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    Clinical Trial Results:
    A Phase 2, Randomized, Open-label Study of Nivolumab or Nivolumab/BMS-986205 Alone or Combined with Intravesical BCG in Participants with BCG-Unresponsive, High-Risk, Non-Muscle Invasive Bladder Cancer (CheckMate 9UT: CHECKpoint pathway and nivoluMAb clinical Trial Evaluation 9UT)

    Summary
    EudraCT number
    		 2017-003581-27
    Trial protocol
    		 FR   ES   GB   NL   IT  
    Global end of trial date
    22 Aug 2022

    Results information
    Results version number
    		 v1(current)
    This version publication date
    19 May 2023
    First version publication date
    19 May 2023
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    CA209-9UT
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT03519256
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Bristol-Myers Squibb
    Sponsor organisation address
    Chaussee de la Hulpe 185, Brussels, Belgium, 1170
    Public contact
    EU Study Start-Up Unit, Bristol-Myers Squibb International Corporation, Clinical.Trials@bms.com
    Scientific contact
    Bristol-Myers Squibb Study Director, Bristol-Myers Squibb, Clinical.Trials@bms.com
    Paediatric regulatory details
    Is trial part of an agreed paediatric investigation plan (PIP)
    No
    Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Results analysis stage
    Analysis stage
    Final
    Date of interim/final analysis
    17 Nov 2022
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    22 Aug 2022
    Global end of trial reached?
    Yes
    Global end of trial date
    22 Aug 2022
    Was the trial ended prematurely?
    Yes
    General information about the trial
    Main objective of the trial
    To demonstrate that treatment with nivolumab, alone or in combination with BMS-986205, and with or without intravesical BCG, will be efficacious in participants with BCG-unresponsive NMIBC. As a result of Protocol Amendment 04, there are no formal hypotheses or efficacy objectives for this study. Only safety and immunogenicity assessments were conducted.
    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 Aug 2018
    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
    Argentina: 4
    Country: Number of subjects enrolled
    Australia: 1
    Country: Number of subjects enrolled
    Brazil: 3
    Country: Number of subjects enrolled
    Canada: 8
    Country: Number of subjects enrolled
    Chile: 1
    Country: Number of subjects enrolled
    China: 3
    Country: Number of subjects enrolled
    Italy: 9
    Country: Number of subjects enrolled
    Netherlands: 5
    Country: Number of subjects enrolled
    Russian Federation: 3
    Country: Number of subjects enrolled
    Spain: 3
    Country: Number of subjects enrolled
    United Kingdom: 2
    Country: Number of subjects enrolled
    United States: 27
    Worldwide total number of subjects
    69
    EEA total number of subjects
    17
    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)
    21
    From 65 to 84 years
    46
    85 years and over
    2

    Subject disposition

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    Recruitment
    Recruitment details
    		 -

    Pre-assignment
    Screening details
    		 A safety lead-in was conducted in participants randomized to receive bacillus Calmette-Guerin (BCG) and nivolumab without BMS-986205 (Arm B), and Nivolumab Plus BMS-986205 Plus Intravesical BCG (Arm D) to determine safe-dose levels to be administered during the treatment phase.

    Period 1
    Period 1 title
    Overall Study (overall period)
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Not blinded

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Arm A: Nivolumab
    Arm description
    		 Nivolumab 480 mg IV every 4 weeks (Q4W) for up to 52 weeks (12 months).
    Arm type
    		 Experimental

    Investigational medicinal product name
    Nivolumab (BMS-936558-01)
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Concentrate for solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    480 mg as 30-minute IV every 4 weeks

    Arm title
    		 Arm B: Nivolumab Plus Intravesical BCG
    Arm description
    		 Nivolumab 480 mg IV every 4 weeks (Q4W) for up to 52 weeks (12 months) and intravesical BCG (induction) weekly for 6 weeks followed by maintenance intravesical BCG weekly for 3 weeks at 3 months, 6 months and 12 months following the first intravesical dose.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Bacillus Calmette-Guerin
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Intravesical solution
    Routes of administration
    Intravesical use
    Dosage and administration details
    Dose according to prescribing information for BCG strain and preparation. Taken once weekly for 6 weeks, followed by once weekly for 3 weeks at 3 months, 6 months, and 12 months after first BCG dose.

    Investigational medicinal product name
    Nivolumab (BMS-936558-01)
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Concentrate for solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    480 mg as 30-minute IV every 4 weeks

    Arm title
    		 Arm C: Nivolumab Plus BMS-986205
    Arm description
    		 Nivolumab 480 mg IV every 4 weeks (Q4W) and 100 mg oral BMS-986205 daily for up to 52 weeks (12 months).
    Arm type
    		 Experimental

    Investigational medicinal product name
    Nivolumab (BMS-936558-01)
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Concentrate for solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    480 mg as 30-minute IV every 4 weeks

    Investigational medicinal product name
    BMS-986205
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    100 mg orally per day for up to 52 weeks (12 months)

    Arm title
    		 Arm D: Nivolumab Plus BMS-986205 Plus Intravesical BCG
    Arm description
    		 Nivolumab 480 mg IV every 4 weeks (Q4W), 100 mg oral BMS-986205 daily for up to 52 weeks (12 months), and intravesical BCG (induction) weekly for 6 weeks followed by maintenance intravesical BCG weekly for 3 weeks at 3 months, 6 months, and 12 months following the first intravesical dose.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Nivolumab (BMS-936558-01)
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Concentrate for solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    480 mg as 30-minute IV every 4 weeks

    Investigational medicinal product name
    BMS-986205
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    100 mg orally per day for up to 52 weeks (12 months)

    Investigational medicinal product name
    Bacillus Calmette-Guerin
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Intravesical solution
    Routes of administration
    Intravesical use
    Dosage and administration details
    Dose according to prescribing information for BCG strain and preparation. Taken once weekly for 6 weeks, followed by once weekly for 3 weeks at 3 months, 6 months, and 12 months after first BCG dose.

