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A Study Comparing Trametinib and Dabrafenib Combination Therapy to Dabrafenib Monotherapy in Subjects With BRAF-mutant Melanoma

Sponsor
Novartis Pharmaceuticals (Industry)
Overall Status
Completed
CT.gov ID
NCT01584648
Collaborator
(none)
423
Enrollment
121
Locations
2
Arms
81.8
Actual Duration (Months)
3.5
Patients Per Site
0
Patients Per Site Per Month

Study Details

Study Description

Brief Summary

This was a two-arm, double-blinded, randomized, Phase III study comparing dabrafenib and trametinib combination therapy to dabrafenib administered with a placebo (dabrafenib monotherapy). Subjects with histologically confirmed cutaneous melanoma that is either Stage IIIC (unresectable) or Stage IV, and BRAF V600E/K mutation positive were screened for eligibility. Subjects who had prior systemic anti-cancer treatment in the advanced or metastatic setting were not eligible although prior systemic treatment in the adjuvant setting was allowed. Subjects were stratified according to the baseline lactate dehydrogenase level and BRAF genotype.

Condition or Disease Intervention/Treatment Phase
Phase 3

Detailed Description

Dabrafenib and trametinib was administered orally at their recommended monotherapy doses of 150 mg b.i.d and 2 mg q.d., respectively. Subjects in the combination therapy arm received both agents; subjects in the dabrafenib monotherapy arm received dabrafenib and placebo. Treatment was continued in both arms until disease progression, death, unacceptable toxicity, or withdrawal of consent.

After treatment discontinuation, subjects were followed for survival and disease progression as applicable to collect data for the secondary objective of overall survival (OS).

Crossover to the combination therapy arm was allowed for subjects still receiving study treatment on the dabrafenib monotherapy arm after the positive result for the final OS analysis.

Study Design

Study Type:
Interventional
Actual Enrollment :
423 participants
Allocation:
Randomized
Intervention Model:
Parallel Assignment
Masking:
Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary Purpose:
Treatment
Official Title:
A Phase III, Randomized, Double-blinded Study Comparing the Combination of the BRAF Inhibitor, Dabrafenib and the MEK Inhibitor, Trametinib to Dabrafenib and Placebo as First-line Therapy in Subjects With Unresectable (Stage IIIC) or Metastatic (Stage IV) BRAF V600E/K Mutation-positive Cutaneous Melanoma
Actual Study Start Date :
May 4, 2012
Actual Primary Completion Date :
Aug 26, 2013
Actual Study Completion Date :
Feb 28, 2019

Arms and Interventions

Arm Intervention/Treatment
Experimental: Dabrafenib + Trametinib

Dabrafenib and Trametinib combination

Drug: Dabrafenib
Dabrafenib 150 mg twice daily
Other Names:
  • GSK2118436

    • Drug: Trametinib
    Trametinib 2 mg once daily
    Other Names:
  • GSK1120212

    		•
    Active Comparator: Dabrafenib + Placebo

    Dabrafenib and Trametinib placebo

    Drug: Dabrafenib
    Dabrafenib 150 mg twice daily
    Other Names:
  • GSK2118436

    • Drug: Trametinib placebo
    Dabrafenib 150 mg twice daily and trametinib placebo
    Other Names:
  • Placebo

    		•

    Outcome Measures

    Primary Outcome Measures

    1. Progression-Free Survival (PFS) as Assessed by the Investigator [From randomization until the earliest date of disease progression (PD) or death due to any cause (up to approximately 6 years)]

      PFS is defined as the interval between the date of randomization and the earliest date of PD or death due to any cause. PD was based on radiographic or photographic evidence, and assessments were made by the investigator according to RECIST, version 1.1. PD is defined as at least a 20% increase in the sum of the diameters of target lesions, taking as a reference, the smallest sum of diameters recorded since the treatment started. In addition, the sum must have an absolute increase from nadir of 5 mm. The appearance of one or more new lesions, or the worsening of non-target lesions significant enough to require study treatment discontinuation, was also included as PD. Participants who received anti-cancer therapy prior to the date of documented events, were censored at the last adequate assessment prior to the initiation of therapy. If the participant did not have documented progression or death, PFS was censored at the date of the last adequate assessment.

    Secondary Outcome Measures

    1. Overall Survival (OS) [From the date of randomization until date of death due to any cause (up to approximately 6 years)]

      OS is defined as the interval of time between the date of randomization and the date of death due to any cause. For the participants who did not die, overall survival was censored at the date of last contact.

    2. Objective Response Rate (ORR) as Assessed by the Investigator [From randomization until the first documented complete response or partial response (up to approximately 6 years)]

      ORR is defined as the percentage of participants with a confirmed complete response (CR) or partial response (PR). A participant was defined as a responder if he/she sustained a complete response (CR: the disappearance of all target lesions and any pathological lymph nodes must have a short axis of <10 mm and the disappearance of all non-target lesions) or partial response (PR: at least a 30% decrease in the sum of the diameters of target lesions, taking as a reference, the Baseline sum of the diameters or the persistence of 1 or more non-target lesions or lymph nodes identified as a site of disease at Baseline with a short axis of ≥10mm). Only descriptive analysis performed.

    3. Duration of Response (DoR) [From the time of the first documented response (CR or PR) until disease progression (up to approximately 6 years)]

      Duration of response is defined as the time from the first documented complete response (CR: the disappearance of all target lesions and any pathological lymph nodes must have a short axis of <10 mm and the disappearance of all non-target lesions) or partial response (PR: at least a 30% decrease in the sum of the diameters of target lesions, taking as a reference, the Baseline sum of the diameters or the persistence of 1 or more non-target lesions or lymph nodes identified as a site of disease at Baseline with a short axis of ≥10mm) until disease progression (PD) or death due to any cause. PD is defined as at least a 20% increase in the sum of the diameters of target lesions with an absolute increase of at least 5mm or the appearance of one or more new lesions, or the worsening of non target lesions significant enough to require study treatment discontinuation. PD was based on the radiological evidence by investigator. Only descriptive analysis performed.

    4. Trametinib Pharmacokinetic Concentrations [Week 8 (0, 1-3, 4-6 hours post dose), Weeks 16 and 24 (0 hour pre-dose)]

      Blood samples were collected for Pharmacokinetic (PK) analysis in all participants. Three blood samples were collected at Week 8: pre-dose, 1-3 hours post dose, and 4-6 hours post dose. One pre-dose blood sample was obtained at Weeks 16 and 24. Only descriptive analysis performed.

    5. Dabrafenib and Dabrafenib Metabolites (Hydroxy-, Carboxy- and Desmethyl-Dabrafenib) Concentrations [Week 8 (0, 1-3, 4-6 hours post dose), Weeks 16 and 24 (0 hour pre-dose)]

      Blood samples were collected for PK analysis in all participants. Three blood samples were collected at Week 8: pre-dose, 1-3 hours post dose, and 4-6 hours post dose. One pre-dose blood sample was obtained at Weeks 16 and 24. Plasma concentrations of Dabrafenib (GSK2118436) and its metabolites (Hydroxy-Dabrafenib (GSK2285403), Carboxy-Dabrafenib (GSK2298683), and Desmethyl-Dabrafenib (GSK2167542)) were determined using the currently approved analytical methodology. Only descriptive analysis performed.

    6. Number of Participants With Adverse Events and Serious Adverse Events [From the time the first dose of study treatment administered until 30 days after discontinuation of study treatment (up to approximately 6 years).]

      Analysis of absolute and relative frequencies for Adverse Event (AE) and Serious Adverse Event (SAE) by primary System Organ Class (SOC) to characterize the safety of dabrafenib and trametinib combination therapy through the monitoring of relevant clinical and laboratory safety parameters. In addition, new malignancies and AEs possibly related to study treatment were collected even if they occurred more than 30 days post-treatment. Only descriptive analysis performed.

    Eligibility Criteria

    Criteria

    Ages Eligible for Study:
    18 Years and Older
    Sexes Eligible for Study:
    All
    Accepts Healthy Volunteers:
    No
    Inclusion Criteria:

    • Histologically confirmed cutaneous melanoma that is either Stage IIIC (unresectable) or Stage IV (metastatic), and determined to be BRAF V600E/K mutation-positive using the bioMerieux (bMx) investigational use only (IUO) THxID BRAF Assay (IDE: G120011). The assay will be conducted by a central reference laboratory. Subjects with ocular or mucosal melanoma are not eligible.

    • The subject must have a radiologically measurable tumor

    • The subject is able to carry out daily life activities without significant difficulty (ECOG performance status score of 0 or 1).

    • Able to swallow and retain oral medication

    • Sexually active subjects must use acceptable methods of contraception during the course of the study

    • Adequate organ system function and blood counts

    Exclusion Criteria:

    • Prior treatment with a BRAF or a MEK inhibitor

    • Prior systemic anti-cancer treatment for Stage IIIC (unresectable) or Stage IV (metastatic) melanoma. Prior systemic treatment in the adjuvant setting is allowed. (Note: Ipilimumab treatment must end at least 8 weeks prior to randomization.)

