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    Clinical Trial Results:
    A Multi-Center, Randomized, Double-Blind, Two-Arm, Phase III Study in Patients with Untreated Stage III (Unresectable) or IV Melanoma Receiving Dacarbazine Plus 10 mg/kg of Ipilimumab (MDX-010) vs. Dacarbazine With Placebo.

    Summary
    EudraCT number
    		 2005-006082-14
    Trial protocol
    		 NO   IE   BE   HU   ES   PT   DE   GB   CZ   AT   IT   NL  
    Global end of trial date
    14 Nov 2013

    Results information
    Results version number
    		 v1(current)
    This version publication date
    01 Apr 2016
    First version publication date
    01 Apr 2016
    Other versions

    Trial information

    		 Close Top of page
    Trial identification
    Sponsor protocol code
    CA184024
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT00324155
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Bristol-Myers Squibb
    Sponsor organisation address
    Bristol-Myers Squibb International Corporation, Chaussée de la Hulpe 185, Brussels, Belgium, 1170
    Public contact
    Bristol Myers Squibb Study Director, Bristol Myers Squibb, Clinical.Trials@bms.com
    Scientific contact
    Bristol Myers Squibb Study Director, Bristol Myers Squibb, Clinical.Trials@bms.com
    Paediatric regulatory details
    Is trial part of an agreed paediatric investigation plan (PIP)
    No
    Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Results analysis stage
    Analysis stage
    Final
    Date of interim/final analysis
    01 Sep 2014
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    14 Nov 2013
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The primary objective of this study was to compare Overall Survival in subjects with previously untreated Stage IIIc, N3 (unresectable) or Stage IV melanoma receiving dacarbazine plus 10mg/kg ipilimumab vs. dacarbazine with placebo.
    Protection of trial subjects
    The study was in compliance with the ethical principles derived from the Declaration of Helsinki and in compliance with all International Conference on Harmonization Good Clinical Practice Guidelines. All the local regulatory requirements pertinent to safety of trial subjects were followed.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    08 Aug 2006
    Long term follow-up planned
    Yes
    Long term follow-up rationale
    		 Safety, Efficacy
    Long term follow-up duration
    		 60 Months
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Netherlands: 14
    Country: Number of subjects enrolled
    Norway: 9
    Country: Number of subjects enrolled
    Portugal: 1
    Country: Number of subjects enrolled
    Spain: 20
    Country: Number of subjects enrolled
    United Kingdom: 51
    Country: Number of subjects enrolled
    Austria: 8
    Country: Number of subjects enrolled
    Belgium: 26
    Country: Number of subjects enrolled
    Czech Republic: 8
    Country: Number of subjects enrolled
    France: 90
    Country: Number of subjects enrolled
    Germany: 59
    Country: Number of subjects enrolled
    Hungary: 1
    Country: Number of subjects enrolled
    Ireland: 8
    Country: Number of subjects enrolled
    Italy: 65
    Country: Number of subjects enrolled
    Argentina: 16
    Country: Number of subjects enrolled
    Australia: 22
    Country: Number of subjects enrolled
    Brazil: 8
    Country: Number of subjects enrolled
    Canada: 25
    Country: Number of subjects enrolled
    Chile: 14
    Country: Number of subjects enrolled
    Israel: 14
    Country: Number of subjects enrolled
    Poland: 21
    Country: Number of subjects enrolled
    Russian Federation: 35
    Country: Number of subjects enrolled
    South Africa: 24
    Country: Number of subjects enrolled
    Switzerland: 3
    Country: Number of subjects enrolled
    Ukraine: 38
    Country: Number of subjects enrolled
    United States: 101
    Worldwide total number of subjects
    681
    EEA total number of subjects
    381
    Number of subjects enrolled per age group
    In utero
    0
    Preterm newborn - gestational age < 37 wk
    0
    Newborns (0-27 days)
    0
    Infants and toddlers (28 days-23 months)
    0
    Children (2-11 years)
    0
    Adolescents (12-17 years)
    0
    Adults (18-64 years)
    460
    From 65 to 84 years
    215
    85 years and over
    6

    Subject disposition

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    Recruitment
    Recruitment details
    		 The study was initiated on August 8, 2006. Primary endpoint (Survival) was evaluated on February 7, 2011 and again at completion of follow-up period, October 13, 2013. Subjects with a histologic diagnosis of untreated, measurable, and unresectable Stage III or Stage IV malignant melanoma were eligible.

    Pre-assignment
    Screening details
    		 Of the 681 subjects enrolled, 502 were randomised, and 498 received treatment. Reasons for not starting treatment: 147 no longer met study criteria (including 3 who were randomised but did not receive treatment), 25 withdrew consent, 3 died, 2 had adverse events, 2 lost to follow-up, 2 poor compliance or noncompliance, 1 not reported, and 1 other.

    Period 1
    Period 1 title
    Randomised
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Subject, Investigator

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Ipilimumab and Dacarbazine
    Arm description
    		 Ipilimumab: Intravenous solution; intravenous; 10 mg/kg; 1 dose every 3 weeks for 12 weeks, then 1 dose every 12 weeks starting at Week 24, until disease progression (PD), unacceptable toxicity, or withdrawal of consent. Dacarbazine: Intravenous solution; intravenous; 850 mg/m^2; 1 dose every 3 weeks for 22 weeks, until PD, unacceptable toxicity, or withdrawal of consent. In Maintenance Phase: Only Ipilimumab: 10 mg/kg, every 12 weeks was continued until PD. Dacarbazine was given up to Week 22 and was not given in the Maintenance Phase. Subjects who experienced PD or who did not wish to continue study assessments in the Induction or Maintenance Phases entered the Follow-up Phase.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Ipilimumab
    Investigational medicinal product code
    BMS-734016
    Other name
    MDX-010
    Pharmaceutical forms
    Infusion
    Routes of administration
    Intravenous drip use
    Dosage and administration details
    Induction Phase: Subjects were administered with ipilimumab intravenous solution, 10 mg/kg, 1 dose every 3 weeks for 12 weeks, then 1 dose every 12 weeks starting at Week 24, until disease progression (PD), unacceptable toxicity, or withdrawal of consent. Maintenance Phase: Ipilimumab intravenous solution: 10 mg/kg, every 12 weeks was continued until PD.

    Investigational medicinal product name
    Dacarbazine
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Intravenous drip use
    Dosage and administration details
    Dacarbazine intravenous solution 850-mg/m^2 was administered as 30-60 minutes infusion every 3 weeks for 22 weeks, until PD, unacceptable toxicity, or withdrawal of consent.

    Arm title
    		 Placebo and Dacarbazine
    Arm description
    		 Placebo: Intravenous solution, intravenous, 0 mg, 1 dose every 3 weeks for 12 weeks, then 1 dose every 12 weeks starting at Week 24; until disease progression (PD), unacceptable toxicity, or withdrawal of consent. Dacarbazine: Intravenous solution, intravenous, 850 mg/m^2, 1 dose every 3 weeks for 22 weeks, until PD, unacceptable toxicity, or withdrawal of consent. Subjects who experienced PD or who did not wish to continue study assessments in the Induction or Maintenance Phases entered the Follow-up Phase.
    Arm type
    		 Active comparator

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Infusion
    Routes of administration
    Intravenous drip use
    Dosage and administration details
    Placebo matched to ipilimumab intravenous solution was administered every 3 weeks for 12 weeks, then 1 dose every 12 weeks starting at Week 24; until disease progression, unacceptable toxicity, or withdrawal of consent.

    Investigational medicinal product name
    Dacarbazine
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Intravenous drip use
    Dosage and administration details
    Dacarbazine intravenous solution 850-mg/m^2 was administered as 30-60 minutes infusion every 3 weeks for 22 weeks, until PD, unacceptable toxicity, or withdrawal of consent.

    Number of subjects in period 1 [1]
    		Ipilimumab and Dacarbazine Placebo and Dacarbazine
    Started
    250
    252
    Completed
    247
    251
    Not completed
    3
    1
         Subject no longer meet study criteria
    3
    -
         Lost to follow-up
    -
    1
    Notes
    [1] - The number of subjects reported to be in the baseline period are not the same as the worldwide number enrolled in the trial. It is expected that these numbers will be the same.
    Justification: Out of 681 subjects who were enrolled, only 502 were randomised.
    Period 2
    Period 2 title
    Received Treatment in Induction Phase
    Is this the baseline period?
    		 No
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Subject, Investigator

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Ipilimumab and Dacarbazine
    Arm description
    		 Ipilimumab: Intravenous solution; intravenous; 10 mg/kg; 1 dose every 3 weeks for 12 weeks, then 1 dose every 12 weeks starting at Week 24, until disease progression (PD), unacceptable toxicity, or withdrawal of consent. Dacarbazine: Intravenous solution; intravenous; 850 mg/m^2; 1 dose every 3 weeks for 22 weeks, until PD, unacceptable toxicity, or withdrawal of consent. In Maintenance Phase: Only Ipilimumab: 10 mg/kg, every 12 weeks was continued until PD. Dacarbazine was given up to Week 22 and was not given in the Maintenance Phase. Subjects who experienced PD or who did not wish to continue study assessments in the Induction or Maintenance Phases entered the Follow-up Phase.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Ipilimumab
    Investigational medicinal product code
    BMS-734016
    Other name
    MDX-010
    Pharmaceutical forms
    Infusion
    Routes of administration
    Intravenous drip use
    Dosage and administration details
    Induction Phase: Subjects were administered with ipilimumab intravenous solution, 10 mg/kg, 1 dose every 3 weeks for 12 weeks, then 1 dose every 12 weeks starting at Week 24, until disease progression (PD), unacceptable toxicity, or withdrawal of consent. Maintenance Phase: Ipilimumab intravenous solution: 10 mg/kg, every 12 weeks was continued until PD.

    Investigational medicinal product name
    Dacarbazine
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Intravenous drip use
    Dosage and administration details
    Dacarbazine intravenous solution 850-mg/m^2 was administered as 30-60 minutes infusion every 3 weeks for 22 weeks, until PD, unacceptable toxicity, or withdrawal of consent.

