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Investigate Safety, Pharmacokinetics and Pharmacodynamics of GSK2118436 & GSK1120212

This study is ongoing, but not recruiting participants.
Sponsor:
Information provided by (Responsible Party):
GlaxoSmithKline
ClinicalTrials.gov Identifier:
NCT01072175
First received: February 12, 2010
Last updated: September 19, 2013
Last verified: September 2013
Results First Received: June 27, 2013  
Study Type: Interventional
Study Design: Allocation: Non-Randomized;   Endpoint Classification: Pharmacokinetics/Dynamics Study;   Intervention Model: Parallel Assignment;   Masking: Open Label;   Primary Purpose: Treatment
Condition: Cancer
Interventions: Drug: GSK2118436
Drug: GSK1120212

  Participant Flow
  Hide Participant Flow

Recruitment Details
Key information relevant to the recruitment process for the overall study, such as dates of the recruitment period and locations
No text entered.

Pre-Assignment Details
Significant events and approaches for the overall study following participant enrollment, but prior to group assignment
The study was comprised of Parts A, B, and D, which constitute the Phase I part of the study, and Part C, which constitutes the randomized Phase II part of the study. Participants did not enroll in all parts of the study sequentially. Each part of the study was comprised of a separate population of participants.

Reporting Groups
  Description
Part A: Dabrafenib 75 mg + Trametinib 2 mg Participants received a single dose of dabrafenib 75 mg gelatin capsules with repeat dose trametinib (Day 15).
Part B: Dabrafenib 75 mg + Trametinib 1 mg Melanoma BRAF-positive participants who did not receive prior treatment with BRAF inhibitors received dabrafenib 75 mg gelatin capsules BID and trametinib 1 mg tablets QD as continuous daily dosing. Dose escalation decisions were made based on all available pharmacokinetic (PK), safety, and other data from the first 4 evaluable participants, and additional participants were enrolled based on dose-limiting toxicities (DLTs) occurring during the first 3 weeks of treatment.
Part B: Dabrafenib 150 mg + Trametinib 1 mg Melanoma BRAF-positive participants who did not receive prior treatment with BRAF inhibitors and participants who had salivary ductal cancer received dabrafenib 150 mg gelatin capsules BID and trametinib 1 mg tablets QD as continuous daily dosing. Dose escalation decisions were made based on all available PK, safety, and other data from the first 4 evaluable participants and additional participants were enrolled based on DLTs occurring during the first 3 weeks of treatment.
Part B: Dabrafenib 150 mg + Trametinib 1.5 mg Melanoma BRAF-positive participants who did not receive prior treatment with BRAF inhibitors received dabrafenib 150 mg gelatin capsules BID and trametinib 1.5 mg tablets QD as continuous daily dosing. Dose escalation decisions were made based on all available PK, safety, and other data from the first 4 evaluable participants, and additional participants were enrolled based on DLTs occurring during the first 3 weeks of treatment.
Part B: Dabrafenib 150 mg + Trametinib 2 mg Melanoma BRAF-positive participants who received prior treatment with BRAF inhibitors and participants who had colorectal cancer and BRAFi naïve melanoma received dabrafenib 150 mg gelatin capsules BID and trametinib 2 mg tablets QD as continuous daily dosing. Dose escalation did not proceed beyond these doses of dabrafenib and trametinib.
Part C (Randomized): Dabrafenib 150 mg Participants received dabrafenib 150 mg gelatin capsules BID.
Part C (Randomized): Dabrafenib 150 mg + Trametinib 1 mg Participants received dabrafenib 150 mg gelatin capsules BID and trametinib 1 mg tablets QD.
Part C (Randomized): Dabrafenib 150 mg + Trametinib 2 mg Participants received dabrafenib 150 mg gelatin capsules BID and trametinib 2 mg tablets QD.
Part C (Crossover): Dabrafenib 150 mg + Trametinib 2 mg Participants who received dabrafenib 150 mg capsules BID alone in the Randomized Phase were given the opportunity to receive combination dosing of dabrafenib 150 mg gelatin capsules BID and trametinib 2 mg tablets QD upon disease progression with approval of the GlaxoSmithKline (GSK) Medical Monitor.
Part D: Dabrafenib (DAB) 75 mg to DAB 75 mg + Trametinib 2 mg Participants received dabrefinib 75 mg HPMC capsules BID. These participants, after completion of serial PK collection in the first treatment period, were allowed to continue with dabrafenib 75 mg BID and trametinib 2 mg tablets QD as combination dosing starting on Day 29.
Part D: Dabrafenib 150 mg to DAB 150 mg + Trametinib 2 mg Participants received dabrefinib 150 mg HPMC capsules BID. These participants, after completion of serial PK collection in the first treatment period, were allowed to continue with dabrafenib 150 mg BID and trametinib 2 mg tablets QD as combination dosing starting on Day 29.
Part D: Dabrafenib 75 mg + Trametinib 2 mg Participants received dabrefinib 75 mg HPMC capsules BID and trametinib 2 mg tablets QD.
Part D: Dabrafenib 150 mg + Trametinib 2 mg Participants received dabrefinib 150 mg HPMC capsules BID and trametinib 2 mg tablets QD.

Participant Flow for 5 periods

Period 1:   Part A (Drug-Drug Interaction)
    Part A: Dabrafenib 75 mg + Trametinib 2 mg     Part B: Dabrafenib 75 mg + Trametinib 1 mg     Part B: Dabrafenib 150 mg + Trametinib 1 mg     Part B: Dabrafenib 150 mg + Trametinib 1.5 mg     Part B: Dabrafenib 150 mg + Trametinib 2 mg     Part C (Randomized): Dabrafenib 150 mg     Part C (Randomized): Dabrafenib 150 mg + Trametinib 1 mg     Part C (Randomized): Dabrafenib 150 mg + Trametinib 2 mg     Part C (Crossover): Dabrafenib 150 mg + Trametinib 2 mg     Part D: Dabrafenib (DAB) 75 mg to DAB 75 mg + Trametinib 2 mg     Part D: Dabrafenib 150 mg to DAB 150 mg + Trametinib 2 mg     Part D: Dabrafenib 75 mg + Trametinib 2 mg     Part D: Dabrafenib 150 mg + Trametinib 2 mg  
STARTED     8     0     0     0     0     0     0     0     0     0     0     0     0  
COMPLETED     0     0     0     0     0     0     0     0     0     0     0     0     0  
NOT COMPLETED     8     0     0     0     0     0     0     0     0     0     0     0     0  
Physician Decision                 6                 0                 0                 0                 0                 0                 0                 0                 0                 0                 0                 0                 0  
Withdrawal by Subject                 1                 0                 0                 0                 0                 0                 0                 0                 0                 0                 0                 0                 0  
Death                 1                 0                 0                 0                 0                 0                 0                 0                 0                 0                 0                 0                 0  

Period 2:   Part B (Dose Escalation and Expansion)
    Part A: Dabrafenib 75 mg + Trametinib 2 mg     Part B: Dabrafenib 75 mg + Trametinib 1 mg     Part B: Dabrafenib 150 mg + Trametinib 1 mg     Part B: Dabrafenib 150 mg + Trametinib 1.5 mg     Part B: Dabrafenib 150 mg + Trametinib 2 mg     Part C (Randomized): Dabrafenib 150 mg     Part C (Randomized): Dabrafenib 150 mg + Trametinib 1 mg     Part C (Randomized): Dabrafenib 150 mg + Trametinib 2 mg     Part C (Crossover): Dabrafenib 150 mg + Trametinib 2 mg     Part D: Dabrafenib (DAB) 75 mg to DAB 75 mg + Trametinib 2 mg     Part D: Dabrafenib 150 mg to DAB 150 mg + Trametinib 2 mg     Part D: Dabrafenib 75 mg + Trametinib 2 mg     Part D: Dabrafenib 150 mg + Trametinib 2 mg  
STARTED     0     6     23     27     79     0     0     0     0     0     0     0     0  
Ongoing     0     2     10     9     28     0     0     0     0     0     0     0     0  
COMPLETED     0     0     0     0     0     0     0     0     0     0     0     0     0  
NOT COMPLETED     0     6     23     27     79     0     0     0     0     0     0     0     0  
Physician Decision                 0                 1                 3                 4                 13                 0                 0                 0                 0                 0                 0                 0                 0  
Withdrawal by Subject                 0                 0                 0                 2                 2                 0                 0                 0                 0                 0                 0                 0                 0  
Death                 0                 3                 10                 12                 36                 0                 0                 0                 0                 0                 0                 0                 0  
Ongoing                 0                 2                 10                 9                 28                 0                 0                 0                 0                 0                 0                 0                 0  

Period 3:   Part C (Phase II: Randomized Phase)
    Part A: Dabrafenib 75 mg + Trametinib 2 mg     Part B: Dabrafenib 75 mg + Trametinib 1 mg     Part B: Dabrafenib 150 mg + Trametinib 1 mg     Part B: Dabrafenib 150 mg + Trametinib 1.5 mg     Part B: Dabrafenib 150 mg + Trametinib 2 mg     Part C (Randomized): Dabrafenib 150 mg     Part C (Randomized): Dabrafenib 150 mg + Trametinib 1 mg     Part C (Randomized): Dabrafenib 150 mg + Trametinib 2 mg     Part C (Crossover): Dabrafenib 150 mg + Trametinib 2 mg     Part D: Dabrafenib (DAB) 75 mg to DAB 75 mg + Trametinib 2 mg     Part D: Dabrafenib 150 mg to DAB 150 mg + Trametinib 2 mg     Part D: Dabrafenib 75 mg + Trametinib 2 mg     Part D: Dabrafenib 150 mg + Trametinib 2 mg  
STARTED     0     0     0     0     0     54     54     54     0     0     0     0     0  
Ongoing     0     0     0     0     0     35     32     40     0     0     0     0     0  
COMPLETED     0     0     0     0     0     0     0     0     0     0     0     0     0  
NOT COMPLETED     0     0     0     0     0     54     54     54     0     0     0     0     0  
Withdrawal by Subject                 0                 0                 0                 0                 0                 0                 4                 0                 0                 0                 0                 0                 0  
Death                 0                 0                 0                 0                 0                 19                 18                 14                 0                 0                 0                 0                 0  
Ongoing                 0                 0                 0                 0                 0                 35                 32                 40                 0                 0                 0                 0                 0  

Period 4:   Part C (Phase II: Crossover Phase [CP])
    Part A: Dabrafenib 75 mg + Trametinib 2 mg     Part B: Dabrafenib 75 mg + Trametinib 1 mg     Part B: Dabrafenib 150 mg + Trametinib 1 mg     Part B: Dabrafenib 150 mg + Trametinib 1.5 mg     Part B: Dabrafenib 150 mg + Trametinib 2 mg     Part C (Randomized): Dabrafenib 150 mg     Part C (Randomized): Dabrafenib 150 mg + Trametinib 1 mg     Part C (Randomized): Dabrafenib 150 mg + Trametinib 2 mg     Part C (Crossover): Dabrafenib 150 mg + Trametinib 2 mg     Part D: Dabrafenib (DAB) 75 mg to DAB 75 mg + Trametinib 2 mg     Part D: Dabrafenib 150 mg to DAB 150 mg + Trametinib 2 mg     Part D: Dabrafenib 75 mg + Trametinib 2 mg     Part D: Dabrafenib 150 mg + Trametinib 2 mg  
STARTED     0     0     0     0     0     0     0     0     43     0     0     0     0  
Ongoing     0     0     0     0     0     0     0     0     28     0     0     0     0  
COMPLETED     0     0     0     0     0     0     0     0     0     0     0     0     0  
NOT COMPLETED     0     0     0     0     0     0     0     0     43     0     0     0     0  
Death                 0                 0                 0                 0                 0                 0                 0                 0                 15                 0                 0                 0                 0  
Ongoing                 0                 0                 0                 0                 0                 0                 0                 0                 28                 0                 0                 0                 0  

