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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
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
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
Hide 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
Arm/Group Title Dabrafenib Plus Trametinib Vemurafenib Total
Hide 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
Hide 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
1.Primary Outcome
Title Overall Survival (OS)
Hide 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)
Hide Outcome Measure Data
Hide Analysis Population Description
Intent-to-Treat (ITT) Population.
Arm/Group Title Dabrafenib Plus Trametinib Vemurafenib
Hide 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)
Hide 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
Hide 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)
Hide Outcome Measure Data
Hide Analysis Population Description
Intent-to-Treat (ITT) Population.
Arm/Group Title Dabrafenib Plus Trametinib Vemurafenib
Hide 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)
Hide 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
Hide 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)
Hide Outcome Measure Data
Hide Analysis Population Description
Intent-to-Treat (ITT) Population. Only participants with measurable disease at baseline were included.
Arm/Group Title Dabrafenib Plus Trametinib Vemurafenib
Hide 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
Hide 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)
Hide Outcome Measure Data
Hide 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
Hide 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)
Hide 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
Hide 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)
Hide Outcome Measure Data
Hide 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
Hide 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%
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
Hide 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%) 
Hide 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
Hide 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
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
Layout table for Results Point of Contact information
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):
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