    Number of subjects in period 1
    		Arm A: Nivolumab Arm B: Nivolumab Plus Intravesical BCG Arm C: Nivolumab Plus BMS-986205 Arm D: Nivolumab Plus BMS-986205 Plus Intravesical BCG
    Started
    16
    26
    17
    10
    Safety-Lead In Phase
    0 [1]
    10 [2]
    0 [3]
    10
    Completed
    6
    15
    2
    3
    Not completed
    10
    11
    15
    7
         Disease recurrence
    4
    4
    5
    2
         Disease progression
    6
    3
    2
    1
         Study drug toxicity
    -
    2
    5
    2
         Adverse event unrelated to study drug
    -
    1
    1
    -
         Other reasons
    -
    -
    2
    -
         Lost to follow-up
    -
    1
    -
    -
         Participant request to discontinue study treatment
    -
    -
    -
    2
    Notes
    [1] - The number of subjects at this milestone seems inconsistent with the number of subjects in the arm. It is expected that the number of subjects will be greater than, or equal to the number that completed, minus those who left.
    Justification: Safety lead in was for Arms B and D only.
    [2] - The number of subjects at this milestone seems inconsistent with the number of subjects in the arm. It is expected that the number of subjects will be greater than, or equal to the number that completed, minus those who left.
    Justification: Safety lead in was for Arms B and D only.
    [3] - The number of subjects at this milestone seems inconsistent with the number of subjects in the arm. It is expected that the number of subjects will be greater than, or equal to the number that completed, minus those who left.
    Justification: Safety lead in was for Arms B and D only.

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Arm A: Nivolumab
    Reporting group description
    		 Nivolumab 480 mg IV every 4 weeks (Q4W) for up to 52 weeks (12 months).

    Reporting group title
    Arm B: Nivolumab Plus Intravesical BCG
    Reporting group description
    		 Nivolumab 480 mg IV every 4 weeks (Q4W) for up to 52 weeks (12 months) and intravesical BCG (induction) weekly for 6 weeks followed by maintenance intravesical BCG weekly for 3 weeks at 3 months, 6 months and 12 months following the first intravesical dose.

    Reporting group title
    Arm C: Nivolumab Plus BMS-986205
    Reporting group description
    		 Nivolumab 480 mg IV every 4 weeks (Q4W) and 100 mg oral BMS-986205 daily for up to 52 weeks (12 months).

    Reporting group title
    Arm D: Nivolumab Plus BMS-986205 Plus Intravesical BCG
    Reporting group description
    		 Nivolumab 480 mg IV every 4 weeks (Q4W), 100 mg oral BMS-986205 daily for up to 52 weeks (12 months), and intravesical BCG (induction) weekly for 6 weeks followed by maintenance intravesical BCG weekly for 3 weeks at 3 months, 6 months, and 12 months following the first intravesical dose.

    Reporting group values
    		 Arm A: Nivolumab Arm B: Nivolumab Plus Intravesical BCG Arm C: Nivolumab Plus BMS-986205 Arm D: Nivolumab Plus BMS-986205 Plus Intravesical BCG Total
    Number of subjects
    		 16 26 17 10 69
    Age categorical
    Units: Subjects
        In utero
    		 0 0 0 0 0
        Preterm newborn infants (gestational age < 37 wks)
    		 0 0 0 0 0
        Newborns (0-27 days)
    		 0 0 0 0 0
        Infants and toddlers (28 days-23 months)
    		 0 0 0 0 0
        Children (2-11 years)
    		 0 0 0 0 0
        Adolescents (12-17 years)
    		 0 0 0 0 0
        Adults (18-64 years)
    		 9 6 4 2 21
        From 65-84 years
    		 7 20 12 7 46
        85 years and over
    		 0 0 1 1 2
    Age Continuous
    Units: Years
        arithmetic mean (standard deviation)
    		 61.8 ( 11.1 ) 69.0 ( 9.4 ) 69.1 ( 12.3 ) 69.9 ( 16.4 ) -
    Sex: Female, Male
    Units: Participants
        Female
    		 2 4 5 1 12
        Male
    		 14 22 12 9 57
    Ethnicity (NIH/OMB)
    Units: Subjects
        Hispanic or Latino
    		 0 2 3 1 6
        Not Hispanic or Latino
    		 11 23 8 9 51
        Unknown or Not Reported
    		 5 1 6 0 12
    Race/Ethnicity, Customized
    Units: Subjects
        White
    		 13 26 17 10 66
        Asian
    		 3 0 0 0 3

    End points

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    End points reporting groups
    Reporting group title
    Arm A: Nivolumab
    Reporting group description
    		 Nivolumab 480 mg IV every 4 weeks (Q4W) for up to 52 weeks (12 months).

    Reporting group title
    Arm B: Nivolumab Plus Intravesical BCG
    Reporting group description
    		 Nivolumab 480 mg IV every 4 weeks (Q4W) for up to 52 weeks (12 months) and intravesical BCG (induction) weekly for 6 weeks followed by maintenance intravesical BCG weekly for 3 weeks at 3 months, 6 months and 12 months following the first intravesical dose.

    Reporting group title
    Arm C: Nivolumab Plus BMS-986205
    Reporting group description
    		 Nivolumab 480 mg IV every 4 weeks (Q4W) and 100 mg oral BMS-986205 daily for up to 52 weeks (12 months).

    Reporting group title
    Arm D: Nivolumab Plus BMS-986205 Plus Intravesical BCG
    Reporting group description
    		 Nivolumab 480 mg IV every 4 weeks (Q4W), 100 mg oral BMS-986205 daily for up to 52 weeks (12 months), and intravesical BCG (induction) weekly for 6 weeks followed by maintenance intravesical BCG weekly for 3 weeks at 3 months, 6 months, and 12 months following the first intravesical dose.

