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    Clinical Trial Results:
    A Phase 2, Fast Real-time Assessment of Combination Therapies in Immuno-ONcology Study in Participants with Advanced Renal Cell Carcinoma (FRACTION-RCC)

    Summary
    EudraCT number
    		 2016-003082-26
    Trial protocol
    		 AT   IT  
    Global end of trial date
    23 Nov 2021

    Results information
    Results version number
    		 v1(current)
    This version publication date
    15 Dec 2022
    First version publication date
    15 Dec 2022
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    CA018-005
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT02996110
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Bristol-Myers Squibb
    Sponsor organisation address
    Chaussée de la Hulpe 185, Brussels, Belgium, 1170
    Public contact
    EU Study Start-Up Unit, Bristol-Myers Squibb International Corporation, Bristol-Myers Squibb International Corporation, Clinical.Trials@bms.com
    Scientific contact
    Bristol-Myers Squibb Study Director, Bristol-Myers Squibb International Corporation, 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
    16 May 2022
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    23 Nov 2021
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To assess the efficacy (objective response rate (ORR), duration of response (DOR), and progression-free survival rate (PFSR) at 24-weeks) of each FRACTION-RCC study treatment combination (relative to nivolumab in combination with ipilimumab, when applicable) in participants with advanced renal cell carcinoma (RCC).
    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 participants were followed.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    02 Feb 2017
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Australia: 12
    Country: Number of subjects enrolled
    Austria: 2
    Country: Number of subjects enrolled
    Canada: 17
    Country: Number of subjects enrolled
    Israel: 13
    Country: Number of subjects enrolled
    Italy: 18
    Country: Number of subjects enrolled
    United States: 120
    Worldwide total number of subjects
    182
    EEA total number of subjects
    20
    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)
    120
    From 65 to 84 years
    62
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 -

    Pre-assignment
    Screening details
    		 178 participants total were treated in the study. 60 were initially randomized and received treatment in Track 1. 118 were initially randomized to Track 2 but 152 participants in total were treated in track 2 due to 35 participants from either track 1 or 2 being re-randomized to receive a different treatment combination in Track 2.

    Period 1
    Period 1 title
    Pre-Treatment
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Not blinded

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Arm 1: Nivolumab plus Ipilimumab (BMS-734016)
    Arm description
    		 Nivolumab was administered at 3 mg/kg via IV infusion followed by ipilimumab 1 mg/kg administered IV over approximately 30 minutes every 3 weeks for 4 doses. Six weeks after the last dose of combination study treatment nivolumab 480 mg was administered IV over approximately 30 minutes every 4 weeks until completion of approximately 2 years of study treatment, clinical deterioration suggesting that no further benefit from study treatment is likely, intolerable toxicity, meeting of criteria for discontinuation of study treatment, or withdrawal of consent, whichever occurred first.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Nivolumab (BMS-936558-01)
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Intravenous use
    Dosage and administration details
    Nivolumab 3 mg/kg IV infusion every 3 weeks for 4 doses

    Investigational medicinal product name
    Ipilimumab (BMS-734016)
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Intravenous use
    Dosage and administration details
    Ipilimumab 1 mg/kg every three weeks for 4 doses

    Investigational medicinal product name
    Nivolumab (BMS-936558-01)
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Intravenous use
    Dosage and administration details
    Nivolumab 480 mg by IV infusion every 4 weeks

    Arm title
    		 Arm 2: Nivolumab plus Relatlimab (BMS-986016)
    Arm description
    		 Nivolumab was administered at a flat dose of 240 mg via IV infusion every 2 weeks followed by 80 mg BMS-986016 administered IV approximately 60 minutes every 2 weeks until completion of approximately 2 years of study treatment, clinical deterioration suggesting that no further benefit from study treatment is likely, intolerable toxicity, meeting of criteria for discontinuation of study treatment, or withdrawal of consent, whichever occurred first.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Nivolumab (BMS-936558-01)
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Intravenous use
    Dosage and administration details
    Nivolumab 240-mg flat dose via IV infusion every 2 weeks

    Investigational medicinal product name
    Relatlimab (BMS-986016-01)
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Intravenous use
    Dosage and administration details
    BMS-986016 80 mg administered IV approximately 60 minutes every two weeks

    Arm title
    		 Arm 3: Nivolumab plus BMS-986205
    Arm description
    		 Nivolumab was administered as a flat dose of 480 mg via IV infusion every 4 weeks, and BMS-986205 taken orally at a dose of 100 mg daily for up to 2 years, clinical deterioration suggesting that no further benefit from study treatment is likely, intolerable toxicity, meeting of criteria for discontinuation of study treatment, or withdrawal of consent, whichever occurred first.
    Arm type
    		 Experimental

    Investigational medicinal product name
    BMS-986205
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet, Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    BMS-986205 at a dose of 100 mg per day following a meal

    Investigational medicinal product name
    Nivolumab (BMS-936558-01)
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Intravenous use
    Dosage and administration details
    Nivolumab 480 mg by IV infusion every 4 weeks

    Arm title
    		 Arm 4: Nivolumab plus BMS-813160 150 mg
    Arm description
    		 Nivolumab was administered as a flat dose of 480 mg by IV infusion every 4 weeks combined with oral BMS-813160, 150 mg daily for up to 2 years, clinical deterioration suggesting that no further benefit from study treatment is likely, intolerable toxicity, meeting of criteria for discontinuation of study treatment, or withdrawal of consent, whichever occurred first.
    Arm type
    		 Experimental

    Investigational medicinal product name
    BMS-813160
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule, Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    BMS-813160 taken orally at 150 mg daily

    Investigational medicinal product name
    Nivolumab (BMS-936558-01)
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Intravenous use
    Dosage and administration details
    Nivolumab 480 mg by IV infusion every 4 weeks

    Arm title
    		 Arm 5: Nivolumab plus BMS-813160 300mg
    Arm description
    		 Nivolumab was administered as a flat dose of 480 mg by IV infusion every 4 weeks combined with oral BMS-813160, 300 mg twice daily for up to 2 years, clinical deterioration suggesting that no further benefit from study treatment is likely, intolerable toxicity, meeting of criteria for discontinuation of study treatment, or withdrawal of consent, whichever occurred first.
    Arm type
    		 Experimental

    Investigational medicinal product name
    BMS-813160
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule, Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    BMS-813160 taken orally at 300 mg daily

    Investigational medicinal product name
    Nivolumab (BMS-936558-01)
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Intravenous use
    Dosage and administration details
    Nivolumab 480 mg by IV infusion every 4 weeks

    Number of subjects in period 1
    		Arm 1: Nivolumab plus Ipilimumab (BMS-734016) Arm 2: Nivolumab plus Relatlimab (BMS-986016) Arm 3: Nivolumab plus BMS-986205 Arm 4: Nivolumab plus BMS-813160 150 mg Arm 5: Nivolumab plus BMS-813160 300mg
    Started
    65
    56
    26
    17
    18
    Completed
    65
    55
    25
    17
    16
    Not completed
    0
    1
    1
    0
    2
         Other Reasons
    -
    1
    -
    -
    1
         Participant Withdrew Consent
    -
    -
    1
    -
    1
    Period 2
    Period 2 title
    Treatment Period
    Is this the baseline period?
    		 No
    Allocation method
    Randomised - controlled
    Blinding used
    		 Not blinded

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Arm 1: Nivolumab plus Ipilimumab (BMS-734016)
    Arm description
    		 Nivolumab was administered at 3 mg/kg via IV infusion followed by ipilimumab 1 mg/kg administered IV over approximately 30 minutes every 3 weeks for 4 doses. Six weeks after the last dose of combination study treatment nivolumab 480 mg was administered IV over approximately 30 minutes every 4 weeks until completion of approximately 2 years of study treatment, clinical deterioration suggesting that no further benefit from study treatment is likely, intolerable toxicity, meeting of criteria for discontinuation of study treatment, or withdrawal of consent, whichever occurred first.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Nivolumab (BMS-936558-01)
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Intravenous use
    Dosage and administration details
    Nivolumab 3 mg/kg IV infusion every 3 weeks for 4 doses

    Investigational medicinal product name
    Nivolumab (BMS-936558-01)
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Intravenous use
    Dosage and administration details
    Nivolumab 480 mg by IV infusion every 4 weeks

    Investigational medicinal product name
    Ipilimumab (BMS-734016)
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Intravenous use
    Dosage and administration details
    Ipilimumab 1 mg/kg every three weeks for 4 doses

    Arm title
    		 Arm 2: Nivolumab plus Relatlimab (BMS-986016)
    Arm description
    		 Nivolumab was administered at a flat dose of 240 mg via IV infusion every 2 weeks followed by 80 mg BMS-986016 administered IV approximately 60 minutes every 2 weeks until completion of approximately 2 years of study treatment, clinical deterioration suggesting that no further benefit from study treatment is likely, intolerable toxicity, meeting of criteria for discontinuation of study treatment, or withdrawal of consent, whichever occurred first.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Relatlimab (BMS-986016-01)
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Intravenous use
    Dosage and administration details
    BMS-986016 80 mg administered IV approximately 60 minutes every two weeks

    Investigational medicinal product name
    Nivolumab (BMS-936558-01)
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Intravenous use
    Dosage and administration details
    Nivolumab 240-mg flat dose via IV infusion every 2 weeks

    Arm title
    		 Arm 3: Nivolumab plus BMS-986205
    Arm description
    		 Nivolumab was administered as a flat dose of 480 mg via IV infusion every 4 weeks, and BMS-986205 taken orally at a dose of 100 mg daily for up to 2 years, clinical deterioration suggesting that no further benefit from study treatment is likely, intolerable toxicity, meeting of criteria for discontinuation of study treatment, or withdrawal of consent, whichever occurred first.
    Arm type
    		 Experimental

    Investigational medicinal product name
    BMS-986205
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet, Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    BMS-986205 at a dose of 100 mg per day following a meal

    Investigational medicinal product name
    Nivolumab (BMS-936558-01)
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Intravenous use
    Dosage and administration details
    Nivolumab 480 mg by IV infusion every 4 weeks

    Arm title
    		 Arm 4: Nivolumab plus BMS-813160 150 mg
    Arm description
    		 Nivolumab was administered as a flat dose of 480 mg by IV infusion every 4 weeks combined with oral BMS-813160, 150 mg daily for up to 2 years, clinical deterioration suggesting that no further benefit from study treatment is likely, intolerable toxicity, meeting of criteria for discontinuation of study treatment, or withdrawal of consent, whichever occurred first.
    Arm type
    		 Experimental

    Investigational medicinal product name
    BMS-813160
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule, Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    BMS-813160 taken orally at 150 mg daily

    Investigational medicinal product name
    Nivolumab (BMS-936558-01)
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Intravenous use
    Dosage and administration details
    Nivolumab 480 mg by IV infusion every 4 weeks

    Arm title
    		 Arm 5: Nivolumab plus BMS-813160 300mg
    Arm description
    		 Nivolumab was administered as a flat dose of 480 mg by IV infusion every 4 weeks combined with oral BMS-813160, 300 mg twice daily for up to 2 years, clinical deterioration suggesting that no further benefit from study treatment is likely, intolerable toxicity, meeting of criteria for discontinuation of study treatment, or withdrawal of consent, whichever occurred first.
    Arm type
    		 Experimental

    Investigational medicinal product name
    BMS-813160
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule, Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    BMS-813160 taken orally at 300 mg daily

    Investigational medicinal product name
    Nivolumab (BMS-936558-01)
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Intravenous use
    Dosage and administration details
    Nivolumab 480 mg by IV infusion every 4 weeks

    Number of subjects in period 2 [1]
    		Arm 1: Nivolumab plus Ipilimumab (BMS-734016) Arm 2: Nivolumab plus Relatlimab (BMS-986016) Arm 3: Nivolumab plus BMS-986205 Arm 4: Nivolumab plus BMS-813160 150 mg Arm 5: Nivolumab plus BMS-813160 300mg
    Started
    65
    55
    25
    17
    16
    Completed
    4
    3
    1
    1
    1
    Not completed
    72
    59
    30
    20
    21
         Consent withdrawn by subject
    1
    2
    3
    1
    1
         Completed treatment in Track 1
    7
    8
    -
    -
    -
         Other Reasons
    -
    -
    1
    -
    1
         Death
    -
    -
    1
    -
    1
         Subject Request to Discontinue Treatment
    1
    -
    2
    1
    2
         Subject No Longer Meets Study Criteria
    1
    -
    -
    -
    -
         Adverse Event Unrelated to Study Drug
    5
    1
    -
    1
    1
         Study Drug Toxicity
    9
    4
    4
    1
    -
         Disease Progression
    48
    43
    19
    16
    15
         Administrative Reason by Sponsor
    -
    1
    -
    -
    -
    Joined
    11
    7
    6
    4
    6
         Transferred in from other group/arm
    11
    7
    6
    4
    6
    Notes
    [1] - The number of subjects transferring in and out of the arms in the period are not the same. It is expected the net number of transfers in and out of the arms in a period, will be zero.
    Justification: 35 participants from either Track 1 or 2 were re-randomized to receive a different treatment combination in Track 2

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Arm 1: Nivolumab plus Ipilimumab (BMS-734016)
    Reporting group description
    		 Nivolumab was administered at 3 mg/kg via IV infusion followed by ipilimumab 1 mg/kg administered IV over approximately 30 minutes every 3 weeks for 4 doses. Six weeks after the last dose of combination study treatment nivolumab 480 mg was administered IV over approximately 30 minutes every 4 weeks until completion of approximately 2 years of study treatment, clinical deterioration suggesting that no further benefit from study treatment is likely, intolerable toxicity, meeting of criteria for discontinuation of study treatment, or withdrawal of consent, whichever occurred first.

    Reporting group title
    Arm 2: Nivolumab plus Relatlimab (BMS-986016)
    Reporting group description
    		 Nivolumab was administered at a flat dose of 240 mg via IV infusion every 2 weeks followed by 80 mg BMS-986016 administered IV approximately 60 minutes every 2 weeks until completion of approximately 2 years of study treatment, clinical deterioration suggesting that no further benefit from study treatment is likely, intolerable toxicity, meeting of criteria for discontinuation of study treatment, or withdrawal of consent, whichever occurred first.

    Reporting group title
    Arm 3: Nivolumab plus BMS-986205
    Reporting group description
    		 Nivolumab was administered as a flat dose of 480 mg via IV infusion every 4 weeks, and BMS-986205 taken orally at a dose of 100 mg daily for up to 2 years, clinical deterioration suggesting that no further benefit from study treatment is likely, intolerable toxicity, meeting of criteria for discontinuation of study treatment, or withdrawal of consent, whichever occurred first.