    Arm title
    		 Placebo and Dacarbazine
    Arm description
    		 Placebo: Intravenous solution, intravenous, 0 mg, 1 dose every 3 weeks for 12 weeks, then 1 dose every 12 weeks starting at Week 24; until disease progression (PD), unacceptable toxicity, or withdrawal of consent. Dacarbazine: Intravenous solution, intravenous, 850 mg/m^2, 1 dose every 3 weeks for 22 weeks, until PD, unacceptable toxicity, or withdrawal of consent. Subjects who experienced PD or who did not wish to continue study assessments in the Induction or Maintenance Phases entered the Follow-up Phase.
    Arm type
    		 Active comparator

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Infusion
    Routes of administration
    Intravenous drip use
    Dosage and administration details
    Placebo matched to ipilimumab intravenous solution was administered every 3 weeks for 12 weeks, then 1 dose every 12 weeks starting at Week 24; until disease progression, unacceptable toxicity, or withdrawal of consent.

    Investigational medicinal product name
    Dacarbazine
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Intravenous drip use
    Dosage and administration details
    Dacarbazine intravenous solution 850-mg/m^2 was administered as 30-60 minutes infusion every 3 weeks for 22 weeks, until PD, unacceptable toxicity, or withdrawal of consent.

    Number of subjects in period 2
    		Ipilimumab and Dacarbazine Placebo and Dacarbazine
    Started
    247
    251
    Completed
    45
    54
    Not completed
    202
    197
         Consent withdrawn by subject
    6
    5
         Physician decision
    2
    -
         Adverse event, non-fatal
    6
    7
         Death
    8
    15
         Deterioration/Undocumented Progression
    9
    8
         Study Drug Toxicity
    83
    10
         Disease Progression
    88
    152
    Period 3
    Period 3 title
    Received Treatment in Maintenance Phase
    Is this the baseline period?
    		 No
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Subject, Investigator

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Ipilimumab and Dacarbazine
    Arm description
    		 Ipilimumab: Intravenous solution; intravenous; 10 mg/kg; 1 dose every 3 weeks for 12 weeks, then 1 dose every 12 weeks starting at Week 24, until disease progression (PD), unacceptable toxicity, or withdrawal of consent. Dacarbazine: Intravenous solution; intravenous; 850 mg/m^2; 1 dose every 3 weeks for 22 weeks, until PD, unacceptable toxicity, or withdrawal of consent. In Maintenance Phase: Only Ipilimumab: 10 mg/kg, every 12 weeks was continued until PD. Dacarbazine was given up to Week 22 and was not given in the Maintenance Phase. Subjects who experienced PD or who did not wish to continue study assessments in the Induction or Maintenance Phases entered the Follow-up Phase.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Ipilimumab
    Investigational medicinal product code
    BMS-734016
    Other name
    MDX-010
    Pharmaceutical forms
    Infusion
    Routes of administration
    Intravenous drip use
    Dosage and administration details
    Induction Phase: Subjects were administered with ipilimumab intravenous solution, 10 mg/kg, 1 dose every 3 weeks for 12 weeks, then 1 dose every 12 weeks starting at Week 24, until disease progression (PD), unacceptable toxicity, or withdrawal of consent. Maintenance Phase: Ipilimumab intravenous solution: 10 mg/kg, every 12 weeks was continued until PD.

    Investigational medicinal product name
    Dacarbazine
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Intravenous drip use
    Dosage and administration details
    Dacarbazine intravenous solution 850-mg/m^2 was administered as 30-60 minutes infusion every 3 weeks for 22 weeks, until PD, unacceptable toxicity, or withdrawal of consent.

    Arm title
    		 Placebo and Dacarbazine
    Arm description
    		 Placebo: Intravenous solution, intravenous, 0 mg, 1 dose every 3 weeks for 12 weeks, then 1 dose every 12 weeks starting at Week 24; until disease progression (PD), unacceptable toxicity, or withdrawal of consent. Dacarbazine: Intravenous solution, intravenous, 850 mg/m^2, 1 dose every 3 weeks for 22 weeks, until PD, unacceptable toxicity, or withdrawal of consent. Subjects who experienced PD or who did not wish to continue study assessments in the Induction or Maintenance Phases entered the Follow-up Phase.
    Arm type
    		 Active comparator

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Infusion
    Routes of administration
    Intravenous drip use
    Dosage and administration details
    Placebo matched to ipilimumab intravenous solution was administered every 3 weeks for 12 weeks, then 1 dose every 12 weeks starting at Week 24; until disease progression, unacceptable toxicity, or withdrawal of consent.

    Investigational medicinal product name
    Dacarbazine
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Intravenous drip use
    Dosage and administration details
    Dacarbazine intravenous solution 850-mg/m^2 was administered as 30-60 minutes infusion every 3 weeks for 22 weeks, until PD, unacceptable toxicity, or withdrawal of consent.

    Number of subjects in period 3 [2]
    		Ipilimumab and Dacarbazine Placebo and Dacarbazine
    Started
    43
    53
    Completed
    11
    6
    Not completed
    32
    47
         Consent withdrawn by subject
    1
    3
         Adverse event, non-fatal
    -
    3
         Deterioration/Undocumented Progression
    1
    -
         Study Drug Toxicity
    4
    -
         Disease Progression
    26
    41
    Notes
    [2] - The number of subjects starting the period is not consistent with the number completing the preceding period. It is expected the number of subjects starting the subsequent period will be the same as the number completing the preceding period.
    Justification: Out of 99 subjects who completed induction phase, only 96 subjects entered maintenance phase.
    Period 4
    Period 4 title
    Follow-up Phase
    Is this the baseline period?
    		 No
    Allocation method
    Not applicable
    Blinding used
    		 Not blinded

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Ipilimumab and Dacarbazine
    Arm description
    		 Ipilimumab: Intravenous solution; intravenous; 10 mg/kg; 1 dose every 3 weeks for 12 weeks, then 1 dose every 12 weeks starting at Week 24, until disease progression (PD), unacceptable toxicity, or withdrawal of consent. Dacarbazine: Intravenous solution; intravenous; 850 mg/m^2; 1 dose every 3 weeks for 22 weeks, until PD, unacceptable toxicity, or withdrawal of consent. In Maintenance Phase: Only Ipilimumab: 10 mg/kg, every 12 weeks was continued until PD. Dacarbazine was given up to Week 22 and was not given in the Maintenance Phase. Subjects who experienced PD or who did not wish to continue study assessments in the Induction or Maintenance Phases entered the Follow-up Phase.
    Arm type
    		 No intervention

    Investigational medicinal product name
    No investigational medicinal product assigned in this arm
    Arm title
    		 Placebo and Dacarbazine
    Arm description
    		 Placebo: Intravenous solution, intravenous, 0 mg, 1 dose every 3 weeks for 12 weeks, then 1 dose every 12 weeks starting at Week 24; until disease progression (PD), unacceptable toxicity, or withdrawal of consent. Dacarbazine: Intravenous solution, intravenous, 850 mg/m^2, 1 dose every 3 weeks for 22 weeks, until PD, unacceptable toxicity, or withdrawal of consent. Subjects who experienced PD or who did not wish to continue study assessments in the Induction or Maintenance Phases entered the Follow-up Phase.
    Arm type
    		 No intervention

    Investigational medicinal product name
    No investigational medicinal product assigned in this arm
    Number of subjects in period 4
    		Ipilimumab and Dacarbazine Placebo and Dacarbazine
    Started
    11
    6
    Completed
    0
    0
    Not completed
    247
    251
         Physician decision
    2
    -
         Documented Disease Progression
    114
    194
         Still on Treatment
    1
    -
         Other Reasons
    5
    3
         Death
    8
    15
         Deterioration/Undocumented Progression
    10
    8
         Adverse Event Unrelated to Study Drug
    6
    10
         Study Drug Toxicity
    89
    10
         Subject Request
    7
    8
         Administrative Reason by Sponsor
    5
    3
    Joined
    236
    245
         Re-joined for follow-up
    236
    245

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Ipilimumab and Dacarbazine
    Reporting group description
    		 Ipilimumab: Intravenous solution; intravenous; 10 mg/kg; 1 dose every 3 weeks for 12 weeks, then 1 dose every 12 weeks starting at Week 24, until disease progression (PD), unacceptable toxicity, or withdrawal of consent. Dacarbazine: Intravenous solution; intravenous; 850 mg/m^2; 1 dose every 3 weeks for 22 weeks, until PD, unacceptable toxicity, or withdrawal of consent. In Maintenance Phase: Only Ipilimumab: 10 mg/kg, every 12 weeks was continued until PD. Dacarbazine was given up to Week 22 and was not given in the Maintenance Phase. Subjects who experienced PD or who did not wish to continue study assessments in the Induction or Maintenance Phases entered the Follow-up Phase.

    Reporting group title
    Placebo and Dacarbazine
    Reporting group description
    		 Placebo: Intravenous solution, intravenous, 0 mg, 1 dose every 3 weeks for 12 weeks, then 1 dose every 12 weeks starting at Week 24; until disease progression (PD), unacceptable toxicity, or withdrawal of consent. Dacarbazine: Intravenous solution, intravenous, 850 mg/m^2, 1 dose every 3 weeks for 22 weeks, until PD, unacceptable toxicity, or withdrawal of consent. Subjects who experienced PD or who did not wish to continue study assessments in the Induction or Maintenance Phases entered the Follow-up Phase.