    • The subject has received major surgery or certain tyes of cancer therapy with 21 days of starting treatment

    • Current use of prohibited medication listed in the protocol

    • Left ventricular ejection fraction less than the lower limit of normal

    • Uncontrolled blood pressurl

    • History or current evidence of retinal vein occlusion or central serous retinopathy

    • Brain metastases unless previously treated with surgery or stereotactic radiosurgery and the disease has been stable for at least 12 weeks

    • The subject is pregnant or nursing

    Contacts and Locations

    Locations

    Site City State Country Postal Code
    1 Novartis Investigative Site Scottsdale Arizona United States 85258
    2 Novartis Investigative Site Tucson Arizona United States 85719
    3 Novartis Investigative Site Los Angeles California United States 90024
    4 Novartis Investigative Site Fort Myers Florida United States 33916
    5 Novartis Investigative Site Saint Petersburg Florida United States 33705
    6 Novartis Investigative Site Tampa Florida United States 33612
    7 Novartis Investigative Site West Palm Beach Florida United States 33401
    8 Novartis Investigative Site Peoria Illinois United States 61615-7822
    9 Novartis Investigative Site Indianapolis Indiana United States 46202
    10 Novartis Investigative Site Boston Massachusetts United States 02114
    11 Novartis Investigative Site Boston Massachusetts United States 02215
    12 Novartis Investigative Site New York New York United States 10065
    13 Novartis Investigative Site Cincinnati Ohio United States 45242
    14 Novartis Investigative Site Philadelphia Pennsylvania United States 19104
    15 Novartis Investigative Site Columbia South Carolina United States 29210
    16 Novartis Investigative Site Chattanooga Tennessee United States 37404
    17 Novartis Investigative Site Nashville Tennessee United States 37203
    18 Novartis Investigative Site Fort Worth Texas United States 76104
    19 Novartis Investigative Site Richmond Virginia United States 23230
    20 Novartis Investigative Site Caba Buenos Aires Argentina C1425DTG
    21 Novartis Investigative Site Capital Federal Buenos Aires Argentina C1426ANZ
    22 Novartis Investigative Site Ciudad Autonoma de Buenos Aires Buenos Aires Argentina C1050AAK
    23 Novartis Investigative Site North Sydney New South Wales Australia 2060
    24 Novartis Investigative Site Westmead New South Wales Australia 2145
    25 Novartis Investigative Site Woolloongabba Queensland Australia 4102
    26 Novartis Investigative Site Adelaide South Australia Australia 5000
    27 Novartis Investigative Site Heidelberg Victoria Australia 3084
    28 Novartis Investigative Site Nedlands Western Australia Australia 6009
    29 Novartis Investigative Site Edmonton Alberta Canada T6G 1Z2
    30 Novartis Investigative Site Hamilton Ontario Canada L8V 5C2
    31 Novartis Investigative Site London Ontario Canada N6A 4L6
    32 Novartis Investigative Site Toronto Ontario Canada M5G 2M9
    33 Novartis Investigative Site Montreal Quebec Canada H2W 1S6
    34 Novartis Investigative Site Montreal Quebec Canada H3A 1A1
    35 Novartis Investigative Site Bordeaux France 33075
    36 Novartis Investigative Site Boulogne-Billancourt France 92100
    37 Novartis Investigative Site Lyon Cedex 08 France 69373
    38 Novartis Investigative Site Marseille cedex 5 France 13385
    39 Novartis Investigative Site Paris Cedex 10 France 75475
    40 Novartis Investigative Site Paris France 75006
    41 Novartis Investigative Site Paris France 75018
    42 Novartis Investigative Site Toulouse Cedex France 31052
    43 Novartis Investigative Site Vandoeuvre les Nancy France 54511
    44 Novartis Investigative Site Heidelberg Baden-Wuerttemberg Germany 69120
    45 Novartis Investigative Site Heilbronn Baden-Wuerttemberg Germany 74078
    46 Novartis Investigative Site Mannheim Baden-Wuerttemberg Germany 68167
    47 Novartis Investigative Site Tuebingen Baden-Wuerttemberg Germany 72076
    48 Novartis Investigative Site Ulm Baden-Wuerttemberg Germany 89081
    49 Novartis Investigative Site Augsburg Bayern Germany 86179
    50 Novartis Investigative Site Erlangen Bayern Germany 91054
    51 Novartis Investigative Site Muenchen Bayern Germany 80337
    52 Novartis Investigative Site Muenchen Bayern Germany 80804
    53 Novartis Investigative Site Muenchen Bayern Germany 81675
    54 Novartis Investigative Site Nuernberg Bayern Germany 90419
    55 Novartis Investigative Site Regensburg Bayern Germany 93053
    56 Novartis Investigative Site Wuerzburg Bayern Germany 97080
    57 Novartis Investigative Site Darmstadt Hessen Germany 64283
    58 Novartis Investigative Site Marburg Hessen Germany 35033
    59 Novartis Investigative Site Buxtehude Niedersachsen Germany 21614
    60 Novartis Investigative Site Hannover Niedersachsen Germany 30625
    61 Novartis Investigative Site Bonn Nordrhein-Westfalen Germany 53127
    62 Novartis Investigative Site Essen Nordrhein-Westfalen Germany 45122
    63 Novartis Investigative Site Koeln Nordrhein-Westfalen Germany 50937
    64 Novartis Investigative Site Mainz Rheinland-Pfalz Germany 55131
    65 Novartis Investigative Site Homburg Saarland Germany 66421
    66 Novartis Investigative Site Magdeburg Sachsen-Anhalt Germany 39120
    67 Novartis Investigative Site Dresden Sachsen Germany 01307
    68 Novartis Investigative Site Leipzig Sachsen Germany 04103
    69 Novartis Investigative Site Kiel Schleswig-Holstein Germany 24105
    70 Novartis Investigative Site Luebeck Schleswig-Holstein Germany 23538
    71 Novartis Investigative Site Erfurt Thueringen Germany 99089
    72 Novartis Investigative Site Gera Thueringen Germany 07548
    73 Novartis Investigative Site Jena Thueringen Germany 07740
    74 Novartis Investigative Site Berlin Germany 10117
    75 Novartis Investigative Site Athens Greece 11527
    76 Novartis Investigative Site N. Faliro Greece 185 47
    77 Novartis Investigative Site Thessaloniki Greece 564 29
    78 Novartis Investigative Site Roma Lazio Italy 00144
    79 Novartis Investigative Site Roma Lazio Italy 00167
    80 Novartis Investigative Site Genova Liguria Italy 16132
    81 Novartis Investigative Site Bergamo Lombardia Italy 24127
    82 Novartis Investigative Site Milano Lombardia Italy 20133
    83 Novartis Investigative Site Milano Lombardia Italy 20141
    84 Novartis Investigative Site Candiolo (TO) Piemonte Italy 10060
    85 Novartis Investigative Site Padova Veneto Italy 35128
    86 Novartis Investigative Site Amsterdam Netherlands 1066 CX
    87 Novartis Investigative Site Amsterdam Netherlands 1081 HV
    88 Novartis Investigative Site Zwolle Netherlands 8025 AB
    89 Novartis Investigative Site Kazan Russian Federation 420029
    90 Novartis Investigative Site Moscow Russian Federation 143423
    91 Novartis Investigative Site St. Petersburg Russian Federation 197758
    92 Novartis Investigative Site Stavropol Russian Federation 355047
    93 Novartis Investigative Site Barcelona Spain 08035
    94 Novartis Investigative Site Barcelona Spain 08036
    95 Novartis Investigative Site Madrid Spain 28034
    96 Novartis Investigative Site Madrid Spain 28041
    97 Novartis Investigative Site Madrid Spain 28046
    98 Novartis Investigative Site Pamplona Spain 31008
    99 Novartis Investigative Site Valencia Spain 46010
    100 Novartis Investigative Site Goteborg Sweden SE-413 45
    101 Novartis Investigative Site Lund Sweden SE-221 85
    102 Novartis Investigative Site Stockholm Sweden SE-171 76
    103 Novartis Investigative Site Uppsala Sweden SE-751 85
    104 Novartis Investigative Site Dnipropetrovsk Ukraine 49100
    105 Novartis Investigative Site Dnipropetrovsk Ukraine 49102
    106 Novartis Investigative Site Donetsk Ukraine 83092
    107 Novartis Investigative Site Khmelnytskyi Ukraine 29009
    108 Novartis Investigative Site Kyiv Ukraine 03022
    109 Novartis Investigative Site Lviv Ukraine 79031
    110 Novartis Investigative Site Sumy Ukraine 40005
    111 Novartis Investigative Site Northwood Middlesex United Kingdom HA6 2RN
    112 Novartis Investigative Site Sutton Surrey United Kingdom SM2 5PT
    113 Novartis Investigative Site Aberdeen United Kingdom AB25 2ZN
    114 Novartis Investigative Site Bebington United Kingdom CH63 4JY
    115 Novartis Investigative Site Edgbaston, Birmingham United Kingdom B15 2TH
    116 Novartis Investigative Site Leeds United Kingdom LS9 7TF
    117 Novartis Investigative Site London United Kingdom SW3 6JJ
    118 Novartis Investigative Site Newcastle upon Tyne United Kingdom NE7 7DN
    119 Novartis Investigative Site Nottingham United Kingdom NG5 1PB
    120 Novartis Investigative Site Oxford United Kingdom OX3 7LJ
    121 Novartis Investigative Site Preston United Kingdom PR2 9HT

    Sponsors and Collaborators

    • Novartis Pharmaceuticals

    Investigators

    • Study Director: Novartis Pharmaceuticals, Novartis Pharmaceuticals

    Study Documents (Full-Text)

    None provided.