    Reporting group title
    Arm 4: Nivolumab plus BMS-813160 150 mg
    Reporting group description
    		 Nivolumab was administered as a flat dose of 480 mg by IV infusion every 4 weeks combined with oral BMS-813160, 150 mg daily for up to 2 years, clinical deterioration suggesting that no further benefit from study treatment is likely, intolerable toxicity, meeting of criteria for discontinuation of study treatment, or withdrawal of consent, whichever occurred first.

    Reporting group title
    Arm 5: Nivolumab plus BMS-813160 300mg
    Reporting group description
    		 Nivolumab was administered as a flat dose of 480 mg by IV infusion every 4 weeks combined with oral BMS-813160, 300 mg twice daily for up to 2 years, clinical deterioration suggesting that no further benefit from study treatment is likely, intolerable toxicity, meeting of criteria for discontinuation of study treatment, or withdrawal of consent, whichever occurred first.

    Reporting group values
    		 Arm 1: Nivolumab plus Ipilimumab (BMS-734016) Arm 2: Nivolumab plus Relatlimab (BMS-986016) Arm 3: Nivolumab plus BMS-986205 Arm 4: Nivolumab plus BMS-813160 150 mg Arm 5: Nivolumab plus BMS-813160 300mg Total
    Number of subjects
    		 65 56 26 17 18 182
    Age Categorical
    Units: Participants
        <=18 years
    		 0 0 0 0 0 0
        Between 18 and 65 years
    		 40 41 16 12 11 120
        >=65 years
    		 25 15 10 5 7 62
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    		 61.1 ( 9.8 ) 57.4 ( 9.7 ) 60.8 ( 11.6 ) 57.6 ( 11.4 ) 61.1 ( 12.0 ) -
    Sex: Female, Male
    Units: Participants
        Female
    		 14 16 6 4 9 49
        Male
    		 51 40 20 13 9 133
    Race/Ethnicity, Customized
    Units: Subjects
        White
    		 62 52 23 14 17 168
        Asian Indian
    		 1 0 0 0 0 1
        Chinese
    		 0 1 0 0 0 1
        Asian Other
    		 1 1 0 0 0 2
        Other
    		 1 2 2 2 0 7
        Black or African American
    		 0 0 1 1 1 3
    Ethnicity (NIH/OMB)
    Units: Subjects
        Hispanic or Latino
    		 3 2 2 1 0 8
        Not Hispanic or Latino
    		 37 34 19 12 10 112
        Unknown or Not Reported
    		 25 20 5 4 8 62

    End points

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    End points reporting groups
    Reporting group title
    Arm 1: Nivolumab plus Ipilimumab (BMS-734016)
    Reporting group description
    		 Nivolumab was administered at 3 mg/kg via IV infusion followed by ipilimumab 1 mg/kg administered IV over approximately 30 minutes every 3 weeks for 4 doses. Six weeks after the last dose of combination study treatment nivolumab 480 mg was administered IV over approximately 30 minutes every 4 weeks until completion of approximately 2 years of study treatment, clinical deterioration suggesting that no further benefit from study treatment is likely, intolerable toxicity, meeting of criteria for discontinuation of study treatment, or withdrawal of consent, whichever occurred first.

    Reporting group title
    Arm 2: Nivolumab plus Relatlimab (BMS-986016)
    Reporting group description
    		 Nivolumab was administered at a flat dose of 240 mg via IV infusion every 2 weeks followed by 80 mg BMS-986016 administered IV approximately 60 minutes every 2 weeks until completion of approximately 2 years of study treatment, clinical deterioration suggesting that no further benefit from study treatment is likely, intolerable toxicity, meeting of criteria for discontinuation of study treatment, or withdrawal of consent, whichever occurred first.

    Reporting group title
    Arm 3: Nivolumab plus BMS-986205
    Reporting group description
    		 Nivolumab was administered as a flat dose of 480 mg via IV infusion every 4 weeks, and BMS-986205 taken orally at a dose of 100 mg daily for up to 2 years, clinical deterioration suggesting that no further benefit from study treatment is likely, intolerable toxicity, meeting of criteria for discontinuation of study treatment, or withdrawal of consent, whichever occurred first.

    Reporting group title
    Arm 4: Nivolumab plus BMS-813160 150 mg
    Reporting group description
    		 Nivolumab was administered as a flat dose of 480 mg by IV infusion every 4 weeks combined with oral BMS-813160, 150 mg daily for up to 2 years, clinical deterioration suggesting that no further benefit from study treatment is likely, intolerable toxicity, meeting of criteria for discontinuation of study treatment, or withdrawal of consent, whichever occurred first.

    Reporting group title
    Arm 5: Nivolumab plus BMS-813160 300mg
    Reporting group description
    		 Nivolumab was administered as a flat dose of 480 mg by IV infusion every 4 weeks combined with oral BMS-813160, 300 mg twice daily for up to 2 years, clinical deterioration suggesting that no further benefit from study treatment is likely, intolerable toxicity, meeting of criteria for discontinuation of study treatment, or withdrawal of consent, whichever occurred first.
    Reporting group title
    Arm 1: Nivolumab plus Ipilimumab (BMS-734016)
    Reporting group description
    		 Nivolumab was administered at 3 mg/kg via IV infusion followed by ipilimumab 1 mg/kg administered IV over approximately 30 minutes every 3 weeks for 4 doses. Six weeks after the last dose of combination study treatment nivolumab 480 mg was administered IV over approximately 30 minutes every 4 weeks until completion of approximately 2 years of study treatment, clinical deterioration suggesting that no further benefit from study treatment is likely, intolerable toxicity, meeting of criteria for discontinuation of study treatment, or withdrawal of consent, whichever occurred first.

    Reporting group title
    Arm 2: Nivolumab plus Relatlimab (BMS-986016)
    Reporting group description
    		 Nivolumab was administered at a flat dose of 240 mg via IV infusion every 2 weeks followed by 80 mg BMS-986016 administered IV approximately 60 minutes every 2 weeks until completion of approximately 2 years of study treatment, clinical deterioration suggesting that no further benefit from study treatment is likely, intolerable toxicity, meeting of criteria for discontinuation of study treatment, or withdrawal of consent, whichever occurred first.

    Reporting group title
    Arm 3: Nivolumab plus BMS-986205
    Reporting group description
    		 Nivolumab was administered as a flat dose of 480 mg via IV infusion every 4 weeks, and BMS-986205 taken orally at a dose of 100 mg daily for up to 2 years, clinical deterioration suggesting that no further benefit from study treatment is likely, intolerable toxicity, meeting of criteria for discontinuation of study treatment, or withdrawal of consent, whichever occurred first.

    Reporting group title
    Arm 4: Nivolumab plus BMS-813160 150 mg
    Reporting group description
    		 Nivolumab was administered as a flat dose of 480 mg by IV infusion every 4 weeks combined with oral BMS-813160, 150 mg daily for up to 2 years, clinical deterioration suggesting that no further benefit from study treatment is likely, intolerable toxicity, meeting of criteria for discontinuation of study treatment, or withdrawal of consent, whichever occurred first.

    Reporting group title
    Arm 5: Nivolumab plus BMS-813160 300mg
    Reporting group description
    		 Nivolumab was administered as a flat dose of 480 mg by IV infusion every 4 weeks combined with oral BMS-813160, 300 mg twice daily for up to 2 years, clinical deterioration suggesting that no further benefit from study treatment is likely, intolerable toxicity, meeting of criteria for discontinuation of study treatment, or withdrawal of consent, whichever occurred first.

    Subject analysis set title
    Arm 1: Nivolumab plus Ipilimumab (BMS-734016) (Experimental)
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    Nivolumab was administered at 3 mg/kg via IV infusion followed by ipilimumab 1 mg/kg administered IV over approximately 30 minutes every 3 weeks for 4 doses. Six weeks after the last dose of combination study treatment nivolumab 480 mg was administered IV over approximately 30 minutes every 4 weeks until completion of approximately 2 years of study treatment, clinical deterioration suggesting that no further benefit from study treatment is likely, intolerable toxicity, meeting of criteria for discontinuation of study treatment, or withdrawal of consent, whichever occurred first.

    Subject analysis set title
    Arm 2: Nivolumab plus Relatlimab (BMS-986016) (Experimental)
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    Nivolumab was administered at a flat dose of 240 mg via IV infusion every 2 weeks followed by 80 mg BMS-986016 administered IV approximately 60 minutes every 2 weeks until completion of approximately 2 years of study treatment, clinical deterioration suggesting that no further benefit from study treatment is likely, intolerable toxicity, meeting of criteria for discontinuation of study treatment, or withdrawal of consent, whichever occurred first.

    Subject analysis set title
    Arm 3: Nivolumab plus BMS-986205 (Experimental)
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    Nivolumab was administered as a flat dose of 480 mg via IV infusion every 4 weeks, and BMS-986205 taken orally at a dose of 100 mg daily for up to 2 years, clinical deterioration suggesting that no further benefit from study treatment is likely, intolerable toxicity, meeting of criteria for discontinuation of study treatment, or withdrawal of consent, whichever occurred first.

    Subject analysis set title
    Arm 4: Nivolumab plus BMS-813160 150 mg (Experimental)
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    Nivolumab was administered as a flat dose of 480 mg by IV infusion every 4 weeks combined with oral BMS-813160, 150 mg daily for up to 2 years, clinical deterioration suggesting that no further benefit from study treatment is likely, intolerable toxicity, meeting of criteria for discontinuation of study treatment, or withdrawal of consent, whichever occurred first.

    Subject analysis set title
    Arm 5: Nivolumab plus BMS-813160 300mg (Experimental)
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    Nivolumab was administered as a flat dose of 480 mg by IV infusion every 4 weeks combined with oral BMS-813160, 300 mg twice daily for up to 2 years, clinical deterioration suggesting that no further benefit from study treatment is likely, intolerable toxicity, meeting of criteria for discontinuation of study treatment, or withdrawal of consent, whichever occurred first.

    Primary: Objective Response Rate (ORR) per Investigator

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    End point title
    		 Objective Response Rate (ORR) per Investigator [1]
    End point description
    ORR is percent of participants whose best overall response (BOR) is complete response (CR) or partial response (PR). BOR is the best response from the start of the study treatment until objectively documented progression per RECIST v1.1 or subsequent anticancer therapy, whichever occurs first. For participants who received re-treatment or were re-randomized, the re-treatment and re-randomized therapies were considered subsequent anticancer therapy. CR is the disappearance of all target lesions. Any pathological lymph nodes (whether target or non-target) have reduction in short axis to <10 mm. PR is at least a 30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum diameters. The Response Evaluation Criteria in Solid Tumors (RECIST) is a standard way to measure the response of a tumor to treatment. CR+PR, confidence interval based on Clopper and Pearson method. 99999 =Not-Applicable/Available
    End point type
    Primary
    End point timeframe
    From first dose of study treatment until progression or subsequent anticancer therapy, whichever occurs first (assessed up to approximately 247 weeks)
    Notes
    [1] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: Only summary statistics were planned for this endpoint.
    End point values
    		 Arm 1: Nivolumab plus Ipilimumab (BMS-734016) (Experimental) Arm 2: Nivolumab plus Relatlimab (BMS-986016) (Experimental) Arm 3: Nivolumab plus BMS-986205 (Experimental) Arm 4: Nivolumab plus BMS-813160 150 mg (Experimental) Arm 5: Nivolumab plus BMS-813160 300mg (Experimental)
    Number of subjects analysed
    76
    62
    31
    21
    22
    Units: Percent of participants
    number (confidence interval 95%)
        Track 1
    20 (7.7 to 38.6)
    30 (14.7 to 49.4)
    99999 (99999 to 99999)
    99999 (99999 to 99999)
    99999 (99999 to 99999)
        Track 2
    17.4 (7.8 to 31.4)
    3.1 (0.1 to 16.2)
    3.2 (0.1 to 16.7)
    9.5 (1.2 to 30.4)
    0.0 (0.0 to 15.4)
    No statistical analyses for this end point

    Primary: Median Duration of Response (DOR) per Investigator

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    End point title
    		 Median Duration of Response (DOR) per Investigator [2]
    End point description
    Duration of Response is defined as the time between the date of first response and the date of first documented disease progression as determined by RECIST 1.1 or death due to any cause (death occurring after re-treatment or randomization to new combination treatment was not considered), whichever occurred first. Complete Response (CR) is the disappearance of all target lesions. Any pathological lymph nodes (whether target or non-target) must have reduction in short axis to <10 mm. Partial Response (PR) is at least a 30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum diameters. Median computed using Kaplan -Meier method. 99999 = Not-Applicable
    End point type
    Primary
    End point timeframe
    Time between the date of first response and the date of first documented disease progression or death due to any cause (assessed from an average of 22 weeks up to approximately 140 weeks).
    Notes
    [2] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: Only summary statistics were planned for this endpoint.
    End point values
    		 Arm 1: Nivolumab plus Ipilimumab (BMS-734016) (Experimental) Arm 2: Nivolumab plus Relatlimab (BMS-986016) (Experimental) Arm 3: Nivolumab plus BMS-986205 (Experimental) Arm 4: Nivolumab plus BMS-813160 150 mg (Experimental) Arm 5: Nivolumab plus BMS-813160 300mg (Experimental)
    Number of subjects analysed
    14
    10
    1
    2
    0 [3]
    Units: Weeks
    median (full range (min-max))
        Track 1
    99999 (99999 to 99999)
    32.57 (0.1 to 52.6)
    99999 (99999 to 99999)
    99999 (99999 to 99999)
    ( to )
        Track 2
    68.00 (0.1 to 117.6)
    99.4 (99.4 to 99.4)
    99999 (99999 to 99999)
    99999 (99999 to 99999)
    ( to )
    Notes
    [3] - No participants had a response to treatment
    No statistical analyses for this end point

    Primary: Progression Free Survival Rate (PFSR) at 24 Weeks.