Period 5:   Part D (HPMC Capsules)
    Part A: Dabrafenib 75 mg + Trametinib 2 mg     Part B: Dabrafenib 75 mg + Trametinib 1 mg     Part B: Dabrafenib 150 mg + Trametinib 1 mg     Part B: Dabrafenib 150 mg + Trametinib 1.5 mg     Part B: Dabrafenib 150 mg + Trametinib 2 mg     Part C (Randomized): Dabrafenib 150 mg     Part C (Randomized): Dabrafenib 150 mg + Trametinib 1 mg     Part C (Randomized): Dabrafenib 150 mg + Trametinib 2 mg     Part C (Crossover): Dabrafenib 150 mg + Trametinib 2 mg     Part D: Dabrafenib (DAB) 75 mg to DAB 75 mg + Trametinib 2 mg     Part D: Dabrafenib 150 mg to DAB 150 mg + Trametinib 2 mg     Part D: Dabrafenib 75 mg + Trametinib 2 mg     Part D: Dabrafenib 150 mg + Trametinib 2 mg  
STARTED     0     0     0     0     0     0     0     0     0     12     16     43     39  
Ongoing     0     0     0     0     0     0     0     0     0     10     12     34     34  
COMPLETED     0     0     0     0     0     0     0     0     0     0     0     0     0  
NOT COMPLETED     0     0     0     0     0     0     0     0     0     12     16     43     39  
Lost to Follow-up                 0                 0                 0                 0                 0                 0                 0                 0                 0                 0                 0                 2                 0  
Withdrawal by Subject                 0                 0                 0                 0                 0                 0                 0                 0                 0                 0                 0                 1                 0  
Death                 0                 0                 0                 0                 0                 0                 0                 0                 0                 2                 4                 6                 5  
Ongoing                 0                 0                 0                 0                 0                 0                 0                 0                 0                 10                 12                 34                 34  



  Baseline Characteristics
  Hide Baseline Characteristics

Population Description
Explanation of how the number of participants for analysis was determined. Includes whether analysis was per protocol, intention to treat, or another method. Also provides relevant details such as imputation technique, as appropriate.
No text entered.

Reporting Groups
  Description
Part A: Dabrafenib 75 mg + Trametinib 2 mg Participants received a single dose of dabrafenib 75 mg gelatin capsules with repeat dose trametinib (Day 15).
Part B: Dabrafenib 75 mg + Trametinib 1 mg Melanoma BRAF-positive participants who did not receive prior treatment with BRAF inhibitors received dabrafenib 75 mg gelatin capsules BID and trametinib 1 mg tablets QD as continuous daily dosing. Dose escalation decisions were made based on all available pharmacokinetic (PK), safety, and other data from the first 4 evaluable participants, and additional participants were enrolled based on dose-limiting toxicities (DLTs) occurring during the first 3 weeks of treatment.
Part B: Dabrafenib 150 mg + Trametinib 1 mg Melanoma BRAF-positive participants who did not receive prior treatment with BRAF inhibitors and participants who had salivary ductal cancer received dabrafenib 150 mg gelatin capsules BID and trametinib 1 mg tablets QD as continuous daily dosing. Dose escalation decisions were made based on all available PK, safety, and other data from the first 4 evaluable participants and additional participants were enrolled based on DLTs occurring during the first 3 weeks of treatment.
Part B: Dabrafenib 150 mg + Trametinib 1.5 mg Melanoma BRAF-positive participants who did not receive prior treatment with BRAF inhibitors received dabrafenib 150 mg gelatin capsules BID and trametinib 1.5 mg tablets QD as continuous daily dosing. Dose escalation decisions were made based on all available PK, safety, and other data from the first 4 evaluable participants, and additional participants were enrolled based on DLTs occurring during the first 3 weeks of treatment.
Part B: Dabrafenib 150 mg + Trametinib 2 mg Melanoma BRAF-positive participants who received prior treatment with BRAF inhibitors and participants who had colorectal cancer and BRAFi naïve melanoma received dabrafenib 150 mg gelatin capsules BID and trametinib 2 mg tablets QD as continuous daily dosing. Dose escalation did not proceed beyond these doses of dabrafenib and trametinib.
Part C: Dabrafenib 150 mg Participants received dabrafenib 150 mg gelatin capsules BID.
Part C: Dabrafenib 150 mg + Trametinib 1 mg Participants received dabrafenib 150 mg gelatin capsules BID and trametinib 1 mg tablets QD.
Part C: Dabrafenib 150 mg + Trametinib 2 mg Participants received dabrafenib 150 mg gelatin capsules BID and trametinib 2 mg tablets QD.
Part D: Dabrafenib (DAB) 75 mg to DAB 75 mg + Trametinib 2 mg Participants received dabrefinib 75 mg HPMC capsules BID. These participants, after completion of serial PK collection in the first treatment period, were allowed to continue with dabrafenib 75 mg BID and trametinib 2 mg tablets QD as combination dosing starting on Day 29.
Part D: Dabrafenib 150 mg to DAB 150 mg + Trametinib 2 mg Participants received dabrefinib 150 mg HPMC capsules BID. These participants, after completion of serial PK collection in the first treatment period, were allowed to continue with dabrafenib 150 mg BID and trametinib 2 mg tablets QD as combination dosing starting on Day 29.
Part D: Dabrafenib 75 mg + Trametinib 2 mg Participants received dabrefinib 75 mg HPMC capsules BID and trametinib 2 mg tablets QD.
Part D: Dabrafenib 150 mg + Trametinib 2 mg Participants received dabrefinib 150 mg HPMC capsules BID and trametinib 2 mg tablets QD.
Total Total of all reporting groups

Baseline Measures
    Part A: Dabrafenib 75 mg + Trametinib 2 mg     Part B: Dabrafenib 75 mg + Trametinib 1 mg     Part B: Dabrafenib 150 mg + Trametinib 1 mg     Part B: Dabrafenib 150 mg + Trametinib 1.5 mg     Part B: Dabrafenib 150 mg + Trametinib 2 mg     Part C: Dabrafenib 150 mg     Part C: Dabrafenib 150 mg + Trametinib 1 mg     Part C: Dabrafenib 150 mg + Trametinib 2 mg     Part D: Dabrafenib (DAB) 75 mg to DAB 75 mg + Trametinib 2 mg     Part D: Dabrafenib 150 mg to DAB 150 mg + Trametinib 2 mg     Part D: Dabrafenib 75 mg + Trametinib 2 mg     Part D: Dabrafenib 150 mg + Trametinib 2 mg     Total  
Number of Participants  
[units: participants]
  8     6     23     27     79     54     54     54     12     16     43     39     415  
Age  
[units: Years]
Mean ± Standard Deviation
  52.8  ± 16.04     48.2  ± 7.28     54.2  ± 13.24     52.2  ± 12.09     51.5  ± 12.82     51.8  ± 15.19     49.9  ± 14.70     55.9  ± 11.85     51.8  ± 12.39     53.1  ± 17.04     52.8  ± 14.57     56.7  ± 14.08     52.8  ± 13.74  
Gender  
[units: Participants]
                         
Female     2     2     10     12     44     25     24     20     6     8     18     14     185  
Male     6     4     13     15     35     29     30     34     6     8     25     25     230  
Race/Ethnicity, Customized  
[units: Participants]
                         
White     7     6     22     26     77     52     54     53     12     16     43     39     407  
Asian & White     1     0     0     0     0     0     0     0     0     0     0     0     1  
African American     0     0     0     1     0     0     0     0     0     0     0     0     1  
Asian     0     0     0     0     2     0     0     1     0     0     0     0     3  
Missing     0     0     1     0     0     2     0     0     0     0     0     0     3  



  Outcome Measures
  Show All Outcome Measures

1.  Primary:   Maximum Plasma Concentration (Cmax) of a Single Dose of Dabrafenib Administered Alone and in Combination With Trametnib in Part A   [ Time Frame: Day 15 ]

2.  Primary:   AUC (0-t) and AUC (0-inf) of Dabrafenib and Its Metabolites in Part A   [ Time Frame: Day 15 ]

3.  Primary:   Number of Participants With Any Adverse Event (AE) or Serious Adverse Event (SAE) in Part B   [ Time Frame: From Baseline (Day 1) until Follow-up visit (up to approximately 103 weeks ) ]

4.  Primary:   Number of Participants With the Indicated Worst-case Grade (G) Change From Baseline in the Indicated Clinical Chemistry Parameters in Part B   [ Time Frame: From Baseline (Day 1) until Follow-up visit (up to approximately 103 weeks) ]

5.  Primary:   Number of Participants With the Indicated Worst-case Grade Change From Baseline in the Indicated Hematology Parameters in Part B   [ Time Frame: From Baseline (Day 1) until Follow-up visit (up to approximately 103 weeks) ]

6.  Primary:   Number of Participants With the Indicated Worst-case Change From Baseline in Heart Rate and Blood Pressure in Part B   [ Time Frame: From Baseline (Day 1) until Follow-up visit (up to approximately 103 weeks) ]

7.  Primary:   Number of Participants With BRAF Mutant Metastatic Melanoma With Best Overall Response as Assessed by the Investigator in Part C (Randomized)   [ Time Frame: From the first dose of study medication to the first documented evidence of a confirmed complete response or partial response (up to approximately 47 weeks) ]

8.  Primary:   Number of Participants With BRAF Mutant Metastatic Melanoma With Best Overall Response Assessed by Blinded Independent Central Review (BICR) in Part C (Randomized)   [ Time Frame: From the first dose of study medication to the first documented evidence of a confirmed complete response or partial response (up to approximately 36 weeks) ]

9.  Primary:   Number of Participants With BRAF Mutant Metastatic Melanoma With Best Overall Response as Assessed by the Investigator in Part C (Crossover)   [ Time Frame: From the first dose of study medication to the first documented evidence of a confirmed complete response or partial response (up to approximately 15 weeks) ]

10.  Primary:   Duration of Response as Assessed by the Investigator and Blinded Independent Central Review (BICR) in Part C (Randomized)   [ Time Frame: First documented evidence of PR or CR until the date of the first documented sign of disease progression or the date of death due to any cause (up to approximately 17 months) ]

11.  Primary:   Progression-free Survival (PFS) as Assessed by the Investigator in Part C (Randomized)   [ Time Frame: From the first dose of study medication to the earliest date of disease progression (PD) or death due to any cause (up to approximately 17 months) ]

12.  Primary:   Progression-free Survival (PFS) as Assessed by the Blinded Independent Central Review (BICR) in Part C (Randomized)   [ Time Frame: From the first dose of study medication to the earliest date of disease progression (PD) or death due to any cause (up to approximately 17 months) ]

13.  Primary:   Progression-free Survival (PFS) as Assessed by the Investigator in Part C (Crossover)   [ Time Frame: From the first dose of study medication to the earliest date of disease progression (PD) or death due to any cause (up to approximately 9 months) ]

14.  Primary:   Number of Participants With Any Adverse Event (AE) or Serious Adverse Event (SAE) in Part C (Randomized)   [ Time Frame: From Baseline (Day 1) until Follow-up visit (up to approximatley 75 weeks) ]

15.  Primary:   Number of Participants With the Indicated Worst-case Grade (G) Change From Baseline in the Indicated Clinical Chemistry Parameters in Part C (Randomized)   [ Time Frame: From Baseline (Day 1) until Follow-up visit (up to approximately 75 weeks) ]

16.  Primary:   Number of Participants With the Indicated Worst-case Grade Change From Baseline in the Indicated Hematology Parameters in Part C (Randomized)   [ Time Frame: From Baseline (Day 1) until Follow-up visit (up to approximately 75 weeks) ]

17.  Primary:   Number of Participants With the Indicated Worst-case Change From Baseline in Heart Rate and Blood Pressure in Part C (Randomized)   [ Time Frame: From Baseline (Day 1) until Follow-up visit (up to approximlately 75 weeks) ]