    More Information

    Publications

    None provided.
    Responsible Party:
    Novartis Pharmaceuticals
    ClinicalTrials.gov Identifier:
    NCT01584648
    Other Study ID Numbers:
    • 115306
    • 2011-006087-49
    • CDRB436B2301
    First Posted:
    Apr 25, 2012
    Last Update Posted:
    Feb 17, 2021
    Last Verified:
    Feb 1, 2021
    Studies a U.S. FDA-regulated Drug Product:
    Yes
    Studies a U.S. FDA-regulated Device Product:
    No
    Keywords provided by Novartis Pharmaceuticals
    Randomized study
    combination therapy
    BRAF inhibitor
    GSK1120212
    BRAF V600E/K mutation-positive cutaneous melanoma
    trametinib
    GSK2118436
    MEK inhibitor
    Phase III
    dabrafenib
    Additional relevant MeSH terms:
    Melanoma
    Trametinib
    Dabrafenib

    Study Results

    Participant Flow

    Recruitment Details This study was conducted in 103 centers in 14 countries worldwide: Argentina (1), Australia (6), Canada (5), France (8), Germany (25), Greece (3), Italy (8), Netherlands (3), Russia (4), Spain (7), Sweden (4), Ukraine (7), United Kingdom (10), and USA (12).
    Pre-assignment Detail Approximately, 340 subjects were planned to be randomized in a 1:1 ratio (170 subjects each in combination therapy and monotherapy). A total of 423 subjects with unresectable or metastatic, BRAF V600E or V600K mutation-positive melanoma were randomized to dabrafenib and trametinib (n=211) or dabrafenib and placebo (n=212).
    Arm/Group Title Dabrafenib + Trametinib Dabrafenib + Placebo
    Arm/Group Description Participants received dabrafenib 150 milligram (mg) HPMC capsules orally twice daily (BID), once in the morning and a second dose approximately 12 hours after the morning dose, and trametinib 2 mg once daily in the morning. Treatment was continued until disease progression, death, unacceptable toxicity, or withdrawal of consent. Participants received dabrafenib 150 mg HPMC capsules orally BID, once in the morning and a second dose approximately 12 hours after the morning dose, and trametinib placebo once daily in the morning. Treatment was continued until disease progression, death, unacceptable toxicity, or withdrawal of consent. Crossover to the combination therapy arm was allowed for subjects still receiving study treatment on the dabrafenib monotherapy arm after the positive result for the final OS analysis.
    Period Title: Overall Study
    STARTED 211 212
    Safety Set 209 211
    Crossover Population 0 28
    COMPLETED 0 0
    NOT COMPLETED 211 212

    Baseline Characteristics

    Arm/Group Title Dabrafenib + Trametinib Dabrafenib + Placebo Total
    Arm/Group Description Participants received dabrafenib 150 milligram (mg) HPMC capsules orally twice daily (BID), once in the morning and a second dose approximately 12 hours after the morning dose, and trametinib 2 mg once daily in the morning. Treatment was continued until disease progression, death, unacceptable toxicity, or withdrawal of consent. Participants received dabrafenib 150 mg HPMC capsules orally BID, once in the morning and a second dose approximately 12 hours after the morning dose, and trametinib placebo once daily in the morning. Treatment was continued until disease progression, death, unacceptable toxicity, or withdrawal of consent. Crossover to the combination therapy arm was allowed for subjects still receiving study treatment on the dabrafenib monotherapy arm after the positive result for the final OS analysis. Total of all reporting groups
    Overall Participants 211 212 423
    Age (Years) [Mean (Standard Deviation) ]
    Mean (Standard Deviation) [Years]
    55.1
    (13.33)
    55.3
    (13.75)
    55.2
    (13.52)
    Sex: Female, Male (Count of Participants)
    Female
    100
    47.4%
    98
    46.2%
    198
    46.8%
    Male
    111
    52.6%
    114
    53.8%
    225
    53.2%
    Race/Ethnicity, Customized (Number) [Number]
    African American/African Heritage
    0
    0%
    1
    0.5%
    1
    0.2%
    White - White/Caucasian/European Heritage
    211
    100%
    211
    99.5%
    422
    99.8%

    Outcome Measures

    1. Primary Outcome
    Title Progression-Free Survival (PFS) as Assessed by the Investigator
    Description PFS is defined as the interval between the date of randomization and the earliest date of PD or death due to any cause. PD was based on radiographic or photographic evidence, and assessments were made by the investigator according to RECIST, version 1.1. PD is defined as at least a 20% increase in the sum of the diameters of target lesions, taking as a reference, the smallest sum of diameters recorded since the treatment started. In addition, the sum must have an absolute increase from nadir of 5 mm. The appearance of one or more new lesions, or the worsening of non-target lesions significant enough to require study treatment discontinuation, was also included as PD. Participants who received anti-cancer therapy prior to the date of documented events, were censored at the last adequate assessment prior to the initiation of therapy. If the participant did not have documented progression or death, PFS was censored at the date of the last adequate assessment.
    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 was considered.
    Arm/Group Title Dabrafenib + Trametinib Dabrafenib + Placebo
    Arm/Group Description Participants received dabrafenib 150 milligram (mg) HPMC capsules orally twice daily (BID), once in the morning and a second dose approximately 12 hours after the morning dose, and trametinib 2 mg once daily in the morning. Treatment was continued until disease progression, death, unacceptable toxicity, or withdrawal of consent. Participants received dabrafenib 150 mg HPMC capsules orally BID, once in the morning and a second dose approximately 12 hours after the morning dose, and trametinib placebo once daily in the morning. Treatment was continued until disease progression, death, unacceptable toxicity, or withdrawal of consent. Crossover to the combination therapy arm was allowed for subjects still receiving study treatment on the dabrafenib monotherapy arm after the positive result for the final OS analysis.
    Measure Participants 211 212
    Median (95% Confidence Interval) [Months]
    10.2
    8.8
    Statistical Analysis 1
    Statistical Analysis Overview Comparison Group Selection Dabrafenib + Trametinib, Dabrafenib + Placebo
    Comments
    Type of Statistical Test Superiority or Other (legacy)
    Comments
    Statistical Test of Hypothesis p-Value
    Comments
    Method
    Comments
    Method of Estimation Estimation Parameter Hazard Ratio (HR)
    Estimated Value 0.73
    Confidence Interval (2-Sided) 95%
    0.59 to 0.91
    Parameter Dispersion Type:
    Value:
    Estimation Comments Hazard ratios (HRs) were estimated using a Pike estimator.
    2. Secondary Outcome
    Title Overall Survival (OS)
    Description OS is defined as the interval of time between the date of randomization and the date of death due to any cause. For the participants who did not die, overall survival 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 was considered.
    Arm/Group Title Dabrafenib + Trametinib Dabrafenib + Placebo
    Arm/Group Description Participants received dabrafenib 150 milligram (mg) HPMC capsules orally twice daily (BID), once in the morning and a second dose approximately 12 hours after the morning dose, and trametinib 2 mg once daily in the morning. Treatment was continued until disease progression, death, unacceptable toxicity, or withdrawal of consent. Participants received dabrafenib 150 mg HPMC capsules orally BID, once in the morning and a second dose approximately 12 hours after the morning dose, and trametinib placebo once daily in the morning. Treatment was continued until disease progression, death, unacceptable toxicity, or withdrawal of consent. Crossover to the combination therapy arm was allowed for subjects still receiving study treatment on the dabrafenib monotherapy arm after the positive result for the final OS analysis.
    Measure Participants 211 212
    Median (95% Confidence Interval) [Months]
    25.8
    18.7
    Statistical Analysis 1
    Statistical Analysis Overview Comparison Group Selection Dabrafenib + Trametinib, Dabrafenib + Placebo
    Comments
    Type of Statistical Test Superiority or Other (legacy)
    Comments
    Statistical Test of Hypothesis p-Value
    Comments
    Method
    Comments
    Method of Estimation Estimation Parameter Hazard Ratio (HR)
    Estimated Value 0.81
    Confidence Interval (2-Sided) 95%
    0.64 to 1.02
    Parameter Dispersion Type:
    Value:
    Estimation Comments Hazard ratios (HRs) were estimated using a Pike estimator.
    3. Secondary Outcome
    Title Objective Response Rate (ORR) as Assessed by the Investigator
    Description ORR is defined as the percentage of participants with a confirmed complete response (CR) or partial response (PR). A participant was defined as a responder if he/she sustained a complete response (CR: the disappearance of all target lesions and any pathological lymph nodes must have a short axis of <10 mm and the disappearance of all non-target lesions) or partial response (PR: at least a 30% decrease in the sum of the diameters of target lesions, taking as a reference, the Baseline sum of the diameters or the persistence of 1 or more non-target lesions or lymph nodes identified as a site of disease at Baseline with a short axis of ≥10mm). Only descriptive analysis performed.
    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 was considered. Only participants with measurable disease at Baseline per RECIST were analyzed.
    Arm/Group Title Dabrafenib + Trametinib Dabrafenib + Placebo
    Arm/Group Description Participants received dabrafenib 150 milligram (mg) HPMC capsules orally twice daily (BID), once in the morning and a second dose approximately 12 hours after the morning dose, and trametinib 2 mg once daily in the morning. Treatment was continued until disease progression, death, unacceptable toxicity, or withdrawal of consent. Participants received dabrafenib 150 mg HPMC capsules orally BID, once in the morning and a second dose approximately 12 hours after the morning dose, and trametinib placebo once daily in the morning. Treatment was continued until disease progression, death, unacceptable toxicity, or withdrawal of consent. Crossover to the combination therapy arm was allowed for subjects still receiving study treatment on the dabrafenib monotherapy arm after the positive result for the final OS analysis.
    Measure Participants 210 210
    Count of Participants [Participants]
    146
    69.2%
    113
    53.3%
    4. Secondary Outcome
    Title Duration of Response (DoR)
    Description Duration of response is defined as the time from the first documented complete response (CR: the disappearance of all target lesions and any pathological lymph nodes must have a short axis of <10 mm and the disappearance of all non-target lesions) or partial response (PR: at least a 30% decrease in the sum of the diameters of target lesions, taking as a reference, the Baseline sum of the diameters or the persistence of 1 or more non-target lesions or lymph nodes identified as a site of disease at Baseline with a short axis of ≥10mm) until disease progression (PD) or death due to any cause. PD is defined as at least a 20% increase in the sum of the diameters of target lesions with an absolute increase of at least 5mm or the appearance of one or more new lesions, or the worsening of non target lesions significant enough to require study treatment discontinuation. PD was based on the radiological evidence by investigator. Only descriptive analysis performed.
    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
    ITT population. Only those participants with a confirmed CR or PR were analyzed (with or without measurabe disease at Baseline).
    Arm/Group Title Dabrafenib + Trametinib Dabrafenib + Placebo
    Arm/Group Description Participants received dabrafenib 150 milligram (mg) HPMC capsules orally twice daily (BID), once in the morning and a second dose approximately 12 hours after the morning dose, and trametinib 2 mg once daily in the morning. Treatment was continued until disease progression, death, unacceptable toxicity, or withdrawal of consent. Participants received dabrafenib 150 mg HPMC capsules orally BID, once in the morning and a second dose approximately 12 hours after the morning dose, and trametinib placebo once daily in the morning. Treatment was continued until disease progression, death, unacceptable toxicity, or withdrawal of consent. Crossover to the combination therapy arm was allowed for subjects still receiving study treatment on the dabrafenib monotherapy arm after the positive result for the final OS analysis.
    Measure Participants 146 114
    Median (95% Confidence Interval) [Months]
    12.9
    10.2
    5. Secondary Outcome
    Title Trametinib Pharmacokinetic Concentrations
    Description Blood samples were collected for Pharmacokinetic (PK) analysis in all participants. Three blood samples were collected at Week 8: pre-dose, 1-3 hours post dose, and 4-6 hours post dose. One pre-dose blood sample was obtained at Weeks 16 and 24. Only descriptive analysis performed.
    Time Frame Week 8 (0, 1-3, 4-6 hours post dose), Weeks 16 and 24 (0 hour pre-dose)