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    End point title
    		 Progression Free Survival Rate (PFSR) at 24 Weeks. [4]
    End point description
    The PFSR at 24 weeks is defined as the proportion of treated participants remaining progression free and surviving at 24 weeks since the first dosing date. Progressive Disease (PD) is at least a 20% increase in the sum of diameters of target lesions, taking as reference the smallest sum on study (this includes the baseline sum if that is the smallest on study). In addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of at least 5 mm. (Note: the appearance of one or more new lesions is also considered progression). Point estimates are derived from Kaplan-Meier analyses, the 95% CIs are derived from Greenwood formula. 99999 = Not Applicable/Available
    End point type
    Primary
    End point timeframe
    24 weeks after first treatment dose.
    Notes
    [4] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: Only summary statistics were planned for this endpoint
    End point values
    		 Arm 1: Nivolumab plus Ipilimumab (BMS-734016) (Experimental) Arm 2: Nivolumab plus Relatlimab (BMS-986016) (Experimental) Arm 3: Nivolumab plus BMS-986205 (Experimental) Arm 4: Nivolumab plus BMS-813160 150 mg (Experimental) Arm 5: Nivolumab plus BMS-813160 300mg (Experimental)
    Number of subjects analysed
    76
    62
    31
    21
    22
    Units: Proportion of participants
    number (confidence interval 95%)
        Track 1
    0.491 (0.294 to 0.661)
    0.429 (0.246 to 0.600)
    99999 (99999 to 99999)
    99999 (99999 to 99999)
    99999 (99999 to 99999)
        Track 2
    0.432 (0.277 to 0.577)
    0.194 (0.079 to 0.346)
    0.278 (0.118 to 0.464)
    0.468 (0.237 to 0.670)
    99999 (99999 to 99999)
    No statistical analyses for this end point

    Secondary: Number of Participants with Adverse Events (AEs)

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    End point title
    		 Number of Participants with Adverse Events (AEs)
    End point description
    An Adverse Event (AE) is defined as any new untoward medical occurrence or worsening of a preexisting medical condition in a clinical investigation participant administered study treatment and that does not necessarily have a causal relationship with this treatment. 99999 = Not Applicable/Available
    End point type
    Secondary
    End point timeframe
    From first dose to 100 days after last dose of study therapy (assessed up to approximately 118 weeks)
    End point values
    		 Arm 1: Nivolumab plus Ipilimumab (BMS-734016) (Experimental) Arm 2: Nivolumab plus Relatlimab (BMS-986016) (Experimental) Arm 3: Nivolumab plus BMS-986205 (Experimental) Arm 4: Nivolumab plus BMS-813160 150 mg (Experimental) Arm 5: Nivolumab plus BMS-813160 300mg (Experimental)
    Number of subjects analysed
    76
    62
    31
    21
    22
    Units: Participants
        Track 1
    29
    30
    99999
    99999
    99999
        Track 2
    45
    32
    31
    19
    21
    No statistical analyses for this end point

    Secondary: Number of Participants with Serious Adverse Events (SAEs)

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    End point title
    		 Number of Participants with Serious Adverse Events (SAEs)
    End point description
    Serious Adverse Event (SAE) is defined as any untoward medical occurrence that, at any dose results in death, is life-threatening (defined as an event in which the participant was at risk of death at the time of the event; it does not refer to an event which hypothetically might have caused death if it were more severe), requires inpatient hospitalization or causes prolongation of existing hospitalization. 99999 = Not Available/Applicable
    End point type
    Secondary
    End point timeframe
    From first dose to 100 days after last dose of study therapy (assessed up to approximately 118 weeks)
    End point values
    		 Arm 1: Nivolumab plus Ipilimumab (BMS-734016) (Experimental) Arm 2: Nivolumab plus Relatlimab (BMS-986016) (Experimental) Arm 3: Nivolumab plus BMS-986205 (Experimental) Arm 4: Nivolumab plus BMS-813160 150 mg (Experimental) Arm 5: Nivolumab plus BMS-813160 300mg (Experimental)
    Number of subjects analysed
    76
    62
    31
    21
    22
    Units: Participants
        Track 1
    17
    15
    99999
    99999
    99999
        Track 2
    28
    16
    16
    9
    15
    No statistical analyses for this end point

    Secondary: Number of Participants with Adverse Events (AEs) Leading to Discontinuation

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    End point title
    		 Number of Participants with Adverse Events (AEs) Leading to Discontinuation
    End point description
    An Adverse Event (AE) is defined as any new untoward medical occurrence or worsening of a preexisting medical condition in a clinical investigation participant administered study treatment and that does not necessarily have a causal relationship with this treatment. 99999 = Not Applicable/Available
    End point type
    Secondary
    End point timeframe
    From first dose to 100 days after last dose of study therapy (assessed up to approximately 118 weeks)
    End point values
    		 Arm 1: Nivolumab plus Ipilimumab (BMS-734016) (Experimental) Arm 2: Nivolumab plus Relatlimab (BMS-986016) (Experimental) Arm 3: Nivolumab plus BMS-986205 (Experimental) Arm 4: Nivolumab plus BMS-813160 150 mg (Experimental) Arm 5: Nivolumab plus BMS-813160 300mg (Experimental)
    Number of subjects analysed
    76
    62
    31
    21
    22
    Units: Participants
        Track 1
    7
    7
    99999
    99999
    99999
        Track 2
    10
    3
    6
    2
    4
    No statistical analyses for this end point

    Secondary: Number of Participants who Died

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    End point title
    		 Number of Participants who Died
    End point description
    Death is defined as the cessation of all vital functions of the body including the heartbeat, brain activity (including the brain stem), and breathing. 99999 = Not Applicable/Available
    End point type
    Secondary
    End point timeframe
    From first dose to 100 days after last dose of study therapy (assessed up to approximately 118 weeks)
    End point values
    		 Arm 1: Nivolumab plus Ipilimumab (BMS-734016) (Experimental) Arm 2: Nivolumab plus Relatlimab (BMS-986016) (Experimental) Arm 3: Nivolumab plus BMS-986205 (Experimental) Arm 4: Nivolumab plus BMS-813160 150 mg (Experimental) Arm 5: Nivolumab plus BMS-813160 300mg (Experimental)
    Number of subjects analysed
    76
    62
    31
    21
    22
    Units: Participants
        Track 1
    12
    15
    99999
    99999
    99999
        Track 2
    27
    17
    13
    10
    13
    No statistical analyses for this end point

    Secondary: Number of Participants with Abnormal Thyroid Test Results - Track 1

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    End point title
    		 Number of Participants with Abnormal Thyroid Test Results - Track 1
    End point description
    The number of participants with laboratory abnormalities in specific thyroid tests based on SI conventional units. TSH = Thyroid Stimulating Hormone LLN = Lower Limit of Normal ULN = Upper Limit of Normal. 99999 = Not Applicable/Available
    End point type
    Secondary
    End point timeframe
    From first dose to 30 days after last dose of study therapy (approximately 108 weeks)
    End point values
    		 Arm 1: Nivolumab plus Ipilimumab (BMS-734016) (Experimental) Arm 2: Nivolumab plus Relatlimab (BMS-986016) (Experimental) Arm 3: Nivolumab plus BMS-986205 (Experimental) Arm 4: Nivolumab plus BMS-813160 150 mg (Experimental) Arm 5: Nivolumab plus BMS-813160 300mg (Experimental)
    Number of subjects analysed
    28
    27
    0 [5]
    0 [6]
    0 [7]
    Units: Participants
        TSH > ULN
    8
    8
        TSH > ULN WITH TSH <= ULN AT BASELINE
    5
    8
        TSH >ULN WITH ATLEAST ONE FT3/FT4 TEST VALUE <LLN
    3
    3
        TSH >ULN WITH ALL OTHER FT3/FT4 TEST VALUES >= LLN
    3
    2
        TSH > ULN WITH FT3/FT4 TEST MISSING
    2
    3
        TSH < LLN
    10
    5
        TSH <LLN WITH TSH >= LLN AT BASELINE
    9
    5
        TSH <LLN WITH ATLEAST ONE FT3/FT4 TEST VALUE > ULN
    3
    0
        TSH <LLN WITH ALL OTHER FT3/FT4 TEST VALUES <= ULN
    2
    1
        TSH < LLN WITH FT3/FT4 TEST MISSING
    5
    4
    Notes
    [5] - No Track 1
    [6] - No Track 1
    [7] - No Track 1
    No statistical analyses for this end point

    Secondary: Number of Participants with Abnormal Thyroid Test Results - Track 2

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    End point title
    		 Number of Participants with Abnormal Thyroid Test Results - Track 2
    End point description
    The number of participants with laboratory abnormalities in specific thyroid tests based on SI conventional units. TSH = Thyroid Stimulating Hormone LLN = Lower Limit of Normal ULN = Upper Limit of Normal. 99999 = Not Applicable/Available
    End point type
    Secondary
    End point timeframe
    From first dose to 30 days after last dose of study therapy (approximately 108 weeks)
    End point values
    		 Arm 1: Nivolumab plus Ipilimumab (BMS-734016) (Experimental) Arm 2: Nivolumab plus Relatlimab (BMS-986016) (Experimental) Arm 3: Nivolumab plus BMS-986205 (Experimental) Arm 4: Nivolumab plus BMS-813160 150 mg (Experimental) Arm 5: Nivolumab plus BMS-813160 300mg (Experimental)
    Number of subjects analysed
    42
    30
    25
    17
    13
    Units: Participants
        TSH > ULN
    14
    14
    6
    3
    4
        TSH > ULN WITH TSH <= ULN AT BASELINE
    8
    6
    3
    2
    2
        TSH >ULN WITH ATLEAST ONE FT3/FT4 TEST VALUE <LLN
    5
    3
    1
    1
    0
        TSH >ULN WITH ALL OTHER FT3/FT4 TEST VALUES >= LLN
    5
    4
    3
    2
    3
        TSH > ULN WITH FT3/FT4 TEST MISSING
    4
    7
    2
    0
    1
        TSH < LLN
    4
    5
    2
    2
    1
        TSH <LLN WITH TSH >= LLN AT BASELINE
    2
    4
    1
    2
    1
        TSH <LLN WITH ATLEAST ONE FT3/FT4 TEST VALUE > ULN
    1
    0
    1
    1
    0
        TSH <LLN WITH ALL OTHER FT3/FT4 TEST VALUES <= ULN
    0
    3
    0
    0
    0
        TSH < LLN WITH FT3/FT4 TEST MISSING
    3
    2
    1
    1
    1
    No statistical analyses for this end point

    Secondary: Number of Participants with Abnormal Hepatic Test Results - Track 1

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    End point title
    		 Number of Participants with Abnormal Hepatic Test Results - Track 1
    End point description
    The number of participants with laboratory abnormalities in specific liver tests based on SI conventional units. ALT = Alanine Aminotransferase AST = Aspartate Aminotransferase ULN = Upper Limit of Normal. 99999= Not Applicable/Available
    End point type
    Secondary
    End point timeframe
    From first dose to 30 days after last dose of study therapy (approximately 108 weeks)
    End point values
    		 Arm 1: Nivolumab plus Ipilimumab (BMS-734016) (Experimental) Arm 2: Nivolumab plus Relatlimab (BMS-986016) (Experimental) Arm 3: Nivolumab plus BMS-986205 (Experimental) Arm 4: Nivolumab plus BMS-813160 150 mg (Experimental) Arm 5: Nivolumab plus BMS-813160 300mg (Experimental)
    Number of subjects analysed
    28
    30
    0 [8]
    0 [9]
    0 [10]
    Units: Participants
        ALT OR AST > 3XULN
    2
    4
        ALT OR AST> 5XULN
    1
    2
        ALT OR AST> 10XULN
    0
    0
        ALT OR AST > 20XULN
    0
    0
        TOTAL BILIRUBIN > 2XULN
    0
    0
        ALT/AST ELEV>3XULN;TOTAL BILIRUBIN>2XULN IN 1 DAY
    0
    0
        ALT/AST ELEV>3XULN;TOT BILIRUBIN>2XULN IN 30 DAYS
    0
    0
    Notes
    [8] - No Track 1
    [9] - No Track 1
    [10] - No Track 1
    No statistical analyses for this end point

    Secondary: Number of Participants with Abnormal Hepatic Test Results - Track 2

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    End point title
    		 Number of Participants with Abnormal Hepatic Test Results - Track 2
    End point description
    The number of participants with laboratory abnormalities in specific liver tests based on SI conventional units. ALT = Alanine Aminotransferase AST = Aspartate Aminotransferase ULN = Upper Limit of Normal. 99999 = Not Applicable/Available
    End point type
    Secondary
    End point timeframe
    From first dose to 30 days after last dose of study therapy (approximately 108 weeks)
    End point values
    		 Arm 1: Nivolumab plus Ipilimumab (BMS-734016) (Experimental) Arm 2: Nivolumab plus Relatlimab (BMS-986016) (Experimental) Arm 3: Nivolumab plus BMS-986205 (Experimental) Arm 4: Nivolumab plus BMS-813160 150 mg (Experimental) Arm 5: Nivolumab plus BMS-813160 300mg (Experimental)
    Number of subjects analysed
    44
    32
    29
    17
    18
    Units: Participants
        ALT OR AST > 3XULN
    3
    1
    1
    0
    0
        ALT OR AST> 5XULN
    2
    0
    1
    0
    0
        ALT OR AST> 10XULN
    0
    0
    0
    0
    0
        ALT OR AST > 20XULN
    0
    0
    0
    0
    0
        TOTAL BILIRUBIN > 2XULN
    2
    0
    0
    0
    0
        ALT/AST ELEV>3XULN;TOTAL BILIRUBIN>2XULN IN 1 DAY
    0
    0
    0
    0
    0
        ALT/AST ELEV>3XULN;TOT BILIRUBIN>2XULN IN 30 DAYS
    0
    0
    0
    0
    0
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    All-Cause Mortality was assessed from first dose until study completion (up to approximately 258 weeks). SAEs and NSAEs were assessed from first dose to 100 days after last dose of study therapy (assessed up to approximately 118 weeks).
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    25.0
    Reporting groups
    Reporting group title
    Track 1 NIV+IPI
    Reporting group description
    		 -

    Reporting group title
    Track 1 NIV+BMS986016
    Reporting group description
    		 -

    Reporting group title
    Track 2 NIV+IPI
    Reporting group description
    		 -

    Reporting group title
    Track 2 NIV+BMS986016
    Reporting group description
    		 -

    Reporting group title
    Track 2 NIV+BMS986205
    Reporting group description
    		 -

    Reporting group title
    Track 2 NIV+BMS813160 150MG QD
    Reporting group description
    		 -

    Reporting group title
    Track 2 NIV+BMS813160 300MG BID
    Reporting group description
    		 -