    Reporting group values
    		 Ipilimumab and Dacarbazine Placebo and Dacarbazine Total
    Number of subjects
    		 250 252 502
    Age categorical
    Units: Subjects
        <65 years
    		 165 177 342
        >=65 years
    		 85 75 160
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    		 57.5 ( 13.51 ) 56.4 ( 13.71 ) -
    Gender categorical
    Units: Subjects
        Female
    		 98 103 201
        Male
    		 152 149 301

    End points

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    End points reporting groups
    Reporting group title
    Ipilimumab and Dacarbazine
    Reporting group description
    		 Ipilimumab: Intravenous solution; intravenous; 10 mg/kg; 1 dose every 3 weeks for 12 weeks, then 1 dose every 12 weeks starting at Week 24, until disease progression (PD), unacceptable toxicity, or withdrawal of consent. Dacarbazine: Intravenous solution; intravenous; 850 mg/m^2; 1 dose every 3 weeks for 22 weeks, until PD, unacceptable toxicity, or withdrawal of consent. In Maintenance Phase: Only Ipilimumab: 10 mg/kg, every 12 weeks was continued until PD. Dacarbazine was given up to Week 22 and was not given in the Maintenance Phase. Subjects who experienced PD or who did not wish to continue study assessments in the Induction or Maintenance Phases entered the Follow-up Phase.

    Reporting group title
    Placebo and Dacarbazine
    Reporting group description
    		 Placebo: Intravenous solution, intravenous, 0 mg, 1 dose every 3 weeks for 12 weeks, then 1 dose every 12 weeks starting at Week 24; until disease progression (PD), unacceptable toxicity, or withdrawal of consent. Dacarbazine: Intravenous solution, intravenous, 850 mg/m^2, 1 dose every 3 weeks for 22 weeks, until PD, unacceptable toxicity, or withdrawal of consent. Subjects who experienced PD or who did not wish to continue study assessments in the Induction or Maintenance Phases entered the Follow-up Phase.
    Reporting group title
    Ipilimumab and Dacarbazine
    Reporting group description
    		 Ipilimumab: Intravenous solution; intravenous; 10 mg/kg; 1 dose every 3 weeks for 12 weeks, then 1 dose every 12 weeks starting at Week 24, until disease progression (PD), unacceptable toxicity, or withdrawal of consent. Dacarbazine: Intravenous solution; intravenous; 850 mg/m^2; 1 dose every 3 weeks for 22 weeks, until PD, unacceptable toxicity, or withdrawal of consent. In Maintenance Phase: Only Ipilimumab: 10 mg/kg, every 12 weeks was continued until PD. Dacarbazine was given up to Week 22 and was not given in the Maintenance Phase. Subjects who experienced PD or who did not wish to continue study assessments in the Induction or Maintenance Phases entered the Follow-up Phase.

    Reporting group title
    Placebo and Dacarbazine
    Reporting group description
    		 Placebo: Intravenous solution, intravenous, 0 mg, 1 dose every 3 weeks for 12 weeks, then 1 dose every 12 weeks starting at Week 24; until disease progression (PD), unacceptable toxicity, or withdrawal of consent. Dacarbazine: Intravenous solution, intravenous, 850 mg/m^2, 1 dose every 3 weeks for 22 weeks, until PD, unacceptable toxicity, or withdrawal of consent. Subjects who experienced PD or who did not wish to continue study assessments in the Induction or Maintenance Phases entered the Follow-up Phase.
    Reporting group title
    Ipilimumab and Dacarbazine
    Reporting group description
    		 Ipilimumab: Intravenous solution; intravenous; 10 mg/kg; 1 dose every 3 weeks for 12 weeks, then 1 dose every 12 weeks starting at Week 24, until disease progression (PD), unacceptable toxicity, or withdrawal of consent. Dacarbazine: Intravenous solution; intravenous; 850 mg/m^2; 1 dose every 3 weeks for 22 weeks, until PD, unacceptable toxicity, or withdrawal of consent. In Maintenance Phase: Only Ipilimumab: 10 mg/kg, every 12 weeks was continued until PD. Dacarbazine was given up to Week 22 and was not given in the Maintenance Phase. Subjects who experienced PD or who did not wish to continue study assessments in the Induction or Maintenance Phases entered the Follow-up Phase.

    Reporting group title
    Placebo and Dacarbazine
    Reporting group description
    		 Placebo: Intravenous solution, intravenous, 0 mg, 1 dose every 3 weeks for 12 weeks, then 1 dose every 12 weeks starting at Week 24; until disease progression (PD), unacceptable toxicity, or withdrawal of consent. Dacarbazine: Intravenous solution, intravenous, 850 mg/m^2, 1 dose every 3 weeks for 22 weeks, until PD, unacceptable toxicity, or withdrawal of consent. Subjects who experienced PD or who did not wish to continue study assessments in the Induction or Maintenance Phases entered the Follow-up Phase.
    Reporting group title
    Ipilimumab and Dacarbazine
    Reporting group description
    		 Ipilimumab: Intravenous solution; intravenous; 10 mg/kg; 1 dose every 3 weeks for 12 weeks, then 1 dose every 12 weeks starting at Week 24, until disease progression (PD), unacceptable toxicity, or withdrawal of consent. Dacarbazine: Intravenous solution; intravenous; 850 mg/m^2; 1 dose every 3 weeks for 22 weeks, until PD, unacceptable toxicity, or withdrawal of consent. In Maintenance Phase: Only Ipilimumab: 10 mg/kg, every 12 weeks was continued until PD. Dacarbazine was given up to Week 22 and was not given in the Maintenance Phase. Subjects who experienced PD or who did not wish to continue study assessments in the Induction or Maintenance Phases entered the Follow-up Phase.

    Reporting group title
    Placebo and Dacarbazine
    Reporting group description
    		 Placebo: Intravenous solution, intravenous, 0 mg, 1 dose every 3 weeks for 12 weeks, then 1 dose every 12 weeks starting at Week 24; until disease progression (PD), unacceptable toxicity, or withdrawal of consent. Dacarbazine: Intravenous solution, intravenous, 850 mg/m^2, 1 dose every 3 weeks for 22 weeks, until PD, unacceptable toxicity, or withdrawal of consent. Subjects who experienced PD or who did not wish to continue study assessments in the Induction or Maintenance Phases entered the Follow-up Phase.

    Primary: Overall survival (OS)

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    End point title
    		 Overall survival (OS)
    End point description
    OS was defined as the time from the date of randomisation until the date of death. Analysis of OS was to be done once 416 deaths had occurred (primary endpoint). However, analysis occurred at 414 deaths (February 7, 2011), due to operational timing of the study. Median number of months of OS and associated confidence interval calculated using the method of Brookmeyer and Crowley. The analysis was performed in all randomised subjects whose survival follow-up was current (defined as having died or last known alive date occurring on or after the data cutoff date, which was when a total of 414 deaths occurred).
    End point type
    Primary
    End point timeframe
    Date of randomisation to 37 months through 5-year follow-up and up to approximately 76 months
    End point values
    		 Ipilimumab and Dacarbazine Placebo and Dacarbazine
    Number of subjects analysed
    250
    252
    Units: Months
        median (confidence interval 95%)
    11.17 (9.4 to 13.6)
    9.07 (7.75 to 10.51)
    Statistical analysis title
    		 Overall survival
    Statistical analysis description
    The improvement in OS for ipilimumab plus Dacarbazine versus placebo plus Dacarbazine was analysed using Kaplan-Meier plot.
    Comparison groups
    Placebo and Dacarbazine v Ipilimumab and Dacarbazine
    Number of subjects included in analysis
    502
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.0009
    Method
    		 Logrank
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.716
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.588
         upper limit
    		 0.872

    Secondary: Survival Rate at 1 Year, 18 Months, 2 Years, and 3 Years

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    End point title
    		 Survival Rate at 1 Year, 18 Months, 2 Years, and 3 Years
    End point description
    The survival rate (percentage of subjects alive) was defined as the probability that a subject is alive at 1 year (or 18 months, 2 years, or 3 years) following randomisation and was estimated via the Kaplan-Meier method. The analysis was performed in all the subjects who were randomised to a treatment group.
    End point type
    Secondary
    End point timeframe
    Date of randomisation to 3 years following randomisation
    End point values
    		 Ipilimumab and Dacarbazine Placebo and Dacarbazine
    Number of subjects analysed
    250
    252
    Units: Percentage of subjects
    number (confidence interval 95%)
        At 1 year
    47.3 (41 to 53.6)
    36.3 (30.4 to 42.4)
        At 18 months
    35.6 (29.7 to 41.6)
    26.1 (20.7 to 31.6)
        At 2 years
    28.5 (22.9 to 34.2)
    17.9 (13.3 to 22.8)
        At 3 years
    20.8 (15.7 to 26.1)
    12.2 (8.2 to 16.5)
    No statistical analyses for this end point

    Secondary: Disease Control Rate (DCR)

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    End point title
    		 Disease Control Rate (DCR)
    End point description
    DCR=number whose best overall response (BOR) was partial response (PR), complete response (CR) or stable disease (SD), divided by all randomised subjects (unevaluable subjects included). BOR=date of first dose to last tumor assessment prior to subsequent cancer therapy (including tumor resection, excluding palliative local radiotherapy). Modified World Health Organization criteria: CR=disappearance of all lesions; no evidence of progressive disease (PD); PR=50% or more decrease in the sum of products of the longest diameter and greatest perpendicular diameter of all index lesions compared with baseline; SD=neither sufficient decrease to qualify for PR nor sufficient increase to qualify for PD; PD=at least 25% increase in sum of products of all index lesions and/or appearance of any new lesions; nonindex lesions: appearance of any new lesions and/or unequivocal progression of nonindex lesions. The analysis was performed in all the subjects who were randomised to a treatment group.
    End point type
    Secondary
    End point timeframe
    First dose to last tumor assessment prior to subsequent therapy at data cutoff for Primary Endpoint (approximately 5 years)
    End point values
    		 Ipilimumab and Dacarbazine Placebo and Dacarbazine
    Number of subjects analysed
    250
    252
    Units: Percentage of subjects
        number (confidence interval 95%)
    33.2 (27.4 to 39.4)
    30.2 (24.6 to 36.2)
    No statistical analyses for this end point

    Secondary: Median Number of Months of Progression-free Survival (PFS)