    Outcome Measure Data

    Analysis Population Description
    Pharmacokinetic (PK) Population: all participants included in the safety population for whom a PK sample was obtained and analyzed. Only participants with data available at the specified time points were analyzed.
    Arm/Group Title Dabrafenib + Trametinib Dabrafenib + Placebo
    Arm/Group Description Participants received dabrafenib 150 milligram (mg) HPMC capsules orally twice daily (BID), once in the morning and a second dose approximately 12 hours after the morning dose, and trametinib 2 mg once daily in the morning. Treatment was continued until disease progression, death, unacceptable toxicity, or withdrawal of consent. Participants received dabrafenib 150 mg HPMC capsules orally BID, once in the morning and a second dose approximately 12 hours after the morning dose, and trametinib placebo once daily in the morning. Treatment was continued until disease progression, death, unacceptable toxicity, or withdrawal of consent. Crossover to the combination therapy arm was allowed for subjects still receiving study treatment on the dabrafenib monotherapy arm after the positive result for the final OS analysis.
    Measure Participants 203 194
    Week 8, pre-dose
    9.9209
    (3.86587)
    0.0000
    (0.00000)
    Week 8, 1-3 hours
    19.0382
    (6.86542)
    0.0261
    (0.34598)
    Week 8, 4-6 hours
    16.7496
    (5.64363)
    0.0000
    (0.00000)
    Week 16 pre-dose
    11.0385
    (4.79185)
    0.0039
    (0.03548)
    Week 24 pre-dose
    11.5167
    (5.19171)
    0.0548
    (0.62447)
    6. Secondary Outcome
    Title Dabrafenib and Dabrafenib Metabolites (Hydroxy-, Carboxy- and Desmethyl-Dabrafenib) Concentrations
    Description Blood samples were collected for PK analysis in all participants. Three blood samples were collected at Week 8: pre-dose, 1-3 hours post dose, and 4-6 hours post dose. One pre-dose blood sample was obtained at Weeks 16 and 24. Plasma concentrations of Dabrafenib (GSK2118436) and its metabolites (Hydroxy-Dabrafenib (GSK2285403), Carboxy-Dabrafenib (GSK2298683), and Desmethyl-Dabrafenib (GSK2167542)) were determined using the currently approved analytical methodology. Only descriptive analysis performed.
    Time Frame Week 8 (0, 1-3, 4-6 hours post dose), Weeks 16 and 24 (0 hour pre-dose)

    Outcome Measure Data

    Analysis Population Description
    PK Population.
    Arm/Group Title Dabrafenib + Trametinib Dabrafenib + Placebo
    Arm/Group Description Participants received dabrafenib 150 milligram (mg) HPMC capsules orally twice daily (BID), once in the morning and a second dose approximately 12 hours after the morning dose, and trametinib 2 mg once daily in the morning. Treatment was continued until disease progression, death, unacceptable toxicity, or withdrawal of consent. Participants received dabrafenib 150 mg HPMC capsules orally BID, once in the morning and a second dose approximately 12 hours after the morning dose, and trametinib placebo once daily in the morning. Treatment was continued until disease progression, death, unacceptable toxicity, or withdrawal of consent. Crossover to the combination therapy arm was allowed for subjects still receiving study treatment on the dabrafenib monotherapy arm after the positive result for the final OS analysis.
    Measure Participants 203 194
    GSK2118436, Week 8, pre-dose
    92.1
    (204.85)
    64.4
    (96.98)
    GSK2118436, Week 8, 1-3 hours
    1309.6
    (982.25)
    1362.3
    (992.97)
    GSK2118436, Week 8, 4-6 hours
    458.9
    (318.59)
    539.7
    (553.09)
    GSK2118436, Week 16 pre-dose
    151.6
    (261.31)
    151.02
    (381.32)
    GSK2118436, Week 24 pre-dose
    167.0
    (346.97)
    156.5
    (357.50)
    GSK2285403, Week 8, pre-dose
    346.6
    (261.73)
    308.9
    (224.56)
    GSK2285403, Week 8, 1-3 hours
    361.7
    (245.92)
    341.8
    (240.96)
    GSK2285403, Week 8, 4-6 hours
    316.9
    (208.51)
    328.1
    (234.95)
    GSK2285403, Week 16 pre-dose
    335.0
    (228.26)
    331.0
    (250.04)
    GSK2285403, Week 24 pre-dose
    306.2
    (203.77)
    312.8
    (250.28)
    GSK2298683, Week 8, pre-dose
    82.0
    (123.93)
    76.7
    (109.09)
    GSK2298683,Week 8, 1-3 hours
    648.5
    (459.01)
    672.7
    (519.45)
    GSK2298683, Week 8, 4-6 hours
    391.3
    (206.70)
    502.2
    (356.72)
    GSK2298683, Week 16 pre-dose
    128.7
    (174.26)
    121.1
    (195.15)
    GSK2298683,Week 24 pre-dose
    126.1
    (219.82)
    145.7
    (265.57)
    GSK2167542, Week 8, pre-dose
    3237.2
    (1694.66)
    3469.4
    (1854.02)
    GSK2167542, Week 8, 1-3 hours
    4286.3
    (2514.50)
    4456.6
    (2687.32)
    GSK2167542, Week 8, 4-6 hours
    6238.3
    (2716.05)
    6891.6
    (2739.07)
    GSK2167542, Week 16 pre-dose
    3842.4
    (2428.74)
    4114.1
    (2432.72)
    GSK2167542, Week 24 pre-dose
    3617.9
    (2645.51)
    4193.2
    (2730.78)
    7. Secondary Outcome
    Title Number of Participants With Adverse Events and Serious Adverse Events
    Description Analysis of absolute and relative frequencies for Adverse Event (AE) and Serious Adverse Event (SAE) by primary System Organ Class (SOC) to characterize the safety of dabrafenib and trametinib combination therapy through the monitoring of relevant clinical and laboratory safety parameters. In addition, new malignancies and AEs possibly related to study treatment were collected even if they occurred more than 30 days post-treatment. Only descriptive analysis performed.
    Time Frame From the time the first dose of study treatment administered until 30 days after discontinuation of study treatment (up to approximately 6 years).