    Serious adverse events
    		 Track 1 NIV+IPI Track 1 NIV+BMS986016 Track 2 NIV+IPI Track 2 NIV+BMS986016 Track 2 NIV+BMS986205 Track 2 NIV+BMS813160 150MG QD Track 2 NIV+BMS813160 300MG BID
    Total subjects affected by serious adverse events
         subjects affected / exposed
    17 / 30 (56.67%)
    15 / 30 (50.00%)
    28 / 46 (60.87%)
    16 / 32 (50.00%)
    16 / 31 (51.61%)
    9 / 21 (42.86%)
    15 / 22 (68.18%)
         number of deaths (all causes)
    13
    15
    28
    17
    13
    10
    13
         number of deaths resulting from adverse events
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Bladder cancer
         subjects affected / exposed
    1 / 30 (3.33%)
    0 / 30 (0.00%)
    0 / 46 (0.00%)
    0 / 32 (0.00%)
    0 / 31 (0.00%)
    0 / 21 (0.00%)
    0 / 22 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cancer pain
         subjects affected / exposed
    0 / 30 (0.00%)
    1 / 30 (3.33%)
    0 / 46 (0.00%)
    0 / 32 (0.00%)
    0 / 31 (0.00%)
    1 / 21 (4.76%)
    1 / 22 (4.55%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Malignant neoplasm progression
         subjects affected / exposed
    2 / 30 (6.67%)
    5 / 30 (16.67%)
    6 / 46 (13.04%)
    5 / 32 (15.63%)
    3 / 31 (9.68%)
    1 / 21 (4.76%)
    4 / 22 (18.18%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 5
    0 / 6
    0 / 5
    0 / 3
    0 / 1
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 3
    0 / 3
    0 / 4
    0 / 3
    0 / 1
    0 / 3
    Metastases to bone
         subjects affected / exposed
    0 / 30 (0.00%)
    0 / 30 (0.00%)
    0 / 46 (0.00%)
    0 / 32 (0.00%)
    1 / 31 (3.23%)
    0 / 21 (0.00%)
    0 / 22 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 3
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Metastases to central nervous system
         subjects affected / exposed
    0 / 30 (0.00%)
    1 / 30 (3.33%)
    0 / 46 (0.00%)
    0 / 32 (0.00%)
    1 / 31 (3.23%)
    0 / 21 (0.00%)
    0 / 22 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 4
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Metastases to lung
         subjects affected / exposed
    0 / 30 (0.00%)
    1 / 30 (3.33%)
    0 / 46 (0.00%)
    0 / 32 (0.00%)
    0 / 31 (0.00%)
    0 / 21 (0.00%)
    0 / 22 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Metastatic renal cell carcinoma
         subjects affected / exposed
    0 / 30 (0.00%)
    0 / 30 (0.00%)
    1 / 46 (2.17%)
    0 / 32 (0.00%)
    0 / 31 (0.00%)
    0 / 21 (0.00%)
    0 / 22 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Prostate cancer
         subjects affected / exposed
    0 / 30 (0.00%)
    0 / 30 (0.00%)
    0 / 46 (0.00%)
    0 / 32 (0.00%)
    1 / 31 (3.23%)
    0 / 21 (0.00%)
    0 / 22 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Tumour pain
         subjects affected / exposed
    0 / 30 (0.00%)
    0 / 30 (0.00%)
    0 / 46 (0.00%)
    1 / 32 (3.13%)
    0 / 31 (0.00%)
    0 / 21 (0.00%)
    0 / 22 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 3
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Vascular disorders
    Deep vein thrombosis
         subjects affected / exposed
    1 / 30 (3.33%)
    0 / 30 (0.00%)
    0 / 46 (0.00%)
    0 / 32 (0.00%)
    0 / 31 (0.00%)
    0 / 21 (0.00%)
    0 / 22 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Embolism
         subjects affected / exposed
    0 / 30 (0.00%)
    0 / 30 (0.00%)
    0 / 46 (0.00%)
    0 / 32 (0.00%)
    0 / 31 (0.00%)
    1 / 21 (4.76%)
    0 / 22 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Haematoma
         subjects affected / exposed
    0 / 30 (0.00%)
    0 / 30 (0.00%)
    0 / 46 (0.00%)
    1 / 32 (3.13%)
    0 / 31 (0.00%)
    0 / 21 (0.00%)
    0 / 22 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hypotension
         subjects affected / exposed
    0 / 30 (0.00%)
    1 / 30 (3.33%)
    0 / 46 (0.00%)
    0 / 32 (0.00%)
    0 / 31 (0.00%)
    0 / 21 (0.00%)
    0 / 22 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Lymphoedema
         subjects affected / exposed
    0 / 30 (0.00%)
    0 / 30 (0.00%)
    1 / 46 (2.17%)
    0 / 32 (0.00%)
    0 / 31 (0.00%)
    0 / 21 (0.00%)
    0 / 22 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Asthenia
         subjects affected / exposed
    0 / 30 (0.00%)
    0 / 30 (0.00%)
    0 / 46 (0.00%)
    0 / 32 (0.00%)
    0 / 31 (0.00%)
    0 / 21 (0.00%)
    1 / 22 (4.55%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Fatigue
         subjects affected / exposed
    1 / 30 (3.33%)
    0 / 30 (0.00%)
    1 / 46 (2.17%)
    0 / 32 (0.00%)
    0 / 31 (0.00%)
    0 / 21 (0.00%)
    0 / 22 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    1 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    General physical health deterioration
         subjects affected / exposed
    0 / 30 (0.00%)
    0 / 30 (0.00%)
    1 / 46 (2.17%)
    0 / 32 (0.00%)
    0 / 31 (0.00%)
    0 / 21 (0.00%)
    1 / 22 (4.55%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    Non-cardiac chest pain
         subjects affected / exposed
    0 / 30 (0.00%)
    0 / 30 (0.00%)
    1 / 46 (2.17%)
    0 / 32 (0.00%)
    0 / 31 (0.00%)
    1 / 21 (4.76%)
    0 / 22 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pain
         subjects affected / exposed
    0 / 30 (0.00%)
    1 / 30 (3.33%)
    0 / 46 (0.00%)
    0 / 32 (0.00%)
    0 / 31 (0.00%)
    0 / 21 (0.00%)
    0 / 22 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pyrexia
         subjects affected / exposed
    0 / 30 (0.00%)
    0 / 30 (0.00%)
    1 / 46 (2.17%)
    0 / 32 (0.00%)
    0 / 31 (0.00%)
    0 / 21 (0.00%)
    1 / 22 (4.55%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Acute respiratory distress syndrome
         subjects affected / exposed
    0 / 30 (0.00%)
    0 / 30 (0.00%)
    0 / 46 (0.00%)
    0 / 32 (0.00%)
    1 / 31 (3.23%)
    0 / 21 (0.00%)
    0 / 22 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Atelectasis
         subjects affected / exposed
    0 / 30 (0.00%)
    0 / 30 (0.00%)
    0 / 46 (0.00%)
    0 / 32 (0.00%)
    1 / 31 (3.23%)
    0 / 21 (0.00%)
    0 / 22 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cough
         subjects affected / exposed
    0 / 30 (0.00%)
    0 / 30 (0.00%)
    0 / 46 (0.00%)
    0 / 32 (0.00%)
    0 / 31 (0.00%)
    1 / 21 (4.76%)
    0 / 22 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Dyspnoea
         subjects affected / exposed
    0 / 30 (0.00%)
    0 / 30 (0.00%)
    1 / 46 (2.17%)
    1 / 32 (3.13%)
    2 / 31 (6.45%)
    2 / 21 (9.52%)
    0 / 22 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    0 / 1
    0 / 2
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pleural effusion
         subjects affected / exposed
    1 / 30 (3.33%)
    0 / 30 (0.00%)
    0 / 46 (0.00%)
    1 / 32 (3.13%)
    2 / 31 (6.45%)
    0 / 21 (0.00%)
    0 / 22 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 1
    0 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pneumonitis
         subjects affected / exposed
    0 / 30 (0.00%)
    0 / 30 (0.00%)
    0 / 46 (0.00%)
    0 / 32 (0.00%)
    1 / 31 (3.23%)
    0 / 21 (0.00%)
    0 / 22 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pneumothorax
         subjects affected / exposed
    1 / 30 (3.33%)
    0 / 30 (0.00%)
    0 / 46 (0.00%)
    0 / 32 (0.00%)
    1 / 31 (3.23%)
    0 / 21 (0.00%)
    1 / 22 (4.55%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pulmonary embolism
         subjects affected / exposed
    1 / 30 (3.33%)
    0 / 30 (0.00%)
    0 / 46 (0.00%)
    1 / 32 (3.13%)
    2 / 31 (6.45%)
    0 / 21 (0.00%)
    0 / 22 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 1
    0 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Respiratory arrest
         subjects affected / exposed
    0 / 30 (0.00%)
    0 / 30 (0.00%)
    0 / 46 (0.00%)
    0 / 32 (0.00%)
    0 / 31 (0.00%)
    1 / 21 (4.76%)
    0 / 22 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    Investigations
    Amylase increased
         subjects affected / exposed
    0 / 30 (0.00%)
    0 / 30 (0.00%)
    1 / 46 (2.17%)
    0 / 32 (0.00%)
    0 / 31 (0.00%)
    0 / 21 (0.00%)
    0 / 22 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Blood alkaline phosphatase increased
         subjects affected / exposed
    0 / 30 (0.00%)
    0 / 30 (0.00%)
    0 / 46 (0.00%)
    1 / 32 (3.13%)
    0 / 31 (0.00%)
    0 / 21 (0.00%)
    0 / 22 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Blood creatinine increased
         subjects affected / exposed
    1 / 30 (3.33%)
    0 / 30 (0.00%)
    0 / 46 (0.00%)
    0 / 32 (0.00%)
    0 / 31 (0.00%)
    0 / 21 (0.00%)
    0 / 22 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Blood potassium increased
         subjects affected / exposed
    0 / 30 (0.00%)
    1 / 30 (3.33%)
    0 / 46 (0.00%)
    0 / 32 (0.00%)
    0 / 31 (0.00%)
    0 / 21 (0.00%)
    0 / 22 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Lipase increased
         subjects affected / exposed
    0 / 30 (0.00%)
    0 / 30 (0.00%)
    1 / 46 (2.17%)
    0 / 32 (0.00%)
    0 / 31 (0.00%)
    0 / 21 (0.00%)
    0 / 22 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Transaminases increased
         subjects affected / exposed
    0 / 30 (0.00%)
    1 / 30 (3.33%)
    0 / 46 (0.00%)
    0 / 32 (0.00%)
    0 / 31 (0.00%)
    0 / 21 (0.00%)
    0 / 22 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Acetabulum fracture
         subjects affected / exposed
    0 / 30 (0.00%)
    0 / 30 (0.00%)
    0 / 46 (0.00%)
    0 / 32 (0.00%)
    1 / 31 (3.23%)
    0 / 21 (0.00%)
    0 / 22 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Fall
         subjects affected / exposed
    0 / 30 (0.00%)
    0 / 30 (0.00%)
    0 / 46 (0.00%)
    0 / 32 (0.00%)
    0 / 31 (0.00%)
    0 / 21 (0.00%)
    1 / 22 (4.55%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Fracture
         subjects affected / exposed
    0 / 30 (0.00%)
    0 / 30 (0.00%)
    0 / 46 (0.00%)
    0 / 32 (0.00%)
    0 / 31 (0.00%)
    0 / 21 (0.00%)
    1 / 22 (4.55%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Post procedural haematuria
         subjects affected / exposed
    0 / 30 (0.00%)
    0 / 30 (0.00%)
    0 / 46 (0.00%)
    0 / 32 (0.00%)
    0 / 31 (0.00%)
    0 / 21 (0.00%)
    1 / 22 (4.55%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Wound dehiscence
         subjects affected / exposed
    0 / 30 (0.00%)
    0 / 30 (0.00%)
    0 / 46 (0.00%)
    1 / 32 (3.13%)
    2 / 31 (6.45%)
    0 / 21 (0.00%)
    0 / 22 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cardiac disorders
    Angina pectoris
         subjects affected / exposed
    0 / 30 (0.00%)
    0 / 30 (0.00%)
    1 / 46 (2.17%)
    0 / 32 (0.00%)
    0 / 31 (0.00%)
    0 / 21 (0.00%)
    0 / 22 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Atrial fibrillation
         subjects affected / exposed
    1 / 30 (3.33%)
    1 / 30 (3.33%)
    0 / 46 (0.00%)
    0 / 32 (0.00%)
    1 / 31 (3.23%)
    0 / 21 (0.00%)
    0 / 22 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 1
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cardiac arrest
         subjects affected / exposed
    0 / 30 (0.00%)
    0 / 30 (0.00%)
    2 / 46 (4.35%)
    0 / 32 (0.00%)
    0 / 31 (0.00%)
    0 / 21 (0.00%)
    0 / 22 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 2
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 2
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cardiac failure congestive
         subjects affected / exposed
    1 / 30 (3.33%)
    0 / 30 (0.00%)
    1 / 46 (2.17%)
    0 / 32 (0.00%)
    0 / 31 (0.00%)
    1 / 21 (4.76%)
    0 / 22 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Myocarditis
         subjects affected / exposed
    0 / 30 (0.00%)
    0 / 30 (0.00%)
    0 / 46 (0.00%)