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    End point title
    		 Median Number of Months of Progression-free Survival (PFS)
    End point description
    PFS=time between randomisation and date of progression or death, whichever occurs first. Subjects who died without reported prior progression were considered to have progressed on date of death. For those alive and not progressed, PFS was censored on date of last evaluable tumor assessment (TA). Those who have not died and have no recorded postbaseline TA were censored at randomisation. Those who died without any recorded postbaseline TA were considered to have progressed on date of death. Progressive disease defined using modified criteria of the World Health Organization: demonstration of at least a 25% increase in the sum of products of all index lesions or the appearance of any new lesions. For nonindex lesions: appearance of any new lesions or unequivocal progression of nonindex lesions. The analysis was performed in all the subjects who were randomised to a treatment group.
    End point type
    Secondary
    End point timeframe
    Randomisation to date of progression or death to approximately 5 years
    End point values
    		 Ipilimumab and Dacarbazine Placebo and Dacarbazine
    Number of subjects analysed
    250
    252
    Units: Month
    median (confidence interval 95%)
        PFS per IRC
    2.76 (2.63 to 3.29)
    2.6 (2.56 to 2.66)
        PFS per investigator
    2.73 (2.63 to 3.48)
    2.63 (2.6 to 2.73)
    No statistical analyses for this end point

    Secondary: Progression-free Survival (PFS) Rate Truncated at Week 12

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    End point title
    		 Progression-free Survival (PFS) Rate Truncated at Week 12
    End point description
    PFS rate=probability subject was progression-free at Day 78, calculated as total subjects receiving treatment and with an overall response of stable disease (SD), partial response (PR), or complete response (CR) at Week 12, divided by total subjects. For those alive and not progressed at or before Week 12, PFS censored on date of last evaluable tumor assessment (TA) at or before Week 12. Those with an assessment of PD prior to Week 12 and subsequent assessment of SD, PR, or CR at Week 12 were called progression-free at Week 12. Those with no recorded postbaseline TA dated on or before Day 109, and who had not died on or before Day 109, were censored at randomisation. PD=at least 25% increase in sum of products of all index lesions or appearance of any new lesions. Investigator and independent review committee (IRC) assessed radiologic imaging studies, photographs of skin lesions, and clinical data. The analysis was performed in all subjects who were randomised to a treatment group.
    End point type
    Secondary
    End point timeframe
    Day 78
    End point values
    		 Ipilimumab and Dacarbazine Placebo and Dacarbazine
    Number of subjects analysed
    250
    252
    Units: Percentage of subjects
    number (confidence interval 95%)
        PFS rate at Week 12 by IRC
    55.4 (48.6 to 62.1)
    50.7 (44.2 to 57.3)
        PFS rate at Week 12 by Investigator
    58.5 (51.9 to 65)
    54 (47.5 to 60.4)
    No statistical analyses for this end point

    Secondary: Best Overall Response Rate (BORR)

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    End point title
    		 Best Overall Response Rate (BORR)
    End point description
    BORR=number with Best Overall Response (BOR) of complete response (CR) or partial response (PR), divided by total number of randomised subjects. BOR=date of first dose to the last tumor assessment prior to subsequent cancer therapy. Independent review committee (IRC) assessment using modified criteria of the World Health Organization (mWHO): CR=disappearance of all lesions; no evidence of progressive disease; PR=50% or greater decrease in the sum of products of the longest diameter and greatest perpendicular diameter of all index lesions compared with baseline. Immune-related (ir) response criteria assess tumor response in subjects on immunotherapy: irCR=disappearance of all lesions in 2 consecutive observations at least 4 weeks apart; irPR=50% or greater decrease in total measureable tumor burden compared with peak in 2 observations at least 4 weeks apart. Analysis was performed in all subjects who were randomised.
    End point type
    Secondary
    End point timeframe
    First dose to last tumor assessment at data cutoff for primary endpoint (approximately 5 years)
    End point values
    		 Ipilimumab and Dacarbazine Placebo and Dacarbazine
    Number of subjects analysed
    250
    252
    Units: Percentage of subjects
    number (confidence interval 95%)
        IRC BORR
    15.2 (11 to 20.3)
    10.3 (6.9 to 14.8)
        irBORR
    16.8 (12.4 to 22)
    11.1 (7.5 to 15.7)
    No statistical analyses for this end point

    Secondary: Duration of Response (DOR): Randomised Subjects With Response of Complete Response (CR) or Partial Response (PR)

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    End point title
    		 Duration of Response (DOR): Randomised Subjects With Response of Complete Response (CR) or Partial Response (PR)
    End point description
    DOR was defined as time between first date of CR or PR, and the date of no progressive disease or death (whichever occurred first) in subjects with best overall response as CR or PR. Subjects who remained alive, DOR was last evaluable Tumor Assessment. IRC assessment using mWHO criteria : CR as disappearance of all lesions within 4 weeks, PR as >=50% decrease in index lesions from baseline, 25% increase compared to nadir or 50% decrease in SPD from baseline for PD and SD respectively. Immune-related (ir) response criteria defined CR as disappearance of all lesions within 4 weeks, PR as >=50% decrease in Total Measurable Tumor Burden (TMTB) from baseline, 25% increase compared to nadir or 50% decrease in TMTB from baseline for PD and SD respectively. Analysis was performed in subjects who were randomised and responded to CR, PR, irCR, or irPR. Here, ‘n’ signifies subjects who responded by mWHO and irRC criteria.
    End point type
    Secondary
    End point timeframe
    Day of CR or PR to day of PD or death up to data cutoff for primary endpoint (approximately 5 years)
    End point values
    		 Ipilimumab and Dacarbazine Placebo and Dacarbazine
    Number of subjects analysed
    250
    252
    Units: Months
    median (confidence interval 95%)
        IRC DOR (n=38, 26)
    19.3 (12.1 to 26.1)
    8.1 (5.2 to 19.8)
        ir-DOR (n=42, 28)
    21.1 (16.5 to 26.1)
    10.2 (5.6 to 24)
    No statistical analyses for this end point

    Secondary: Time to Response: All Randomised Subjects With Response to Treatment

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    End point title
    		 Time to Response: All Randomised Subjects With Response to Treatment
    End point description
    Time to response was defined as the time between the first dose of study therapy and the date when measurement criteria were met for Best Overall Response (BOR) of partial response (PR) or complete response (CR), whichever occurred first, per independent review committee. Note that if an overall response of PR occurred before confirmation of CR, the time to response endpoint was not determined by the time that the BOR of CR was shown but rather by the earlier time point showing PR. Modified criteria of the World Health Organization: CR=disappearance of all lesions; no evidence of progressive disease (PD); PR=50% or more decrease in the sum of products of the longest and greatest perpendicular diameters (SPD) of all index lesions compared with baseline; PD=an increase of 25% or greater in the SPD of index lesions compared with the smallest recorded sum, or the appearance of 1 or more new lesions. The analysis was performed in all the subjects who were randomised to a treatment group.
    End point type
    Secondary
    End point timeframe
    First dose to date of BOR up to data cutoff for primary endpoint (approximately 5 years)
    End point values
    		 Ipilimumab and Dacarbazine Placebo and Dacarbazine
    Number of subjects analysed
    250
    252
    Units: Month
        median (full range (min-max))
    2.6 (2.3 to 3.9)
    2.7 (2.5 to 5.7)
    No statistical analyses for this end point

    Secondary: Duration of Stable Disease (SD): Randomised Subjects With Stable Disease

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    End point title
    		 Duration of Stable Disease (SD): Randomised Subjects With Stable Disease
    End point description
    Duration of SD was defined as the time between Week 12 and date of progressive disease (PD) or death, whichever occurs first in subjects whose Best Overall Response (BOR) was SD. Subjects who underwent tumor resection following Week 12 but prior to PD, duration of SD was censored on date of last evaluable tumor assessment (TA) prior to resection. For those with BOR of SD at Week 12, date of PD was used in analysis of duration of SD. For those with BOR=SD who have not subsequently progressed and who remain alive, duration of SD censored on date of last evaluable TA. Independent review committee (IRC) assessment using mWHO criteria:SD=insufficient decrease to qualify for partial response or sufficient increase to qualify for PD; PD=an increase of 25% or more in sum of products of longest diameter and greatest perpendicular diameter of index lesions compared with smallest recorded sum, or appearance of 1 or more new lesions. Analysis was performed in all the subjects who were randomised.
    End point type
    Secondary
    End point timeframe
    Week 12 to date of disease progression or death up to data cutoff for primary endpoint (approximately 5 years)
    End point values
    		 Ipilimumab and Dacarbazine Placebo and Dacarbazine
    Number of subjects analysed
    250
    252
    Units: Months
    median (confidence interval 95%)
        IRC (n=45, 50)
    4.7 (1.9 to 9.2)
    4.6 (3.2 to 6.9)
        Immune-related (n=45, 57)
    4.8 (2.8 to 7.7)
    3.4 (2.5 to 5.2)
    No statistical analyses for this end point

    Secondary: Percentage of Subjects With Brain Metastasis-Free Survival at Time of Data Cutoff

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    End point title
    		 Percentage of Subjects With Brain Metastasis-Free Survival at Time of Data Cutoff
    End point description
    Brain metastasis-free survival was defined as the time from randomisation to the date of progression with a new lesion located in the brain. New brain lesions prior to Week 12 constituted a progression event (unlike main progression-free survival analysis). A subject who dies without documentation of a brain lesion was considered to have progressed with brain metastasis on the date of death. Subjects who are free of brain metastasis were censored on the date of their last tumor assessment. An independent review committee evaluated images of subjects with clinical symptoms to determine the number of those free of brain metastasis. The brain metastasis-free status was reported as a percent of subjects (n/N), where n= subjects with metastasis-free brains at data cutoff for the Primary Endpoint and N= randomised subjects. A 2-sided Clopper and Pearson confidence interval was performed. Analysis was performed in all the subjects who were randomised.
    End point type
    Secondary
    End point timeframe
    Date of randomisation up to data cutoff for primary endpoint (approximately 5 years)
    End point values
    		 Ipilimumab and Dacarbazine Placebo and Dacarbazine
    Number of subjects analysed
    250
    252
    Units: Percentage of subjects
        number (confidence interval 95%)
    93.6 (89.8 to 96.3)
    90.9 (86.6 to 94.1)
    No statistical analyses for this end point