    Outcome Measure Data

    Analysis Population Description
    Safety Population: all randomized participants who received at least one dose of study medication and were based on the actual treatment received if this differed from that to which the participant was randomized.
    Arm/Group Title Dabrafenib + Trametinib Dabrafenib + Placebo Crossover Dabrafenib + Trametinib
    Arm/Group Description Participants received dabrafenib 150 milligram (mg) HPMC capsules orally twice daily (BID), once in the morning and a second dose approximately 12 hours after the morning dose, and trametinib 2 mg once daily in the morning. Treatment was continued until disease progression, death, unacceptable toxicity, or withdrawal of consent. Participants received dabrafenib 150 mg HPMC capsules orally BID, once in the morning and a second dose approximately 12 hours after the morning dose, and trametinib placebo once daily in the morning. Treatment was continued until disease progression, death, unacceptable toxicity, or withdrawal of consent. Crossover to the combination therapy arm was allowed for subjects still receiving study treatment on the dabrafenib monotherapy arm after the positive result for the final OS analysis. Crossover Dabrafenib + Trametinib
    Measure Participants 209 211 28
    Adverse Event (AEs)
    203
    96.2%
    205
    96.7%
    24
    5.7%
    Serious Adverse Event (SAEs)
    100
    47.4%
    80
    37.7%
    8
    1.9%
    8. Post-Hoc Outcome
    Title All Collected Deaths
    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 77.4 months (treatment duration ranged from 0.1 to 76.4 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 77.4 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 + Trametinib Dabrafenib + Placebo Crossover Dabrafenib + Trametinib
    Arm/Group Description Participants received dabrafenib 150 milligram (mg) HPMC capsules orally twice daily (BID), once in the morning and a second dose approximately 12 hours after the morning dose, and trametinib 2 mg once daily in the morning. Treatment was continued until disease progression, death, unacceptable toxicity, or withdrawal of consent. Participants received dabrafenib 150 mg HPMC capsules orally BID, once in the morning and a second dose approximately 12 hours after the morning dose, and trametinib placebo once daily in the morning. Treatment was continued until disease progression, death, unacceptable toxicity, or withdrawal of consent. Crossover to the combination therapy arm was allowed for subjects still receiving study treatment on the dabrafenib monotherapy arm after the positive result for the final OS analysis. Crossover Dabrafenib + Trametinib
    Measure Participants 210 211 28
    Pre-treatment deaths
    1
    0.5%
    0
    0%
    0
    0%
    On-treatment deaths
    29
    13.7%
    25
    11.8%
    0
    0%
    Post-treatment deaths
    106
    50.2%
    121
    57.1%
    5
    1.2%
    All deaths
    136
    64.5%
    146
    68.9%
    5
    1.2%