    0 / 32 (0.00%)
    0 / 31 (0.00%)
    1 / 21 (4.76%)
    0 / 22 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pericarditis
         subjects affected / exposed
    1 / 30 (3.33%)
    0 / 30 (0.00%)
    0 / 46 (0.00%)
    0 / 32 (0.00%)
    0 / 31 (0.00%)
    0 / 21 (0.00%)
    0 / 22 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Ventricular tachycardia
         subjects affected / exposed
    0 / 30 (0.00%)
    0 / 30 (0.00%)
    1 / 46 (2.17%)
    0 / 32 (0.00%)
    0 / 31 (0.00%)
    0 / 21 (0.00%)
    0 / 22 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Nervous system disorders
    Aphasia
         subjects affected / exposed
    0 / 30 (0.00%)
    0 / 30 (0.00%)
    1 / 46 (2.17%)
    0 / 32 (0.00%)
    0 / 31 (0.00%)
    0 / 21 (0.00%)
    0 / 22 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Brain oedema
         subjects affected / exposed
    0 / 30 (0.00%)
    1 / 30 (3.33%)
    0 / 46 (0.00%)
    0 / 32 (0.00%)
    0 / 31 (0.00%)
    0 / 21 (0.00%)
    0 / 22 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Dizziness
         subjects affected / exposed
    0 / 30 (0.00%)
    1 / 30 (3.33%)
    0 / 46 (0.00%)
    0 / 32 (0.00%)
    0 / 31 (0.00%)
    0 / 21 (0.00%)
    0 / 22 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Encephalopathy
         subjects affected / exposed
    0 / 30 (0.00%)
    1 / 30 (3.33%)
    0 / 46 (0.00%)
    0 / 32 (0.00%)
    0 / 31 (0.00%)
    0 / 21 (0.00%)
    0 / 22 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Facial paralysis
         subjects affected / exposed
    1 / 30 (3.33%)
    0 / 30 (0.00%)
    0 / 46 (0.00%)
    0 / 32 (0.00%)
    0 / 31 (0.00%)
    0 / 21 (0.00%)
    0 / 22 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Immune-mediated neuropathy
         subjects affected / exposed
    1 / 30 (3.33%)
    0 / 30 (0.00%)
    0 / 46 (0.00%)
    0 / 32 (0.00%)
    0 / 31 (0.00%)
    0 / 21 (0.00%)
    0 / 22 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Neuralgia
         subjects affected / exposed
    0 / 30 (0.00%)
    0 / 30 (0.00%)
    0 / 46 (0.00%)
    0 / 32 (0.00%)
    0 / 31 (0.00%)
    0 / 21 (0.00%)
    1 / 22 (4.55%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pyramidal tract syndrome
         subjects affected / exposed
    0 / 30 (0.00%)
    0 / 30 (0.00%)
    0 / 46 (0.00%)
    0 / 32 (0.00%)
    0 / 31 (0.00%)
    0 / 21 (0.00%)
    1 / 22 (4.55%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Seizure
         subjects affected / exposed
    0 / 30 (0.00%)
    1 / 30 (3.33%)
    1 / 46 (2.17%)
    0 / 32 (0.00%)
    0 / 31 (0.00%)
    0 / 21 (0.00%)
    0 / 22 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 2
    0 / 2
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Spinal cord compression
         subjects affected / exposed
    0 / 30 (0.00%)
    2 / 30 (6.67%)
    1 / 46 (2.17%)
    1 / 32 (3.13%)
    1 / 31 (3.23%)
    0 / 21 (0.00%)
    0 / 22 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 3
    0 / 1
    1 / 1
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    0 / 30 (0.00%)
    0 / 30 (0.00%)
    1 / 46 (2.17%)
    0 / 32 (0.00%)
    0 / 31 (0.00%)
    0 / 21 (0.00%)
    0 / 22 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Abdominal pain
         subjects affected / exposed
    0 / 30 (0.00%)
    0 / 30 (0.00%)
    0 / 46 (0.00%)
    1 / 32 (3.13%)
    0 / 31 (0.00%)
    0 / 21 (0.00%)
    0 / 22 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Abdominal pain lower
         subjects affected / exposed
    0 / 30 (0.00%)
    0 / 30 (0.00%)
    1 / 46 (2.17%)
    0 / 32 (0.00%)
    0 / 31 (0.00%)
    0 / 21 (0.00%)
    0 / 22 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Colitis
         subjects affected / exposed
    1 / 30 (3.33%)
    0 / 30 (0.00%)
    0 / 46 (0.00%)
    0 / 32 (0.00%)
    0 / 31 (0.00%)
    0 / 21 (0.00%)
    0 / 22 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Diarrhoea
         subjects affected / exposed
    0 / 30 (0.00%)
    0 / 30 (0.00%)
    0 / 46 (0.00%)
    0 / 32 (0.00%)
    1 / 31 (3.23%)
    0 / 21 (0.00%)
    1 / 22 (4.55%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    1 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Enteritis
         subjects affected / exposed
    1 / 30 (3.33%)
    0 / 30 (0.00%)
    0 / 46 (0.00%)
    0 / 32 (0.00%)
    0 / 31 (0.00%)
    0 / 21 (0.00%)
    0 / 22 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Enterocolitis
         subjects affected / exposed
    0 / 30 (0.00%)
    0 / 30 (0.00%)
    1 / 46 (2.17%)
    0 / 32 (0.00%)
    0 / 31 (0.00%)
    0 / 21 (0.00%)
    0 / 22 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal haemorrhage
         subjects affected / exposed
    0 / 30 (0.00%)
    0 / 30 (0.00%)
    0 / 46 (0.00%)
    1 / 32 (3.13%)
    0 / 31 (0.00%)
    0 / 21 (0.00%)
    0 / 22 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Large intestinal obstruction
         subjects affected / exposed
    1 / 30 (3.33%)
    0 / 30 (0.00%)
    0 / 46 (0.00%)
    0 / 32 (0.00%)
    0 / 31 (0.00%)
    0 / 21 (0.00%)
    0 / 22 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Lip swelling
         subjects affected / exposed
    0 / 30 (0.00%)
    1 / 30 (3.33%)
    0 / 46 (0.00%)
    0 / 32 (0.00%)
    0 / 31 (0.00%)
    0 / 21 (0.00%)
    0 / 22 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Lower gastrointestinal haemorrhage
         subjects affected / exposed
    0 / 30 (0.00%)
    0 / 30 (0.00%)
    0 / 46 (0.00%)
    0 / 32 (0.00%)
    0 / 31 (0.00%)
    0 / 21 (0.00%)
    1 / 22 (4.55%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Mouth haemorrhage
         subjects affected / exposed
    0 / 30 (0.00%)
    1 / 30 (3.33%)
    0 / 46 (0.00%)
    0 / 32 (0.00%)
    0 / 31 (0.00%)
    0 / 21 (0.00%)
    0 / 22 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Nausea
         subjects affected / exposed
    0 / 30 (0.00%)
    1 / 30 (3.33%)
    0 / 46 (0.00%)
    0 / 32 (0.00%)
    1 / 31 (3.23%)
    0 / 21 (0.00%)
    0 / 22 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Oesophagitis
         subjects affected / exposed
    0 / 30 (0.00%)
    0 / 30 (0.00%)
    1 / 46 (2.17%)
    0 / 32 (0.00%)
    0 / 31 (0.00%)
    0 / 21 (0.00%)
    0 / 22 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Small intestinal haemorrhage
         subjects affected / exposed
    0 / 30 (0.00%)
    0 / 30 (0.00%)
    1 / 46 (2.17%)
    0 / 32 (0.00%)
    0 / 31 (0.00%)
    0 / 21 (0.00%)
    0 / 22 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 2
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Small intestinal obstruction
         subjects affected / exposed
    1 / 30 (3.33%)
    0 / 30 (0.00%)
    0 / 46 (0.00%)
    0 / 32 (0.00%)
    0 / 31 (0.00%)
    0 / 21 (0.00%)
    0 / 22 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Upper gastrointestinal haemorrhage
         subjects affected / exposed
    0 / 30 (0.00%)
    0 / 30 (0.00%)
    0 / 46 (0.00%)
    0 / 32 (0.00%)
    0 / 31 (0.00%)
    1 / 21 (4.76%)
    0 / 22 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Vomiting
         subjects affected / exposed
    0 / 30 (0.00%)
    2 / 30 (6.67%)
    0 / 46 (0.00%)
    0 / 32 (0.00%)
    1 / 31 (3.23%)
    0 / 21 (0.00%)
    0 / 22 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hepatobiliary disorders
    Biliary obstruction
         subjects affected / exposed
    0 / 30 (0.00%)
    0 / 30 (0.00%)
    1 / 46 (2.17%)
    0 / 32 (0.00%)
    0 / 31 (0.00%)
    0 / 21 (0.00%)
    0 / 22 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cholecystitis
         subjects affected / exposed
    0 / 30 (0.00%)
    0 / 30 (0.00%)
    1 / 46 (2.17%)
    1 / 32 (3.13%)
    0 / 31 (0.00%)
    0 / 21 (0.00%)
    0 / 22 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hepatotoxicity
         subjects affected / exposed
    1 / 30 (3.33%)
    0 / 30 (0.00%)
    0 / 46 (0.00%)
    0 / 32 (0.00%)
    0 / 31 (0.00%)
    0 / 21 (0.00%)
    0 / 22 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Skin and subcutaneous tissue disorders
    Intertrigo
         subjects affected / exposed
    0 / 30 (0.00%)
    1 / 30 (3.33%)
    0 / 46 (0.00%)
    0 / 32 (0.00%)
    0 / 31 (0.00%)
    0 / 21 (0.00%)
    0 / 22 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Rash
         subjects affected / exposed
    1 / 30 (3.33%)
    0 / 30 (0.00%)
    0 / 46 (0.00%)
    0 / 32 (0.00%)
    0 / 31 (0.00%)
    0 / 21 (0.00%)
    0 / 22 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Renal and urinary disorders
    Acute kidney injury
         subjects affected / exposed
    0 / 30 (0.00%)
    0 / 30 (0.00%)
    0 / 46 (0.00%)
    0 / 32 (0.00%)
    0 / 31 (0.00%)
    2 / 21 (9.52%)
    1 / 22 (4.55%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Bladder perforation
         subjects affected / exposed
    1 / 30 (3.33%)
    0 / 30 (0.00%)
    0 / 46 (0.00%)
    0 / 32 (0.00%)
    0 / 31 (0.00%)
    0 / 21 (0.00%)
    0 / 22 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Immune-mediated nephritis
         subjects affected / exposed
    0 / 30 (0.00%)
    1 / 30 (3.33%)
    0 / 46 (0.00%)
    0 / 32 (0.00%)
    0 / 31 (0.00%)
    0 / 21 (0.00%)
    0 / 22 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Oliguria
         subjects affected / exposed
    1 / 30 (3.33%)
    0 / 30 (0.00%)
    0 / 46 (0.00%)
    0 / 32 (0.00%)
    0 / 31 (0.00%)
    0 / 21 (0.00%)
    0 / 22 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Renal haematoma
         subjects affected / exposed
    0 / 30 (0.00%)
    0 / 30 (0.00%)
    0 / 46 (0.00%)
    0 / 32 (0.00%)
    0 / 31 (0.00%)
    0 / 21 (0.00%)
    1 / 22 (4.55%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Endocrine disorders
    Adrenal insufficiency
         subjects affected / exposed
    1 / 30 (3.33%)
    0 / 30 (0.00%)
    0 / 46 (0.00%)
    1 / 32 (3.13%)
    1 / 31 (3.23%)
    0 / 21 (0.00%)
    0 / 22 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    1 / 1
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Immune-mediated adrenal insufficiency
         subjects affected / exposed
    0 / 30 (0.00%)
    0 / 30 (0.00%)
    1 / 46 (2.17%)
    0 / 32 (0.00%)
    0 / 31 (0.00%)
    0 / 21 (0.00%)
    0 / 22 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Inappropriate antidiuretic hormone secretion
         subjects affected / exposed
    0 / 30 (0.00%)
    0 / 30 (0.00%)
    0 / 46 (0.00%)
    0 / 32 (0.00%)
    0 / 31 (0.00%)
    1 / 21 (4.76%)
    0 / 22 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    0 / 30 (0.00%)
    0 / 30 (0.00%)
    1 / 46 (2.17%)
    0 / 32 (0.00%)
    0 / 31 (0.00%)
    0 / 21 (0.00%)
    0 / 22 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Autoimmune myositis
         subjects affected / exposed
    1 / 30 (3.33%)
    0 / 30 (0.00%)
    0 / 46 (0.00%)
    0 / 32 (0.00%)
    0 / 31 (0.00%)
    0 / 21 (0.00%)
    0 / 22 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Back pain
         subjects affected / exposed
    0 / 30 (0.00%)
    1 / 30 (3.33%)
    1 / 46 (2.17%)
    0 / 32 (0.00%)
    1 / 31 (3.23%)
    0 / 21 (0.00%)
    0 / 22 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Flank pain
         subjects affected / exposed
    0 / 30 (0.00%)
    0 / 30 (0.00%)
    0 / 46 (0.00%)
    0 / 32 (0.00%)
    1 / 31 (3.23%)
    0 / 21 (0.00%)
    0 / 22 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Groin pain
         subjects affected / exposed
    0 / 30 (0.00%)
    0 / 30 (0.00%)
    1 / 46 (2.17%)
    0 / 32 (0.00%)
    0 / 31 (0.00%)
    0 / 21 (0.00%)
    0 / 22 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Muscular weakness
         subjects affected / exposed
    1 / 30 (3.33%)
    0 / 30 (0.00%)
    0 / 46 (0.00%)
    2 / 32 (6.25%)
    0 / 31 (0.00%)
    1 / 21 (4.76%)