    Secondary: Number of Subjects With Adverse Events (AEs), Drug-related AEs, AEs Leading to Discontinuation, Serious Adverse Events (SAEs), Drug-related SAEs, Drug-related Hypersensitivity, Immune-related AEs/SAEs, and Inflammatory AEs/SAEs

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    End point title
    		 Number of Subjects With Adverse Events (AEs), Drug-related AEs, AEs Leading to Discontinuation, Serious Adverse Events (SAEs), Drug-related SAEs, Drug-related Hypersensitivity, Immune-related AEs/SAEs, and Inflammatory AEs/SAEs
    End point description
    AE=any new undesirable symptom, sign, clinically significant laboratory abnormality, or medical condition occurring after starting study treatment, even if the event was not considered to be drug-related. SAE=a medical event that at any dose results in death, persistent or significant disability/incapacity, or drug dependency/abuse; is life-threatening, an important medical event, or a congenital anomaly/birth defect; or requires or prolongs hospitalization. Treatment-related=having certain, probable, possible, or missing relationship to study drug. Grade (Gr) 1=Mild, Gr 2=Moderate, Gr 3=Severe, Gr 4= Potentially Life-threatening or disabling. Randomisation=Day 1; start of treatment (first dose) =Week 1. Summarization time frame is from first dose to 70 days after last dose of study at time of 414 deaths. The analysis was performed in all the subjects who received at least 1 dose of the study drug.
    End point type
    Secondary
    End point timeframe
    Week 1 (First Dose) to 70 days after last dose of study up to data cutoff for primary endpoint (approximately 5 years)
    End point values
    		 Ipilimumab and Dacarbazine Placebo and Dacarbazine
    Number of subjects analysed
    247
    251
    Units: Subjects
        AEs
    244
    236
        Drug-related AEs
    221
    192
        Discontinuations due to AEs
    114
    46
        SAEs
    170
    121
        Drug-related SAEs
    116
    17
        Drug-related hypersensitivity
    15
    6
        Immune-related AEs
    187
    77
        Immune-related SAEs
    91
    3
        Inflammatory AEs
    201
    117
        Inflammatory SAEs
    101
    9
    No statistical analyses for this end point

    Secondary: Number of subjects With Grade 2-4 and Grade 3-4 Immune-related Adverse Events (irAEs) With Resolution Resolved

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    End point title
    		 Number of subjects With Grade 2-4 and Grade 3-4 Immune-related Adverse Events (irAEs) With Resolution Resolved
    End point description
    IrAEs included the categories: gastrointestinal (GI), diarrhea, liver, endocrine, and skin. Grade 2=moderate adverse events (AEs); minimal, local, or noninvasive intervention indicated. Grade 3=severe AEs, medically significant but not immediately life-threatening. Grade 4=life-threatening consequences; urgent intervention indicated. Resolution is defined as improvement to Grade 1 or less or to the Grade at baseline (prior to treatment). The analysis was performed in all the subjects who received at least 1 dose of the study drug and had this specific event. Here 'n' signifies number of subjects evaluable for this outcome measure in both treatment arm respectively.
    End point type
    Secondary
    End point timeframe
    Week 1 (first dose) to 70 days after last dose up to data cutoff for primary endpoint (approximately 5 years)
    End point values
    		 Ipilimumab and Dacarbazine Placebo and Dacarbazine
    Number of subjects analysed
    247
    251
    Units: Subjects
        GI AE Grade 2-4 (n=39, 7)
    36
    7
        GI AE Grade 3-4 (n=14, 0)
    13
    0
        Liver AE Grade 2-4 (n=89, 8)
    81
    4
        Liver AE Grade 3-4 (n=69, 5)
    63
    2
        Skin AE Grade 2-4 (n=46, 2)
    42
    2
        Skin AE Grade 3-4 (n=8, 0)
    6
    0
        Diarrhea AE Grade 2-4 (n=31, 7)
    29
    7
        Diarrhea AE Grade 3-4 (n=10, 0)
    9
    0
    No statistical analyses for this end point

    Secondary: Time to Resolution of Grade 2-4, Grade 3-4 Immune-related Adverse Events (IrAEs)

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    End point title
    		 Time to Resolution of Grade 2-4, Grade 3-4 Immune-related Adverse Events (IrAEs)
    End point description
    IrAEs included the categories: gastrointestinal (GI), diarrhea, liver, endocrine, and skin. Grade 2=Moderate adverse events (AEs); minimal, local or noninvasive intervention indicated. Grade 3=severe AEs, medically significant but not immediately life-threatening. Grade 4=life-threatening consequences; urgent intervention indicated. Time to resolution is defined as improvement to Grade 1 or less or to the Grade at baseline (prior to treatment). The analysis was performed in all the subjects who received at least 1 dose of the study drug and had this specific event that resolved. Here “99999” represents that median time to resolution could not be computed due to low/no occurrence of either the resolution of the AE or low/no occurrence the AE in this arm. Here 'n' signifies number of subjects evaluable for this outcome measure.
    End point type
    Secondary
    End point timeframe
    Week 1 (first dose) to 70 days after last dose up to database lock for primary endpoint (approximately 5 years)
    End point values
    		 Ipilimumab and Dacarbazine Placebo and Dacarbazine
    Number of subjects analysed
    247
    251
    Units: Weeks
    median (confidence interval 95%)
        GI AE Grade 2-4 (n=36, 7)
    2 (1.14 to 2.71)
    0.14 (0.14 to 0.29)
        GI Grade 3-4 (n=13, 0)
    2.14 (2 to 4.57)
    99999 (99999 to 99999)
        Liver AE Grade 2-4 (n=81, 4)
    3.43 (3.14 to 4.43)
    99999 (99999 to 99999)
        Liver AE Grade 3-4 (n=63, 2)
    3.43 (3 to 4.43)
    99999 (99999 to 99999)
        Skin AE Grade 2-4 (n=42, 2)
    4.71 (3.14 to 7)
    0.93 (0.57 to 1.29)
        Skin AE Grade 3-4 (n=6, 0)
    4.71 (3.14 to 5.29)
    99999 (99999 to 99999)
        Diarrhea AE Grade 2-4 (n=29, 7)
    1.43 (0.71 to 2.57)
    0.14 (0.14 to 0.29)
        Diarrhea AE Grade 3-4 (n=9, 0)
    2 (0.71 to 2.57)
    99999 (99999 to 99999)
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Week 1 (First Dose) to 70 days after last dose of study drug up to last subject, last visit (LPLV) of follow up period; approximately 7 years.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    16.1
    Reporting groups
    Reporting group title
    Ipilimumab and Dacarbazine
    Reporting group description
    		 Ipilimumab: Intravenous solution; intravenous; 10 mg/kg; 1 dose every 3 weeks for 12 weeks, then 1 dose every 12 weeks starting at Week 24, until disease progression (PD), unacceptable toxicity, or withdrawal of consent. Dacarbazine: Intravenous solution; intravenous; 850 mg/m^2; 1 dose every 3 weeks for 22 weeks, until PD, unacceptable toxicity, or withdrawal of consent. In Maintenance Phase: Only Ipilimumab: 10 mg/kg, every 12 weeks was continued until PD. Dacarbazine was given up to Week 22 and was not given in the Maintenance Phase. Subjects who experienced PD or who did not wish to continue study assessments in the Induction or Maintenance Phases entered the Follow-up Phase.

    Reporting group title
    Placebo and Dacarbazine
    Reporting group description
    		 Placebo: Intravenous solution, intravenous, 0 mg, 1 dose every 3 weeks for 12 weeks, then 1 dose every 12 weeks starting at Week 24; until disease progression (PD), unacceptable toxicity, or withdrawal of consent. Dacarbazine: Intravenous solution, intravenous, 850 mg/m^2, 1 dose every 3 weeks for 22 weeks, until PD, unacceptable toxicity, or withdrawal of consent. Subjects who experienced PD or who did not wish to continue study assessments in the Induction or Maintenance Phases entered the Follow-up Phase.