    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 77.4 months (treatment duration ranged from 0.1 to 76.4 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 + Trametinib Dabrafenib + Placebo Crossover Dabrafenib + Trametinib All Patients
    Arm/Group Description Participants received dabrafenib 150 milligram (mg) HPMC capsules orally twice daily (BID), once in the morning and a second dose approximately 12 hours after the morning dose, and trametinib 2 mg once daily in the morning. Treatment was continued until disease progression, death, unacceptable toxicity, or withdrawal of consent. Participants received dabrafenib 150 mg HPMC capsules orally BID, once in the morning and a second dose approximately 12 hours after the morning dose, and trametinib placebo once daily in the morning. Treatment was continued until disease progression, death, unacceptable toxicity, or withdrawal of consent. Crossover to the combination therapy arm was allowed for subjects still receiving study treatment on the dabrafenib monotherapy arm after the positive result for the final OS analysis. Crossover Dabrafenib + Trametinib All Patients
    All Cause Mortality
    Dabrafenib + Trametinib Dabrafenib + Placebo Crossover Dabrafenib + Trametinib All Patients
    Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events
    Total 135/209 (64.6%) 146/211 (69.2%) 5/28 (17.9%) 286/420 (68.1%)
    Serious Adverse Events
    Dabrafenib + Trametinib Dabrafenib + Placebo Crossover Dabrafenib + Trametinib All Patients
    Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events
    Total 100/209 (47.8%) 80/211 (37.9%) 8/28 (28.6%) 183/420 (43.6%)
    Blood and lymphatic system disorders
    Anaemia 5/209 (2.4%) 3/211 (1.4%) 0/28 (0%) 8/420 (1.9%)
    Febrile neutropenia 0/209 (0%) 2/211 (0.9%) 0/28 (0%) 2/420 (0.5%)
    Haemolytic uraemic syndrome 1/209 (0.5%) 0/211 (0%) 0/28 (0%) 1/420 (0.2%)
    Hypochromic anaemia 1/209 (0.5%) 0/211 (0%) 0/28 (0%) 1/420 (0.2%)
    Neutropenia 1/209 (0.5%) 0/211 (0%) 0/28 (0%) 1/420 (0.2%)
    Pancytopenia 1/209 (0.5%) 0/211 (0%) 0/28 (0%) 1/420 (0.2%)
    Thrombocytopenia 2/209 (1%) 0/211 (0%) 0/28 (0%) 2/420 (0.5%)
    Cardiac disorders
    Acute coronary syndrome 1/209 (0.5%) 0/211 (0%) 0/28 (0%) 1/420 (0.2%)
    Atrial fibrillation 3/209 (1.4%) 2/211 (0.9%) 0/28 (0%) 5/420 (1.2%)
    Cardiac failure 0/209 (0%) 2/211 (0.9%) 1/28 (3.6%) 3/420 (0.7%)
    Cardiovascular insufficiency 1/209 (0.5%) 0/211 (0%) 0/28 (0%) 1/420 (0.2%)
    Myocardial infarction 1/209 (0.5%) 0/211 (0%) 0/28 (0%) 1/420 (0.2%)
    Supraventricular tachycardia 1/209 (0.5%) 0/211 (0%) 0/28 (0%) 1/420 (0.2%)
    Tachycardia 0/209 (0%) 1/211 (0.5%) 0/28 (0%) 1/420 (0.2%)
    Eye disorders
    Chorioretinopathy 1/209 (0.5%) 1/211 (0.5%) 0/28 (0%) 2/420 (0.5%)
    Iridocyclitis 1/209 (0.5%) 0/211 (0%) 0/28 (0%) 1/420 (0.2%)
    Uveitis 0/209 (0%) 1/211 (0.5%) 0/28 (0%) 1/420 (0.2%)
    Visual impairment 0/209 (0%) 1/211 (0.5%) 0/28 (0%) 1/420 (0.2%)
    Gastrointestinal disorders
    Abdominal pain 4/209 (1.9%) 2/211 (0.9%) 0/28 (0%) 6/420 (1.4%)
    Abdominal pain upper 1/209 (0.5%) 0/211 (0%) 0/28 (0%) 1/420 (0.2%)
    Acute abdomen 1/209 (0.5%) 0/211 (0%) 0/28 (0%) 1/420 (0.2%)
    Colitis 0/209 (0%) 1/211 (0.5%) 0/28 (0%) 1/420 (0.2%)
    Constipation 1/209 (0.5%) 0/211 (0%) 0/28 (0%) 1/420 (0.2%)
    Diarrhoea 2/209 (1%) 0/211 (0%) 0/28 (0%) 2/420 (0.5%)
    Gastrointestinal disorder 0/209 (0%) 1/211 (0.5%) 0/28 (0%) 1/420 (0.2%)
    Gastrooesophageal reflux disease 0/209 (0%) 1/211 (0.5%) 0/28 (0%) 1/420 (0.2%)
    Intestinal perforation 1/209 (0.5%) 0/211 (0%) 0/28 (0%) 1/420 (0.2%)
    Jejunal perforation 1/209 (0.5%) 0/211 (0%) 0/28 (0%) 1/420 (0.2%)
    Melaena 1/209 (0.5%) 0/211 (0%) 0/28 (0%) 1/420 (0.2%)
    Nausea 2/209 (1%) 0/211 (0%) 0/28 (0%) 2/420 (0.5%)
    Pancreatitis acute 1/209 (0.5%) 0/211 (0%) 0/28 (0%) 1/420 (0.2%)
    Peritoneal haemorrhage 0/209 (0%) 1/211 (0.5%) 0/28 (0%) 1/420 (0.2%)
    Rectal haemorrhage 2/209 (1%) 0/211 (0%) 0/28 (0%) 2/420 (0.5%)
    Small intestinal obstruction 1/209 (0.5%) 0/211 (0%) 0/28 (0%) 1/420 (0.2%)
    Upper gastrointestinal haemorrhage 0/209 (0%) 1/211 (0.5%) 0/28 (0%) 1/420 (0.2%)
    Vomiting 3/209 (1.4%) 0/211 (0%) 0/28 (0%) 3/420 (0.7%)
    General disorders
    Chest pain 0/209 (0%) 1/211 (0.5%) 0/28 (0%) 1/420 (0.2%)
    Chills 10/209 (4.8%) 3/211 (1.4%) 0/28 (0%) 13/420 (3.1%)
    Drowning 1/209 (0.5%) 0/211 (0%) 0/28 (0%) 1/420 (0.2%)
    Fatigue 3/209 (1.4%) 1/211 (0.5%) 0/28 (0%) 4/420 (1%)
    General physical health deterioration 3/209 (1.4%) 0/211 (0%) 0/28 (0%) 3/420 (0.7%)
    Influenza like illness 1/209 (0.5%) 0/211 (0%) 0/28 (0%) 1/420 (0.2%)
    Malaise 0/209 (0%) 1/211 (0.5%) 0/28 (0%) 1/420 (0.2%)
    Pyrexia 36/209 (17.2%) 15/211 (7.1%) 2/28 (7.1%) 51/420 (12.1%)
    Hepatobiliary disorders
    Cholecystitis 1/209 (0.5%) 0/211 (0%) 0/28 (0%) 1/420 (0.2%)
    Cholelithiasis 0/209 (0%) 1/211 (0.5%) 0/28 (0%) 1/420 (0.2%)
    Hepatic haematoma 1/209 (0.5%) 0/211 (0%) 0/28 (0%) 1/420 (0.2%)
    Immune system disorders
    Contrast media allergy 1/209 (0.5%) 0/211 (0%) 0/28 (0%) 1/420 (0.2%)
    Infections and infestations
    Bacteraemia 1/209 (0.5%) 0/211 (0%) 0/28 (0%) 1/420 (0.2%)
    Cellulitis 2/209 (1%) 1/211 (0.5%) 0/28 (0%) 3/420 (0.7%)
    Clostridium difficile colitis 1/209 (0.5%) 0/211 (0%) 0/28 (0%) 1/420 (0.2%)
    Cystitis 1/209 (0.5%) 0/211 (0%) 0/28 (0%) 1/420 (0.2%)
    Diverticulitis 0/209 (0%) 1/211 (0.5%) 0/28 (0%) 1/420 (0.2%)
    Febrile infection 0/209 (0%) 0/211 (0%) 1/28 (3.6%) 1/420 (0.2%)
    Herpes zoster 1/209 (0.5%) 1/211 (0.5%) 0/28 (0%) 2/420 (0.5%)
    Kidney infection 1/209 (0.5%) 0/211 (0%) 0/28 (0%) 1/420 (0.2%)
    Laryngitis 1/209 (0.5%) 0/211 (0%) 0/28 (0%) 1/420 (0.2%)
    Neutropenic sepsis 1/209 (0.5%) 0/211 (0%) 0/28 (0%) 1/420 (0.2%)
    Peritonitis 0/209 (0%) 1/211 (0.5%) 0/28 (0%) 1/420 (0.2%)
    Pneumonia 6/209 (2.9%) 2/211 (0.9%) 0/28 (0%) 8/420 (1.9%)
    Pseudomonas infection 1/209 (0.5%) 0/211 (0%) 0/28 (0%) 1/420 (0.2%)
    Pyelonephritis 1/209 (0.5%) 0/211 (0%) 0/28 (0%) 1/420 (0.2%)
    Sepsis 1/209 (0.5%) 1/211 (0.5%) 0/28 (0%) 2/420 (0.5%)
    Septic shock 1/209 (0.5%) 0/211 (0%) 0/28 (0%) 1/420 (0.2%)
    Staphylococcal sepsis 1/209 (0.5%) 0/211 (0%) 0/28 (0%) 1/420 (0.2%)
    Superinfection 1/209 (0.5%) 0/211 (0%) 0/28 (0%) 1/420 (0.2%)
    Upper respiratory tract infection 0/209 (0%) 0/211 (0%) 1/28 (3.6%) 1/420 (0.2%)
    Urinary tract infection 2/209 (1%) 1/211 (0.5%) 0/28 (0%) 3/420 (0.7%)
    Urosepsis 2/209 (1%) 0/211 (0%) 0/28 (0%) 2/420 (0.5%)
    Injury, poisoning and procedural complications
    Humerus fracture 1/209 (0.5%) 0/211 (0%) 0/28 (0%) 1/420 (0.2%)
    Joint dislocation 1/209 (0.5%) 0/211 (0%) 0/28 (0%) 1/420 (0.2%)
    Ligament rupture 1/209 (0.5%) 0/211 (0%) 0/28 (0%) 1/420 (0.2%)
    Ligament sprain 1/209 (0.5%) 0/211 (0%) 0/28 (0%) 1/420 (0.2%)
    Meniscus injury 1/209 (0.5%) 0/211 (0%) 0/28 (0%) 1/420 (0.2%)
    Post procedural persistent drain fluid 1/209 (0.5%) 0/211 (0%) 0/28 (0%) 1/420 (0.2%)
    Radius fracture 1/209 (0.5%) 0/211 (0%) 0/28 (0%) 1/420 (0.2%)
    Subarachnoid haemorrhage 0/209 (0%) 1/211 (0.5%) 0/28 (0%) 1/420 (0.2%)
    Upper limb fracture 1/209 (0.5%) 0/211 (0%) 0/28 (0%) 1/420 (0.2%)
    Investigations
    Alanine aminotransferase increased 3/209 (1.4%) 0/211 (0%) 1/28 (3.6%) 4/420 (1%)
    Aspartate aminotransferase increased 1/209 (0.5%) 0/211 (0%) 1/28 (3.6%) 2/420 (0.5%)
    Blood alkaline phosphatase increased 1/209 (0.5%) 0/211 (0%) 0/28 (0%) 1/420 (0.2%)