18.  Primary:   Maximum Plasma Concentration (Cmax) of a Single and Repeat Dose of Dabrafenib Alone and in Combination With Trametinib in Part D (Analyte=GSK2118436)   [ Time Frame: Day 1 and Day 21 ]

19.  Primary:   The Tmax of a Single and Repeat Dose of Dabrafenib Alone and in Combination With Trametinib in Part D (Analyte=GSK2118436)   [ Time Frame: Day 1 and Day 21 ]

20.  Primary:   AUC (0-tau) and AUC (0-inf) of Single and Repeat Doses of Dabrafenib Alone and in Combination With Trametinib in Part D (Analyte=GSK2118436)   [ Time Frame: Day 1 and Day 21 ]

21.  Primary:   Number of Participants With Any Adverse Event (AE) or Serious Adverse Event (SAE) in Part D   [ Time Frame: From Baseline (Day 1) until Follow-up visit (up to approximately 61 weeks) ]

22.  Primary:   Number of Participants With the Indicated Worst-case Grade (G) Change From Baseline in the Indicated Clinical Chemistry Parameters in Part D   [ Time Frame: From Baseline (Day 1) until Follow-up visit (up to approximately 61 weeks) ]

23.  Primary:   Number of Participants With the Indicated Worst-case Grade Change From Baseline in the Indicated Hematology Parameters in Part D   [ Time Frame: From Baseline (Day 1) until Follow-up visit (up to approximately 61 weeks) ]

24.  Primary:   Number of Participants With the Indicated Worst-case Change From Baseline in Heart Rate and Blood Pressure in Part D   [ Time Frame: From Baseline (Day 1) until Follow-up visit (up to approximately 61 weeks) ]

25.  Secondary:   Steady State Concentration of Trametinib With Concomitant Administration of Dabrafenib in Part A   [ Time Frame: Day 15 and Day 16 ]

26.  Secondary:   The AUC [0-tau] of Dabrafenib (DAB) and Its Metabolite in Combination With Trametinib (T) in Part B   [ Time Frame: Day 15 and Day 21 ]

27.  Secondary:   Pre-dose (Trough) Concentration at the End of the Dosing Interval (Ctau) and Maximum Plasma Concentration (Cmax) of Dabrafenib and Its Metabolite in Combination With Trametinib in Part B   [ Time Frame: Day 15 and Day 21 ]

28.  Secondary:   The Tmax of Dabrafenib and Its Metabolite in Combination With Trametinib in Part B   [ Time Frame: Day 15 and Day 21 ]

29.  Secondary:   The AUC (0-tau) Assessment of Trametinib in Combination With Dabrafenib in Part B (Analyte=GSK1120212)   [ Time Frame: Day 15 and Day 21 ]

30.  Secondary:   The Ctau and Cmax Assessments of Trametinib in Combination With Dabrafenib in Part B (Analyte=GSK1120212)   [ Time Frame: Day 15 and Day 21 ]

31.  Secondary:   The Tmax Assessment of Trametinib in Combination With Dabrafenib in Part B (Analyte=GSK1120212)   [ Time Frame: Day 15 and Day 21 ]

32.  Secondary:   Number of Participants With BRAFi-naïve Mutant Metastatic Melanoma With the Best Overall Response as Assessed by Investigator in Part B   [ Time Frame: From the first dose of study medication to the first documented evidence of a confirmed complete response or partial response (up to 103 weeks) ]

33.  Secondary:   Duration of Response as Assessed by the Investigator in Participants With BRAFi-naïve Mutant Metastatic Melanoma in Part B   [ Time Frame: First documented evidence of PR or CR until the earlier of date of disease progression or date of death due to any cause (up to approximately 22 months) ]

34.  Secondary:   Progression-free Survival (PFS) as Assessed by the Investigator in Participants With BRAFi-naïve Mutant Metastatic Melanoma in Part B   [ Time Frame: From the date of first dose to the earliest date of disease progression (PD) or death due to any cause (up to approximately 22 months) ]

35.  Secondary:   Overall Survival (OS) in Part B BRAFi Naïve Melanoma Participants   [ Time Frame: From the date of first dose until date of death due to any cause (up to approximately 22 months) ]

36.  Secondary:   Overall Survival (OS) in Part C   [ Time Frame: From the date of randomization until date of death due to any cause (up to approximately 17 months) ]

37.  Secondary:   Plasma Concentrations of Dabrafenib and Its Metabolites in Part C   [ Time Frame: Day 15, Week 8, Week 16, Week 24, Week 32, Week 40, Week 48, and Week 56 ]

38.  Secondary:   Plasma Concentrations of Trametinib in Part C   [ Time Frame: Day 15, Week 8, Week 16, Week 24, Week 32, Week 40, Week 48, and Week 56 ]

39.  Secondary:   Oral Clearance (CL/F) of Dabrafenib and Trametinib   [ Time Frame: Day 15, Week 8, Week 16, Week 24, Week 32, Week 40, and Week 48 ]

40.  Secondary:   Oral Volume of Distribution (V/F) of Dabrafenib and Trametinib   [ Time Frame: Day 15, Week 8, Week 16, Week 24, Week 32, Week 40, and Week 48 ]

41.  Secondary:   Cmax of Dabrafenib Metabolites in Part D   [ Time Frame: Day 1: pre-dose, and 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, and 24 hours post dose. Day 21: pre-dose and 0.5, 1, 1.5, 2, 3, 4, 6, 8, and 10 hours post-dose ]

42.  Secondary:   The Tmax of Dabrafenib Metabolites in Part D   [ Time Frame: Day 1: pre-dose, and 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, and 24 hours post dose. Day 21: pre-dose and 0.5, 1, 1.5, 2, 3, 4, 6, 8, and 10 hours post-dose ]

43.  Secondary:   Area Under the Concentration-time Curve (AUC) of Dabrafenib Metabolites in Part D   [ Time Frame: Day 1: pre-dose, and 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, and 24 hours post dose. Day 21: pre-dose and 0.5, 1, 1.5, 2, 3, 4, 6, 8, and 10 hours post-dose ]

44.  Secondary:   The Cmax Assessment of Trametinib in Part D   [ Time Frame: Day 1: pre-dose, and 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, and 24 hours post dose. Day 21: pre-dose and 0.5, 1, 1.5, 2, 3, 4, 6, 8, and 10 hours post-dose ]

45.  Secondary:   The Tmax Assessment of Trametinib in Part D   [ Time Frame: Day 1: pre-dose, and 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, and 24 hours post dose. Day 21: pre-dose and 0.5, 1, 1.5, 2, 3, 4, 6, 8, and 10 hours post-dose ]

46.  Secondary:   Area Under the Concentration-time Curve Assessment of Trametinib in Part D   [ Time Frame: Day 1: pre-dose, and 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, and 24 hours post dose. Day 21: pre-dose and 0.5, 1, 1.5, 2, 3, 4, 6, 8, and 10 hours post-dose ]

47.  Secondary:   Number of Participants With the Best Overall Response as Assessed by the Investigator in Participants in Part D   [ Time Frame: From the date of first dose of study medication to the first documented evidence of a confirmed complete response or partial response (up to approximately 280 days ) ]

48.  Secondary:   Duration of Response as Assessed by the Investigator in Part D   [ Time Frame: First documented evidence of PR or CR until the earlier of date of disease progression or date of death due to any cause (up to approximately 13 months) ]

49.  Secondary:   Progression-free Survival (PFS) as Assessed by the Investigator in Part D   [ Time Frame: From the date of randomization to the earliest date of disease progression (PD) or death due to any cause (up to approximately 13 months) ]

50.  Secondary:   Change From Baseline in p-ERK and Other Biomarkers in Tumor Biopsies in Participants With BRAF Mutant Colorectal Cancer in Part B   [ Time Frame: Screening and at disease progression (up to approximately 8 months) ]
Results not yet reported.   Anticipated Reporting Date:   06/2014   Safety Issue:   No

51.  Secondary:   Overall Survival in Part D   [ Time Frame: From the date of first dose until date of death due to any cause (up to approximately 14 months) ]
Results not yet reported.   Anticipated Reporting Date:   10/2014   Safety Issue:   No


  Serious Adverse Events


  Other Adverse Events
  Hide Other Adverse Events

Time Frame Serious adverse events (SAEs) and non-serious AEs were collected from Baseline (Day 1) until Follow-up visit (up to approximately 103 weeks).
Additional Description SAEs and non-serious Aes were collected in the All Treated Population which was based on the actual treatment received. For Part D, 3 participants received treatment that differed from the randomized treatment. For Part C: 1 participant received treatment that differed from the randomized treatment.

Frequency Threshold
Threshold above which other adverse events are reported   5%  

Reporting Groups
  Description
Part A: Dabrafenib 75 mg + Trametinib 2 mg Participants received a single dose of dabrafenib 75 mg gelatin capsules with repeat dose trametinib (Day 15).
Part B: Dabrafenib 75 mg + Trametinib 1 mg Melanoma BRAF-positive participants who did not receive prior treatment with BRAF inhibitors received dabrafenib 75 mg gelatin capsules BID and trametinib 1 mg tablets QD as continuous daily dosing. Dose escalation decisions were made based on all available pharmacokinetic (PK), safety, and other data from the first 4 evaluable participants, and additional participants were enrolled based on dose-limiting toxicities (DLTs) occurring during the first 3 weeks of treatment.
Part B: Dabrafenib 150 mg + Trametinib 1 mg Melanoma BRAF-positive participants who did not receive prior treatment with BRAF inhibitors and participants who had salivary ductal cancer received dabrafenib 150 mg gelatin capsules BID and trametinib 1 mg tablets QD as continuous daily dosing. Dose escalation decisions were made based on all available PK, safety, and other data from the first 4 evaluable participants and additional participants were enrolled based on DLTs occurring during the first 3 weeks of treatment.
Part B: Dabrafenib 150 mg + Trametinib 1.5 mg Melanoma BRAF-positive participants who did not receive prior treatment with BRAF inhibitors received dabrafenib 150 mg gelatin capsules BID and trametinib 1.5 mg tablets QD as continuous daily dosing. Dose escalation decisions were made based on all available PK, safety, and other data from the first 4 evaluable participants, and additional participants were enrolled based on DLTs occurring during the first 3 weeks of treatment.
Part B: Dabrafenib 150 mg + Trametinib 2 mg Melanoma BRAF-positive participants who received prior treatment with BRAF inhibitors and participants who had colorectal cancer and BRAFi naïve melanoma received dabrafenib 150 mg gelatin capsules BID and trametinib 2 mg tablets QD as continuous daily dosing. Dose escalation did not proceed beyond these doses of dabrafenib and trametinib.
Part C: Dabrafenib 150 mg Participants received dabrafenib 150 mg gelatin capsules BID.
Part C (Crossover): Dabrafenib 150 mg + Trametinib 2 mg Participants who received dabrafenib 150 mg capsules BID alone in the Randomized Phase were given the opportunity to receive combination dosing of dabrafenib 150 mg gelatin capsules BID and trametinib 2 mg tablets QD upon disease progression with approval of the GlaxoSmithKline (GSK) Medical Monitor.
Part C: Dabrafenib 150 mg + Trametinib 1 mg Participants received dabrafenib 150 mg gelatin capsules BID and trametinib 1 mg tablets QD.
Part C: Dabrafenib 150 mg + Trametinib 2 mg Participants received dabrafenib 150 mg gelatin capsules BID and trametinib 2 mg tablets QD.
Part D: Dabrafenib (DAB) 75 mg to DAB 75 mg + Trametinib 2 mg Participants received dabrefinib 75 mg HPMC capsules BID. These participants, after completion of serial PK collection in the first treatment period, were allowed to continue with dabrafenib 75 mg BID and trametinib 2 mg tablets QD as combination dosing starting on Day 29.
Part D: Dabrafenib 150 mg to DAB 150 mg + Trametinib 2 mg Participants received dabrefinib 150 mg HPMC capsules BID. These participants, after completion of serial PK collection in the first treatment period, were allowed to continue with dabrafenib 150 mg BID and trametinib 2 mg tablets QD as combination dosing starting on Day 29.
Part D: Dabrafenib 75 mg + Trametinib 2 mg Participants received dabrefinib 75 mg HPMC capsules BID and trametinib 2 mg tablets QD.
Part D: Dabrafenib 150 mg + Trametinib 2 mg Participants received dabrefinib 150 mg HPMC capsules BID and trametinib 2 mg tablets QD.