    Serious adverse events
    		 Ipilimumab and Dacarbazine Placebo and Dacarbazine
    Total subjects affected by serious adverse events
         subjects affected / exposed
    170 / 247 (68.83%)
    121 / 251 (48.21%)
         number of deaths (all causes)
    193
    217
         number of deaths resulting from adverse events
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Malignant melanoma
         subjects affected / exposed
    1 / 247 (0.40%)
    2 / 251 (0.80%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 6
    0 / 6
    Laryngeal neoplasm
         subjects affected / exposed
    0 / 247 (0.00%)
    1 / 251 (0.40%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Neoplasm progression
         subjects affected / exposed
    2 / 247 (0.81%)
    2 / 251 (0.80%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 2
         deaths causally related to treatment / all
    0 / 3
    0 / 3
    Malignant pleural effusion
         subjects affected / exposed
    1 / 247 (0.40%)
    0 / 251 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Rectal cancer
         subjects affected / exposed
    0 / 247 (0.00%)
    1 / 251 (0.40%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Brain neoplasm
         subjects affected / exposed
    0 / 247 (0.00%)
    1 / 251 (0.40%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Malignant neoplasm progression
         subjects affected / exposed
    35 / 247 (14.17%)
    58 / 251 (23.11%)
         occurrences causally related to treatment / all
    0 / 36
    0 / 58
         deaths causally related to treatment / all
    0 / 58
    0 / 81
    Transitional cell carcinoma
         subjects affected / exposed
    0 / 247 (0.00%)
    1 / 251 (0.40%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Tumour haemorrhage
         subjects affected / exposed
    1 / 247 (0.40%)
    1 / 251 (0.40%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Metastases to central nervous system
         subjects affected / exposed
    1 / 247 (0.40%)
    5 / 251 (1.99%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 5
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Metastases to skin
         subjects affected / exposed
    0 / 247 (0.00%)
    2 / 251 (0.80%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Myelodysplastic syndrome
         subjects affected / exposed
    0 / 247 (0.00%)
    1 / 251 (0.40%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Malignant ascites
         subjects affected / exposed
    1 / 247 (0.40%)
    0 / 251 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Tumour pain
         subjects affected / exposed
    1 / 247 (0.40%)
    0 / 251 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Metastatic malignant melanoma
         subjects affected / exposed
    2 / 247 (0.81%)
    3 / 251 (1.20%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 3
         deaths causally related to treatment / all
    0 / 1
    0 / 1
    Vascular disorders
    Hypotension
         subjects affected / exposed
    3 / 247 (1.21%)
    1 / 251 (0.40%)
         occurrences causally related to treatment / all
    2 / 3
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Peripheral artery thrombosis
         subjects affected / exposed
    1 / 247 (0.40%)
    0 / 251 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Phlebitis
         subjects affected / exposed
    0 / 247 (0.00%)
    1 / 251 (0.40%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Poor venous access
         subjects affected / exposed
    0 / 247 (0.00%)
    1 / 251 (0.40%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Thrombophlebitis
         subjects affected / exposed
    0 / 247 (0.00%)
    1 / 251 (0.40%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Haemorrhage
         subjects affected / exposed
    0 / 247 (0.00%)
    1 / 251 (0.40%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Thrombosis
         subjects affected / exposed
    1 / 247 (0.40%)
    0 / 251 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Superior vena cava syndrome
         subjects affected / exposed
    0 / 247 (0.00%)
    1 / 251 (0.40%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Aortic disorder
         subjects affected / exposed
    1 / 247 (0.40%)
    0 / 251 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Deep vein thrombosis
         subjects affected / exposed
    0 / 247 (0.00%)
    1 / 251 (0.40%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypertension
         subjects affected / exposed
    1 / 247 (0.40%)
    0 / 251 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    General disorders and administration site conditions
    General physical health deterioration
         subjects affected / exposed
    2 / 247 (0.81%)
    0 / 251 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 2
    0 / 0
    Malaise
         subjects affected / exposed
    1 / 247 (0.40%)
    0 / 251 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Asthenia
         subjects affected / exposed
    0 / 247 (0.00%)
    2 / 251 (0.80%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Condition aggravated
         subjects affected / exposed
    0 / 247 (0.00%)
    1 / 251 (0.40%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Fatigue
         subjects affected / exposed
    6 / 247 (2.43%)
    5 / 251 (1.99%)
         occurrences causally related to treatment / all
    3 / 7
    2 / 6
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Pyrexia
         subjects affected / exposed
    19 / 247 (7.69%)
    4 / 251 (1.59%)
         occurrences causally related to treatment / all
    15 / 19
    4 / 5
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Sudden death
         subjects affected / exposed
    0 / 247 (0.00%)
    1 / 251 (0.40%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Hyperpyrexia
         subjects affected / exposed
    1 / 247 (0.40%)
    0 / 251 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Mucosal inflammation
         subjects affected / exposed
    1 / 247 (0.40%)
    0 / 251 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Systemic inflammatory response syndrome
         subjects affected / exposed
    1 / 247 (0.40%)
    0 / 251 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    1 / 1
    0 / 0
    Chills
         subjects affected / exposed
    2 / 247 (0.81%)
    0 / 251 (0.00%)
         occurrences causally related to treatment / all
    2 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pain
         subjects affected / exposed
    1 / 247 (0.40%)
    3 / 251 (1.20%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Performance status decreased
         subjects affected / exposed
    1 / 247 (0.40%)
    0 / 251 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Chest pain
         subjects affected / exposed
    1 / 247 (0.40%)
    0 / 251 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Disease progression
         subjects affected / exposed
    0 / 247 (0.00%)
    1 / 251 (0.40%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    0 / 1
    Hyperthermia
         subjects affected / exposed
    1 / 247 (0.40%)
    1 / 251 (0.40%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hernia pain
         subjects affected / exposed
    1 / 247 (0.40%)
    0 / 251 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Oedema
         subjects affected / exposed
    1 / 247 (0.40%)
    0 / 251 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Oedema peripheral
         subjects affected / exposed
    1 / 247 (0.40%)
    0 / 251 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Immune system disorders
    Autoimmune disorder
         subjects affected / exposed
    2 / 247 (0.81%)
    0 / 251 (0.00%)
         occurrences causally related to treatment / all
    2 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Sarcoidosis
         subjects affected / exposed
    1 / 247 (0.40%)
    0 / 251 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypersensitivity
         subjects affected / exposed
    2 / 247 (0.81%)
    0 / 251 (0.00%)
         occurrences causally related to treatment / all
    2 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Bronchospasm
         subjects affected / exposed
    1 / 247 (0.40%)
    0 / 251 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pleuritic pain
         subjects affected / exposed
    0 / 247 (0.00%)
    1 / 251 (0.40%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Chronic obstructive pulmonary disease
         subjects affected / exposed
    1 / 247 (0.40%)
    0 / 251 (0.00%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Haemoptysis
         subjects affected / exposed
    0 / 247 (0.00%)
    1 / 251 (0.40%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pleural effusion
         subjects affected / exposed
    2 / 247 (0.81%)
    4 / 251 (1.59%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pulmonary sarcoidosis
         subjects affected / exposed
    1 / 247 (0.40%)
    0 / 251 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Aspiration
         subjects affected / exposed
    0 / 247 (0.00%)
    1 / 251 (0.40%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Dyspnoea
         subjects affected / exposed
    3 / 247 (1.21%)
    6 / 251 (2.39%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 6
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonitis
         subjects affected / exposed
    2 / 247 (0.81%)
    0 / 251 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory failure
         subjects affected / exposed
    1 / 247 (0.40%)
    1 / 251 (0.40%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Pulmonary embolism
         subjects affected / exposed
    0 / 247 (0.00%)
    4 / 251 (1.59%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 4
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Psychiatric disorders
    Confusional state
         subjects affected / exposed
    2 / 247 (0.81%)
    1 / 251 (0.40%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Mental status changes
         subjects affected / exposed
    0 / 247 (0.00%)
    2 / 251 (0.80%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Completed suicide
         subjects affected / exposed
    0 / 247 (0.00%)
    1 / 251 (0.40%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Investigations
    Blood alkaline phosphatase increased
         subjects affected / exposed
    2 / 247 (0.81%)
    0 / 251 (0.00%)
         occurrences causally related to treatment / all
    2 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Haemoglobin decreased
         subjects affected / exposed
    1 / 247 (0.40%)
    1 / 251 (0.40%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Weight decreased
         subjects affected / exposed
    1 / 247 (0.40%)
    0 / 251 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Aspartate aminotransferase increased
         subjects affected / exposed
    48 / 247 (19.43%)
    1 / 251 (0.40%)
         occurrences causally related to treatment / all
    72 / 73
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Blood creatinine increased
         subjects affected / exposed
    0 / 247 (0.00%)
    1 / 251 (0.40%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Liver function test abnormal
         subjects affected / exposed
    1 / 247 (0.40%)
    0 / 251 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gamma-glutamyltransferase increased
         subjects affected / exposed
    4 / 247 (1.62%)
    1 / 251 (0.40%)
         occurrences causally related to treatment / all
    3 / 4
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Glucose tolerance increased
         subjects affected / exposed
    1 / 247 (0.40%)
    0 / 251 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatic enzyme increased
         subjects affected / exposed
    1 / 247 (0.40%)
    0 / 251 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Alanine aminotransferase increased
         subjects affected / exposed
    49 / 247 (19.84%)
    1 / 251 (0.40%)
         occurrences causally related to treatment / all
    68 / 70
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Platelet count decreased
         subjects affected / exposed
    0 / 247 (0.00%)
    1 / 251 (0.40%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Blood bilirubin increased
         subjects affected / exposed
    3 / 247 (1.21%)
    0 / 251 (0.00%)
         occurrences causally related to treatment / all
    2 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Femoral neck fracture
         subjects affected / exposed
    0 / 247 (0.00%)
    2 / 251 (0.80%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Femur fracture
         subjects affected / exposed
    0 / 247 (0.00%)
    1 / 251 (0.40%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Fall
         subjects affected / exposed
    0 / 247 (0.00%)
    1 / 251 (0.40%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infusion related reaction
         subjects affected / exposed