    Primary: Number of Participants with Adverse Events (AEs)

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    End point title
    		 Number of Participants with Adverse Events (AEs) [1]
    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. An AE can therefore be any unfavorable and unintended sign (such as an abnormal laboratory finding), symptom, or disease temporally associated with the use of study treatment, whether or not considered related to the study treatment. AEs are reported using the National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) version 4.03.
    End point type
    Primary
    End point timeframe
    From first dose to 30 days post last dose of study treatment (an average of 45 weeks up to approximately 64 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 A: Nivolumab Arm B: Nivolumab Plus Intravesical BCG Arm C: Nivolumab Plus BMS-986205 Arm D: Nivolumab Plus BMS-986205 Plus Intravesical BCG
    Number of subjects analysed
    16
    26
    17
    10
    Units: Participants
    15
    26
    15
    10
    No statistical analyses for this end point

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

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    End point title
    		 Number of Participants with Serious Adverse Events (SAEs) [2]
    End point description
    Serious Adverse Event (SAE) is defined as any untoward medical occurrence that, at any dose: - Results in death - Is life-threatening (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. SAEs are reported using the National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) version 4.03.
    End point type
    Primary
    End point timeframe
    From first dose to 30 days post last dose of study treatment (an average of 45 weeks up to approximately 64 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 A: Nivolumab Arm B: Nivolumab Plus Intravesical BCG Arm C: Nivolumab Plus BMS-986205 Arm D: Nivolumab Plus BMS-986205 Plus Intravesical BCG
    Number of subjects analysed
    16
    26
    17
    10
    Units: Participants
    2
    2
    5
    3
    No statistical analyses for this end point

    Primary: Number of Participants with Adverse Events (AEs) Leading to Discontinuation of Study Treatment

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    End point title
    		 Number of Participants with Adverse Events (AEs) Leading to Discontinuation of Study Treatment [3]
    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. An AE can therefore be any unfavorable and unintended sign (such as an abnormal laboratory finding), symptom, or disease temporally associated with the use of study treatment, whether or not considered related to the study treatment. AEs leading to discontinuation are reported using the National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) version 4.03.
    End point type
    Primary
    End point timeframe
    From first dose to 30 days post last dose of study treatment (an average of 45 weeks up to approximately 64 weeks)
    Notes
    [3] - 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 A: Nivolumab Arm B: Nivolumab Plus Intravesical BCG Arm C: Nivolumab Plus BMS-986205 Arm D: Nivolumab Plus BMS-986205 Plus Intravesical BCG
    Number of subjects analysed
    16
    26
    17
    10
    Units: Participants
    1
    4
    8
    7
    No statistical analyses for this end point

    Primary: Number of Participants Immune-Mediated Adverse Events (IMAEs)

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    End point title
    		 Number of Participants Immune-Mediated Adverse Events (IMAEs) [4]
    End point description
    IMAEs are AEs consistent with an immune-mediated mechanism or immune-mediated component for which non-inflammatory etiologies (eg, infection or tumor progression) have been ruled out. IMAEs can include events with an alternate etiology which were exacerbated by the induction of autoimmunity. IMAEs are reported using the National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) version 4.03.
    End point type
    Primary
    End point timeframe
    From first dose to 30 days post last dose of study treatment (an average of 45 weeks up to approximately 64 weeks)
    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 A: Nivolumab Arm B: Nivolumab Plus Intravesical BCG Arm C: Nivolumab Plus BMS-986205 Arm D: Nivolumab Plus BMS-986205 Plus Intravesical BCG
    Number of subjects analysed
    16
    26
    17
    10
    Units: Participants
    1
    10
    6
    5
    No statistical analyses for this end point

    Primary: Number of Participants Who Died

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    End point title
    		 Number of Participants Who Died [5]
    End point description
    Number of participants who died.
    End point type
    Primary
    End point timeframe
    From first dose to 100 days post last dose of study treatment (an average of 45 weeks up to approximately 74 weeks)
    Notes
    [5] - 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 A: Nivolumab Arm B: Nivolumab Plus Intravesical BCG Arm C: Nivolumab Plus BMS-986205 Arm D: Nivolumab Plus BMS-986205 Plus Intravesical BCG
    Number of subjects analysed
    16
    26
    17
    10
    Units: Participants
    0
    1
    1
    0
    No statistical analyses for this end point

    Primary: Number of Participants With Specific Liver Laboratory Abnormalities

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    End point title
    		 Number of Participants With Specific Liver Laboratory Abnormalities [6]
    End point description
    On-treatment laboratory evaluations are evaluations taken after the day (and time, if collected and not missing) of first dose of study treatment. For participants who are off study treatment, evaluations were within a safety window of 30 days after the last dose of study treatment. ALT = Alanine Aminotransferase AST = Aspartate Aminotransferase ULN = Upper Limit of Normal.
    End point type
    Primary
    End point timeframe
    From first dose to 30 days post last dose of study treatment (an average of 45 weeks up to approximately 64 weeks)
    Notes
    [6] - 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 A: Nivolumab Arm B: Nivolumab Plus Intravesical BCG Arm C: Nivolumab Plus BMS-986205 Arm D: Nivolumab Plus BMS-986205 Plus Intravesical BCG
    Number of subjects analysed
    16
    26
    17
    10
    Units: Participants
        ALT OR AST > 3XULN
    0
    1
    7
    2
        ALT OR AST> 5XULN
    0
    0
    5
    1
        ALT OR AST> 10XULN
    0
    0
    1
    1
        ALT OR AST > 20XULN
    0
    0
    1
    0
        TOTAL BILIRUBIN > 2XULN
    0
    0
    1
    1
        ALT/AST ELEV>3XULN;TOTAL BILIRUBIN>1.5XULN IN 1DAY
    0
    0
    1
    0
        ALT/AST ELEV>3XULN;TOTAL BILIRUBIN>1.5XULN 30DAYS
    0
    0
    1
    0
        ALT/AST ELEV>3XULN;TOTAL BILIRUBIN>2XULN IN 1 DAY
    0
    0
    1
    0
        ALT/AST ELEV>3XULN;TOTAL BILIRUBIN>2XULN 30DAYS
    0
    0
    1
    0
        ALP>1.5XULN
    0
    2
    1
    0
    No statistical analyses for this end point

