)
Vomiting ^† 1	111/350 (31.71%)	57/349 (16.33%)	4/34 (11.76%)	172/699 (24.61%)
General disorders
Asthenia ^† 1	65/350 (18.57%)	62/349 (17.77%)	8/34 (23.53%)	131/699 (18.74%)
Chills ^† 1	113/350 (32.29%)	28/349 (8.02%)	6/34 (17.65%)	147/699 (21.03%)
Fatigue ^† 1	116/350 (33.14%)	116/349 (33.24%)	1/34 (2.94%)	232/699 (33.19%)
Hypothermia ^† 1	2/350 (0.57%)	1/349 (0.29%)	2/34 (5.88%)	4/699 (0.57%)
Influenza like illness ^† 1	36/350 (10.29%)	13/349 (3.72%)	2/34 (5.88%)	51/699 (7.30%)
Malaise ^† 1	16/350 (4.57%)	8/349 (2.29%)	2/34 (5.88%)	24/699 (3.43%)
Oedema peripheral ^† 1	61/350 (17.43%)	45/349 (12.89%)	3/34 (8.82%)	108/699 (15.45%)
Pain ^† 1	18/350 (5.14%)	15/349 (4.30%)	2/34 (5.88%)	35/699 (5.01%)
Peripheral swelling ^† 1	25/350 (7.14%)	12/349 (3.44%)	3/34 (8.82%)	40/699 (5.72%)
Pyrexia ^† 1	184/350 (52.57%)	72/349 (20.63%)	16/34 (47.06%)	267/699 (38.20%)
Infections and infestations
Angular cheilitis ^† 1	3/350 (0.86%)	0/349 (0.00%)	2/34 (5.88%)	5/699 (0.72%)
Conjunctivitis ^† 1	14/350 (4.00%)	37/349 (10.60%)	1/34 (2.94%)	52/699 (7.44%)
Folliculitis ^† 1	18/350 (5.14%)	25/349 (7.16%)	1/34 (2.94%)	43/699 (6.15%)
Influenza ^† 1	31/350 (8.86%)	9/349 (2.58%)	2/34 (5.88%)	41/699 (5.87%)
Nasopharyngitis ^† 1	64/350 (18.29%)	32/349 (9.17%)	6/34 (17.65%)	100/699 (14.31%)
Onychomycosis ^† 1	4/350 (1.14%)	1/349 (0.29%)	2/34 (5.88%)	7/699 (1.00%)
Pharyngitis ^† 1	19/350 (5.43%)	7/349 (2.01%)	1/34 (2.94%)	27/699 (3.86%)
Pneumonia ^† 1	4/350 (1.14%)	1/349 (0.29%)	4/34 (11.76%)	9/699 (1.29%)
Rhinitis ^† 1	14/350 (4.00%)	8/349 (2.29%)	2/34 (5.88%)	24/699 (3.43%)
Upper respiratory tract infection ^† 1	23/350 (6.57%)	14/349 (4.01%)	3/34 (8.82%)	40/699 (5.72%)
Urinary tract infection ^† 1	31/350 (8.86%)	7/349 (2.01%)	3/34 (8.82%)	41/699 (5.87%)
Injury, poisoning and procedural complications
Fall ^† 1	6/350 (1.71%)	5/349 (1.43%)	2/34 (5.88%)	12/699 (1.72%)
Sunburn ^† 1	5/350 (1.43%)	47/349 (13.47%)	0/34 (0.00%)	52/699 (7.44%)
Investigations
Alanine aminotransferase increased ^† 1	54/350 (15.43%)	54/349 (15.47%)	2/34 (5.88%)	110/699 (15.74%)
Aspartate aminotransferase increased ^† 1	47/350 (13.43%)	42/349 (12.03%)	3/34 (8.82%)	92/699 (13.16%)
Blood alkaline phosphatase increased ^† 1	30/350 (8.57%)	29/349 (8.31%)	0/34 (0.00%)	59/699 (8.44%)
Blood creatine phosphokinase increased ^† 1	12/350 (3.43%)	4/349 (1.15%)	5/34 (14.71%)	20/699 (2.86%)