    Ejection fraction decreased 13/209 (6.2%) 5/211 (2.4%) 1/28 (3.6%) 19/420 (4.5%)
    Forced expiratory volume decreased 1/209 (0.5%) 0/211 (0%) 0/28 (0%) 1/420 (0.2%)
    Haemoglobin decreased 1/209 (0.5%) 0/211 (0%) 0/28 (0%) 1/420 (0.2%)
    Hepatic enzyme increased 1/209 (0.5%) 0/211 (0%) 0/28 (0%) 1/420 (0.2%)
    Neutrophil count decreased 1/209 (0.5%) 0/211 (0%) 0/28 (0%) 1/420 (0.2%)
    Oxygen saturation decreased 0/209 (0%) 1/211 (0.5%) 0/28 (0%) 1/420 (0.2%)
    Renal function test abnormal 0/209 (0%) 0/211 (0%) 1/28 (3.6%) 1/420 (0.2%)
    Transaminases increased 1/209 (0.5%) 0/211 (0%) 0/28 (0%) 1/420 (0.2%)
    White blood cell count decreased 1/209 (0.5%) 0/211 (0%) 0/28 (0%) 1/420 (0.2%)
    Metabolism and nutrition disorders
    Dehydration 1/209 (0.5%) 2/211 (0.9%) 1/28 (3.6%) 4/420 (1%)
    Hypercalcaemia 0/209 (0%) 1/211 (0.5%) 0/28 (0%) 1/420 (0.2%)
    Hyperglycaemia 1/209 (0.5%) 0/211 (0%) 0/28 (0%) 1/420 (0.2%)
    Hypoglycaemia 2/209 (1%) 0/211 (0%) 0/28 (0%) 2/420 (0.5%)
    Hypokalaemia 1/209 (0.5%) 0/211 (0%) 0/28 (0%) 1/420 (0.2%)
    Hyponatraemia 0/209 (0%) 1/211 (0.5%) 1/28 (3.6%) 2/420 (0.5%)
    Hypophosphataemia 1/209 (0.5%) 0/211 (0%) 0/28 (0%) 1/420 (0.2%)
    Type 2 diabetes mellitus 0/209 (0%) 1/211 (0.5%) 0/28 (0%) 1/420 (0.2%)
    Musculoskeletal and connective tissue disorders
    Back pain 0/209 (0%) 2/211 (0.9%) 0/28 (0%) 2/420 (0.5%)
    Compartment syndrome 0/209 (0%) 1/211 (0.5%) 0/28 (0%) 1/420 (0.2%)
    Haemarthrosis 1/209 (0.5%) 0/211 (0%) 0/28 (0%) 1/420 (0.2%)
    Hypercreatinaemia 1/209 (0.5%) 0/211 (0%) 0/28 (0%) 1/420 (0.2%)
    Immunoglobulin G4 related disease 1/209 (0.5%) 0/211 (0%) 0/28 (0%) 1/420 (0.2%)
    Intervertebral disc degeneration 1/209 (0.5%) 1/211 (0.5%) 0/28 (0%) 2/420 (0.5%)
    Muscle haemorrhage 1/209 (0.5%) 0/211 (0%) 0/28 (0%) 1/420 (0.2%)
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Adenocarcinoma gastric 0/209 (0%) 1/211 (0.5%) 0/28 (0%) 1/420 (0.2%)
    Basal cell carcinoma 8/209 (3.8%) 14/211 (6.6%) 0/28 (0%) 22/420 (5.2%)
    Bile duct adenocarcinoma 0/209 (0%) 1/211 (0.5%) 0/28 (0%) 1/420 (0.2%)
    Bowen's disease 2/209 (1%) 2/211 (0.9%) 1/28 (3.6%) 5/420 (1.2%)
    Breast cancer 0/209 (0%) 1/211 (0.5%) 0/28 (0%) 1/420 (0.2%)
    Hodgkin's disease 0/209 (0%) 1/211 (0.5%) 0/28 (0%) 1/420 (0.2%)
    Invasive ductal breast carcinoma 0/209 (0%) 1/211 (0.5%) 0/28 (0%) 1/420 (0.2%)
    Keratoacanthoma 0/209 (0%) 1/211 (0.5%) 0/28 (0%) 1/420 (0.2%)
    Lipofibroma 0/209 (0%) 1/211 (0.5%) 0/28 (0%) 1/420 (0.2%)
    Malignant melanoma 1/209 (0.5%) 2/211 (0.9%) 0/28 (0%) 3/420 (0.7%)
    Osteosarcoma 1/209 (0.5%) 0/211 (0%) 0/28 (0%) 1/420 (0.2%)
    Papillary thyroid cancer 1/209 (0.5%) 0/211 (0%) 0/28 (0%) 1/420 (0.2%)
    Phaeochromocytoma 1/209 (0.5%) 0/211 (0%) 0/28 (0%) 1/420 (0.2%)
    Prostate cancer 1/209 (0.5%) 0/211 (0%) 0/28 (0%) 1/420 (0.2%)
    Schwannoma 0/209 (0%) 1/211 (0.5%) 0/28 (0%) 1/420 (0.2%)
    Squamous cell carcinoma 3/209 (1.4%) 7/211 (3.3%) 1/28 (3.6%) 11/420 (2.6%)
    Squamous cell carcinoma of skin 2/209 (1%) 15/211 (7.1%) 1/28 (3.6%) 18/420 (4.3%)
    Superficial spreading melanoma stage unspecified 0/209 (0%) 1/211 (0.5%) 0/28 (0%) 1/420 (0.2%)
    Transitional cell carcinoma 0/209 (0%) 1/211 (0.5%) 0/28 (0%) 1/420 (0.2%)
    Tumour haemorrhage 0/209 (0%) 1/211 (0.5%) 0/28 (0%) 1/420 (0.2%)
    Nervous system disorders
    Aphasia 1/209 (0.5%) 0/211 (0%) 0/28 (0%) 1/420 (0.2%)
    Brain oedema 1/209 (0.5%) 1/211 (0.5%) 0/28 (0%) 2/420 (0.5%)
    Central nervous system lesion 0/209 (0%) 0/211 (0%) 1/28 (3.6%) 1/420 (0.2%)
    Cerebral haemorrhage 2/209 (1%) 0/211 (0%) 0/28 (0%) 2/420 (0.5%)
    Cerebral infarction 1/209 (0.5%) 0/211 (0%) 0/28 (0%) 1/420 (0.2%)
    Cerebrovascular accident 1/209 (0.5%) 0/211 (0%) 0/28 (0%) 1/420 (0.2%)
    Dizziness 1/209 (0.5%) 0/211 (0%) 0/28 (0%) 1/420 (0.2%)
    Epilepsy 1/209 (0.5%) 1/211 (0.5%) 0/28 (0%) 2/420 (0.5%)
    Facial paralysis 1/209 (0.5%) 0/211 (0%) 0/28 (0%) 1/420 (0.2%)
    Hemiplegia 1/209 (0.5%) 0/211 (0%) 0/28 (0%) 1/420 (0.2%)
    Nervous system disorder 1/209 (0.5%) 0/211 (0%) 0/28 (0%) 1/420 (0.2%)
    Paraesthesia 0/209 (0%) 0/211 (0%) 1/28 (3.6%) 1/420 (0.2%)
    Presyncope 1/209 (0.5%) 0/211 (0%) 0/28 (0%) 1/420 (0.2%)
    Sciatica 1/209 (0.5%) 0/211 (0%) 0/28 (0%) 1/420 (0.2%)
    Seizure 1/209 (0.5%) 1/211 (0.5%) 0/28 (0%) 2/420 (0.5%)
    Syncope 4/209 (1.9%) 1/211 (0.5%) 0/28 (0%) 5/420 (1.2%)
    Tremor 1/209 (0.5%) 0/211 (0%) 0/28 (0%) 1/420 (0.2%)
    Psychiatric disorders
    Confusional state 3/209 (1.4%) 1/211 (0.5%) 0/28 (0%) 4/420 (1%)
    Delirium 1/209 (0.5%) 0/211 (0%) 0/28 (0%) 1/420 (0.2%)
    Mania 0/209 (0%) 1/211 (0.5%) 0/28 (0%) 1/420 (0.2%)
    Organic brain syndrome 0/209 (0%) 1/211 (0.5%) 0/28 (0%) 1/420 (0.2%)
    Renal and urinary disorders
    Acute kidney injury 1/209 (0.5%) 1/211 (0.5%) 0/28 (0%) 2/420 (0.5%)
    Azotaemia 1/209 (0.5%) 0/211 (0%) 0/28 (0%) 1/420 (0.2%)
    Haematuria 0/209 (0%) 1/211 (0.5%) 0/28 (0%) 1/420 (0.2%)
    Hydronephrosis 0/209 (0%) 1/211 (0.5%) 0/28 (0%) 1/420 (0.2%)
    Nephritis 1/209 (0.5%) 0/211 (0%) 0/28 (0%) 1/420 (0.2%)
    Pelvi-ureteric obstruction 1/209 (0.5%) 0/211 (0%) 0/28 (0%) 1/420 (0.2%)
    Renal colic 2/209 (1%) 0/211 (0%) 0/28 (0%) 2/420 (0.5%)
    Renal failure 0/209 (0%) 0/211 (0%) 1/28 (3.6%) 1/420 (0.2%)
    Urinary retention 1/209 (0.5%) 0/211 (0%) 0/28 (0%) 1/420 (0.2%)
    Reproductive system and breast disorders
    Uterine prolapse 0/209 (0%) 0/211 (0%) 1/28 (3.6%) 1/420 (0.2%)
    Respiratory, thoracic and mediastinal disorders
    Chronic obstructive pulmonary disease 0/209 (0%) 1/211 (0.5%) 0/28 (0%) 1/420 (0.2%)
    Dyspnoea 0/209 (0%) 1/211 (0.5%) 0/28 (0%) 1/420 (0.2%)
    Nasal polyps 1/209 (0.5%) 0/211 (0%) 0/28 (0%) 1/420 (0.2%)
    Pleural effusion 1/209 (0.5%) 0/211 (0%) 0/28 (0%) 1/420 (0.2%)
    Pneumonitis 1/209 (0.5%) 0/211 (0%) 0/28 (0%) 1/420 (0.2%)
    Pulmonary embolism 3/209 (1.4%) 1/211 (0.5%) 0/28 (0%) 4/420 (1%)
    Respiratory depression 0/209 (0%) 1/211 (0.5%) 0/28 (0%) 1/420 (0.2%)
    Skin and subcutaneous tissue disorders
    Dermatitis allergic 1/209 (0.5%) 0/211 (0%) 0/28 (0%) 1/420 (0.2%)
    Dermatosis 1/209 (0.5%) 0/211 (0%) 0/28 (0%) 1/420 (0.2%)
    Hyperhidrosis 1/209 (0.5%) 0/211 (0%) 0/28 (0%) 1/420 (0.2%)
    Hyperkeratosis 0/209 (0%) 1/211 (0.5%) 0/28 (0%) 1/420 (0.2%)
    Skin lesion 0/209 (0%) 1/211 (0.5%) 0/28 (0%) 1/420 (0.2%)
    Skin ulcer 0/209 (0%) 1/211 (0.5%) 0/28 (0%) 1/420 (0.2%)
    Vascular disorders
    Deep vein thrombosis 1/209 (0.5%) 1/211 (0.5%) 0/28 (0%) 2/420 (0.5%)
    Hypertension 1/209 (0.5%) 0/211 (0%) 0/28 (0%) 1/420 (0.2%)
    Hypotension 6/209 (2.9%) 2/211 (0.9%) 1/28 (3.6%) 9/420 (2.1%)
    Hypovolaemic shock 0/209 (0%) 1/211 (0.5%) 0/28 (0%) 1/420 (0.2%)
    Peripheral ischaemia 0/209 (0%) 1/211 (0.5%) 0/28 (0%) 1/420 (0.2%)
    Thrombophlebitis superficial 0/209 (0%) 1/211 (0.5%) 0/28 (0%) 1/420 (0.2%)
    Other (Not Including Serious) Adverse Events
    Dabrafenib + Trametinib Dabrafenib + Placebo Crossover Dabrafenib + Trametinib All Patients
    Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events
    Total 194/209 (92.8%) 200/211 (94.8%) 23/28 (82.1%) 394/420 (93.8%)
    Blood and lymphatic system disorders
    Anaemia 16/209 (7.7%) 22/211 (10.4%) 3/28 (10.7%) 38/420 (9%)
    Leukopenia 7/209 (3.3%) 1/211 (0.5%) 2/28 (7.1%) 10/420 (2.4%)
    Neutropenia 20/209 (9.6%) 5/211 (2.4%) 3/28 (10.7%) 28/420 (6.7%)
    Thrombocytopenia 9/209 (4.3%) 2/211 (0.9%) 2/28 (7.1%) 13/420 (3.1%)
    Cardiac disorders
    Atrial fibrillation 2/209 (1%) 2/211 (0.9%) 2/28 (7.1%) 6/420 (1.4%)