    0 / 22 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 2
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Musculoskeletal chest pain
         subjects affected / exposed
    0 / 30 (0.00%)
    0 / 30 (0.00%)
    0 / 46 (0.00%)
    0 / 32 (0.00%)
    1 / 31 (3.23%)
    0 / 21 (0.00%)
    0 / 22 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pain in extremity
         subjects affected / exposed
    0 / 30 (0.00%)
    0 / 30 (0.00%)
    0 / 46 (0.00%)
    1 / 32 (3.13%)
    1 / 31 (3.23%)
    0 / 21 (0.00%)
    0 / 22 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Polymyalgia rheumatica
         subjects affected / exposed
    0 / 30 (0.00%)
    0 / 30 (0.00%)
    0 / 46 (0.00%)
    1 / 32 (3.13%)
    0 / 31 (0.00%)
    0 / 21 (0.00%)
    0 / 22 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    1 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Infections and infestations
    Bronchitis
         subjects affected / exposed
    0 / 30 (0.00%)
    0 / 30 (0.00%)
    0 / 46 (0.00%)
    0 / 32 (0.00%)
    1 / 31 (3.23%)
    1 / 21 (4.76%)
    0 / 22 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cellulitis
         subjects affected / exposed
    0 / 30 (0.00%)
    0 / 30 (0.00%)
    1 / 46 (2.17%)
    0 / 32 (0.00%)
    0 / 31 (0.00%)
    0 / 21 (0.00%)
    0 / 22 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Device related infection
         subjects affected / exposed
    0 / 30 (0.00%)
    0 / 30 (0.00%)
    1 / 46 (2.17%)
    0 / 32 (0.00%)
    0 / 31 (0.00%)
    0 / 21 (0.00%)
    0 / 22 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Epididymitis
         subjects affected / exposed
    1 / 30 (3.33%)
    0 / 30 (0.00%)
    0 / 46 (0.00%)
    0 / 32 (0.00%)
    0 / 31 (0.00%)
    0 / 21 (0.00%)
    0 / 22 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pneumonia
         subjects affected / exposed
    4 / 30 (13.33%)
    0 / 30 (0.00%)
    0 / 46 (0.00%)
    3 / 32 (9.38%)
    2 / 31 (6.45%)
    0 / 21 (0.00%)
    2 / 22 (9.09%)
         occurrences causally related to treatment / all
    1 / 4
    0 / 0
    0 / 0
    0 / 3
    0 / 2
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    Pneumonia influenzal
         subjects affected / exposed
    0 / 30 (0.00%)
    0 / 30 (0.00%)
    0 / 46 (0.00%)
    0 / 32 (0.00%)
    0 / 31 (0.00%)
    1 / 21 (4.76%)
    0 / 22 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pulmonary sepsis
         subjects affected / exposed
    0 / 30 (0.00%)
    1 / 30 (3.33%)
    0 / 46 (0.00%)
    0 / 32 (0.00%)
    0 / 31 (0.00%)
    0 / 21 (0.00%)
    0 / 22 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Sepsis
         subjects affected / exposed
    0 / 30 (0.00%)
    0 / 30 (0.00%)
    1 / 46 (2.17%)
    0 / 32 (0.00%)
    0 / 31 (0.00%)
    0 / 21 (0.00%)
    0 / 22 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 2
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Sialoadenitis
         subjects affected / exposed
    0 / 30 (0.00%)
    0 / 30 (0.00%)
    1 / 46 (2.17%)
    0 / 32 (0.00%)
    0 / 31 (0.00%)
    0 / 21 (0.00%)
    0 / 22 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Sinusitis
         subjects affected / exposed
    0 / 30 (0.00%)
    0 / 30 (0.00%)
    1 / 46 (2.17%)
    0 / 32 (0.00%)
    0 / 31 (0.00%)
    0 / 21 (0.00%)
    0 / 22 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Urinary tract infection
         subjects affected / exposed
    1 / 30 (3.33%)
    0 / 30 (0.00%)
    0 / 46 (0.00%)
    0 / 32 (0.00%)
    0 / 31 (0.00%)
    0 / 21 (0.00%)
    1 / 22 (4.55%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Urosepsis
         subjects affected / exposed
    1 / 30 (3.33%)
    1 / 30 (3.33%)
    0 / 46 (0.00%)
    0 / 32 (0.00%)
    0 / 31 (0.00%)
    0 / 21 (0.00%)
    0 / 22 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Wound infection
         subjects affected / exposed
    0 / 30 (0.00%)
    0 / 30 (0.00%)
    0 / 46 (0.00%)
    1 / 32 (3.13%)
    0 / 31 (0.00%)
    0 / 21 (0.00%)
    0 / 22 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Dehydration
         subjects affected / exposed
    2 / 30 (6.67%)
    0 / 30 (0.00%)
    0 / 46 (0.00%)
    0 / 32 (0.00%)
    0 / 31 (0.00%)
    0 / 21 (0.00%)
    0 / 22 (0.00%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Diabetic ketoacidosis
         subjects affected / exposed
    0 / 30 (0.00%)
    0 / 30 (0.00%)
    1 / 46 (2.17%)
    0 / 32 (0.00%)
    0 / 31 (0.00%)
    0 / 21 (0.00%)
    0 / 22 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Failure to thrive
         subjects affected / exposed
    0 / 30 (0.00%)
    0 / 30 (0.00%)
    0 / 46 (0.00%)
    0 / 32 (0.00%)
    1 / 31 (3.23%)
    0 / 21 (0.00%)
    0 / 22 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hypercalcaemia
         subjects affected / exposed
    2 / 30 (6.67%)
    3 / 30 (10.00%)
    2 / 46 (4.35%)
    0 / 32 (0.00%)
    1 / 31 (3.23%)
    0 / 21 (0.00%)
    0 / 22 (0.00%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 3
    0 / 3
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hyperkalaemia
         subjects affected / exposed
    0 / 30 (0.00%)
    0 / 30 (0.00%)
    0 / 46 (0.00%)
    1 / 32 (3.13%)
    0 / 31 (0.00%)
    0 / 21 (0.00%)
    0 / 22 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hypocalcaemia
         subjects affected / exposed
    1 / 30 (3.33%)
    0 / 30 (0.00%)
    0 / 46 (0.00%)
    0 / 32 (0.00%)
    0 / 31 (0.00%)
    0 / 21 (0.00%)
    0 / 22 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hyponatraemia
         subjects affected / exposed
    0 / 30 (0.00%)
    0 / 30 (0.00%)
    0 / 46 (0.00%)
    1 / 32 (3.13%)
    0 / 31 (0.00%)
    0 / 21 (0.00%)
    0 / 22 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Track 1 NIV+IPI Track 1 NIV+BMS986016 Track 2 NIV+IPI Track 2 NIV+BMS986016 Track 2 NIV+BMS986205 Track 2 NIV+BMS813160 150MG QD Track 2 NIV+BMS813160 300MG BID
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    28 / 30 (93.33%)
    29 / 30 (96.67%)
    42 / 46 (91.30%)
    31 / 32 (96.88%)
    29 / 31 (93.55%)
    18 / 21 (85.71%)
    17 / 22 (77.27%)
    Vascular disorders
    Hot flush
         subjects affected / exposed
    1 / 30 (3.33%)
    2 / 30 (6.67%)
    1 / 46 (2.17%)
    0 / 32 (0.00%)
    2 / 31 (6.45%)
    0 / 21 (0.00%)
    0 / 22 (0.00%)
         occurrences all number
    1
    2
    1
    0
    2
    0
    0
    Hypertension
         subjects affected / exposed
    1 / 30 (3.33%)
    2 / 30 (6.67%)
    4 / 46 (8.70%)
    1 / 32 (3.13%)
    1 / 31 (3.23%)
    2 / 21 (9.52%)
    0 / 22 (0.00%)
         occurrences all number
    1
    3
    4
    1
    1
    2
    0
    Hypotension
         subjects affected / exposed
    1 / 30 (3.33%)
    1 / 30 (3.33%)
    2 / 46 (4.35%)
    2 / 32 (6.25%)
    1 / 31 (3.23%)
    0 / 21 (0.00%)
    0 / 22 (0.00%)
         occurrences all number
    2
    1
    3
    2
    1
    0
    0
    General disorders and administration site conditions
    Chest discomfort
         subjects affected / exposed
    1 / 30 (3.33%)
    0 / 30 (0.00%)
    0 / 46 (0.00%)
    1 / 32 (3.13%)
    0 / 31 (0.00%)
    2 / 21 (9.52%)
    0 / 22 (0.00%)
         occurrences all number
    1
    0
    0
    1
    0
    3
    0
    Asthenia
         subjects affected / exposed
    2 / 30 (6.67%)
    0 / 30 (0.00%)
    3 / 46 (6.52%)
    2 / 32 (6.25%)
    3 / 31 (9.68%)
    2 / 21 (9.52%)
    1 / 22 (4.55%)
         occurrences all number
    2
    0
    3
    3
    3
    2
    1
    Fatigue
         subjects affected / exposed
    9 / 30 (30.00%)
    13 / 30 (43.33%)
    15 / 46 (32.61%)
    11 / 32 (34.38%)
    8 / 31 (25.81%)
    7 / 21 (33.33%)
    6 / 22 (27.27%)
         occurrences all number
    12
    16
    16
    13
    8
    7
    6
    Chills
         subjects affected / exposed
    3 / 30 (10.00%)
    2 / 30 (6.67%)
    4 / 46 (8.70%)
    3 / 32 (9.38%)
    0 / 31 (0.00%)
    0 / 21 (0.00%)
    0 / 22 (0.00%)
         occurrences all number
    3
    2
    5
    3
    0
    0
    0
    Gait disturbance
         subjects affected / exposed
    1 / 30 (3.33%)
    0 / 30 (0.00%)
    2 / 46 (4.35%)
    2 / 32 (6.25%)
    0 / 31 (0.00%)
    0 / 21 (0.00%)
    0 / 22 (0.00%)
         occurrences all number
    1
    0
    2
    2
    0
    0
    0
    Non-cardiac chest pain
         subjects affected / exposed
    3 / 30 (10.00%)
    1 / 30 (3.33%)
    1 / 46 (2.17%)
    3 / 32 (9.38%)
    0 / 31 (0.00%)
    1 / 21 (4.76%)
    0 / 22 (0.00%)
         occurrences all number
    3
    1
    1
    3
    0
    1
    0
    Mucosal inflammation
         subjects affected / exposed
    1 / 30 (3.33%)
    0 / 30 (0.00%)
    0 / 46 (0.00%)
    1 / 32 (3.13%)
    0 / 31 (0.00%)
    2 / 21 (9.52%)
    0 / 22 (0.00%)
         occurrences all number
    1
    0
    0
    1
    0
    3
    0
    Oedema peripheral
         subjects affected / exposed
    4 / 30 (13.33%)
    3 / 30 (10.00%)
    6 / 46 (13.04%)
    4 / 32 (12.50%)
    6 / 31 (19.35%)
    1 / 21 (4.76%)
    0 / 22 (0.00%)
         occurrences all number
    5
    3
    7
    4
    6
    1
    0
    Pyrexia
         subjects affected / exposed
    5 / 30 (16.67%)
    2 / 30 (6.67%)
    5 / 46 (10.87%)
    5 / 32 (15.63%)
    2 / 31 (6.45%)
    1 / 21 (4.76%)
    2 / 22 (9.09%)
         occurrences all number
    5
    2
    5
    5
    2
    1
    2
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    11 / 30 (36.67%)
    6 / 30 (20.00%)
    10 / 46 (21.74%)
    8 / 32 (25.00%)
    6 / 31 (19.35%)
    6 / 21 (28.57%)
    2 / 22 (9.09%)
         occurrences all number
    12
    6
    10
    9
    6
    6
    2
    Dysphonia
         subjects affected / exposed
    2 / 30 (6.67%)
    0 / 30 (0.00%)
    3 / 46 (6.52%)
    0 / 32 (0.00%)
    0 / 31 (0.00%)
    1 / 21 (4.76%)
    0 / 22 (0.00%)
         occurrences all number
    2
    0
    3
    0
    0
    1
    0
    Dyspnoea
         subjects affected / exposed
    7 / 30 (23.33%)
    4 / 30 (13.33%)
    6 / 46 (13.04%)
    3 / 32 (9.38%)
    7 / 31 (22.58%)
    2 / 21 (9.52%)
    4 / 22 (18.18%)
         occurrences all number
    7
    4
    6
    3
    7
    2
    4
    Dyspnoea exertional
         subjects affected / exposed
    2 / 30 (6.67%)
    0 / 30 (0.00%)
    0 / 46 (0.00%)
    1 / 32 (3.13%)
    0 / 31 (0.00%)
    1 / 21 (4.76%)
    1 / 22 (4.55%)
         occurrences all number
    2
    0
    0
    2
    0
    1
    1
    Epistaxis
         subjects affected / exposed
    1 / 30 (3.33%)
    0 / 30 (0.00%)
    2 / 46 (4.35%)
    0 / 32 (0.00%)
    0 / 31 (0.00%)
    2 / 21 (9.52%)
    0 / 22 (0.00%)
         occurrences all number
    1
    0
    2
    0
    0
    2
    0
    Nasal congestion
         subjects affected / exposed
    3 / 30 (10.00%)
    0 / 30 (0.00%)
    1 / 46 (2.17%)
    0 / 32 (0.00%)
    0 / 31 (0.00%)
    0 / 21 (0.00%)
    0 / 22 (0.00%)
         occurrences all number
    3
    0
    1
    0
    0
    0
    0
    Oropharyngeal pain
         subjects affected / exposed
    1 / 30 (3.33%)
    4 / 30 (13.33%)
    1 / 46 (2.17%)
    1 / 32 (3.13%)
    0 / 31 (0.00%)
    0 / 21 (0.00%)
    1 / 22 (4.55%)
         occurrences all number
    1
    5
    1
    1
    0
    0
    1
    Pleuritic pain
         subjects affected / exposed
    2 / 30 (6.67%)
    0 / 30 (0.00%)
    1 / 46 (2.17%)
    1 / 32 (3.13%)
    0 / 31 (0.00%)
    0 / 21 (0.00%)
    0 / 22 (0.00%)
         occurrences all number
    2
    0
    1
    1
    0
    0
    0
    Pleural effusion
         subjects affected / exposed
    2 / 30 (6.67%)
    1 / 30 (3.33%)
    0 / 46 (0.00%)
    0 / 32 (0.00%)
    3 / 31 (9.68%)
    1 / 21 (4.76%)
    0 / 22 (0.00%)
         occurrences all number
    2
    1
    0
    0
    5
    1
    0
    Pneumothorax
         subjects affected / exposed
    0 / 30 (0.00%)
    2 / 30 (6.67%)
    1 / 46 (2.17%)