Blood creatinine increased ^† 1	16/350 (4.57%)	36/349 (10.32%)	2/34 (5.88%)	53/699 (7.58%)
Blood lactate dehydrogenase increased ^† 1	23/350 (6.57%)	9/349 (2.58%)	1/34 (2.94%)	33/699 (4.72%)
C-reactive protein increased ^† 1	12/350 (3.43%)	1/349 (0.29%)	2/34 (5.88%)	15/699 (2.15%)
Gamma-glutamyltransferase increased ^† 1	45/350 (12.86%)	35/349 (10.03%)	1/34 (2.94%)	81/699 (11.59%)
Neutrophil count decreased ^† 1	15/350 (4.29%)	1/349 (0.29%)	2/34 (5.88%)	18/699 (2.58%)
Weight decreased ^† 1	21/350 (6.00%)	42/349 (12.03%)	1/34 (2.94%)	64/699 (9.16%)
White blood cell count decreased ^† 1	13/350 (3.71%)	3/349 (0.86%)	2/34 (5.88%)	18/699 (2.58%)
Metabolism and nutrition disorders
Decreased appetite ^† 1	47/350 (13.43%)	72/349 (20.63%)	6/34 (17.65%)	123/699 (17.60%)
Hyperglycaemia ^† 1	20/350 (5.71%)	12/349 (3.44%)	3/34 (8.82%)	35/699 (5.01%)
Increased appetite ^† 1	2/350 (0.57%)	1/349 (0.29%)	3/34 (8.82%)	6/699 (0.86%)
Musculoskeletal and connective tissue disorders
Arthralgia ^† 1	104/350 (29.71%)	182/349 (52.15%)	9/34 (26.47%)	288/699 (41.20%)
Back pain ^† 1	43/350 (12.29%)	29/349 (8.31%)	5/34 (14.71%)	77/699 (11.02%)
Muscle spasms ^† 1	47/350 (13.43%)	13/349 (3.72%)	4/34 (11.76%)	63/699 (9.01%)
Musculoskeletal chest pain ^† 1	19/350 (5.43%)	10/349 (2.87%)	0/34 (0.00%)	29/699 (4.15%)
Musculoskeletal pain ^† 1	24/350 (6.86%)	27/349 (7.74%)	4/34 (11.76%)	54/699 (7.73%)
Myalgia ^† 1	76/350 (21.71%)	56/349 (16.05%)	8/34 (23.53%)	134/699 (19.17%)
Pain in extremity ^† 1	50/350 (14.29%)	42/349 (12.03%)	2/34 (5.88%)	94/699 (13.45%)
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Melanocytic naevus ^† 1	2/350 (0.57%)	21/349 (6.02%)	0/34 (0.00%)	23/699 (3.29%)
Skin papilloma ^† 1	9/350 (2.57%)	85/349 (24.36%)	1/34 (2.94%)	95/699 (13.59%)
Nervous system disorders
Balance disorder ^† 1	4/350 (1.14%)	1/349 (0.29%)	2/34 (5.88%)	7/699 (1.00%)
Dizziness ^† 1	46/350 (13.14%)	24/349 (6.88%)	3/34 (8.82%)	73/699 (10.44%)
Dysgeusia ^† 1	23/350 (6.57%)	48/349 (13.75%)	2/34 (5.88%)	73/699 (10.44%)
Headache ^† 1	123/350 (35.14%)	86/349 (24.64%)	8/34 (23.53%)	214/699 (30.62%)
Hypoaesthesia ^† 1	9/350 (2.57%)	11/349 (3.15%)	2/34 (5.88%)	21/699 (3.00%)
Paraesthesia ^† 1	17/350 (4.86%)	18/349 (5.16%)	0/34 (0.00%)	35/699 (5.01%)
Syncope ^† 1	13/350 (3.71%)	4/349 (1.15%)	3/34 (8.82%)	19/699 (2.72%)