    2 / 247 (0.81%)
    0 / 251 (0.00%)
         occurrences causally related to treatment / all
    3 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Clavicle fracture
         subjects affected / exposed
    0 / 247 (0.00%)
    1 / 251 (0.40%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Humerus fracture
         subjects affected / exposed
    0 / 247 (0.00%)
    1 / 251 (0.40%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Wrist fracture
         subjects affected / exposed
    0 / 247 (0.00%)
    1 / 251 (0.40%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac disorders
    Acute myocardial infarction
         subjects affected / exposed
    1 / 247 (0.40%)
    0 / 251 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Myocardial infarction
         subjects affected / exposed
    0 / 247 (0.00%)
    2 / 251 (0.80%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Ventricular tachycardia
         subjects affected / exposed
    0 / 247 (0.00%)
    1 / 251 (0.40%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Atrial fibrillation
         subjects affected / exposed
    1 / 247 (0.40%)
    0 / 251 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pericardial effusion
         subjects affected / exposed
    0 / 247 (0.00%)
    1 / 251 (0.40%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Atrial flutter
         subjects affected / exposed
    0 / 247 (0.00%)
    1 / 251 (0.40%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Sinus tachycardia
         subjects affected / exposed
    0 / 247 (0.00%)
    1 / 251 (0.40%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Arteriosclerosis coronary artery
         subjects affected / exposed
    1 / 247 (0.40%)
    0 / 251 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Supraventricular tachycardia
         subjects affected / exposed
    1 / 247 (0.40%)
    0 / 251 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nervous system disorders
    Hemiparesis
         subjects affected / exposed
    0 / 247 (0.00%)
    1 / 251 (0.40%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Syncope
         subjects affected / exposed
    2 / 247 (0.81%)
    1 / 251 (0.40%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Dysarthria
         subjects affected / exposed
    0 / 247 (0.00%)
    1 / 251 (0.40%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Epilepsy
         subjects affected / exposed
    0 / 247 (0.00%)
    1 / 251 (0.40%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Peripheral motor neuropathy
         subjects affected / exposed
    1 / 247 (0.40%)
    1 / 251 (0.40%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Speech disorder
         subjects affected / exposed
    0 / 247 (0.00%)
    1 / 251 (0.40%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Aphasia
         subjects affected / exposed
    1 / 247 (0.40%)
    0 / 251 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Dizziness
         subjects affected / exposed
    2 / 247 (0.81%)
    0 / 251 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypoglycaemic seizure
         subjects affected / exposed
    1 / 247 (0.40%)
    0 / 251 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Convulsion
         subjects affected / exposed
    0 / 247 (0.00%)
    1 / 251 (0.40%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Sciatica
         subjects affected / exposed
    0 / 247 (0.00%)
    1 / 251 (0.40%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cerebral ischaemia
         subjects affected / exposed
    1 / 247 (0.40%)
    1 / 251 (0.40%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    0 / 1
    Headache
         subjects affected / exposed
    5 / 247 (2.02%)
    0 / 251 (0.00%)
         occurrences causally related to treatment / all
    4 / 5
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lethargy
         subjects affected / exposed
    1 / 247 (0.40%)
    0 / 251 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nervous system disorder
         subjects affected / exposed
    1 / 247 (0.40%)
    0 / 251 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Peripheral sensory neuropathy
         subjects affected / exposed
    1 / 247 (0.40%)
    0 / 251 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Somnolence
         subjects affected / exposed
    1 / 247 (0.40%)
    0 / 251 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cerebral haemorrhage
         subjects affected / exposed
    0 / 247 (0.00%)
    4 / 251 (1.59%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Presyncope
         subjects affected / exposed
    1 / 247 (0.40%)
    1 / 251 (0.40%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cranial nerve disorder
         subjects affected / exposed
    0 / 247 (0.00%)
    1 / 251 (0.40%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Haemorrhage intracranial
         subjects affected / exposed
    0 / 247 (0.00%)
    1 / 251 (0.40%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    Neutropenia
         subjects affected / exposed
    4 / 247 (1.62%)
    5 / 251 (1.99%)
         occurrences causally related to treatment / all
    4 / 4
    5 / 8
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Coagulopathy
         subjects affected / exposed
    1 / 247 (0.40%)
    0 / 251 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Febrile bone marrow aplasia
         subjects affected / exposed
    0 / 247 (0.00%)
    1 / 251 (0.40%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lymphadenopathy
         subjects affected / exposed
    1 / 247 (0.40%)
    0 / 251 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Anaemia
         subjects affected / exposed
    4 / 247 (1.62%)
    4 / 251 (1.59%)
         occurrences causally related to treatment / all
    2 / 4
    5 / 7
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Eosinophilia
         subjects affected / exposed
    1 / 247 (0.40%)
    0 / 251 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Thrombocytopenia
         subjects affected / exposed
    6 / 247 (2.43%)
    3 / 251 (1.20%)
         occurrences causally related to treatment / all
    7 / 8
    1 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Leukocytosis
         subjects affected / exposed
    0 / 247 (0.00%)
    1 / 251 (0.40%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Leukopenia
         subjects affected / exposed
    0 / 247 (0.00%)
    2 / 251 (0.80%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Febrile neutropenia
         subjects affected / exposed
    3 / 247 (1.21%)
    0 / 251 (0.00%)
         occurrences causally related to treatment / all
    3 / 4
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Eye disorders
    Vitreous haemorrhage
         subjects affected / exposed
    1 / 247 (0.40%)
    0 / 251 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Nausea
         subjects affected / exposed
    3 / 247 (1.21%)
    7 / 251 (2.79%)
         occurrences causally related to treatment / all
    3 / 3
    4 / 8
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ileus
         subjects affected / exposed
    0 / 247 (0.00%)
    1 / 251 (0.40%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ascites
         subjects affected / exposed
    1 / 247 (0.40%)
    5 / 251 (1.99%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 9
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Intestinal polyp haemorrhage
         subjects affected / exposed
    1 / 247 (0.40%)
    0 / 251 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Proctocolitis
         subjects affected / exposed
    1 / 247 (0.40%)
    0 / 251 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Abdominal distension
         subjects affected / exposed
    0 / 247 (0.00%)
    1 / 251 (0.40%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Abdominal pain
         subjects affected / exposed
    3 / 247 (1.21%)
    3 / 251 (1.20%)
         occurrences causally related to treatment / all
    1 / 3
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Colitis
         subjects affected / exposed
    8 / 247 (3.24%)
    0 / 251 (0.00%)
         occurrences causally related to treatment / all
    10 / 10
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Diarrhoea
         subjects affected / exposed
    16 / 247 (6.48%)
    1 / 251 (0.40%)
         occurrences causally related to treatment / all
    23 / 23
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Dysphagia
         subjects affected / exposed
    1 / 247 (0.40%)
    1 / 251 (0.40%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal haemorrhage
         subjects affected / exposed
    0 / 247 (0.00%)
    1 / 251 (0.40%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    1 / 1
    Pancreatitis
         subjects affected / exposed
    1 / 247 (0.40%)
    0 / 251 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vomiting
         subjects affected / exposed
    10 / 247 (4.05%)
    4 / 251 (1.59%)
         occurrences causally related to treatment / all
    10 / 10
    2 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Abdominal pain upper
         subjects affected / exposed
    0 / 247 (0.00%)
    1 / 251 (0.40%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Constipation
         subjects affected / exposed
    1 / 247 (0.40%)
    2 / 251 (0.80%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Small intestinal obstruction
         subjects affected / exposed
    0 / 247 (0.00%)
    1 / 251 (0.40%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastric haemorrhage
         subjects affected / exposed
    0 / 247 (0.00%)
    1 / 251 (0.40%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Haematemesis
         subjects affected / exposed
    0 / 247 (0.00%)
    2 / 251 (0.80%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Proctitis
         subjects affected / exposed
    1 / 247 (0.40%)
    0 / 251 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Upper gastrointestinal haemorrhage
         subjects affected / exposed
    0 / 247 (0.00%)
    1 / 251 (0.40%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal obstruction
         subjects affected / exposed
    0 / 247 (0.00%)
    1 / 251 (0.40%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Hepatobiliary disorders
    Hepatic function abnormal
         subjects affected / exposed
    2 / 247 (0.81%)
    0 / 251 (0.00%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatitis
         subjects affected / exposed
    3 / 247 (1.21%)
    0 / 251 (0.00%)
         occurrences causally related to treatment / all
    4 / 4
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatotoxicity
         subjects affected / exposed
    3 / 247 (1.21%)
    0 / 251 (0.00%)
         occurrences causally related to treatment / all
    3 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hyperbilirubinaemia
         subjects affected / exposed
    1 / 247 (0.40%)
    0 / 251 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatic failure
         subjects affected / exposed
    1 / 247 (0.40%)
    1 / 251 (0.40%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatitis acute
         subjects affected / exposed
    1 / 247 (0.40%)
    1 / 251 (0.40%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cholecystitis acute
         subjects affected / exposed
    0 / 247 (0.00%)
    1 / 251 (0.40%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cholelithiasis
         subjects affected / exposed
    1 / 247 (0.40%)
    0 / 251 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Autoimmune hepatitis
         subjects affected / exposed
    4 / 247 (1.62%)
    0 / 251 (0.00%)
         occurrences causally related to treatment / all
    4 / 4
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cholecystitis
         subjects affected / exposed
    1 / 247 (0.40%)
    0 / 251 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Skin and subcutaneous tissue disorders
    Pruritus
         subjects affected / exposed
    1 / 247 (0.40%)
    0 / 251 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Exfoliative rash
         subjects affected / exposed
    1 / 247 (0.40%)
    0 / 251 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Rash
         subjects affected / exposed
    1 / 247 (0.40%)
    0 / 251 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Rash erythematous
         subjects affected / exposed
    1 / 247 (0.40%)
    0 / 251 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal and urinary disorders
    Nephritis
         subjects affected / exposed
    0 / 247 (0.00%)
    1 / 251 (0.40%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Oliguria
         subjects affected / exposed
    1 / 247 (0.40%)
    0 / 251 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Proteinuria
         subjects affected / exposed
    0 / 247 (0.00%)
    1 / 251 (0.40%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal failure acute
         subjects affected / exposed