Other Adverse Events
    Part A: Dabrafenib 75 mg + Trametinib 2 mg     Part B: Dabrafenib 75 mg + Trametinib 1 mg     Part B: Dabrafenib 150 mg + Trametinib 1 mg     Part B: Dabrafenib 150 mg + Trametinib 1.5 mg     Part B: Dabrafenib 150 mg + Trametinib 2 mg     Part C: Dabrafenib 150 mg     Part C (Crossover): Dabrafenib 150 mg + Trametinib 2 mg     Part C: Dabrafenib 150 mg + Trametinib 1 mg     Part C: Dabrafenib 150 mg + Trametinib 2 mg     Part D: Dabrafenib (DAB) 75 mg to DAB 75 mg + Trametinib 2 mg     Part D: Dabrafenib 150 mg to DAB 150 mg + Trametinib 2 mg     Part D: Dabrafenib 75 mg + Trametinib 2 mg     Part D: Dabrafenib 150 mg + Trametinib 2 mg  
Total, other (not including serious) adverse events                            
# participants affected / at risk     8/8     6/6     23/23     27/27     76/79     53/53     40/43     53/54     55/55     15/15     15/15     41/41     37/39  
Blood and lymphatic system disorders                            
Anaemia † 1                          
# participants affected / at risk     1/8 (12.50%)     0/6 (0.00%)     4/23 (17.39%)     2/27 (7.41%)     15/79 (18.99%)     2/53 (3.77%)     6/43 (13.95%)     9/54 (16.67%)     7/55 (12.73%)     0/15 (0.00%)     6/15 (40.00%)     6/41 (14.63%)     7/39 (17.95%)  
Neutropenia † 1                          
# participants affected / at risk     0/8 (0.00%)     0/6 (0.00%)     2/23 (8.70%)     4/27 (14.81%)     8/79 (10.13%)     1/53 (1.89%)     1/43 (2.33%)     5/54 (9.26%)     8/55 (14.55%)     0/15 (0.00%)     2/15 (13.33%)     3/41 (7.32%)     3/39 (7.69%)  
Leukopenia † 1                          
# participants affected / at risk     1/8 (12.50%)     0/6 (0.00%)     4/23 (17.39%)     2/27 (7.41%)     6/79 (7.59%)     2/53 (3.77%)     2/43 (4.65%)     1/54 (1.85%)     2/55 (3.64%)     0/15 (0.00%)     0/15 (0.00%)     1/41 (2.44%)     1/39 (2.56%)  
Thrombocytopenia † 1                          
# participants affected / at risk     0/8 (0.00%)     1/6 (16.67%)     0/23 (0.00%)     3/27 (11.11%)     7/79 (8.86%)     0/53 (0.00%)     0/43 (0.00%)     2/54 (3.70%)     3/55 (5.45%)     0/15 (0.00%)     0/15 (0.00%)     0/41 (0.00%)     1/39 (2.56%)  
Lymphopenia † 1                          
# participants affected / at risk     0/8 (0.00%)     0/6 (0.00%)     1/23 (4.35%)     0/27 (0.00%)     3/79 (3.80%)     1/53 (1.89%)     0/43 (0.00%)     0/54 (0.00%)     3/55 (5.45%)     0/15 (0.00%)     0/15 (0.00%)     3/41 (7.32%)     1/39 (2.56%)  
Lymphadenopathy † 1                          
# participants affected / at risk     1/8 (12.50%)     1/6 (16.67%)     0/23 (0.00%)     0/27 (0.00%)     0/79 (0.00%)     1/53 (1.89%)     0/43 (0.00%)     0/54 (0.00%)     0/55 (0.00%)     0/15 (0.00%)     1/15 (6.67%)     0/41 (0.00%)     0/39 (0.00%)  
Lymph node pain † 1                          
# participants affected / at risk     1/8 (12.50%)     0/6 (0.00%)     0/23 (0.00%)     0/27 (0.00%)     0/79 (0.00%)     0/53 (0.00%)     0/43 (0.00%)     0/54 (0.00%)     0/55 (0.00%)     0/15 (0.00%)     0/15 (0.00%)     0/41 (0.00%)     0/39 (0.00%)  
Cardiac disorders                            
Tachycardia † 1                          
# participants affected / at risk     1/8 (12.50%)     1/6 (16.67%)     1/23 (4.35%)     2/27 (7.41%)     6/79 (7.59%)     0/53 (0.00%)     0/43 (0.00%)     1/54 (1.85%)     3/55 (5.45%)     0/15 (0.00%)     0/15 (0.00%)     1/41 (2.44%)     1/39 (2.56%)  
Palpitations † 1                          
# participants affected / at risk     0/8 (0.00%)     1/6 (16.67%)     0/23 (0.00%)     0/27 (0.00%)     0/79 (0.00%)     3/53 (5.66%)     1/43 (2.33%)     3/54 (5.56%)     1/55 (1.82%)     0/15 (0.00%)     0/15 (0.00%)     1/41 (2.44%)     1/39 (2.56%)  
Intracardiac mass † 1                          
# participants affected / at risk     0/8 (0.00%)     0/6 (0.00%)     0/23 (0.00%)     0/27 (0.00%)     0/79 (0.00%)     0/53 (0.00%)     0/43 (0.00%)     0/54 (0.00%)     0/55 (0.00%)     0/15 (0.00%)     1/15 (6.67%)     0/41 (0.00%)     0/39 (0.00%)  
Congenital, familial and genetic disorders                            
Dermoid cyst † 1                          
# participants affected / at risk     0/8 (0.00%)     1/6 (16.67%)     0/23 (0.00%)     0/27 (0.00%)     0/79 (0.00%)     0/53 (0.00%)     0/43 (0.00%)     0/54 (0.00%)     0/55 (0.00%)     0/15 (0.00%)     0/15 (0.00%)     0/41 (0.00%)     0/39 (0.00%)  
Ear and labyrinth disorders                            
Ear pain † 1                          
# participants affected / at risk     0/8 (0.00%)     1/6 (16.67%)     0/23 (0.00%)     1/27 (3.70%)     2/79 (2.53%)     0/53 (0.00%)     0/43 (0.00%)     0/54 (0.00%)     1/55 (1.82%)     0/15 (0.00%)     0/15 (0.00%)     0/41 (0.00%)     0/39 (0.00%)  
Endocrine disorders                            
Hypothyroidism † 1                          
# participants affected / at risk     1/8 (12.50%)     0/6 (0.00%)     0/23 (0.00%)     0/27 (0.00%)     3/79 (3.80%)     0/53 (0.00%)     0/43 (0.00%)     0/54 (0.00%)     1/55 (1.82%)     0/15 (0.00%)     0/15 (0.00%)     1/41 (2.44%)     0/39 (0.00%)  
Eye disorders                            
Vision blurred † 1                          
# participants affected / at risk     1/8 (12.50%)     0/6 (0.00%)     3/23 (13.04%)     2/27 (7.41%)     3/79 (3.80%)     4/53 (7.55%)     0/43 (0.00%)     5/54 (9.26%)     5/55 (9.09%)     1/15 (6.67%)     2/15 (13.33%)     4/41 (9.76%)     3/39 (7.69%)  
Visual impairment † 1                          
# participants affected / at risk     1/8 (12.50%)     0/6 (0.00%)     1/23 (4.35%)     1/27 (3.70%)     4/79 (5.06%)     0/53 (0.00%)     3/43 (6.98%)     2/54 (3.70%)     2/55 (3.64%)     1/15 (6.67%)     0/15 (0.00%)     1/41 (2.44%)     0/39 (0.00%)  
Dry eye † 1                          
# participants affected / at risk     0/8 (0.00%)     0/6 (0.00%)     0/23 (0.00%)     0/27 (0.00%)     4/79 (5.06%)     2/53 (3.77%)     1/43 (2.33%)     3/54 (5.56%)     3/55 (5.45%)     0/15 (0.00%)     1/15 (6.67%)     1/41 (2.44%)     0/39 (0.00%)  
Vitreous floaters † 1                          
# participants affected / at risk     0/8 (0.00%)     0/6 (0.00%)     0/23 (0.00%)     0/27 (0.00%)     0/79 (0.00%)     2/53 (3.77%)     1/43 (2.33%)     3/54 (5.56%)     0/55 (0.00%)     1/15 (6.67%)     0/15 (0.00%)     0/41 (0.00%)     1/39 (2.56%)  
Eye pain † 1                          
# participants affected / at risk     1/8 (12.50%)     0/6 (0.00%)     0/23 (0.00%)     1/27 (3.70%)     0/79 (0.00%)     0/53 (0.00%)     0/43 (0.00%)     2/54 (3.70%)     1/55 (1.82%)     1/15 (6.67%)     0/15 (0.00%)     1/41 (2.44%)     0/39 (0.00%)  
Ocular hyperaemia † 1                          
# participants affected / at risk     0/8 (0.00%)     0/6 (0.00%)     1/23 (4.35%)     0/27 (0.00%)     0/79 (0.00%)     0/53 (0.00%)     0/43 (0.00%)     2/54 (3.70%)     1/55 (1.82%)     0/15 (0.00%)     1/15 (6.67%)     1/41 (2.44%)     0/39 (0.00%)  
Photophobia † 1                          
# participants affected / at risk     0/8 (0.00%)     0/6 (0.00%)     0/23 (0.00%)     0/27 (0.00%)     1/79 (1.27%)     0/53 (0.00%)     0/43 (0.00%)     1/54 (1.85%)     1/55 (1.82%)     1/15 (6.67%)     0/15 (0.00%)     0/41 (0.00%)     1/39 (2.56%)  
Vitreous detachment † 1                          
# participants affected / at risk     0/8 (0.00%)     0/6 (0.00%)     0/23 (0.00%)     0/27 (0.00%)     1/79 (1.27%)     1/53 (1.89%)     0/43 (0.00%)     0/54 (0.00%)     0/55 (0.00%)     1/15 (6.67%)     0/15 (0.00%)     0/41 (0.00%)     1/39 (2.56%)  
Chorioretinopathy † 1                          
# participants affected / at risk     0/8 (0.00%)     0/6 (0.00%)     0/23 (0.00%)     2/27 (7.41%)     0/79 (0.00%)     0/53 (0.00%)     0/43 (0.00%)     0/54 (0.00%)     0/55 (0.00%)     0/15 (0.00%)     0/15 (0.00%)     0/41 (0.00%)     0/39 (0.00%)  
Diplopia † 1                          
# participants affected / at risk     0/8 (0.00%)     0/6 (0.00%)     0/23 (0.00%)     0/27 (0.00%)     0/79 (0.00%)     0/53 (0.00%)     0/43 (0.00%)     0/54 (0.00%)     1/55 (1.82%)     0/15 (0.00%)     1/15 (6.67%)     0/41 (0.00%)     0/39 (0.00%)  
Eye haemorrhage † 1                          
# participants affected / at risk     0/8 (0.00%)     0/6 (0.00%)     0/23 (0.00%)     0/27 (0.00%)     0/79 (0.00%)     0/53 (0.00%)     0/43 (0.00%)     1/54 (1.85%)     0/55 (0.00%)     1/15 (6.67%)     0/15 (0.00%)     0/41 (0.00%)     0/39 (0.00%)  
Eye pruritus † 1                          
# participants affected / at risk     0/8 (0.00%)     0/6 (0.00%)     0/23 (0.00%)     0/27 (0.00%)     0/79 (0.00%)     0/53 (0.00%)     0/43 (0.00%)     1/54 (1.85%)     0/55 (0.00%)     1/15 (6.67%)     0/15 (0.00%)     0/41 (0.00%)     0/39 (0.00%)  
Iritis † 1                          