    0 / 32 (0.00%)
    0 / 31 (0.00%)
    0 / 21 (0.00%)
    1 / 22 (4.55%)
         occurrences all number
    0
    2
    1
    0
    0
    0
    1
    Pneumonitis
         subjects affected / exposed
    0 / 30 (0.00%)
    0 / 30 (0.00%)
    0 / 46 (0.00%)
    0 / 32 (0.00%)
    2 / 31 (6.45%)
    0 / 21 (0.00%)
    1 / 22 (4.55%)
         occurrences all number
    0
    0
    0
    0
    2
    0
    1
    Productive cough
         subjects affected / exposed
    0 / 30 (0.00%)
    4 / 30 (13.33%)
    0 / 46 (0.00%)
    1 / 32 (3.13%)
    1 / 31 (3.23%)
    3 / 21 (14.29%)
    0 / 22 (0.00%)
         occurrences all number
    0
    4
    0
    1
    1
    3
    0
    Rhinorrhoea
         subjects affected / exposed
    0 / 30 (0.00%)
    1 / 30 (3.33%)
    1 / 46 (2.17%)
    2 / 32 (6.25%)
    1 / 31 (3.23%)
    0 / 21 (0.00%)
    0 / 22 (0.00%)
         occurrences all number
    0
    1
    1
    2
    1
    0
    0
    Psychiatric disorders
    Anxiety
         subjects affected / exposed
    1 / 30 (3.33%)
    3 / 30 (10.00%)
    1 / 46 (2.17%)
    0 / 32 (0.00%)
    1 / 31 (3.23%)
    0 / 21 (0.00%)
    1 / 22 (4.55%)
         occurrences all number
    1
    3
    1
    0
    1
    0
    1
    Depression
         subjects affected / exposed
    1 / 30 (3.33%)
    2 / 30 (6.67%)
    0 / 46 (0.00%)
    0 / 32 (0.00%)
    2 / 31 (6.45%)
    0 / 21 (0.00%)
    0 / 22 (0.00%)
         occurrences all number
    1
    2
    0
    0
    2
    0
    0
    Insomnia
         subjects affected / exposed
    5 / 30 (16.67%)
    2 / 30 (6.67%)
    4 / 46 (8.70%)
    1 / 32 (3.13%)
    1 / 31 (3.23%)
    2 / 21 (9.52%)
    0 / 22 (0.00%)
         occurrences all number
    5
    2
    4
    1
    1
    2
    0
    Investigations
    Alanine aminotransferase increased
         subjects affected / exposed
    1 / 30 (3.33%)
    2 / 30 (6.67%)
    5 / 46 (10.87%)
    1 / 32 (3.13%)
    2 / 31 (6.45%)
    2 / 21 (9.52%)
    2 / 22 (9.09%)
         occurrences all number
    1
    4
    7
    1
    2
    3
    2
    Amylase increased
         subjects affected / exposed
    2 / 30 (6.67%)
    0 / 30 (0.00%)
    3 / 46 (6.52%)
    1 / 32 (3.13%)
    0 / 31 (0.00%)
    0 / 21 (0.00%)
    0 / 22 (0.00%)
         occurrences all number
    2
    0
    4
    1
    0
    0
    0
    Aspartate aminotransferase increased
         subjects affected / exposed
    1 / 30 (3.33%)
    1 / 30 (3.33%)
    5 / 46 (10.87%)
    2 / 32 (6.25%)
    3 / 31 (9.68%)
    3 / 21 (14.29%)
    2 / 22 (9.09%)
         occurrences all number
    1
    1
    7
    2
    3
    3
    2
    Blood alkaline phosphatase increased
         subjects affected / exposed
    1 / 30 (3.33%)
    3 / 30 (10.00%)
    0 / 46 (0.00%)
    0 / 32 (0.00%)
    1 / 31 (3.23%)
    1 / 21 (4.76%)
    1 / 22 (4.55%)
         occurrences all number
    1
    3
    0
    0
    1
    1
    1
    Blood creatinine increased
         subjects affected / exposed
    5 / 30 (16.67%)
    3 / 30 (10.00%)
    2 / 46 (4.35%)
    0 / 32 (0.00%)
    3 / 31 (9.68%)
    2 / 21 (9.52%)
    2 / 22 (9.09%)
         occurrences all number
    6
    3
    3
    0
    4
    10
    2
    Blood bilirubin increased
         subjects affected / exposed
    0 / 30 (0.00%)
    0 / 30 (0.00%)
    2 / 46 (4.35%)
    0 / 32 (0.00%)
    2 / 31 (6.45%)
    0 / 21 (0.00%)
    0 / 22 (0.00%)
         occurrences all number
    0
    0
    2
    0
    2
    0
    0
    Lipase increased
         subjects affected / exposed
    4 / 30 (13.33%)
    1 / 30 (3.33%)
    3 / 46 (6.52%)
    1 / 32 (3.13%)
    1 / 31 (3.23%)
    0 / 21 (0.00%)
    0 / 22 (0.00%)
         occurrences all number
    5
    1
    6
    1
    1
    0
    0
    Weight decreased
         subjects affected / exposed
    3 / 30 (10.00%)
    1 / 30 (3.33%)
    5 / 46 (10.87%)
    2 / 32 (6.25%)
    1 / 31 (3.23%)
    1 / 21 (4.76%)
    2 / 22 (9.09%)
         occurrences all number
    3
    1
    6
    2
    1
    1
    2
    Injury, poisoning and procedural complications
    Procedural pain
         subjects affected / exposed
    0 / 30 (0.00%)
    3 / 30 (10.00%)
    2 / 46 (4.35%)
    1 / 32 (3.13%)
    0 / 31 (0.00%)
    0 / 21 (0.00%)
    0 / 22 (0.00%)
         occurrences all number
    0
    3
    2
    1
    0
    0
    0
    Fall
         subjects affected / exposed
    1 / 30 (3.33%)
    4 / 30 (13.33%)
    5 / 46 (10.87%)
    2 / 32 (6.25%)
    1 / 31 (3.23%)
    1 / 21 (4.76%)
    1 / 22 (4.55%)
         occurrences all number
    1
    4
    6
    5
    2
    1
    1
    Cardiac disorders
    Sinus tachycardia
         subjects affected / exposed
    1 / 30 (3.33%)
    1 / 30 (3.33%)
    0 / 46 (0.00%)
    1 / 32 (3.13%)
    2 / 31 (6.45%)
    0 / 21 (0.00%)
    0 / 22 (0.00%)
         occurrences all number
    1
    1
    0
    1
    2
    0
    0
    Nervous system disorders
    Amnesia
         subjects affected / exposed
    0 / 30 (0.00%)
    0 / 30 (0.00%)
    2 / 46 (4.35%)
    2 / 32 (6.25%)
    0 / 31 (0.00%)
    0 / 21 (0.00%)
    0 / 22 (0.00%)
         occurrences all number
    0
    0
    2
    2
    0
    0
    0
    Dizziness
         subjects affected / exposed
    5 / 30 (16.67%)
    3 / 30 (10.00%)
    6 / 46 (13.04%)
    4 / 32 (12.50%)
    2 / 31 (6.45%)
    3 / 21 (14.29%)
    1 / 22 (4.55%)
         occurrences all number
    6
    4
    6
    5
    2
    3
    1
    Dizziness postural
         subjects affected / exposed
    2 / 30 (6.67%)
    0 / 30 (0.00%)
    0 / 46 (0.00%)
    0 / 32 (0.00%)
    0 / 31 (0.00%)
    0 / 21 (0.00%)
    0 / 22 (0.00%)
         occurrences all number
    2
    0
    0
    0
    0
    0
    0
    Dysgeusia
         subjects affected / exposed
    1 / 30 (3.33%)
    3 / 30 (10.00%)
    1 / 46 (2.17%)
    0 / 32 (0.00%)
    2 / 31 (6.45%)
    1 / 21 (4.76%)
    0 / 22 (0.00%)
         occurrences all number
    1
    3
    1
    0
    2
    1
    0
    Lethargy
         subjects affected / exposed
    1 / 30 (3.33%)
    1 / 30 (3.33%)
    1 / 46 (2.17%)
    0 / 32 (0.00%)
    2 / 31 (6.45%)
    0 / 21 (0.00%)
    0 / 22 (0.00%)
         occurrences all number
    1
    1
    1
    0
    2
    0
    0
    Headache
         subjects affected / exposed
    4 / 30 (13.33%)
    10 / 30 (33.33%)
    5 / 46 (10.87%)
    1 / 32 (3.13%)
    2 / 31 (6.45%)
    3 / 21 (14.29%)
    3 / 22 (13.64%)
         occurrences all number
    5
    15
    7
    1
    2
    3
    3
    Paraesthesia
         subjects affected / exposed
    1 / 30 (3.33%)
    3 / 30 (10.00%)
    1 / 46 (2.17%)
    4 / 32 (12.50%)
    1 / 31 (3.23%)
    2 / 21 (9.52%)
    1 / 22 (4.55%)
         occurrences all number
    1
    3
    1
    4
    1
    2
    1
    Spinal cord compression
         subjects affected / exposed
    0 / 30 (0.00%)
    2 / 30 (6.67%)
    0 / 46 (0.00%)
    0 / 32 (0.00%)
    1 / 31 (3.23%)
    0 / 21 (0.00%)
    0 / 22 (0.00%)
         occurrences all number
    0
    2
    0
    0
    1
    0
    0
    Taste disorder
         subjects affected / exposed
    0 / 30 (0.00%)
    0 / 30 (0.00%)
    0 / 46 (0.00%)
    0 / 32 (0.00%)
    3 / 31 (9.68%)
    0 / 21 (0.00%)
    0 / 22 (0.00%)
         occurrences all number
    0
    0
    0
    0
    3
    0
    0
    Tremor
         subjects affected / exposed
    2 / 30 (6.67%)
    1 / 30 (3.33%)
    0 / 46 (0.00%)
    1 / 32 (3.13%)
    0 / 31 (0.00%)
    1 / 21 (4.76%)
    0 / 22 (0.00%)
         occurrences all number
    2
    1
    0
    1
    0
    1
    0
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    8 / 30 (26.67%)
    5 / 30 (16.67%)
    8 / 46 (17.39%)
    4 / 32 (12.50%)
    4 / 31 (12.90%)
    2 / 21 (9.52%)
    2 / 22 (9.09%)
         occurrences all number
    8
    6
    9
    4
    4
    2
    2
    Ear and labyrinth disorders
    Vertigo
         subjects affected / exposed
    0 / 30 (0.00%)
    2 / 30 (6.67%)
    1 / 46 (2.17%)
    1 / 32 (3.13%)
    0 / 31 (0.00%)
    1 / 21 (4.76%)
    0 / 22 (0.00%)
         occurrences all number
    0
    2
    1
    1
    0
    1
    0
    Eye disorders
    Dry eye
         subjects affected / exposed
    1 / 30 (3.33%)
    0 / 30 (0.00%)
    0 / 46 (0.00%)
    3 / 32 (9.38%)
    0 / 31 (0.00%)
    0 / 21 (0.00%)
    0 / 22 (0.00%)
         occurrences all number
    1
    0
    0
    3
    0
    0
    0
    Vision blurred
         subjects affected / exposed
    2 / 30 (6.67%)
    2 / 30 (6.67%)
    0 / 46 (0.00%)
    0 / 32 (0.00%)
    0 / 31 (0.00%)
    0 / 21 (0.00%)
    0 / 22 (0.00%)
         occurrences all number
    2
    2
    0
    0
    0
    0
    0
    Gastrointestinal disorders
    Abdominal pain
         subjects affected / exposed
    3 / 30 (10.00%)
    1 / 30 (3.33%)
    5 / 46 (10.87%)
    4 / 32 (12.50%)
    2 / 31 (6.45%)
    1 / 21 (4.76%)
    1 / 22 (4.55%)
         occurrences all number
    4
    1
    5
    4
    2
    1
    1
    Colitis
         subjects affected / exposed
    2 / 30 (6.67%)
    0 / 30 (0.00%)
    0 / 46 (0.00%)
    0 / 32 (0.00%)
    0 / 31 (0.00%)
    0 / 21 (0.00%)
    0 / 22 (0.00%)
         occurrences all number
    2
    0
    0
    0
    0
    0
    0
    Diarrhoea
         subjects affected / exposed
    6 / 30 (20.00%)
    9 / 30 (30.00%)
    14 / 46 (30.43%)
    7 / 32 (21.88%)
    5 / 31 (16.13%)
    6 / 21 (28.57%)
    1 / 22 (4.55%)
         occurrences all number
    14
    14
    18
    7
    5
    7
    1
    Constipation
         subjects affected / exposed
    3 / 30 (10.00%)
    8 / 30 (26.67%)
    5 / 46 (10.87%)
    12 / 32 (37.50%)
    6 / 31 (19.35%)
    2 / 21 (9.52%)
    2 / 22 (9.09%)
         occurrences all number
    3
    8
    5
    12
    6
    2
    2
    Dry mouth
         subjects affected / exposed
    1 / 30 (3.33%)
    4 / 30 (13.33%)
    4 / 46 (8.70%)
    1 / 32 (3.13%)
    0 / 31 (0.00%)
    0 / 21 (0.00%)
    1 / 22 (4.55%)
         occurrences all number
    1
    4
    4
    1
    0
    0
    1
    Epigastric discomfort
         subjects affected / exposed
    1 / 30 (3.33%)
    0 / 30 (0.00%)
    0 / 46 (0.00%)
    2 / 32 (6.25%)
    0 / 31 (0.00%)
    0 / 21 (0.00%)
    0 / 22 (0.00%)
         occurrences all number
    1
    0
    0
    2
    0
    0
    0
    Gastrooesophageal reflux disease
         subjects affected / exposed
    0 / 30 (0.00%)
    0 / 30 (0.00%)
    3 / 46 (6.52%)
    1 / 32 (3.13%)
    2 / 31 (6.45%)
    1 / 21 (4.76%)
    0 / 22 (0.00%)
         occurrences all number
    0
    0
    3
    1
    2
    1
    0
    Nausea
         subjects affected / exposed
    10 / 30 (33.33%)
    7 / 30 (23.33%)
    14 / 46 (30.43%)
    8 / 32 (25.00%)
    8 / 31 (25.81%)
    6 / 21 (28.57%)
    4 / 22 (18.18%)
         occurrences all number
    12
    11
    16
    8
    9
    6
    4
    Oral pain
         subjects affected / exposed
    0 / 30 (0.00%)
    0 / 30 (0.00%)
    2 / 46 (4.35%)
    2 / 32 (6.25%)
    0 / 31 (0.00%)
    2 / 21 (9.52%)
    1 / 22 (4.55%)
         occurrences all number
    0
    0
    2
    2
    0
    2
    1
    Stomatitis
         subjects affected / exposed
    0 / 30 (0.00%)
    0 / 30 (0.00%)
    6 / 46 (13.04%)
    3 / 32 (9.38%)
    1 / 31 (3.23%)
    4 / 21 (19.05%)
    0 / 22 (0.00%)
         occurrences all number
    0
    0
    6
    3
    2
    4
    0
    Vomiting
         subjects affected / exposed
    5 / 30 (16.67%)
    6 / 30 (20.00%)
    7 / 46 (15.22%)
    2 / 32 (6.25%)
    6 / 31 (19.35%)
    2 / 21 (9.52%)
    0 / 22 (0.00%)
         occurrences all number
    11
    6
    10
    3
    7
    3
    0
    Skin and subcutaneous tissue disorders
    Erythema
         subjects affected / exposed
    2 / 30 (6.67%)
    1 / 30 (3.33%)
    0 / 46 (0.00%)
    1 / 32 (3.13%)
    0 / 31 (0.00%)
    0 / 21 (0.00%)
    0 / 22 (0.00%)
         occurrences all number
    2
    1
    0
    1
    0
    0
    0
    Dry skin
         subjects affected / exposed