    Primary: Number of Participants With Specific Thyroid Laboratory Abnormalities

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    End point title
    		 Number of Participants With Specific Thyroid Laboratory Abnormalities [7]
    End point description
    On-treatment laboratory evaluations are evaluations taken after the day (and time, if collected and not missing) of first dose of study treatment. For participants who are off study treatment, evaluations were within a safety window of 30 days after the last dose of study treatment. TSH = Thyroid Stimulating Hormone LLN = Lower Limit of Normal ULN = Upper Limit of Normal
    End point type
    Primary
    End point timeframe
    From first dose to 30 days post last dose of study treatment (an average of 45 weeks up to approximately 64 weeks)
    Notes
    [7] - 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 A: Nivolumab Arm B: Nivolumab Plus Intravesical BCG Arm C: Nivolumab Plus BMS-986205 Arm D: Nivolumab Plus BMS-986205 Plus Intravesical BCG
    Number of subjects analysed
    16
    26
    17
    10
    Units: Participants
        TSH > ULN
    5
    5
    2
    1
        TSH > ULN WITH TSH <= ULN AT BASELINE
    4
    5
    1
    1
        TSH >ULN WITH ATLEAST ONE FT3/FT4 TEST VALUE <LLN
    2
    1
    2
    0
        TSH >ULN WITH ALL OTHER FT3/FT4 TEST VALUES >= LLN
    2
    3
    1
    0
        TSH > ULN WITH FT3/FT4 TEST MISSING
    2
    3
    0
    1
        TSH < LLN
    2
    3
    3
    1
        TSH <LLN WITH TSH >= LLN AT BASELINE
    2
    3
    3
    1
        TSH <LLN WITH ATLEAST ONE FT3/FT4 TEST VALUE > ULN
    2
    1
    1
    1
        TSH <LLN WITH ALL OTHER FT3/FT4 TEST VALUES <= ULN
    1
    3
    0
    0
        TSH < LLN WITH FT3/FT4 TEST MISSING
    0
    0
    2
    0
    No statistical analyses for this end point

    Primary: Number of Participants with Changes from Baseline Laboratory Values

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    End point title
    		 Number of Participants with Changes from Baseline Laboratory Values [8]
    End point description
    On-study laboratory parameters include hematology, chemistry, liver function, and renal function. On-study laboratory evaluations are evaluations taken after the day (and time, if collected and not missing) of first dose of study treatment. For participants who are off study treatment, evaluations were within a safety window of 30 days after the last dose of study treatment. On-study lab parameters are reported using the National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) version 4.03.
    End point type
    Primary
    End point timeframe
    From baseline to 30 days post last dose of study treatment (an average of 45 weeks up to approximately 64 weeks)
    Notes
    [8] - 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 A: Nivolumab Arm B: Nivolumab Plus Intravesical BCG Arm C: Nivolumab Plus BMS-986205 Arm D: Nivolumab Plus BMS-986205 Plus Intravesical BCG
    Number of subjects analysed
    16
    26
    17
    10
    Units: Participants
        Hemoglobin
    1
    7
    5
    6
        Platelet Count
    1
    1
    1
    1
        Leukocytes, Local Lab
    0
    0
    4
    0
        Lymphocytes (Absolute)
    0
    0
    3
    0
        Lymphocytes (Absolute), Local Lab
    2
    7
    2
    5
        Absolute Neutrophil Count
    0
    1
    1
    0
        Alkaline Phosphatase (ALP), Local Lab
    0
    2
    2
    1
        Aspartate Aminotransferase (AST), Local Lab
    3
    5
    12
    3
        Alanine Aminotransferase (ALT), Local Lab
    4
    10
    13
    7
        Bilirubin Total, Local Lab
    1
    2
    5
    3
        Creatinine, Local Lab
    1
    8
    3
    5
        Hypernatremia
    0
    3
    4
    2
        Hyponatremia
    4
    3
    4
    3
        Hyperkalemia
    0
    3
    2
    3
        Hypokalemia
    2
    2
    1
    1
        Hypercalcemia
    2
    4
    0
    3
        Hypocalcemia
    0
    1
    2
    2
        Hypermagnesemia
    3
    1
    2
    0
        Hypomagnesemia
    1
    3
    1
    3
        Hyperglycemia
    4
    1
    3
    1
        Hypoglycemia
    0
    1
    1
    0
    No statistical analyses for this end point

    Primary: Number of Participants with Adverse Events (AEs) by Anti-Drug- Antibody (ADA) Status

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    End point title
    		 Number of Participants with Adverse Events (AEs) by Anti-Drug- Antibody (ADA) Status [9]
    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. An AE can therefore be any unfavorable and unintended sign (such as an abnormal laboratory finding), symptom, or disease temporally associated with the use of study treatment, whether or not considered related to the study treatment. An Anti-drug antibody (ADA) is defined as biologic drug-reactive antibody, including pre-existing host antibodies that are cross-reactive with the administered biologic drug. An ADA-positive participant has at least one ADA positive-sample relative to baseline at any time after initiation of treatment An ADA-negative participant doesn't not have an ADA-positive sample after the initiation of treatment.
    End point type
    Primary
    End point timeframe
    From first dose to 30 days post last dose of study treatment (an average of 45 weeks up to approximately 64 weeks)
    Notes
    [9] - 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 A: Nivolumab Arm B: Nivolumab Plus Intravesical BCG Arm C: Nivolumab Plus BMS-986205 Arm D: Nivolumab Plus BMS-986205 Plus Intravesical BCG
    Number of subjects analysed
    11
    22
    13
    9
    Units: Participants
        Nivolumab ADA Positive
    0
    1
    1
    0
        Nivolumab ADA Negative
    11
    21
    11
    9
    No statistical analyses for this end point

    Primary: Number of Participants with Serious Adverse Events (SAEs) by Anti-Drug- Antibody (ADA) Status

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    End point title
    		 Number of Participants with Serious Adverse Events (SAEs) by Anti-Drug- Antibody (ADA) Status [10]
    End point description
    Serious Adverse Event (SAE) is defined as any untoward medical occurrence that, at any dose: - Results in death - Is life-threatening (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. An Anti-drug antibody (ADA) is defined as biologic drug-reactive antibody, including pre-existing host antibodies that are cross-reactive with the administered biologic drug. An ADA-positive participant has at least one ADA positive-sample relative to baseline at any time after initiation of treatment An ADA-negative participant doesn't not have an ADA-positive sample after the initiation of treatment. "99999" = Not Applicable/Not Available
    End point type
    Primary
    End point timeframe
    From first dose to 30 days post last dose of study treatment (an average of 45 weeks up to approximately 64 weeks)
    Notes
    [10] - 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 A: Nivolumab Arm B: Nivolumab Plus Intravesical BCG Arm C: Nivolumab Plus BMS-986205 Arm D: Nivolumab Plus BMS-986205 Plus Intravesical BCG
    Number of subjects analysed
    11
    22
    13
    9
    Units: Participants
        Nivolumab ADA Positive
    99999
    1
    0
    99999
        Nivolumab ADA Negative
    1
    3
    4
    4
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    SAEs and NSAEs were assessed from first dose to 100 days after last dose of study therapy (an average of 45 weeks up to approximately 74 weeks).
    Adverse event reporting additional description
    SAEs and NSAEs represents all participants that received at least 1 dose of study medication.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    25.1
    Reporting groups
    Reporting group title
    Arm A: Nivolumab
    Reporting group description
    		 Nivolumab 480 mg IV every 4 weeks (Q4W) for up to 52 weeks (12 months).