# participants affected / at risk     0/8 (0.00%)     0/6 (0.00%)     0/23 (0.00%)     0/27 (0.00%)     0/79 (0.00%)     0/53 (0.00%)     0/43 (0.00%)     0/54 (0.00%)     0/55 (0.00%)     1/15 (6.67%)     0/15 (0.00%)     1/41 (2.44%)     0/39 (0.00%)  
Asthenopia † 1                          
# participants affected / at risk     0/8 (0.00%)     0/6 (0.00%)     0/23 (0.00%)     0/27 (0.00%)     0/79 (0.00%)     0/53 (0.00%)     0/43 (0.00%)     0/54 (0.00%)     0/55 (0.00%)     1/15 (6.67%)     0/15 (0.00%)     0/41 (0.00%)     0/39 (0.00%)  
Chalazion † 1                          
# participants affected / at risk     1/8 (12.50%)     0/6 (0.00%)     0/23 (0.00%)     0/27 (0.00%)     0/79 (0.00%)     0/53 (0.00%)     0/43 (0.00%)     0/54 (0.00%)     0/55 (0.00%)     0/15 (0.00%)     0/15 (0.00%)     0/41 (0.00%)     0/39 (0.00%)  
Keratopathy † 1                          
# participants affected / at risk     1/8 (12.50%)     0/6 (0.00%)     0/23 (0.00%)     0/27 (0.00%)     0/79 (0.00%)     0/53 (0.00%)     0/43 (0.00%)     0/54 (0.00%)     0/55 (0.00%)     0/15 (0.00%)     0/15 (0.00%)     0/41 (0.00%)     0/39 (0.00%)  
Lacrimation decreased † 1                          
# participants affected / at risk     1/8 (12.50%)     0/6 (0.00%)     0/23 (0.00%)     0/27 (0.00%)     0/79 (0.00%)     0/53 (0.00%)     0/43 (0.00%)     0/54 (0.00%)     0/55 (0.00%)     0/15 (0.00%)     0/15 (0.00%)     0/41 (0.00%)     0/39 (0.00%)  
Retinal detachment † 1                          
# participants affected / at risk     0/8 (0.00%)     0/6 (0.00%)     0/23 (0.00%)     0/27 (0.00%)     0/79 (0.00%)     0/53 (0.00%)     0/43 (0.00%)     0/54 (0.00%)     0/55 (0.00%)     1/15 (6.67%)     0/15 (0.00%)     0/41 (0.00%)     0/39 (0.00%)  
Gastrointestinal disorders                            
Nausea † 1                          
# participants affected / at risk     4/8 (50.00%)     2/6 (33.33%)     10/23 (43.48%)     10/27 (37.04%)     38/79 (48.10%)     11/53 (20.75%)     7/43 (16.28%)     25/54 (46.30%)     24/55 (43.64%)     5/15 (33.33%)     8/15 (53.33%)     22/41 (53.66%)     17/39 (43.59%)  
Vomiting † 1                          
# participants affected / at risk     4/8 (50.00%)     2/6 (33.33%)     6/23 (26.09%)     10/27 (37.04%)     27/79 (34.18%)     8/53 (15.09%)     10/43 (23.26%)     23/54 (42.59%)     22/55 (40.00%)     2/15 (13.33%)     6/15 (40.00%)     18/41 (43.90%)     16/39 (41.03%)  
Diarrhoea † 1                          
# participants affected / at risk     3/8 (37.50%)     2/6 (33.33%)     9/23 (39.13%)     6/27 (22.22%)     22/79 (27.85%)     15/53 (28.30%)     6/43 (13.95%)     14/54 (25.93%)     20/55 (36.36%)     4/15 (26.67%)     5/15 (33.33%)     15/41 (36.59%)     7/39 (17.95%)  
Constipation † 1                          
# participants affected / at risk     1/8 (12.50%)     1/6 (16.67%)     7/23 (30.43%)     5/27 (18.52%)     21/79 (26.58%)     6/53 (11.32%)     6/43 (13.95%)     9/54 (16.67%)     12/55 (21.82%)     1/15 (6.67%)     3/15 (20.00%)     9/41 (21.95%)     3/39 (7.69%)  
Abdominal pain † 1                          
# participants affected / at risk     1/8 (12.50%)     2/6 (33.33%)     3/23 (13.04%)     1/27 (3.70%)     7/79 (8.86%)     6/53 (11.32%)     2/43 (4.65%)     8/54 (14.81%)     8/55 (14.55%)     5/15 (33.33%)     2/15 (13.33%)     5/41 (12.20%)     1/39 (2.56%)  
Dyspepsia † 1                          
# participants affected / at risk     0/8 (0.00%)     1/6 (16.67%)     1/23 (4.35%)     4/27 (14.81%)     3/79 (3.80%)     3/53 (5.66%)     1/43 (2.33%)     4/54 (7.41%)     3/55 (5.45%)     1/15 (6.67%)     0/15 (0.00%)     5/41 (12.20%)     1/39 (2.56%)  
Gastrooesophageal reflux disease † 1                          
# participants affected / at risk     1/8 (12.50%)     0/6 (0.00%)     1/23 (4.35%)     1/27 (3.70%)     5/79 (6.33%)     1/53 (1.89%)     0/43 (0.00%)     2/54 (3.70%)     3/55 (5.45%)     1/15 (6.67%)     0/15 (0.00%)     0/41 (0.00%)     3/39 (7.69%)  
Abdominal distension † 1                          
# participants affected / at risk     0/8 (0.00%)     0/6 (0.00%)     0/23 (0.00%)     1/27 (3.70%)     4/79 (5.06%)     1/53 (1.89%)     2/43 (4.65%)     2/54 (3.70%)     2/55 (3.64%)     2/15 (13.33%)     1/15 (6.67%)     0/41 (0.00%)     0/39 (0.00%)  
Flatulence † 1                          
# participants affected / at risk     0/8 (0.00%)     0/6 (0.00%)     0/23 (0.00%)     2/27 (7.41%)     2/79 (2.53%)     3/53 (5.66%)     1/43 (2.33%)     0/54 (0.00%)     0/55 (0.00%)     0/15 (0.00%)     1/15 (6.67%)     0/41 (0.00%)     3/39 (7.69%)  
Abdominal discomfort † 1                          
# participants affected / at risk     0/8 (0.00%)     1/6 (16.67%)     1/23 (4.35%)     0/27 (0.00%)     1/79 (1.27%)     1/53 (1.89%)     0/43 (0.00%)     2/54 (3.70%)     2/55 (3.64%)     0/15 (0.00%)     0/15 (0.00%)     1/41 (2.44%)     1/39 (2.56%)  
Haemorrhoids † 1                          
# participants affected / at risk     1/8 (12.50%)     0/6 (0.00%)     0/23 (0.00%)     1/27 (3.70%)     1/79 (1.27%)     2/53 (3.77%)     1/43 (2.33%)     0/54 (0.00%)     2/55 (3.64%)     0/15 (0.00%)     0/15 (0.00%)     1/41 (2.44%)     0/39 (0.00%)  
Dry mouth † 1                          
# participants affected / at risk     0/8 (0.00%)     0/6 (0.00%)     0/23 (0.00%)     2/27 (7.41%)     7/79 (8.86%)     3/53 (5.66%)     4/43 (9.30%)     6/54 (11.11%)     6/55 (10.91%)     0/15 (0.00%)     1/15 (6.67%)     5/41 (12.20%)     4/39 (10.26%)  
Abdominal pain upper † 1                          
# participants affected / at risk     0/8 (0.00%)     0/6 (0.00%)     0/23 (0.00%)     3/27 (11.11%)     6/79 (7.59%)     4/53 (7.55%)     1/43 (2.33%)     4/54 (7.41%)     9/55 (16.36%)     1/15 (6.67%)     0/15 (0.00%)     0/41 (0.00%)     0/39 (0.00%)  
Haematochezia † 1                          
# participants affected / at risk     0/8 (0.00%)     0/6 (0.00%)     1/23 (4.35%)     0/27 (0.00%)     3/79 (3.80%)     0/53 (0.00%)     0/43 (0.00%)     0/54 (0.00%)     0/55 (0.00%)     1/15 (6.67%)     1/15 (6.67%)     2/41 (4.88%)     0/39 (0.00%)  
Stomatitis † 1                          
# participants affected / at risk     1/8 (12.50%)     0/6 (0.00%)     0/23 (0.00%)     0/27 (0.00%)     0/79 (0.00%)     0/53 (0.00%)     1/43 (2.33%)     1/54 (1.85%)     2/55 (3.64%)     0/15 (0.00%)     0/15 (0.00%)     0/41 (0.00%)     1/39 (2.56%)  
Oral pain † 1                          
# participants affected / at risk     1/8 (12.50%)     0/6 (0.00%)     0/23 (0.00%)     1/27 (3.70%)     2/79 (2.53%)     0/53 (0.00%)     0/43 (0.00%)     0/54 (0.00%)     0/55 (0.00%)     0/15 (0.00%)     0/15 (0.00%)     0/41 (0.00%)     1/39 (2.56%)  
Retching † 1                          
# participants affected / at risk     1/8 (12.50%)     0/6 (0.00%)     0/23 (0.00%)     0/27 (0.00%)     1/79 (1.27%)     2/53 (3.77%)     0/43 (0.00%)     1/54 (1.85%)     0/55 (0.00%)     0/15 (0.00%)     0/15 (0.00%)     0/41 (0.00%)     0/39 (0.00%)  
Cheilitis † 1                          
# participants affected / at risk     1/8 (12.50%)     0/6 (0.00%)     0/23 (0.00%)     0/27 (0.00%)     0/79 (0.00%)     0/53 (0.00%)     0/43 (0.00%)     1/54 (1.85%)     1/55 (1.82%)     0/15 (0.00%)     0/15 (0.00%)     1/41 (2.44%)     0/39 (0.00%)  
Mouth ulceration † 1                          
# participants affected / at risk     0/8 (0.00%)     0/6 (0.00%)     0/23 (0.00%)     0/27 (0.00%)     1/79 (1.27%)     0/53 (0.00%)     0/43 (0.00%)     0/54 (0.00%)     1/55 (1.82%)     1/15 (6.67%)     0/15 (0.00%)     0/41 (0.00%)     1/39 (2.56%)  
Diverticulum † 1                          
# participants affected / at risk     1/8 (12.50%)     0/6 (0.00%)     0/23 (0.00%)     0/27 (0.00%)     0/79 (0.00%)     0/53 (0.00%)     0/43 (0.00%)     0/54 (0.00%)     0/55 (0.00%)     0/15 (0.00%)     0/15 (0.00%)     1/41 (2.44%)     0/39 (0.00%)  
Mesenteric artery thrombosis † 1                          
# participants affected / at risk     0/8 (0.00%)     0/6 (0.00%)     0/23 (0.00%)     0/27 (0.00%)     0/79 (0.00%)     0/53 (0.00%)     0/43 (0.00%)     0/54 (0.00%)     0/55 (0.00%)     1/15 (6.67%)     0/15 (0.00%)     0/41 (0.00%)     0/39 (0.00%)  
Oral mucosa erosion † 1                          
# participants affected / at risk     0/8 (0.00%)     0/6 (0.00%)     0/23 (0.00%)     0/27 (0.00%)     0/79 (0.00%)     0/53 (0.00%)     0/43 (0.00%)     0/54 (0.00%)     0/55 (0.00%)     1/15 (6.67%)     0/15 (0.00%)     0/41 (0.00%)     0/39 (0.00%)  
General disorders                            
Pyrexia † 1                          
# participants affected / at risk     3/8 (37.50%)     4/6 (66.67%)     11/23 (47.83%)     12/27 (44.44%)     50/79 (63.29%)     13/53 (24.53%)     11/43 (25.58%)     34/54 (62.96%)     37/55 (67.27%)     7/15 (46.67%)     7/15 (46.67%)     15/41 (36.59%)     16/39 (41.03%)  
Fatigue † 1                          