Psychiatric disorders
Insomnia ^† 1	22/350 (6.29%)	33/349 (9.46%)	0/34 (0.00%)	55/699 (7.87%)
Respiratory, thoracic and mediastinal disorders
Cough ^† 1	88/350 (25.14%)	40/349 (11.46%)	6/34 (17.65%)	132/699 (18.88%)
Dyspnoea ^† 1	34/350 (9.71%)	29/349 (8.31%)	1/34 (2.94%)	64/699 (9.16%)
Epistaxis ^† 1	32/350 (9.14%)	6/349 (1.72%)	4/34 (11.76%)	41/699 (5.87%)
Nasal dryness ^† 1	3/350 (0.86%)	2/349 (0.57%)	2/34 (5.88%)	7/699 (1.00%)
Oropharyngeal pain ^† 1	27/350 (7.71%)	19/349 (5.44%)	1/34 (2.94%)	47/699 (6.72%)
Skin and subcutaneous tissue disorders
Actinic keratosis ^† 1	10/350 (2.86%)	24/349 (6.88%)	2/34 (5.88%)	36/699 (5.15%)
Alopecia ^† 1	26/350 (7.43%)	138/349 (39.54%)	0/34 (0.00%)	164/699 (23.46%)
Dermatitis acneiform ^† 1	25/350 (7.14%)	20/349 (5.73%)	1/34 (2.94%)	46/699 (6.58%)
Dry skin ^† 1	34/350 (9.71%)	70/349 (20.06%)	5/34 (14.71%)	106/699 (15.16%)
Eczema ^† 1	28/350 (8.00%)	13/349 (3.72%)	4/34 (11.76%)	45/699 (6.44%)
Erythema ^† 1	41/350 (11.71%)	44/349 (12.61%)	2/34 (5.88%)	86/699 (12.30%)
Hyperhidrosis ^† 1	18/350 (5.14%)	4/349 (1.15%)	3/34 (8.82%)	25/699 (3.58%)
Hyperkeratosis ^† 1	26/350 (7.43%)	103/349 (29.51%)	0/34 (0.00%)	129/699 (18.45%)
Keratosis pilaris ^† 1	5/350 (1.43%)	44/349 (12.61%)	1/34 (2.94%)	50/699 (7.15%)
Night sweats ^† 1	24/350 (6.86%)	8/349 (2.29%)	2/34 (5.88%)	33/699 (4.72%)
Palmar-plantar erythrodysaesthesia syndrome ^† 1	10/350 (2.86%)	54/349 (15.47%)	1/34 (2.94%)	64/699 (9.16%)
Palmoplantar keratoderma ^† 1	9/350 (2.57%)	21/349 (6.02%)	1/34 (2.94%)	31/699 (4.43%)
Photosensitivity reaction ^† 1	17/350 (4.86%)	88/349 (25.21%)	0/34 (0.00%)	105/699 (15.02%)
Pruritus ^† 1	40/350 (11.43%)	80/349 (22.92%)	0/34 (0.00%)	120/699 (17.17%)
Rash ^† 1	95/350 (27.14%)	153/349 (43.84%)	4/34 (11.76%)	248/699 (35.48%)
Rash maculo-papular ^† 1	12/350 (3.43%)	27/349 (7.74%)	1/34 (2.94%)	39/699 (5.58%)
Skin exfoliation ^† 1	6/350 (1.71%)	11/349 (3.15%)	2/34 (5.88%)	19/699 (2.72%)
Skin lesion ^† 1	13/350 (3.71%)	9/349 (2.58%)	2/34 (5.88%)	23/699 (3.29%)
Skin mass ^† 1	5/350 (1.43%)	4/349 (1.15%)	2/34 (5.88%)	11/699 (1.57%)
Vascular disorders
Hypertension ^† 1	109/350 (31.14%)	83/349 (23.78%)	4/34 (11.76%)	195/699 (27.90%)
Lymphoedema ^† 1	25/350 (7.14%)	6/349 (1.72%)	2/34 (5.88%)	33/699 (4.72%)
1 Term from vocabulary, MedDRA (19.0) † Indicates events were collected by systematic assessment