    Reporting group title
    Arm B: Nivolumab Plus Intravesical BCG
    Reporting group description
    		 Nivolumab 480 mg IV every 4 weeks (Q4W) for up to 52 weeks (12 months) and intravesical BCG (induction) weekly for 6 weeks followed by maintenance intravesical BCG weekly for 3 weeks at 3 months, 6 months and 12 months following the first intravesical dose.

    Reporting group title
    Arm C: Nivolumab Plus BMS-986205
    Reporting group description
    		 Nivolumab 480 mg IV every 4 weeks (Q4W) and 100 mg oral BMS-986205 daily for up to 52 weeks (12 months).

    Reporting group title
    Arm D: Nivolumab Plus BMS-986205 Plus Intravesical BCG
    Reporting group description
    		 Nivolumab 480 mg IV every 4 weeks (Q4W), 100 mg oral BMS-986205 daily for up to 52 weeks (12 months), and intravesical BCG (induction) weekly for 6 weeks followed by maintenance intravesical BCG weekly for 3 weeks at 3 months, 6 months, and 12 months following the first intravesical dose.

    Serious adverse events
    		 Arm A: Nivolumab Arm B: Nivolumab Plus Intravesical BCG Arm C: Nivolumab Plus BMS-986205 Arm D: Nivolumab Plus BMS-986205 Plus Intravesical BCG
    Total subjects affected by serious adverse events
         subjects affected / exposed
    4 / 16 (25.00%)
    7 / 26 (26.92%)
    7 / 17 (41.18%)
    5 / 10 (50.00%)
         number of deaths (all causes)
    0
    3
    2
    0
         number of deaths resulting from adverse events
    0
    1
    1
    0
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Bladder cancer recurrent
         subjects affected / exposed
    3 / 16 (18.75%)
    0 / 26 (0.00%)
    1 / 17 (5.88%)
    1 / 10 (10.00%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Malignant neoplasm progression
         subjects affected / exposed
    0 / 16 (0.00%)
    0 / 26 (0.00%)
    1 / 17 (5.88%)
    1 / 10 (10.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Vascular disorders
    Hypotension
         subjects affected / exposed
    0 / 16 (0.00%)
    0 / 26 (0.00%)
    0 / 17 (0.00%)
    1 / 10 (10.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Disease recurrence
         subjects affected / exposed
    0 / 16 (0.00%)
    1 / 26 (3.85%)
    0 / 17 (0.00%)
    0 / 10 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Death
         subjects affected / exposed
    0 / 16 (0.00%)
    1 / 26 (3.85%)
    0 / 17 (0.00%)
    0 / 10 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Pulmonary embolism
         subjects affected / exposed
    0 / 16 (0.00%)
    0 / 26 (0.00%)
    1 / 17 (5.88%)
    0 / 10 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Psychiatric disorders
    Substance-induced psychotic disorder
         subjects affected / exposed
    0 / 16 (0.00%)
    0 / 26 (0.00%)
    1 / 17 (5.88%)
    0 / 10 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Confusional state
         subjects affected / exposed
    0 / 16 (0.00%)
    0 / 26 (0.00%)
    1 / 17 (5.88%)
    0 / 10 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Investigations
    Alanine aminotransferase increased
         subjects affected / exposed
    0 / 16 (0.00%)
    0 / 26 (0.00%)
    1 / 17 (5.88%)
    0 / 10 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    2 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Hip fracture
         subjects affected / exposed
    0 / 16 (0.00%)
    0 / 26 (0.00%)
    1 / 17 (5.88%)
    0 / 10 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Procedural complication
         subjects affected / exposed
    0 / 16 (0.00%)
    0 / 26 (0.00%)
    1 / 17 (5.88%)
    0 / 10 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cardiac disorders
    Ventricular arrhythmia
         subjects affected / exposed
    0 / 16 (0.00%)
    0 / 26 (0.00%)
    1 / 17 (5.88%)
    0 / 10 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    Nervous system disorders
    Carotid artery stenosis
         subjects affected / exposed
    0 / 16 (0.00%)
    1 / 26 (3.85%)
    0 / 17 (0.00%)
    0 / 10 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Ischaemic stroke
         subjects affected / exposed
    0 / 16 (0.00%)
    1 / 26 (3.85%)
    0 / 17 (0.00%)
    0 / 10 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Diarrhoea
         subjects affected / exposed
    1 / 16 (6.25%)
    0 / 26 (0.00%)
    0 / 17 (0.00%)
    0 / 10 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Colitis ulcerative
         subjects affected / exposed
    0 / 16 (0.00%)
    1 / 26 (3.85%)
    0 / 17 (0.00%)
    0 / 10 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Colitis
         subjects affected / exposed
    0 / 16 (0.00%)
    1 / 26 (3.85%)
    0 / 17 (0.00%)
    0 / 10 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Retroperitoneal haemorrhage
         subjects affected / exposed
    0 / 16 (0.00%)
    0 / 26 (0.00%)
    0 / 17 (0.00%)
    1 / 10 (10.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hepatobiliary disorders
    Bile duct stone
         subjects affected / exposed
    0 / 16 (0.00%)
    0 / 26 (0.00%)
    0 / 17 (0.00%)
    1 / 10 (10.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Renal and urinary disorders
    Urinary tract obstruction
         subjects affected / exposed
    0 / 16 (0.00%)
    1 / 26 (3.85%)
    0 / 17 (0.00%)