# participants affected / at risk     5/8 (62.50%)     4/6 (66.67%)     13/23 (56.52%)     12/27 (44.44%)     39/79 (49.37%)     21/53 (39.62%)     10/43 (23.26%)     31/54 (57.41%)     29/55 (52.73%)     7/15 (46.67%)     3/15 (20.00%)     21/41 (51.22%)     12/39 (30.77%)  
Chills † 1                          
# participants affected / at risk     3/8 (37.50%)     3/6 (50.00%)     10/23 (43.48%)     10/27 (37.04%)     35/79 (44.30%)     8/53 (15.09%)     3/43 (6.98%)     20/54 (37.04%)     29/55 (52.73%)     2/15 (13.33%)     4/15 (26.67%)     11/41 (26.83%)     9/39 (23.08%)  
Oedema peripheral † 1                          
# participants affected / at risk     1/8 (12.50%)     0/6 (0.00%)     4/23 (17.39%)     4/27 (14.81%)     19/79 (24.05%)     9/53 (16.98%)     4/43 (9.30%)     13/54 (24.07%)     16/55 (29.09%)     4/15 (26.67%)     2/15 (13.33%)     8/41 (19.51%)     7/39 (17.95%)  
Influenza like illness † 1                          
# participants affected / at risk     0/8 (0.00%)     0/6 (0.00%)     3/23 (13.04%)     3/27 (11.11%)     2/79 (2.53%)     4/53 (7.55%)     2/43 (4.65%)     10/54 (18.52%)     5/55 (9.09%)     2/15 (13.33%)     3/15 (20.00%)     2/41 (4.88%)     4/39 (10.26%)  
Asthenia † 1                          
# participants affected / at risk     0/8 (0.00%)     0/6 (0.00%)     6/23 (26.09%)     6/27 (22.22%)     10/79 (12.66%)     3/53 (5.66%)     1/43 (2.33%)     1/54 (1.85%)     4/55 (7.27%)     1/15 (6.67%)     0/15 (0.00%)     4/41 (9.76%)     2/39 (5.13%)  
Pain † 1                          
# participants affected / at risk     2/8 (25.00%)     2/6 (33.33%)     2/23 (8.70%)     2/27 (7.41%)     5/79 (6.33%)     4/53 (7.55%)     0/43 (0.00%)     6/54 (11.11%)     2/55 (3.64%)     2/15 (13.33%)     0/15 (0.00%)     2/41 (4.88%)     2/39 (5.13%)  
Mucosal inflammation † 1                          
# participants affected / at risk     0/8 (0.00%)     1/6 (16.67%)     1/23 (4.35%)     1/27 (3.70%)     2/79 (2.53%)     0/53 (0.00%)     0/43 (0.00%)     2/54 (3.70%)     1/55 (1.82%)     0/15 (0.00%)     0/15 (0.00%)     0/41 (0.00%)     1/39 (2.56%)  
Non-cardiac chest pain † 1                          
# participants affected / at risk     0/8 (0.00%)     0/6 (0.00%)     0/23 (0.00%)     2/27 (7.41%)     3/79 (3.80%)     2/53 (3.77%)     1/43 (2.33%)     1/54 (1.85%)     1/55 (1.82%)     0/15 (0.00%)     1/15 (6.67%)     0/41 (0.00%)     1/39 (2.56%)  
Axillary pain † 1                          
# participants affected / at risk     1/8 (12.50%)     0/6 (0.00%)     0/23 (0.00%)     1/27 (3.70%)     1/79 (1.27%)     4/53 (7.55%)     0/43 (0.00%)     2/54 (3.70%)     1/55 (1.82%)     0/15 (0.00%)     0/15 (0.00%)     0/41 (0.00%)     0/39 (0.00%)  
Malaise † 1                          
# participants affected / at risk     0/8 (0.00%)     0/6 (0.00%)     0/23 (0.00%)     2/27 (7.41%)     3/79 (3.80%)     0/53 (0.00%)     0/43 (0.00%)     2/54 (3.70%)     0/55 (0.00%)     0/15 (0.00%)     0/15 (0.00%)     2/41 (4.88%)     1/39 (2.56%)  
Gait disturbance † 1                          
# participants affected / at risk     0/8 (0.00%)     0/6 (0.00%)     1/23 (4.35%)     0/27 (0.00%)     2/79 (2.53%)     0/53 (0.00%)     0/43 (0.00%)     2/54 (3.70%)     1/55 (1.82%)     0/15 (0.00%)     1/15 (6.67%)     2/41 (4.88%)     0/39 (0.00%)  
Local swelling † 1                          
# participants affected / at risk     1/8 (12.50%)     0/6 (0.00%)     1/23 (4.35%)     1/27 (3.70%)     1/79 (1.27%)     0/53 (0.00%)     0/43 (0.00%)     0/54 (0.00%)     0/55 (0.00%)     2/15 (13.33%)     1/15 (6.67%)     1/41 (2.44%)     0/39 (0.00%)  
Nodule † 1                          
# participants affected / at risk     0/8 (0.00%)     0/6 (0.00%)     1/23 (4.35%)     2/27 (7.41%)     1/79 (1.27%)     1/53 (1.89%)     0/43 (0.00%)     0/54 (0.00%)     0/55 (0.00%)     0/15 (0.00%)     0/15 (0.00%)     2/41 (4.88%)     0/39 (0.00%)  
Chest discomfort † 1                          
# participants affected / at risk     1/8 (12.50%)     0/6 (0.00%)     2/23 (8.70%)     1/27 (3.70%)     1/79 (1.27%)     0/53 (0.00%)     0/43 (0.00%)     0/54 (0.00%)     0/55 (0.00%)     0/15 (0.00%)     0/15 (0.00%)     0/41 (0.00%)     1/39 (2.56%)  
Xerosis † 1                          
# participants affected / at risk     0/8 (0.00%)     0/6 (0.00%)     0/23 (0.00%)     2/27 (7.41%)     0/79 (0.00%)     2/53 (3.77%)     0/43 (0.00%)     1/54 (1.85%)     0/55 (0.00%)     0/15 (0.00%)     0/15 (0.00%)     0/41 (0.00%)     0/39 (0.00%)  
Systemic inflammatory response syndrome † 1                          
# participants affected / at risk     0/8 (0.00%)     0/6 (0.00%)     0/23 (0.00%)     0/27 (0.00%)     0/79 (0.00%)     0/53 (0.00%)     0/43 (0.00%)     0/54 (0.00%)     0/55 (0.00%)     0/15 (0.00%)     1/15 (6.67%)     0/41 (0.00%)     0/39 (0.00%)  
Hepatobiliary disorders                            
Hyperbilirubinaemia † 1                          
# participants affected / at risk     0/8 (0.00%)     0/6 (0.00%)     0/23 (0.00%)     1/27 (3.70%)     2/79 (2.53%)     0/53 (0.00%)     0/43 (0.00%)     3/54 (5.56%)     0/55 (0.00%)     0/15 (0.00%)     0/15 (0.00%)     0/41 (0.00%)     0/39 (0.00%)  
Infections and infestations                            
Urinary tract infection † 1                          
# participants affected / at risk     1/8 (12.50%)     0/6 (0.00%)     3/23 (13.04%)     4/27 (14.81%)     13/79 (16.46%)     4/53 (7.55%)     5/43 (11.63%)     3/54 (5.56%)     7/55 (12.73%)     1/15 (6.67%)     1/15 (6.67%)     2/41 (4.88%)     3/39 (7.69%)  
Upper respiratory tract infection † 1                          
# participants affected / at risk     0/8 (0.00%)     0/6 (0.00%)     1/23 (4.35%)     0/27 (0.00%)     4/79 (5.06%)     5/53 (9.43%)     3/43 (6.98%)     4/54 (7.41%)     2/55 (3.64%)     2/15 (13.33%)     2/15 (13.33%)     2/41 (4.88%)     3/39 (7.69%)  
Nasopharyngitis † 1                          
# participants affected / at risk     0/8 (0.00%)     0/6 (0.00%)     2/23 (8.70%)     1/27 (3.70%)     3/79 (3.80%)     0/53 (0.00%)     0/43 (0.00%)     5/54 (9.26%)     2/55 (3.64%)     1/15 (6.67%)     1/15 (6.67%)     5/41 (12.20%)     0/39 (0.00%)  
Folliculitis † 1                          
# participants affected / at risk     0/8 (0.00%)     0/6 (0.00%)     1/23 (4.35%)     2/27 (7.41%)     2/79 (2.53%)     1/53 (1.89%)     2/43 (4.65%)     1/54 (1.85%)     4/55 (7.27%)     0/15 (0.00%)     0/15 (0.00%)     3/41 (7.32%)     0/39 (0.00%)  
Sinusitis † 1                          
# participants affected / at risk     0/8 (0.00%)     0/6 (0.00%)     1/23 (4.35%)     3/27 (11.11%)     5/79 (6.33%)     0/53 (0.00%)     1/43 (2.33%)     0/54 (0.00%)     1/55 (1.82%)     0/15 (0.00%)     0/15 (0.00%)     2/41 (4.88%)     3/39 (7.69%)  
Ear infection † 1                          
# participants affected / at risk     0/8 (0.00%)     0/6 (0.00%)     1/23 (4.35%)     1/27 (3.70%)     2/79 (2.53%)     0/53 (0.00%)     1/43 (2.33%)     1/54 (1.85%)     3/55 (5.45%)     1/15 (6.67%)     0/15 (0.00%)     0/41 (0.00%)     0/39 (0.00%)  
Oral candidiasis † 1                          
# participants affected / at risk     0/8 (0.00%)     0/6 (0.00%)     0/23 (0.00%)     1/27 (3.70%)     1/79 (1.27%)     0/53 (0.00%)     0/43 (0.00%)     1/54 (1.85%)     1/55 (1.82%)     0/15 (0.00%)     0/15 (0.00%)     4/41 (9.76%)     0/39 (0.00%)  
Oral herpes † 1                          
# participants affected / at risk     0/8 (0.00%)     0/6 (0.00%)     0/23 (0.00%)     1/27 (3.70%)     1/79 (1.27%)     2/53 (3.77%)     0/43 (0.00%)     1/54 (1.85%)     0/55 (0.00%)     0/15 (0.00%)     1/15 (6.67%)     2/41 (4.88%)     0/39 (0.00%)  
Bronchitis † 1                          
# participants affected / at risk     0/8 (0.00%)     1/6 (16.67%)     0/23 (0.00%)     1/27 (3.70%)     3/79 (3.80%)     1/53 (1.89%)     0/43 (0.00%)     0/54 (0.00%)     0/55 (0.00%)     0/15 (0.00%)     0/15 (0.00%)     0/41 (0.00%)     0/39 (0.00%)  
Cellulitis † 1                          
# participants affected / at risk     1/8 (12.50%)     0/6 (0.00%)     1/23 (4.35%)     1/27 (3.70%)     0/79 (0.00%)     0/53 (0.00%)     1/43 (2.33%)     0/54 (0.00%)     1/55 (1.82%)     1/15 (6.67%)     0/15 (0.00%)     0/41 (0.00%)     0/39 (0.00%)  
Influenza † 1                          
# participants affected / at risk     0/8 (0.00%)     0/6 (0.00%)     1/23 (4.35%)     2/27 (7.41%)     0/79 (0.00%)     0/53 (0.00%)     0/43 (0.00%)     1/54 (1.85%)     1/55 (1.82%)     0/15 (0.00%)     0/15 (0.00%)     0/41 (0.00%)     0/39 (0.00%)  
Localised infection † 1                          