    Tachycardia 6/209 (2.9%) 13/211 (6.2%) 3/28 (10.7%) 21/420 (5%)
    Ear and labyrinth disorders
    Tinnitus 5/209 (2.4%) 2/211 (0.9%) 3/28 (10.7%) 9/420 (2.1%)
    Endocrine disorders
    Hypothyroidism 3/209 (1.4%) 2/211 (0.9%) 2/28 (7.1%) 7/420 (1.7%)
    Eye disorders
    Blepharitis 2/209 (1%) 0/211 (0%) 2/28 (7.1%) 4/420 (1%)
    Cataract 2/209 (1%) 4/211 (1.9%) 3/28 (10.7%) 8/420 (1.9%)
    Dry eye 11/209 (5.3%) 4/211 (1.9%) 1/28 (3.6%) 15/420 (3.6%)
    Vision blurred 10/209 (4.8%) 5/211 (2.4%) 3/28 (10.7%) 18/420 (4.3%)
    Gastrointestinal disorders
    Abdominal pain 29/209 (13.9%) 17/211 (8.1%) 1/28 (3.6%) 47/420 (11.2%)
    Abdominal pain upper 20/209 (9.6%) 12/211 (5.7%) 3/28 (10.7%) 35/420 (8.3%)
    Constipation 27/209 (12.9%) 22/211 (10.4%) 3/28 (10.7%) 52/420 (12.4%)
    Diarrhoea 67/209 (32.1%) 34/211 (16.1%) 9/28 (32.1%) 107/420 (25.5%)
    Dry mouth 18/209 (8.6%) 6/211 (2.8%) 1/28 (3.6%) 24/420 (5.7%)
    Nausea 79/209 (37.8%) 57/211 (27%) 7/28 (25%) 138/420 (32.9%)
    Vomiting 57/209 (27.3%) 31/211 (14.7%) 3/28 (10.7%) 89/420 (21.2%)
    General disorders
    Asthenia 29/209 (13.9%) 30/211 (14.2%) 4/28 (14.3%) 60/420 (14.3%)
    Chest pain 12/209 (5.7%) 5/211 (2.4%) 0/28 (0%) 17/420 (4%)
    Chills 63/209 (30.1%) 34/211 (16.1%) 3/28 (10.7%) 98/420 (23.3%)
    Fatigue 79/209 (37.8%) 79/211 (37.4%) 7/28 (25%) 161/420 (38.3%)
    Influenza like illness 17/209 (8.1%) 12/211 (5.7%) 3/28 (10.7%) 31/420 (7.4%)
    Oedema peripheral 48/209 (23%) 17/211 (8.1%) 2/28 (7.1%) 66/420 (15.7%)
    Pain 14/209 (6.7%) 9/211 (4.3%) 1/28 (3.6%) 23/420 (5.5%)
    Pyrexia 118/209 (56.5%) 63/211 (29.9%) 10/28 (35.7%) 183/420 (43.6%)
    Immune system disorders
    Hypersensitivity 1/209 (0.5%) 2/211 (0.9%) 2/28 (7.1%) 5/420 (1.2%)
    Infections and infestations
    Bronchitis 12/209 (5.7%) 8/211 (3.8%) 1/28 (3.6%) 21/420 (5%)
    Cystitis 11/209 (5.3%) 2/211 (0.9%) 0/28 (0%) 13/420 (3.1%)
    Folliculitis 12/209 (5.7%) 11/211 (5.2%) 2/28 (7.1%) 25/420 (6%)
    Influenza 17/209 (8.1%) 7/211 (3.3%) 5/28 (17.9%) 28/420 (6.7%)
    Nasopharyngitis 28/209 (13.4%) 21/211 (10%) 4/28 (14.3%) 50/420 (11.9%)
    Upper respiratory tract infection 16/209 (7.7%) 7/211 (3.3%) 1/28 (3.6%) 24/420 (5.7%)
    Urinary tract infection 29/209 (13.9%) 7/211 (3.3%) 2/28 (7.1%) 38/420 (9%)
    Injury, poisoning and procedural complications
    Fall 6/209 (2.9%) 2/211 (0.9%) 2/28 (7.1%) 10/420 (2.4%)
    Tendon rupture 0/209 (0%) 1/211 (0.5%) 2/28 (7.1%) 3/420 (0.7%)
    Investigations
    Alanine aminotransferase increased 25/209 (12%) 12/211 (5.7%) 1/28 (3.6%) 38/420 (9%)
    Aspartate aminotransferase increased 29/209 (13.9%) 8/211 (3.8%) 0/28 (0%) 37/420 (8.8%)
    Blood alkaline phosphatase increased 18/209 (8.6%) 8/211 (3.8%) 3/28 (10.7%) 29/420 (6.9%)
    Blood creatine phosphokinase increased 8/209 (3.8%) 0/211 (0%) 2/28 (7.1%) 10/420 (2.4%)
    Blood creatinine increased 8/209 (3.8%) 2/211 (0.9%) 2/28 (7.1%) 12/420 (2.9%)
    Blood lactate dehydrogenase increased 8/209 (3.8%) 2/211 (0.9%) 2/28 (7.1%) 12/420 (2.9%)
    Ejection fraction decreased 7/209 (3.3%) 2/211 (0.9%) 3/28 (10.7%) 12/420 (2.9%)
    Gamma-glutamyltransferase increased 6/209 (2.9%) 5/211 (2.4%) 4/28 (14.3%) 14/420 (3.3%)
    Neutrophil count decreased 7/209 (3.3%) 0/211 (0%) 2/28 (7.1%) 9/420 (2.1%)
    Weight decreased 13/209 (6.2%) 19/211 (9%) 0/28 (0%) 32/420 (7.6%)
    Metabolism and nutrition disorders
    Decreased appetite 30/209 (14.4%) 28/211 (13.3%) 5/28 (17.9%) 60/420 (14.3%)
    Hyponatraemia 5/209 (2.4%) 1/211 (0.5%) 2/28 (7.1%) 8/420 (1.9%)
    Musculoskeletal and connective tissue disorders
    Arthralgia 57/209 (27.3%) 68/211 (32.2%) 6/28 (21.4%) 127/420 (30.2%)
    Back pain 30/209 (14.4%) 34/211 (16.1%) 3/28 (10.7%) 67/420 (16%)
    Muscle spasms 19/209 (9.1%) 7/211 (3.3%) 3/28 (10.7%) 29/420 (6.9%)
    Muscular weakness 5/209 (2.4%) 4/211 (1.9%) 2/28 (7.1%) 11/420 (2.6%)
    Musculoskeletal chest pain 14/209 (6.7%) 11/211 (5.2%) 0/28 (0%) 25/420 (6%)
    Musculoskeletal pain 12/209 (5.7%) 19/211 (9%) 1/28 (3.6%) 31/420 (7.4%)
    Myalgia 27/209 (12.9%) 28/211 (13.3%) 3/28 (10.7%) 56/420 (13.3%)
    Pain in extremity 34/209 (16.3%) 38/211 (18%) 3/28 (10.7%) 73/420 (17.4%)
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Melanocytic naevus 2/209 (1%) 16/211 (7.6%) 0/28 (0%) 18/420 (4.3%)
    Seborrhoeic keratosis 12/209 (5.7%) 22/211 (10.4%) 0/28 (0%) 34/420 (8.1%)
    Skin papilloma 6/209 (2.9%) 46/211 (21.8%) 1/28 (3.6%) 52/420 (12.4%)
    Nervous system disorders
    Dizziness 32/209 (15.3%) 15/211 (7.1%) 1/28 (3.6%) 47/420 (11.2%)
    Dysgeusia 6/209 (2.9%) 13/211 (6.2%) 2/28 (7.1%) 21/420 (5%)
    Headache 71/209 (34%) 63/211 (29.9%) 6/28 (21.4%) 138/420 (32.9%)
    Paraesthesia 9/209 (4.3%) 12/211 (5.7%) 1/28 (3.6%) 22/420 (5.2%)
    Psychiatric disorders
    Anxiety 12/209 (5.7%) 6/211 (2.8%) 3/28 (10.7%) 21/420 (5%)
    Depression 9/209 (4.3%) 12/211 (5.7%) 1/28 (3.6%) 22/420 (5.2%)
    Insomnia 11/209 (5.3%) 18/211 (8.5%) 1/28 (3.6%) 30/420 (7.1%)
    Respiratory, thoracic and mediastinal disorders
    Cough 51/209 (24.4%) 46/211 (21.8%) 3/28 (10.7%) 97/420 (23.1%)
    Dyspnoea 16/209 (7.7%) 19/211 (9%) 1/28 (3.6%) 36/420 (8.6%)
    Epistaxis 21/209 (10%) 11/211 (5.2%) 1/28 (3.6%) 33/420 (7.9%)
    Oropharyngeal pain 24/209 (11.5%) 11/211 (5.2%) 0/28 (0%) 35/420 (8.3%)
    Skin and subcutaneous tissue disorders
    Actinic keratosis 12/209 (5.7%) 15/211 (7.1%) 1/28 (3.6%) 27/420 (6.4%)
    Alopecia 19/209 (9.1%) 61/211 (28.9%) 0/28 (0%) 80/420 (19%)
    Dermatitis acneiform 21/209 (10%) 8/211 (3.8%) 0/28 (0%) 29/420 (6.9%)
    Dry skin 30/209 (14.4%) 33/211 (15.6%) 3/28 (10.7%) 65/420 (15.5%)
    Eczema 19/209 (9.1%) 8/211 (3.8%) 2/28 (7.1%) 29/420 (6.9%)
    Erythema 24/209 (11.5%) 16/211 (7.6%) 1/28 (3.6%) 41/420 (9.8%)
    Hair texture abnormal 0/209 (0%) 18/211 (8.5%) 0/28 (0%) 18/420 (4.3%)
    Hyperhidrosis 14/209 (6.7%) 9/211 (4.3%) 1/28 (3.6%) 23/420 (5.5%)
    Hyperkeratosis 18/209 (8.6%) 79/211 (37.4%) 3/28 (10.7%) 97/420 (23.1%)
    Night sweats 12/209 (5.7%) 5/211 (2.4%) 1/28 (3.6%) 17/420 (4%)
    Palmar-plantar erythrodysaesthesia syndrome 11/209 (5.3%) 39/211 (18.5%) 2/28 (7.1%) 50/420 (11.9%)
    Pruritus 28/209 (13.4%) 30/211 (14.2%) 2/28 (7.1%) 59/420 (14%)
    Rash 62/209 (29.7%) 45/211 (21.3%) 3/28 (10.7%) 109/420 (26%)
    Rash maculo-papular 13/209 (6.2%) 8/211 (3.8%) 3/28 (10.7%) 24/420 (5.7%)
    Skin lesion 13/209 (6.2%) 10/211 (4.7%) 0/28 (0%) 23/420 (5.5%)
    Vascular disorders
    Hot flush 8/209 (3.8%) 5/211 (2.4%) 2/28 (7.1%) 15/420 (3.6%)
    Hypertension 51/209 (24.4%) 33/211 (15.6%) 2/28 (7.1%) 85/420 (20.2%)

    Limitations/Caveats

    [Not Specified]

    More Information

    Certain Agreements

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

    GSK agreements may vary with individual investigators, but will not prohibit any investigator from publishing. GSK supports the publication of results from all centers of a multi-center trial but requests that reports based on single-site data not precede the primary publication of the entire clinical trial.

    Results Point of Contact

    Name/Title Study Director
    Organization Novartis Pharmaceuticals
    Phone 862-778-8300
    Email Novartis.email@novartis.com
    Responsible Party:
    Novartis Pharmaceuticals
    ClinicalTrials.gov Identifier:
    NCT01584648
    Other Study ID Numbers:
    • 115306
    • 2011-006087-49
    • CDRB436B2301
    First Posted:
    Apr 25, 2012
    Last Update Posted:
    Feb 17, 2021
    Last Verified:
    Feb 1, 2021