    0 / 10 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Haematuria
         subjects affected / exposed
    0 / 16 (0.00%)
    0 / 26 (0.00%)
    0 / 17 (0.00%)
    2 / 10 (20.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Endocrine disorders
    Adrenal insufficiency
         subjects affected / exposed
    0 / 16 (0.00%)
    1 / 26 (3.85%)
    0 / 17 (0.00%)
    0 / 10 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Infections and infestations
    Wound infection
         subjects affected / exposed
    0 / 16 (0.00%)
    1 / 26 (3.85%)
    0 / 17 (0.00%)
    0 / 10 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Sepsis
         subjects affected / exposed
    1 / 16 (6.25%)
    0 / 26 (0.00%)
    0 / 17 (0.00%)
    0 / 10 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Post procedural sepsis
         subjects affected / exposed
    0 / 16 (0.00%)
    0 / 26 (0.00%)
    1 / 17 (5.88%)
    0 / 10 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    COVID-19
         subjects affected / exposed
    0 / 16 (0.00%)
    0 / 26 (0.00%)
    1 / 17 (5.88%)
    0 / 10 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Hyperglycaemia
         subjects affected / exposed
    1 / 16 (6.25%)
    0 / 26 (0.00%)
    0 / 17 (0.00%)
    1 / 10 (10.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hyponatraemia
         subjects affected / exposed
    0 / 16 (0.00%)
    0 / 26 (0.00%)
    0 / 17 (0.00%)
    1 / 10 (10.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Arm A: Nivolumab Arm B: Nivolumab Plus Intravesical BCG Arm C: Nivolumab Plus BMS-986205 Arm D: Nivolumab Plus BMS-986205 Plus Intravesical BCG
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    15 / 16 (93.75%)
    26 / 26 (100.00%)
    15 / 17 (88.24%)
    10 / 10 (100.00%)
    Vascular disorders
    Peripheral coldness
         subjects affected / exposed
    0 / 16 (0.00%)
    0 / 26 (0.00%)
    0 / 17 (0.00%)
    1 / 10 (10.00%)
         occurrences all number
    0
    0
    0
    1
    Flushing
         subjects affected / exposed
    0 / 16 (0.00%)
    0 / 26 (0.00%)
    0 / 17 (0.00%)
    1 / 10 (10.00%)
         occurrences all number
    0
    0
    0
    1
    Hypertension
         subjects affected / exposed
    0 / 16 (0.00%)
    1 / 26 (3.85%)
    0 / 17 (0.00%)
    1 / 10 (10.00%)
         occurrences all number
    0
    1
    0
    1
    Hypotension
         subjects affected / exposed
    0 / 16 (0.00%)
    1 / 26 (3.85%)
    1 / 17 (5.88%)
    1 / 10 (10.00%)
         occurrences all number
    0
    1
    1
    2
    Peripheral arterial occlusive disease
         subjects affected / exposed
    1 / 16 (6.25%)
    0 / 26 (0.00%)
    0 / 17 (0.00%)
    0 / 10 (0.00%)
         occurrences all number
    1
    0
    0
    0
    General disorders and administration site conditions
    Localised oedema
         subjects affected / exposed
    1 / 16 (6.25%)
    0 / 26 (0.00%)
    0 / 17 (0.00%)
    0 / 10 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Influenza like illness
         subjects affected / exposed
    0 / 16 (0.00%)
    1 / 26 (3.85%)
    0 / 17 (0.00%)
    5 / 10 (50.00%)
         occurrences all number
    0
    1
    0
    5
    Gait disturbance
         subjects affected / exposed
    0 / 16 (0.00%)
    0 / 26 (0.00%)
    0 / 17 (0.00%)
    1 / 10 (10.00%)
         occurrences all number
    0
    0
    0
    1
    Fatigue
         subjects affected / exposed
    3 / 16 (18.75%)
    9 / 26 (34.62%)
    3 / 17 (17.65%)
    4 / 10 (40.00%)
         occurrences all number
    3
    9
    4
    4
    Chills
         subjects affected / exposed
    0 / 16 (0.00%)
    0 / 26 (0.00%)
    0 / 17 (0.00%)
    2 / 10 (20.00%)
         occurrences all number
    0
    0
    0
    2
    Asthenia
         subjects affected / exposed
    1 / 16 (6.25%)
    1 / 26 (3.85%)
    2 / 17 (11.76%)
    2 / 10 (20.00%)
         occurrences all number
    2
    1
    2
    2
    Oedema peripheral
         subjects affected / exposed
    0 / 16 (0.00%)
    2 / 26 (7.69%)
    1 / 17 (5.88%)
    0 / 10 (0.00%)
         occurrences all number
    0
    2
    1
    0
    Thirst
         subjects affected / exposed
    0 / 16 (0.00%)
    0 / 26 (0.00%)
    1 / 17 (5.88%)
    0 / 10 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Pyrexia
         subjects affected / exposed
    0 / 16 (0.00%)
    0 / 26 (0.00%)
    0 / 17 (0.00%)
    2 / 10 (20.00%)
         occurrences all number
    0
    0
    0
    3
    Pain
         subjects affected / exposed
    0 / 16 (0.00%)
    0 / 26 (0.00%)
    0 / 17 (0.00%)
    1 / 10 (10.00%)
         occurrences all number
    0
    0
    0
    2
    Immune system disorders
    Hypersensitivity
         subjects affected / exposed
    0 / 16 (0.00%)
    1 / 26 (3.85%)
    0 / 17 (0.00%)
    1 / 10 (10.00%)
         occurrences all number
    0
    1
    0
    1
    Drug hypersensitivity
         subjects affected / exposed
    0 / 16 (0.00%)
    0 / 26 (0.00%)
    1 / 17 (5.88%)
    0 / 10 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Reproductive system and breast disorders
    Testicular pain
         subjects affected / exposed
    0 / 16 (0.00%)
    0 / 26 (0.00%)
    0 / 17 (0.00%)
    1 / 10 (10.00%)
         occurrences all number
    0
    0
    0
    1
    Ejaculation disorder
         subjects affected / exposed
    0 / 16 (0.00%)