# participants affected / at risk     0/8 (0.00%)     0/6 (0.00%)     0/23 (0.00%)     1/27 (3.70%)     0/79 (0.00%)     0/53 (0.00%)     0/43 (0.00%)     1/54 (1.85%)     1/55 (1.82%)     1/15 (6.67%)     0/15 (0.00%)     1/41 (2.44%)     0/39 (0.00%)  
Pneumonia † 1                          
# participants affected / at risk     1/8 (12.50%)     0/6 (0.00%)     2/23 (8.70%)     0/27 (0.00%)     1/79 (1.27%)     0/53 (0.00%)     1/43 (2.33%)     0/54 (0.00%)     0/55 (0.00%)     0/15 (0.00%)     0/15 (0.00%)     0/41 (0.00%)     0/39 (0.00%)  
Rash pustular † 1                          
# participants affected / at risk     1/8 (12.50%)     0/6 (0.00%)     1/23 (4.35%)     0/27 (0.00%)     1/79 (1.27%)     0/53 (0.00%)     0/43 (0.00%)     0/54 (0.00%)     0/55 (0.00%)     0/15 (0.00%)     0/15 (0.00%)     1/41 (2.44%)     1/39 (2.56%)  
Staphylococcal infection † 1                          
# participants affected / at risk     2/8 (25.00%)     0/6 (0.00%)     0/23 (0.00%)     0/27 (0.00%)     1/79 (1.27%)     0/53 (0.00%)     0/43 (0.00%)     0/54 (0.00%)     1/55 (1.82%)     0/15 (0.00%)     1/15 (6.67%)     0/41 (0.00%)     0/39 (0.00%)  
Cystitis † 1                          
# participants affected / at risk     0/8 (0.00%)     0/6 (0.00%)     0/23 (0.00%)     0/27 (0.00%)     2/79 (2.53%)     0/53 (0.00%)     0/43 (0.00%)     1/54 (1.85%)     0/55 (0.00%)     1/15 (6.67%)     0/15 (0.00%)     0/41 (0.00%)     0/39 (0.00%)  
Skin infection † 1                          
# participants affected / at risk     0/8 (0.00%)     0/6 (0.00%)     0/23 (0.00%)     0/27 (0.00%)     0/79 (0.00%)     1/53 (1.89%)     0/43 (0.00%)     0/54 (0.00%)     0/55 (0.00%)     0/15 (0.00%)     1/15 (6.67%)     2/41 (4.88%)     0/39 (0.00%)  
Tinea pedis † 1                          
# participants affected / at risk     0/8 (0.00%)     0/6 (0.00%)     0/23 (0.00%)     1/27 (3.70%)     0/79 (0.00%)     1/53 (1.89%)     0/43 (0.00%)     1/54 (1.85%)     0/55 (0.00%)     1/15 (6.67%)     0/15 (0.00%)     0/41 (0.00%)     0/39 (0.00%)  
Fungal infection † 1                          
# participants affected / at risk     0/8 (0.00%)     0/6 (0.00%)     2/23 (8.70%)     0/27 (0.00%)     0/79 (0.00%)     0/53 (0.00%)     0/43 (0.00%)     0/54 (0.00%)     1/55 (1.82%)     0/15 (0.00%)     0/15 (0.00%)     0/41 (0.00%)     0/39 (0.00%)  
Pharyngitis † 1                          
# participants affected / at risk     0/8 (0.00%)     1/6 (16.67%)     0/23 (0.00%)     1/27 (3.70%)     1/79 (1.27%)     0/53 (0.00%)     0/43 (0.00%)     0/54 (0.00%)     0/55 (0.00%)     0/15 (0.00%)     0/15 (0.00%)     0/41 (0.00%)     0/39 (0.00%)  
Periorbital infection † 1                          
# participants affected / at risk     0/8 (0.00%)     0/6 (0.00%)     0/23 (0.00%)     0/27 (0.00%)     0/79 (0.00%)     0/53 (0.00%)     0/43 (0.00%)     0/54 (0.00%)     1/55 (1.82%)     0/15 (0.00%)     1/15 (6.67%)     0/41 (0.00%)     0/39 (0.00%)  
Anorectal infection † 1                          
# participants affected / at risk     0/8 (0.00%)     0/6 (0.00%)     0/23 (0.00%)     0/27 (0.00%)     0/79 (0.00%)     0/53 (0.00%)     0/43 (0.00%)     0/54 (0.00%)     0/55 (0.00%)     0/15 (0.00%)     1/15 (6.67%)     0/41 (0.00%)     0/39 (0.00%)  
Eye infection † 1                          
# participants affected / at risk     0/8 (0.00%)     1/6 (16.67%)     0/23 (0.00%)     0/27 (0.00%)     0/79 (0.00%)     0/53 (0.00%)     0/43 (0.00%)     0/54 (0.00%)     0/55 (0.00%)     0/15 (0.00%)     0/15 (0.00%)     0/41 (0.00%)     0/39 (0.00%)  
Groin abscess † 1                          
# participants affected / at risk     0/8 (0.00%)     0/6 (0.00%)     0/23 (0.00%)     0/27 (0.00%)     0/79 (0.00%)     0/53 (0.00%)     0/43 (0.00%)     0/54 (0.00%)     0/55 (0.00%)     1/15 (6.67%)     0/15 (0.00%)     0/41 (0.00%)     0/39 (0.00%)  
Infected bites † 1                          
# participants affected / at risk     1/8 (12.50%)     0/6 (0.00%)     0/23 (0.00%)     0/27 (0.00%)     0/79 (0.00%)     0/53 (0.00%)     0/43 (0.00%)     0/54 (0.00%)     0/55 (0.00%)     0/15 (0.00%)     0/15 (0.00%)     0/41 (0.00%)     0/39 (0.00%)  
Sepsis † 1                          
# participants affected / at risk     1/8 (12.50%)     0/6 (0.00%)     0/23 (0.00%)     0/27 (0.00%)     0/79 (0.00%)     0/53 (0.00%)     0/43 (0.00%)     0/54 (0.00%)     0/55 (0.00%)     0/15 (0.00%)     0/15 (0.00%)     0/41 (0.00%)     0/39 (0.00%)  
Wound infection staphylococcal † 1                          
# participants affected / at risk     1/8 (12.50%)     0/6 (0.00%)     0/23 (0.00%)     0/27 (0.00%)     0/79 (0.00%)     0/53 (0.00%)     0/43 (0.00%)     0/54 (0.00%)     0/55 (0.00%)     0/15 (0.00%)     0/15 (0.00%)     0/41 (0.00%)     0/39 (0.00%)  
Injury, poisoning and procedural complications                            
Contusion † 1                          
# participants affected / at risk     0/8 (0.00%)     1/6 (16.67%)     1/23 (4.35%)     0/27 (0.00%)     1/79 (1.27%)     0/53 (0.00%)     1/43 (2.33%)     1/54 (1.85%)     3/55 (5.45%)     0/15 (0.00%)     1/15 (6.67%)     0/41 (0.00%)     3/39 (7.69%)  
Fall † 1                          
# participants affected / at risk     0/8 (0.00%)     0/6 (0.00%)     1/23 (4.35%)     0/27 (0.00%)     1/79 (1.27%)     0/53 (0.00%)     0/43 (0.00%)     2/54 (3.70%)     0/55 (0.00%)     2/15 (13.33%)     0/15 (0.00%)     2/41 (4.88%)     0/39 (0.00%)  
Procedural pain † 1                          
# participants affected / at risk     0/8 (0.00%)     0/6 (0.00%)     0/23 (0.00%)     0/27 (0.00%)     1/79 (1.27%)     1/53 (1.89%)     1/43 (2.33%)     0/54 (0.00%)     1/55 (1.82%)     1/15 (6.67%)     0/15 (0.00%)     0/41 (0.00%)     1/39 (2.56%)  
Sunburn † 1                          
# participants affected / at risk     1/8 (12.50%)     0/6 (0.00%)     2/23 (8.70%)     0/27 (0.00%)     1/79 (1.27%)     0/53 (0.00%)     0/43 (0.00%)     0/54 (0.00%)     0/55 (0.00%)     0/15 (0.00%)     0/15 (0.00%)     1/41 (2.44%)     0/39 (0.00%)  
Ligament sprain † 1                          
# participants affected / at risk     0/8 (0.00%)     0/6 (0.00%)     0/23 (0.00%)     0/27 (0.00%)     0/79 (0.00%)     0/53 (0.00%)     0/43 (0.00%)     0/54 (0.00%)     3/55 (5.45%)     0/15 (0.00%)     0/15 (0.00%)     0/41 (0.00%)     0/39 (0.00%)  
Contrast media reaction † 1                          
# participants affected / at risk     0/8 (0.00%)     0/6 (0.00%)     0/23 (0.00%)     0/27 (0.00%)     0/79 (0.00%)     0/53 (0.00%)     0/43 (0.00%)     1/54 (1.85%)     0/55 (0.00%)     1/15 (6.67%)     0/15 (0.00%)     0/41 (0.00%)     0/39 (0.00%)  
Wrist fracture † 1                          
# participants affected / at risk     0/8 (0.00%)     0/6 (0.00%)     0/23 (0.00%)     0/27 (0.00%)     0/79 (0.00%)     0/53 (0.00%)     0/43 (0.00%)     0/54 (0.00%)     1/55 (1.82%)     1/15 (6.67%)     0/15 (0.00%)     0/41 (0.00%)     0/39 (0.00%)  
Tooth fracture † 1                          
# participants affected / at risk     0/8 (0.00%)     1/6 (16.67%)     0/23 (0.00%)     0/27 (0.00%)     0/79 (0.00%)     0/53 (0.00%)     0/43 (0.00%)     0/54 (0.00%)     0/55 (0.00%)     0/15 (0.00%)     0/15 (0.00%)     0/41 (0.00%)     0/39 (0.00%)  
Wound haemorrhage † 1                          
# participants affected / at risk     0/8 (0.00%)     0/6 (0.00%)     0/23 (0.00%)     0/27 (0.00%)     0/79 (0.00%)     0/53 (0.00%)     0/43 (0.00%)     0/54 (0.00%)     0/55 (0.00%)     1/15 (6.67%)     0/15 (0.00%)     0/41 (0.00%)     0/39 (0.00%)  
Investigations                            
Aspartate aminotransferase increased † 1                          
# participants affected / at risk     0/8 (0.00%)     1/6 (16.67%)     1/23 (4.35%)     4/27 (14.81%)     11/79 (13.92%)     1/53 (1.89%)     0/43 (0.00%)     10/54 (18.52%)     5/55 (9.09%)     0/15 (0.00%)     2/15 (13.33%)     5/41 (12.20%)     5/39 (12.82%)  
Gamma-glutamyltransferase increased † 1                          
# participants affected / at risk     0/8 (0.00%)     0/6 (0.00%)     1/23 (4.35%)     3/27 (11.11%)     11/79 (13.92%)     1/53 (1.89%)     1/43 (2.33%)     11/54 (20.37%)     5/55 (9.09%)     0/15 (0.00%)     4/15 (26.67%)     4/41 (9.76%)     4/39 (10.26%)  
Alanine aminotransferase increased † 1                          
# participants affected / at risk     0/8 (0.00%)     0/6 (0.00%)     1/23 (4.35%)     3/27 (11.11%)     8/79 (10.13%)     1/53 (1.89%)     0/43 (0.00%)     11/54 (20.37%)     5/55 (9.09%)     1/15 (6.67%)     2/15 (13.33%)     6/41 (14.63%)     5/39 (12.82%)  
Blood alkaline phosphatase increased † 1                          