    2 / 247 (0.81%)
    0 / 251 (0.00%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal failure
         subjects affected / exposed
    2 / 247 (0.81%)
    2 / 251 (0.80%)
         occurrences causally related to treatment / all
    1 / 3
    0 / 2
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Urinary retention
         subjects affected / exposed
    2 / 247 (0.81%)
    1 / 251 (0.40%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Endocrine disorders
    Autoimmune thyroiditis
         subjects affected / exposed
    1 / 247 (0.40%)
    0 / 251 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Endocrine disorder
         subjects affected / exposed
    1 / 247 (0.40%)
    0 / 251 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Arthritis
         subjects affected / exposed
    1 / 247 (0.40%)
    0 / 251 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pathological fracture
         subjects affected / exposed
    2 / 247 (0.81%)
    0 / 251 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bone pain
         subjects affected / exposed
    1 / 247 (0.40%)
    0 / 251 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Musculoskeletal pain
         subjects affected / exposed
    1 / 247 (0.40%)
    3 / 251 (1.20%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Neck mass
         subjects affected / exposed
    1 / 247 (0.40%)
    0 / 251 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Arthralgia
         subjects affected / exposed
    1 / 247 (0.40%)
    0 / 251 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Musculoskeletal chest pain
         subjects affected / exposed
    1 / 247 (0.40%)
    0 / 251 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Back pain
         subjects affected / exposed
    3 / 247 (1.21%)
    3 / 251 (1.20%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Flank pain
         subjects affected / exposed
    0 / 247 (0.00%)
    1 / 251 (0.40%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pain in extremity
         subjects affected / exposed
    2 / 247 (0.81%)
    0 / 251 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Axillary mass
         subjects affected / exposed
    1 / 247 (0.40%)
    0 / 251 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Muscular weakness
         subjects affected / exposed
    3 / 247 (1.21%)
    3 / 251 (1.20%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infections and infestations
    Urinary tract infection
         subjects affected / exposed
    1 / 247 (0.40%)
    0 / 251 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bronchopneumonia
         subjects affected / exposed
    0 / 247 (0.00%)
    1 / 251 (0.40%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Device related infection
         subjects affected / exposed
    2 / 247 (0.81%)
    1 / 251 (0.40%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Herpes zoster
         subjects affected / exposed
    1 / 247 (0.40%)
    0 / 251 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lobar pneumonia
         subjects affected / exposed
    2 / 247 (0.81%)
    0 / 251 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Meningitis aseptic
         subjects affected / exposed
    1 / 247 (0.40%)
    0 / 251 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Oral herpes
         subjects affected / exposed
    1 / 247 (0.40%)
    0 / 251 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Soft tissue infection
         subjects affected / exposed
    1 / 247 (0.40%)
    0 / 251 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Groin infection
         subjects affected / exposed
    1 / 247 (0.40%)
    0 / 251 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Kidney infection
         subjects affected / exposed
    0 / 247 (0.00%)
    1 / 251 (0.40%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Cellulitis
         subjects affected / exposed
    1 / 247 (0.40%)
    1 / 251 (0.40%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Rectal abscess
         subjects affected / exposed
    0 / 247 (0.00%)
    1 / 251 (0.40%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonia
         subjects affected / exposed
    5 / 247 (2.02%)
    2 / 251 (0.80%)
         occurrences causally related to treatment / all
    0 / 6
    0 / 2
         deaths causally related to treatment / all
    0 / 2
    0 / 0
    Anal abscess
         subjects affected / exposed
    1 / 247 (0.40%)
    0 / 251 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac infection
         subjects affected / exposed
    1 / 247 (0.40%)
    0 / 251 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infection
         subjects affected / exposed
    1 / 247 (0.40%)
    0 / 251 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Sepsis
         subjects affected / exposed
    0 / 247 (0.00%)
    1 / 251 (0.40%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Hypercalcaemia
         subjects affected / exposed
    1 / 247 (0.40%)
    1 / 251 (0.40%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Tumour lysis syndrome
         subjects affected / exposed
    1 / 247 (0.40%)
    0 / 251 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypovolaemia
         subjects affected / exposed
    1 / 247 (0.40%)
    0 / 251 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hyperkalaemia
         subjects affected / exposed
    1 / 247 (0.40%)
    0 / 251 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Decreased appetite
         subjects affected / exposed
    1 / 247 (0.40%)
    2 / 251 (0.80%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Dehydration
         subjects affected / exposed
    3 / 247 (1.21%)
    6 / 251 (2.39%)
         occurrences causally related to treatment / all
    1 / 3
    0 / 6
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hyponatraemia
         subjects affected / exposed
    1 / 247 (0.40%)
    1 / 251 (0.40%)
         occurrences causally related to treatment / all
    0 / 1
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Ipilimumab and Dacarbazine Placebo and Dacarbazine
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    220 / 247 (89.07%)
    218 / 251 (86.85%)
    Investigations
    Blood alkaline phosphatase increased
         subjects affected / exposed
    16 / 247 (6.48%)
    9 / 251 (3.59%)
         occurrences all number
    24
    18
    Weight decreased
         subjects affected / exposed
    27 / 247 (10.93%)
    13 / 251 (5.18%)
         occurrences all number
    43
    23
    Aspartate aminotransferase increased
         subjects affected / exposed
    50 / 247 (20.24%)
    14 / 251 (5.58%)
         occurrences all number
    117
    22
    Gamma-glutamyltransferase increased
         subjects affected / exposed
    19 / 247 (7.69%)
    9 / 251 (3.59%)
         occurrences all number
    36
    22
    Alanine aminotransferase increased
         subjects affected / exposed
    60 / 247 (24.29%)
    14 / 251 (5.58%)
         occurrences all number
    164
    24
    Nervous system disorders
    Dizziness
         subjects affected / exposed
    16 / 247 (6.48%)
    10 / 251 (3.98%)
         occurrences all number
    24
    12
    Headache
         subjects affected / exposed
    38 / 247 (15.38%)
    33 / 251 (13.15%)
         occurrences all number
    63
    54
    Blood and lymphatic system disorders
    Neutropenia
         subjects affected / exposed
    16 / 247 (6.48%)
    14 / 251 (5.58%)
         occurrences all number
    31
    24
    Anaemia
         subjects affected / exposed
    20 / 247 (8.10%)
    12 / 251 (4.78%)
         occurrences all number
    38
    28
    General disorders and administration site conditions
    Asthenia
         subjects affected / exposed
    29 / 247 (11.74%)
    32 / 251 (12.75%)
         occurrences all number
    57
    63
    Fatigue
         subjects affected / exposed
    100 / 247 (40.49%)
    95 / 251 (37.85%)
         occurrences all number
    265
    200
    Pyrexia
         subjects affected / exposed
    82 / 247 (33.20%)
    20 / 251 (7.97%)
         occurrences all number
    145
    35
    Chills
         subjects affected / exposed
    27 / 247 (10.93%)
    10 / 251 (3.98%)
         occurrences all number
    44
    14
    Chest pain
         subjects affected / exposed
    13 / 247 (5.26%)
    8 / 251 (3.19%)
         occurrences all number
    17
    10
    Influenza like illness
         subjects affected / exposed
    19 / 247 (7.69%)
    11 / 251 (4.38%)
         occurrences all number
    25
    16
    Oedema peripheral
         subjects affected / exposed
    20 / 247 (8.10%)
    12 / 251 (4.78%)
         occurrences all number
    32
    19
    Immune system disorders
    Hypersensitivity
         subjects affected / exposed
    13 / 247 (5.26%)
    6 / 251 (2.39%)
         occurrences all number
    16
    9
    Gastrointestinal disorders
    Nausea
         subjects affected / exposed
    119 / 247 (48.18%)
    120 / 251 (47.81%)
         occurrences all number
    305
    302
    Abdominal pain
         subjects affected / exposed
    28 / 247 (11.34%)
    29 / 251 (11.55%)
         occurrences all number
    39
    49
    Diarrhoea
         subjects affected / exposed
    83 / 247 (33.60%)
    61 / 251 (24.30%)
         occurrences all number
    162
    103
    Vomiting
         subjects affected / exposed
    74 / 247 (29.96%)
    69 / 251 (27.49%)
         occurrences all number
    152
    124
    Constipation
         subjects affected / exposed
    69 / 247 (27.94%)
    68 / 251 (27.09%)
         occurrences all number
    127
    106
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    25 / 247 (10.12%)
    25 / 251 (9.96%)
         occurrences all number
    37
    33
    Dyspnoea
         subjects affected / exposed
    25 / 247 (10.12%)
    28 / 251 (11.16%)
         occurrences all number
    42
    45
    Skin and subcutaneous tissue disorders
    Pruritus
         subjects affected / exposed
    73 / 247 (29.55%)
    22 / 251 (8.76%)
         occurrences all number
    212
    38
    Rash
         subjects affected / exposed
    63 / 247 (25.51%)
    17 / 251 (6.77%)
         occurrences all number
    186
    22
    Psychiatric disorders
    Anxiety
         subjects affected / exposed
    9 / 247 (3.64%)
    13 / 251 (5.18%)
         occurrences all number
    11
    17
    Insomnia
         subjects affected / exposed
    22 / 247 (8.91%)
    16 / 251 (6.37%)
         occurrences all number
    33
    22
    Musculoskeletal and connective tissue disorders
    Musculoskeletal pain
         subjects affected / exposed
    18 / 247 (7.29%)
    20 / 251 (7.97%)
         occurrences all number
    34
    31
    Arthralgia
         subjects affected / exposed
    19 / 247 (7.69%)
    18 / 251 (7.17%)
         occurrences all number
    30
    36
    Back pain
         subjects affected / exposed
    27 / 247 (10.93%)
    23 / 251 (9.16%)
         occurrences all number
    42
    29
    Pain in extremity
         subjects affected / exposed
    15 / 247 (6.07%)
    22 / 251 (8.76%)
         occurrences all number
    31
    29
    Metabolism and nutrition disorders
    Decreased appetite
         subjects affected / exposed
    53 / 247 (21.46%)
    47 / 251 (18.73%)
         occurrences all number
    105
    61

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    07 Apr 2006
    Provided additional information regarding tumour imaging assessments and disease response assessment criteria.
    25 May 2006
    Added an interim analysis of overall survival (OS), to be conducted at the same time as the analyses of other efficacy endpoints, i.e., when at least 416 events for progression-free survival (PFS) have been observed in the study and all subjects have been followed for at least 12 weeks; clarified that the comparison of OS between treatment arms was the main secondary analysis and described the testing procedure to be followed in order to maintain the overall significance level.
    09 Oct 2008
    Changed the primary objective to a comparison of overall survival and rank secondary objectives; added a Prohibited Therapy during the follow-up phase; clarified analyses of time to response and duration of response; made various administrative updates.
    24 Mar 2009
    Modified the dose skipping criteria for ipilimumab/placebo to make the criteria more conservative; changed the contact details for the BMS Study Director.

    Interruptions (globally)
    Were there any global interruptions to the trial? No

    Limitations and caveats
    Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.
    None reported
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    The status and protocol content of GB trials is no longer updated since 1 January 2021. For the UK, as of 31 January 2021, EU Law applies only to the territory of Northern Ireland (NI) to the extent foreseen in the Protocol on Ireland/NI. Legal notice
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