    0 / 26 (0.00%)
    1 / 17 (5.88%)
    0 / 10 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Pelvic pain
         subjects affected / exposed
    0 / 16 (0.00%)
    1 / 26 (3.85%)
    1 / 17 (5.88%)
    0 / 10 (0.00%)
         occurrences all number
    0
    3
    1
    0
    Penile pain
         subjects affected / exposed
    0 / 16 (0.00%)
    2 / 26 (7.69%)
    0 / 17 (0.00%)
    0 / 10 (0.00%)
         occurrences all number
    0
    2
    0
    0
    Testicular mass
         subjects affected / exposed
    0 / 16 (0.00%)
    0 / 26 (0.00%)
    0 / 17 (0.00%)
    1 / 10 (10.00%)
         occurrences all number
    0
    0
    0
    1
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    0 / 16 (0.00%)
    4 / 26 (15.38%)
    1 / 17 (5.88%)
    0 / 10 (0.00%)
         occurrences all number
    0
    5
    1
    0
    Dyspnoea
         subjects affected / exposed
    0 / 16 (0.00%)
    1 / 26 (3.85%)
    0 / 17 (0.00%)
    2 / 10 (20.00%)
         occurrences all number
    0
    1
    0
    2
    Epistaxis
         subjects affected / exposed
    1 / 16 (6.25%)
    1 / 26 (3.85%)
    0 / 17 (0.00%)
    0 / 10 (0.00%)
         occurrences all number
    1
    3
    0
    0
    Hiccups
         subjects affected / exposed
    0 / 16 (0.00%)
    1 / 26 (3.85%)
    0 / 17 (0.00%)
    1 / 10 (10.00%)
         occurrences all number
    0
    1
    0
    1
    Nasal congestion
         subjects affected / exposed
    0 / 16 (0.00%)
    0 / 26 (0.00%)
    0 / 17 (0.00%)
    1 / 10 (10.00%)
         occurrences all number
    0
    0
    0
    1
    Pleural effusion
         subjects affected / exposed
    0 / 16 (0.00%)
    0 / 26 (0.00%)
    0 / 17 (0.00%)
    1 / 10 (10.00%)
         occurrences all number
    0
    0
    0
    1
    Productive cough
         subjects affected / exposed
    0 / 16 (0.00%)
    1 / 26 (3.85%)
    0 / 17 (0.00%)
    1 / 10 (10.00%)
         occurrences all number
    0
    1
    0
    1
    Pulmonary oedema
         subjects affected / exposed
    0 / 16 (0.00%)
    0 / 26 (0.00%)
    0 / 17 (0.00%)
    1 / 10 (10.00%)
         occurrences all number
    0
    0
    0
    1
    Rhinorrhoea
         subjects affected / exposed
    0 / 16 (0.00%)
    0 / 26 (0.00%)
    0 / 17 (0.00%)
    1 / 10 (10.00%)
         occurrences all number
    0
    0
    0
    1
    Pneumonitis
         subjects affected / exposed
    1 / 16 (6.25%)
    0 / 26 (0.00%)
    0 / 17 (0.00%)
    1 / 10 (10.00%)
         occurrences all number
    1
    0
    0
    1
    Psychiatric disorders
    Alcohol withdrawal syndrome
         subjects affected / exposed
    1 / 16 (6.25%)
    0 / 26 (0.00%)
    0 / 17 (0.00%)
    0 / 10 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Anxiety
         subjects affected / exposed
    0 / 16 (0.00%)
    0 / 26 (0.00%)
    1 / 17 (5.88%)
    1 / 10 (10.00%)
         occurrences all number
    0
    0
    1
    1
    Confusional state
         subjects affected / exposed
    0 / 16 (0.00%)
    0 / 26 (0.00%)
    0 / 17 (0.00%)
    1 / 10 (10.00%)
         occurrences all number
    0
    0
    0
    1
    Insomnia
         subjects affected / exposed
    1 / 16 (6.25%)
    0 / 26 (0.00%)
    2 / 17 (11.76%)
    1 / 10 (10.00%)
         occurrences all number
    1
    0
    2
    1
    Persistent depressive disorder
         subjects affected / exposed
    0 / 16 (0.00%)
    0 / 26 (0.00%)
    0 / 17 (0.00%)
    1 / 10 (10.00%)
         occurrences all number
    0
    0
    0
    1
    Investigations
    Antinuclear antibody positive
         subjects affected / exposed
    1 / 16 (6.25%)
    0 / 26 (0.00%)
    0 / 17 (0.00%)
    0 / 10 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Amylase increased
         subjects affected / exposed
    0 / 16 (0.00%)
    0 / 26 (0.00%)
    1 / 17 (5.88%)
    1 / 10 (10.00%)
         occurrences all number
    0
    0
    2
    1
    Alanine aminotransferase increased
         subjects affected / exposed
    1 / 16 (6.25%)
    2 / 26 (7.69%)
    4 / 17 (23.53%)
    4 / 10 (40.00%)
         occurrences all number
    1
    6
    4
    6
    Aspartate aminotransferase increased
         subjects affected / exposed
    0 / 16 (0.00%)
    1 / 26 (3.85%)
    5 / 17 (29.41%)
    4 / 10 (40.00%)
         occurrences all number
    0
    3
    6
    5
    Carbohydrate antigen 19-9 increased
         subjects affected / exposed
    1 / 16 (6.25%)
    0 / 26 (0.00%)
    0 / 17 (0.00%)
    0 / 10 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Blood urine present
         subjects affected / exposed
    0 / 16 (0.00%)
    0 / 26 (0.00%)
    0 / 17 (0.00%)
    1 / 10 (10.00%)
         occurrences all number
    0
    0
    0
    1
    Blood uric acid increased
         subjects affected / exposed
    1 / 16 (6.25%)
    0 / 26 (0.00%)
    0 / 17 (0.00%)
    0 / 10 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Blood triglycerides increased
         subjects affected / exposed
    1 / 16 (6.25%)
    0 / 26 (0.00%)
    0 / 17 (0.00%)
    0 / 10 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Blood thyroid stimulating hormone increased
         subjects affected / exposed
    2 / 16 (12.50%)
    0 / 26 (0.00%)
    0 / 17 (0.00%)
    0 / 10 (0.00%)
         occurrences all number
    2
    0
    0
    0
    Gamma-glutamyltransferase increased