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.

The terms and conditions of Novartis' agreements with its investigators may vary. However, Novartis does not prohibit any investigator from publishing. Any publications from a single-site are postponed until the publication of the pooled data (i.e., data from all sites) in the clinical trial or disclosure of trial results in their entirety.

Results Point of Contact

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Name/Title:	Clinical Disclosure Office
Organization:	Novartis Pharmaceuticals
Phone:	862-778-8300
EMail:	Novartis.email@novartis.com

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

Schadendorf D, Robert C, Dummer R, Flaherty KT, Tawbi HA, Menzies AM, Banerjee H, Lau M, Long GV. Pyrexia in patients treated with dabrafenib plus trametinib across clinical trials in BRAF-mutant cancers. Eur J Cancer. 2021 Aug;153:234-241. doi: 10.1016/j.ejca.2021.05.005. Epub 2021 Jul 2.

Robert C, Grob JJ, Stroyakovskiy D, Karaszewska B, Hauschild A, Levchenko E, Chiarion Sileni V, Schachter J, Garbe C, Bondarenko I, Gogas H, Mandala M, Haanen JBAG, Lebbe C, Mackiewicz A, Rutkowski P, Nathan PD, Ribas A, Davies MA, Flaherty KT, Burgess P, Tan M, Gasal E, Voi M, Schadendorf D, Long GV. Five-Year Outcomes with Dabrafenib plus Trametinib in Metastatic Melanoma. N Engl J Med. 2019 Aug 15;381(7):626-636. doi: 10.1056/NEJMoa1904059. Epub 2019 Jun 4.

Long GV, Grob JJ, Nathan P, Ribas A, Robert C, Schadendorf D, Lane SR, Mak C, Legenne P, Flaherty KT, Davies MA. Factors predictive of response, disease progression, and overall survival after dabrafenib and trametinib combination treatment: a pooled analysis of individual patient data from randomised trials. Lancet Oncol. 2016 Dec;17(12):1743-1754. doi: 10.1016/S1470-2045(16)30578-2. Epub 2016 Nov 16.

Grob JJ, Amonkar MM, Karaszewska B, Schachter J, Dummer R, Mackiewicz A, Stroyakovskiy D, Drucis K, Grange F, Chiarion-Sileni V, Rutkowski P, Lichinitser M, Levchenko E, Wolter P, Hauschild A, Long GV, Nathan P, Ribas A, Flaherty K, Sun P, Legos JJ, McDowell DO, Mookerjee B, Schadendorf D, Robert C. Comparison of dabrafenib and trametinib combination therapy with vemurafenib monotherapy on health-related quality of life in patients with unresectable or metastatic cutaneous BRAF Val600-mutation-positive melanoma (COMBI-v): results of a phase 3, open-label, randomised trial. Lancet Oncol. 2015 Oct;16(13):1389-98. doi: 10.1016/S1470-2045(15)00087-X.

Robert C, Karaszewska B, Schachter J, Rutkowski P, Mackiewicz A, Stroiakovski D, Lichinitser M, Dummer R, Grange F, Mortier L, Chiarion-Sileni V, Drucis K, Krajsova I, Hauschild A, Lorigan P, Wolter P, Long GV, Flaherty K, Nathan P, Ribas A, Martin AM, Sun P, Crist W, Legos J, Rubin SD, Little SM, Schadendorf D. Improved overall survival in melanoma with combined dabrafenib and trametinib. N Engl J Med. 2015 Jan 1;372(1):30-9. doi: 10.1056/NEJMoa1412690. Epub 2014 Nov 16.

Layout table for additonal information

Responsible Party:	Novartis ( Novartis Pharmaceuticals )
ClinicalTrials.gov Identifier:	NCT01597908
Other Study ID Numbers:	116513 CDRB436B2302 ( Other Identifier: Novartis ) 2011-006088-23 ( EudraCT Number )
First Submitted:	May 10, 2012
First Posted:	May 14, 2012
Results First Submitted:	December 1, 2014
Results First Posted:	December 4, 2014
Last Update Posted:	February 24, 2021

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