# participants affected / at risk     0/8 (0.00%)     0/6 (0.00%)     1/23 (4.35%)     2/27 (7.41%)     9/79 (11.39%)     1/53 (1.89%)     0/43 (0.00%)     12/54 (22.22%)     5/55 (9.09%)     0/15 (0.00%)     3/15 (20.00%)     2/41 (4.88%)     3/39 (7.69%)  
Weight decreased † 1                          
# participants affected / at risk     0/8 (0.00%)     0/6 (0.00%)     2/23 (8.70%)     0/27 (0.00%)     4/79 (5.06%)     4/53 (7.55%)     3/43 (6.98%)     7/54 (12.96%)     4/55 (7.27%)     0/15 (0.00%)     2/15 (13.33%)     2/41 (4.88%)     3/39 (7.69%)  
Blood creatinine increased † 1                          
# participants affected / at risk     0/8 (0.00%)     0/6 (0.00%)     0/23 (0.00%)     1/27 (3.70%)     3/79 (3.80%)     2/53 (3.77%)     1/43 (2.33%)     5/54 (9.26%)     2/55 (3.64%)     1/15 (6.67%)     0/15 (0.00%)     1/41 (2.44%)     0/39 (0.00%)  
Lymphocyte count decreased † 1                          
# participants affected / at risk     1/8 (12.50%)     0/6 (0.00%)     0/23 (0.00%)     0/27 (0.00%)     2/79 (2.53%)     1/53 (1.89%)     0/43 (0.00%)     4/54 (7.41%)     0/55 (0.00%)     0/15 (0.00%)     2/15 (13.33%)     2/41 (4.88%)     1/39 (2.56%)  
Neutrophil count decreased † 1                          
# participants affected / at risk     0/8 (0.00%)     1/6 (16.67%)     0/23 (0.00%)     1/27 (3.70%)     2/79 (2.53%)     1/53 (1.89%)     0/43 (0.00%)     2/54 (3.70%)     1/55 (1.82%)     1/15 (6.67%)     0/15 (0.00%)     2/41 (4.88%)     2/39 (5.13%)  
Weight increased † 1                          
# participants affected / at risk     0/8 (0.00%)     1/6 (16.67%)     2/23 (8.70%)     2/27 (7.41%)     2/79 (2.53%)     0/53 (0.00%)     1/43 (2.33%)     1/54 (1.85%)     1/55 (1.82%)     0/15 (0.00%)     0/15 (0.00%)     1/41 (2.44%)     0/39 (0.00%)  
Ejection fraction decreased † 1                          
# participants affected / at risk     0/8 (0.00%)     0/6 (0.00%)     1/23 (4.35%)     0/27 (0.00%)     4/79 (5.06%)     0/53 (0.00%)     1/43 (2.33%)     1/54 (1.85%)     3/55 (5.45%)     0/15 (0.00%)     0/15 (0.00%)     0/41 (0.00%)     0/39 (0.00%)  
Transaminases increased † 1                          
# participants affected / at risk     0/8 (0.00%)     0/6 (0.00%)     0/23 (0.00%)     0/27 (0.00%)     2/79 (2.53%)     0/53 (0.00%)     0/43 (0.00%)     4/54 (7.41%)     0/55 (0.00%)     0/15 (0.00%)     1/15 (6.67%)     1/41 (2.44%)     0/39 (0.00%)  
White blood cell count decreased † 1                          
# participants affected / at risk     0/8 (0.00%)     0/6 (0.00%)     0/23 (0.00%)     0/27 (0.00%)     0/79 (0.00%)     0/53 (0.00%)     0/43 (0.00%)     1/54 (1.85%)     1/55 (1.82%)     1/15 (6.67%)     0/15 (0.00%)     3/41 (7.32%)     2/39 (5.13%)  
Platelet count decreased † 1                          
# participants affected / at risk     0/8 (0.00%)     0/6 (0.00%)     0/23 (0.00%)     0/27 (0.00%)     0/79 (0.00%)     0/53 (0.00%)     0/43 (0.00%)     1/54 (1.85%)     0/55 (0.00%)     1/15 (6.67%)     0/15 (0.00%)     2/41 (4.88%)     3/39 (7.69%)  
Liver function test abnormal † 1                          
# participants affected / at risk     0/8 (0.00%)     0/6 (0.00%)     0/23 (0.00%)     0/27 (0.00%)     0/79 (0.00%)     1/53 (1.89%)     0/43 (0.00%)     0/54 (0.00%)     1/55 (1.82%)     0/15 (0.00%)     1/15 (6.67%)     1/41 (2.44%)     0/39 (0.00%)  
Carbon dioxide increased † 1                          
# participants affected / at risk     0/8 (0.00%)     0/6 (0.00%)     0/23 (0.00%)     0/27 (0.00%)     0/79 (0.00%)     0/53 (0.00%)     0/43 (0.00%)     3/54 (5.56%)     0/55 (0.00%)     0/15 (0.00%)     0/15 (0.00%)     0/41 (0.00%)     0/39 (0.00%)  
Blood magnesium decreased † 1                          
# participants affected / at risk     1/8 (12.50%)     0/6 (0.00%)     0/23 (0.00%)     0/27 (0.00%)     0/79 (0.00%)     0/53 (0.00%)     0/43 (0.00%)     0/54 (0.00%)     1/55 (1.82%)     0/15 (0.00%)     0/15 (0.00%)     0/41 (0.00%)     0/39 (0.00%)  
Blood potassium decreased † 1                          
# participants affected / at risk     1/8 (12.50%)     0/6 (0.00%)     0/23 (0.00%)     0/27 (0.00%)     0/79 (0.00%)     0/53 (0.00%)     0/43 (0.00%)     0/54 (0.00%)     0/55 (0.00%)     0/15 (0.00%)     0/15 (0.00%)     0/41 (0.00%)     0/39 (0.00%)  
Protein urine present † 1                          
# participants affected / at risk     1/8 (12.50%)     0/6 (0.00%)     0/23 (0.00%)     0/27 (0.00%)     0/79 (0.00%)     0/53 (0.00%)     0/43 (0.00%)     0/54 (0.00%)     0/55 (0.00%)     0/15 (0.00%)     0/15 (0.00%)     0/41 (0.00%)     0/39 (0.00%)  
Metabolism and nutrition disorders                            
Decreased appetite † 1                          
# participants affected / at risk     4/8 (50.00%)     3/6 (50.00%)     1/23 (4.35%)     4/27 (14.81%)     19/79 (24.05%)     10/53 (18.87%)     5/43 (11.63%)     16/54 (29.63%)     12/55 (21.82%)     1/15 (6.67%)     2/15 (13.33%)     7/41 (17.07%)     8/39 (20.51%)  
Hyponatraemia † 1                          
# participants affected / at risk     0/8 (0.00%)     0/6 (0.00%)     2/23 (8.70%)     2/27 (7.41%)     10/79 (12.66%)     1/53 (1.89%)     1/43 (2.33%)     5/54 (9.26%)     4/55 (7.27%)     0/15 (0.00%)     2/15 (13.33%)     4/41 (9.76%)     2/39 (5.13%)  
Dehydration † 1                          
# participants affected / at risk     0/8 (0.00%)     0/6 (0.00%)     3/23 (13.04%)     1/27 (3.70%)     9/79 (11.39%)     1/53 (1.89%)     2/43 (4.65%)     3/54 (5.56%)     4/55 (7.27%)     0/15 (0.00%)     0/15 (0.00%)     4/41 (9.76%)     5/39 (12.82%)  
Hypokalaemia † 1                          
# participants affected / at risk     0/8 (0.00%)     0/6 (0.00%)     0/23 (0.00%)     2/27 (7.41%)     11/79 (13.92%)     3/53 (5.66%)     0/43 (0.00%)     1/54 (1.85%)     5/55 (9.09%)     1/15 (6.67%)     3/15 (20.00%)     4/41 (9.76%)     1/39 (2.56%)  
Hypophosphataemia † 1                          
# participants affected / at risk     0/8 (0.00%)     0/6 (0.00%)     2/23 (8.70%)     1/27 (3.70%)     7/79 (8.86%)     4/53 (7.55%)     1/43 (2.33%)     5/54 (9.26%)     0/55 (0.00%)     0/15 (0.00%)     1/15 (6.67%)     4/41 (9.76%)     4/39 (10.26%)  
Hyperglycaemia † 1                          
# participants affected / at risk     0/8 (0.00%)     0/6 (0.00%)     3/23 (13.04%)     0/27 (0.00%)     3/79 (3.80%)     3/53 (5.66%)     0/43 (0.00%)     6/54 (11.11%)     4/55 (7.27%)     0/15 (0.00%)     1/15 (6.67%)     2/41 (4.88%)     2/39 (5.13%)  
Hypoalbuminaemia † 1                          
# participants affected / at risk     0/8 (0.00%)     0/6 (0.00%)     0/23 (0.00%)     0/27 (0.00%)     6/79 (7.59%)     1/53 (1.89%)     0/43 (0.00%)     4/54 (7.41%)     2/55 (3.64%)     0/15 (0.00%)     3/15 (20.00%)     3/41 (7.32%)     1/39 (2.56%)  
Hyperkalaemia † 1                          
# participants affected / at risk     0/8 (0.00%)     0/6 (0.00%)     1/23 (4.35%)     1/27 (3.70%)     3/79 (3.80%)     4/53 (7.55%)     0/43 (0.00%)     1/54 (1.85%)     1/55 (1.82%)     0/15 (0.00%)     1/15 (6.67%)     0/41 (0.00%)     0/39 (0.00%)  
Hypomagnesaemia † 1                          
# participants affected / at risk     1/8 (12.50%)     0/6 (0.00%)     0/23 (0.00%)     0/27 (0.00%)     3/79 (3.80%)     1/53 (1.89%)     1/43 (2.33%)     0/54 (0.00%)     2/55 (3.64%)     0/15 (0.00%)     1/15 (6.67%)     1/41 (2.44%)     0/39 (0.00%)  
Hyperuricaemia † 1                          
# participants affected / at risk     0/8 (0.00%)     0/6 (0.00%)     0/23 (0.00%)     0/27 (0.00%)     0/79 (0.00%)     0/53 (0.00%)     0/43 (0.00%)     2/54 (3.70%)     1/55 (1.82%)     1/15 (6.67%)     0/15 (0.00%)     0/41 (0.00%)     0/39 (0.00%)  
Hypermagnesaemia † 1                          
# participants affected / at risk     0/8 (0.00%)     0/6 (0.00%)     0/23 (0.00%)     0/27 (0.00%)     0/79 (0.00%)     0/53 (0.00%)     0/43 (0.00%)     0/54 (0.00%)     0/55 (0.00%)     0/15 (0.00%)     1/15 (6.67%)     1/41 (2.44%)     0/39 (0.00%)  
Vitamin D deficiency † 1                          
# participants affected / at risk     1/8 (12.50%)     0/6 (0.00%)     0/23 (0.00%)     0/27 (0.00%)     1/79 (1.27%)     0/53 (0.00%)     0/43 (0.00%)     0/54 (0.00%)     0/55 (0.00%)     0/15 (0.00%)     0/15 (0.00%)     0/41 (0.00%)     0/39 (0.00%)  
Impaired fasting glucose † 1                          
# participants affected / at risk     0/8 (0.00%)     0/6 (0.00%)     0/23 (0.00%)     0/27 (0.00%)     0/79 (0.00%)     0/53 (0.00%)     0/43 (0.00%)     0/54 (0.00%)     0/55 (0.00%)     1/15 (6.67%)     0/15 (0.00%)     0/41 (0.00%)     0/39 (0.00%)  
Lactic acidosis † 1                          
# participants affected / at risk     0/8 (0.00%)     0/6 (0.00%)     0/23 (0.00%)     0/27 (0.00%)     0/79 (0.00%)     0/53 (0.00%)     0/43 (0.00%)     0/54 (0.00%)     0/55 (0.00%)     0/15 (0.00%)     1/15 (6.67%)