    2 / 30 (6.67%)
    1 / 30 (3.33%)
    2 / 46 (4.35%)
    2 / 32 (6.25%)
    2 / 31 (6.45%)
    0 / 21 (0.00%)
    0 / 22 (0.00%)
         occurrences all number
    2
    1
    2
    2
    2
    0
    0
    Palmar-plantar erythrodysaesthesia syndrome
         subjects affected / exposed
    0 / 30 (0.00%)
    1 / 30 (3.33%)
    2 / 46 (4.35%)
    1 / 32 (3.13%)
    0 / 31 (0.00%)
    2 / 21 (9.52%)
    1 / 22 (4.55%)
         occurrences all number
    0
    1
    2
    1
    0
    2
    1
    Night sweats
         subjects affected / exposed
    3 / 30 (10.00%)
    1 / 30 (3.33%)
    0 / 46 (0.00%)
    3 / 32 (9.38%)
    1 / 31 (3.23%)
    1 / 21 (4.76%)
    1 / 22 (4.55%)
         occurrences all number
    3
    1
    0
    3
    1
    1
    1
    Rash
         subjects affected / exposed
    8 / 30 (26.67%)
    7 / 30 (23.33%)
    12 / 46 (26.09%)
    7 / 32 (21.88%)
    3 / 31 (9.68%)
    4 / 21 (19.05%)
    2 / 22 (9.09%)
         occurrences all number
    10
    7
    14
    8
    3
    5
    3
    Pruritus
         subjects affected / exposed
    10 / 30 (33.33%)
    6 / 30 (20.00%)
    10 / 46 (21.74%)
    8 / 32 (25.00%)
    2 / 31 (6.45%)
    3 / 21 (14.29%)
    1 / 22 (4.55%)
         occurrences all number
    10
    7
    11
    9
    2
    4
    1
    Rash maculo-papular
         subjects affected / exposed
    5 / 30 (16.67%)
    1 / 30 (3.33%)
    2 / 46 (4.35%)
    0 / 32 (0.00%)
    0 / 31 (0.00%)
    1 / 21 (4.76%)
    1 / 22 (4.55%)
         occurrences all number
    5
    2
    3
    0
    0
    1
    1
    Rash pruritic
         subjects affected / exposed
    2 / 30 (6.67%)
    0 / 30 (0.00%)
    0 / 46 (0.00%)
    0 / 32 (0.00%)
    0 / 31 (0.00%)
    0 / 21 (0.00%)
    0 / 22 (0.00%)
         occurrences all number
    2
    0
    0
    0
    0
    0
    0
    Rosacea
         subjects affected / exposed
    0 / 30 (0.00%)
    0 / 30 (0.00%)
    0 / 46 (0.00%)
    0 / 32 (0.00%)
    0 / 31 (0.00%)
    2 / 21 (9.52%)
    0 / 22 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    2
    0
    Renal and urinary disorders
    Acute kidney injury
         subjects affected / exposed
    3 / 30 (10.00%)
    0 / 30 (0.00%)
    0 / 46 (0.00%)
    0 / 32 (0.00%)
    1 / 31 (3.23%)
    1 / 21 (4.76%)
    1 / 22 (4.55%)
         occurrences all number
    3
    0
    0
    0
    2
    1
    1
    Dysuria
         subjects affected / exposed
    0 / 30 (0.00%)
    0 / 30 (0.00%)
    3 / 46 (6.52%)
    0 / 32 (0.00%)
    1 / 31 (3.23%)
    0 / 21 (0.00%)
    0 / 22 (0.00%)
         occurrences all number
    0
    0
    3
    0
    1
    0
    0
    Pollakiuria
         subjects affected / exposed
    2 / 30 (6.67%)
    0 / 30 (0.00%)
    2 / 46 (4.35%)
    1 / 32 (3.13%)
    0 / 31 (0.00%)
    1 / 21 (4.76%)
    0 / 22 (0.00%)
         occurrences all number
    2
    0
    2
    1
    0
    1
    0
    Urinary retention
         subjects affected / exposed
    2 / 30 (6.67%)
    0 / 30 (0.00%)
    0 / 46 (0.00%)
    1 / 32 (3.13%)
    1 / 31 (3.23%)
    0 / 21 (0.00%)
    0 / 22 (0.00%)
         occurrences all number
    2
    0
    0
    1
    1
    0
    0
    Endocrine disorders
    Hyperthyroidism
         subjects affected / exposed
    4 / 30 (13.33%)
    3 / 30 (10.00%)
    0 / 46 (0.00%)
    0 / 32 (0.00%)
    1 / 31 (3.23%)
    0 / 21 (0.00%)
    1 / 22 (4.55%)
         occurrences all number
    4
    3
    0
    0
    1
    0
    1
    Hypothyroidism
         subjects affected / exposed
    4 / 30 (13.33%)
    6 / 30 (20.00%)
    2 / 46 (4.35%)
    0 / 32 (0.00%)
    3 / 31 (9.68%)
    0 / 21 (0.00%)
    0 / 22 (0.00%)
         occurrences all number
    4
    6
    2
    0
    3
    0
    0
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    6 / 30 (20.00%)
    1 / 30 (3.33%)
    5 / 46 (10.87%)
    7 / 32 (21.88%)
    7 / 31 (22.58%)
    2 / 21 (9.52%)
    4 / 22 (18.18%)
         occurrences all number
    7
    2
    5
    8
    9
    2
    4
    Flank pain
         subjects affected / exposed
    2 / 30 (6.67%)
    0 / 30 (0.00%)
    1 / 46 (2.17%)
    4 / 32 (12.50%)
    2 / 31 (6.45%)
    1 / 21 (4.76%)
    0 / 22 (0.00%)
         occurrences all number
    2
    0
    1
    4
    2
    1
    0
    Back pain
         subjects affected / exposed
    3 / 30 (10.00%)
    5 / 30 (16.67%)
    6 / 46 (13.04%)
    7 / 32 (21.88%)
    6 / 31 (19.35%)
    3 / 21 (14.29%)
    4 / 22 (18.18%)
         occurrences all number
    5
    6
    7
    7
    6
    3
    4
    Groin pain
         subjects affected / exposed
    0 / 30 (0.00%)
    0 / 30 (0.00%)
    1 / 46 (2.17%)
    0 / 32 (0.00%)
    2 / 31 (6.45%)
    2 / 21 (9.52%)
    1 / 22 (4.55%)
         occurrences all number
    0
    0
    1
    0
    2
    2
    1
    Muscular weakness
         subjects affected / exposed
    3 / 30 (10.00%)
    2 / 30 (6.67%)
    6 / 46 (13.04%)
    2 / 32 (6.25%)
    3 / 31 (9.68%)
    2 / 21 (9.52%)
    1 / 22 (4.55%)
         occurrences all number
    4
    2
    7
    2
    3
    2
    1
    Muscle spasms
         subjects affected / exposed
    2 / 30 (6.67%)
    1 / 30 (3.33%)
    0 / 46 (0.00%)
    1 / 32 (3.13%)
    0 / 31 (0.00%)
    2 / 21 (9.52%)
    0 / 22 (0.00%)
         occurrences all number
    2
    1
    0
    1
    0
    2
    0
    Myalgia
         subjects affected / exposed
    2 / 30 (6.67%)
    2 / 30 (6.67%)
    1 / 46 (2.17%)
    5 / 32 (15.63%)
    0 / 31 (0.00%)
    0 / 21 (0.00%)
    1 / 22 (4.55%)
         occurrences all number
    2
    2
    1
    6
    0
    0
    1
    Neck pain
         subjects affected / exposed
    2 / 30 (6.67%)
    1 / 30 (3.33%)
    2 / 46 (4.35%)
    1 / 32 (3.13%)
    1 / 31 (3.23%)
    0 / 21 (0.00%)
    0 / 22 (0.00%)
         occurrences all number
    2
    1
    2
    1
    1
    0
    0
    Pain in extremity
         subjects affected / exposed
    3 / 30 (10.00%)
    3 / 30 (10.00%)
    0 / 46 (0.00%)
    5 / 32 (15.63%)
    4 / 31 (12.90%)
    1 / 21 (4.76%)
    2 / 22 (9.09%)
         occurrences all number
    3
    3
    0
    5
    4
    1
    2
    Infections and infestations
    Bronchitis
         subjects affected / exposed
    0 / 30 (0.00%)
    1 / 30 (3.33%)
    0 / 46 (0.00%)
    0 / 32 (0.00%)
    0 / 31 (0.00%)
    2 / 21 (9.52%)
    0 / 22 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    3
    0
    Conjunctivitis
         subjects affected / exposed
    1 / 30 (3.33%)
    1 / 30 (3.33%)
    3 / 46 (6.52%)
    0 / 32 (0.00%)
    1 / 31 (3.23%)
    0 / 21 (0.00%)
    0 / 22 (0.00%)
         occurrences all number
    1
    1
    3
    0
    1
    0
    0
    Gastroenteritis
         subjects affected / exposed
    0 / 30 (0.00%)
    1 / 30 (3.33%)
    0 / 46 (0.00%)
    3 / 32 (9.38%)
    0 / 31 (0.00%)
    0 / 21 (0.00%)
    0 / 22 (0.00%)
         occurrences all number
    0
    1
    0
    4
    0
    0
    0
    Influenza
         subjects affected / exposed
    0 / 30 (0.00%)
    1 / 30 (3.33%)
    1 / 46 (2.17%)
    2 / 32 (6.25%)
    1 / 31 (3.23%)
    1 / 21 (4.76%)
    1 / 22 (4.55%)
         occurrences all number
    0
    1
    1
    2
    1
    1
    1
    Pneumonia
         subjects affected / exposed
    1 / 30 (3.33%)
    1 / 30 (3.33%)
    0 / 46 (0.00%)
    3 / 32 (9.38%)
    0 / 31 (0.00%)
    1 / 21 (4.76%)
    1 / 22 (4.55%)
         occurrences all number
    1
    1
    0
    3
    0
    1
    1
    Urinary tract infection
         subjects affected / exposed
    1 / 30 (3.33%)
    0 / 30 (0.00%)
    4 / 46 (8.70%)
    0 / 32 (0.00%)
    1 / 31 (3.23%)
    0 / 21 (0.00%)
    2 / 22 (9.09%)
         occurrences all number
    1
    0
    4
    0
    1
    0
    2
    Upper respiratory tract infection
         subjects affected / exposed
    3 / 30 (10.00%)
    2 / 30 (6.67%)
    5 / 46 (10.87%)
    4 / 32 (12.50%)
    3 / 31 (9.68%)
    2 / 21 (9.52%)
    0 / 22 (0.00%)
         occurrences all number
    3
    3
    5
    5
    3
    2
    0
    Metabolism and nutrition disorders
    Decreased appetite
         subjects affected / exposed
    5 / 30 (16.67%)
    5 / 30 (16.67%)
    12 / 46 (26.09%)
    8 / 32 (25.00%)
    4 / 31 (12.90%)
    5 / 21 (23.81%)
    3 / 22 (13.64%)
         occurrences all number
    7
    5
    13
    8
    4
    5
    3
    Hypercalcaemia
         subjects affected / exposed
    4 / 30 (13.33%)
    2 / 30 (6.67%)
    3 / 46 (6.52%)
    3 / 32 (9.38%)
    1 / 31 (3.23%)
    2 / 21 (9.52%)
    1 / 22 (4.55%)
         occurrences all number
    4
    2
    3
    3
    1
    3
    1
    Hyperglycaemia
         subjects affected / exposed
    3 / 30 (10.00%)
    1 / 30 (3.33%)
    2 / 46 (4.35%)
    1 / 32 (3.13%)
    3 / 31 (9.68%)
    0 / 21 (0.00%)
    1 / 22 (4.55%)
         occurrences all number
    3
    1
    2
    1
    3
    0
    1
    Hyperkalaemia
         subjects affected / exposed
    1 / 30 (3.33%)
    1 / 30 (3.33%)
    3 / 46 (6.52%)
    2 / 32 (6.25%)
    1 / 31 (3.23%)
    0 / 21 (0.00%)
    0 / 22 (0.00%)
         occurrences all number
    1
    1
    4
    2
    1
    0
    0
    Hypoalbuminaemia
         subjects affected / exposed
    2 / 30 (6.67%)
    1 / 30 (3.33%)
    1 / 46 (2.17%)
    2 / 32 (6.25%)
    0 / 31 (0.00%)
    0 / 21 (0.00%)
    0 / 22 (0.00%)
         occurrences all number
    2
    1
    1
    2
    0
    0
    0
    Hypokalaemia
         subjects affected / exposed
    4 / 30 (13.33%)
    0 / 30 (0.00%)
    0 / 46 (0.00%)
    1 / 32 (3.13%)
    1 / 31 (3.23%)
    0 / 21 (0.00%)
    1 / 22 (4.55%)
         occurrences all number
    5
    0
    0
    1
    1
    0
    1
    Hypomagnesaemia
         subjects affected / exposed
    2 / 30 (6.67%)
    1 / 30 (3.33%)
    0 / 46 (0.00%)
    1 / 32 (3.13%)
    1 / 31 (3.23%)
    1 / 21 (4.76%)
    0 / 22 (0.00%)
         occurrences all number
    2
    1
    0
    1
    1
    1
    0
    Hyponatraemia
         subjects affected / exposed
    1 / 30 (3.33%)
    2 / 30 (6.67%)
    1 / 46 (2.17%)
    2 / 32 (6.25%)
    2 / 31 (6.45%)
    0 / 21 (0.00%)
    0 / 22 (0.00%)
         occurrences all number
    1
    2
    5
    4
    2
    0
    0
    Hypophosphataemia
         subjects affected / exposed
    2 / 30 (6.67%)
    2 / 30 (6.67%)
    1 / 46 (2.17%)
    1 / 32 (3.13%)
    1 / 31 (3.23%)
    2 / 21 (9.52%)
    0 / 22 (0.00%)
         occurrences all number
    2
    2
    1
    1
    1
    2
    0

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    28 Sep 2016
    Clarification of the overall study design
    01 Mar 2017
    Removal of Legally Authorized Representative language, Clarification of Inclusion Criteria, updates to the procedural outline
    15 Jun 2017
    Change of Study Director/Medical Monitor, Restoration of inadvertently deleted neutrophil inclusion criterion and clarification of hemoglobin inclusion criterion
    23 Nov 2021
    Given the rapidly evolving treatment landscape in renal cell carcinoma (RCC), having only 1 patient left on safety follow-up, and the complexity and operational challenges faced, the FRACTION-RCC study is planned for closure once the last patient finishes the safety follow-up. The planned termination of the FRACTION-RCC study is not due to any safety concerns. Due to planned early closure of the trial, the study schedule was adjusted to remove retreatment/re-randomization options, response follow-up, and survival follow-up periods for all parts of the study. No changes were made to the treatment period or safety follow-up period.

    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
    As of 31 January 2023, all EU/EEA initial clinical trial applications must be submitted through CTIS . Updated EudraCT trials information and information on PIP/Art 46 trials conducted exclusively in third countries continues to be submitted through EudraCT and published on this website.

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