         subjects affected / exposed
    1 / 16 (6.25%)
    0 / 26 (0.00%)
    1 / 17 (5.88%)
    0 / 10 (0.00%)
         occurrences all number
    1
    0
    1
    0
    Blood methaemoglobin present
         subjects affected / exposed
    0 / 16 (0.00%)
    0 / 26 (0.00%)
    0 / 17 (0.00%)
    1 / 10 (10.00%)
         occurrences all number
    0
    0
    0
    1
    Blood magnesium decreased
         subjects affected / exposed
    0 / 16 (0.00%)
    0 / 26 (0.00%)
    1 / 17 (5.88%)
    0 / 10 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Blood lactate dehydrogenase increased
         subjects affected / exposed
    1 / 16 (6.25%)
    0 / 26 (0.00%)
    0 / 17 (0.00%)
    0 / 10 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Blood creatinine increased
         subjects affected / exposed
    0 / 16 (0.00%)
    1 / 26 (3.85%)
    0 / 17 (0.00%)
    4 / 10 (40.00%)
         occurrences all number
    0
    1
    0
    4
    Blood creatine phosphokinase increased
         subjects affected / exposed
    1 / 16 (6.25%)
    0 / 26 (0.00%)
    0 / 17 (0.00%)
    0 / 10 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Blood bilirubin increased
         subjects affected / exposed
    0 / 16 (0.00%)
    0 / 26 (0.00%)
    1 / 17 (5.88%)
    1 / 10 (10.00%)
         occurrences all number
    0
    0
    1
    1
    Blood thyroid stimulating hormone decreased
         subjects affected / exposed
    1 / 16 (6.25%)
    1 / 26 (3.85%)
    0 / 17 (0.00%)
    0 / 10 (0.00%)
         occurrences all number
    1
    1
    0
    0
    Heart rate irregular
         subjects affected / exposed
    1 / 16 (6.25%)
    0 / 26 (0.00%)
    0 / 17 (0.00%)
    0 / 10 (0.00%)
         occurrences all number
    1
    0
    0
    0
    International normalised ratio increased
         subjects affected / exposed
    0 / 16 (0.00%)
    1 / 26 (3.85%)
    0 / 17 (0.00%)
    1 / 10 (10.00%)
         occurrences all number
    0
    1
    0
    2
    Lipase increased
         subjects affected / exposed
    0 / 16 (0.00%)
    0 / 26 (0.00%)
    1 / 17 (5.88%)
    1 / 10 (10.00%)
         occurrences all number
    0
    0
    2
    1
    Neutrophil count increased
         subjects affected / exposed
    1 / 16 (6.25%)
    0 / 26 (0.00%)
    0 / 17 (0.00%)
    0 / 10 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Neutrophil percentage increased
         subjects affected / exposed
    1 / 16 (6.25%)
    0 / 26 (0.00%)
    0 / 17 (0.00%)
    0 / 10 (0.00%)
         occurrences all number
    2
    0
    0
    0
    PCO2 increased
         subjects affected / exposed
    1 / 16 (6.25%)
    0 / 26 (0.00%)
    0 / 17 (0.00%)
    0 / 10 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Transaminases increased
         subjects affected / exposed
    0 / 16 (0.00%)
    0 / 26 (0.00%)
    1 / 17 (5.88%)
    0 / 10 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Weight decreased
         subjects affected / exposed
    1 / 16 (6.25%)
    1 / 26 (3.85%)
    0 / 17 (0.00%)
    0 / 10 (0.00%)
         occurrences all number
    1
    1
    0
    0
    Injury, poisoning and procedural complications
    Vascular access site rash
         subjects affected / exposed
    1 / 16 (6.25%)
    0 / 26 (0.00%)
    0 / 17 (0.00%)
    0 / 10 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Stoma site hypergranulation
         subjects affected / exposed
    1 / 16 (6.25%)
    0 / 26 (0.00%)
    0 / 17 (0.00%)
    0 / 10 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Procedural pain
         subjects affected / exposed
    2 / 16 (12.50%)
    1 / 26 (3.85%)
    1 / 17 (5.88%)
    0 / 10 (0.00%)
         occurrences all number
    2
    1
    1
    0
    Postoperative respiratory failure
         subjects affected / exposed
    0 / 16 (0.00%)
    0 / 26 (0.00%)
    0 / 17 (0.00%)
    1 / 10 (10.00%)
         occurrences all number
    0
    0
    0
    1
    Postoperative ileus
         subjects affected / exposed
    1 / 16 (6.25%)
    0 / 26 (0.00%)
    0 / 17 (0.00%)
    0 / 10 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Infusion related reaction
         subjects affected / exposed
    0 / 16 (0.00%)
    1 / 26 (3.85%)
    0 / 17 (0.00%)
    3 / 10 (30.00%)
         occurrences all number
    0
    1
    0
    4
    Hip fracture
         subjects affected / exposed
    0 / 16 (0.00%)
    0 / 26 (0.00%)
    1 / 17 (5.88%)
    0 / 10 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Fall
         subjects affected / exposed
    0 / 16 (0.00%)
    0 / 26 (0.00%)
    0 / 17 (0.00%)
    1 / 10 (10.00%)
         occurrences all number
    0
    0
    0
    1
    Cardiac disorders
    Palpitations
         subjects affected / exposed
    0 / 16 (0.00%)
    0 / 26 (0.00%)
    1 / 17 (5.88%)
    1 / 10 (10.00%)
         occurrences all number
    0
    0
    1
    1
    Ventricular extrasystoles
         subjects affected / exposed
    0 / 16 (0.00%)
    0 / 26 (0.00%)
    1 / 17 (5.88%)
    0 / 10 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Supraventricular tachycardia
         subjects affected / exposed
    0 / 16 (0.00%)
    0 / 26 (0.00%)
    1 / 17 (5.88%)
    0 / 10 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Nervous system disorders
    Syncope
         subjects affected / exposed
    0 / 16 (0.00%)
    0 / 26 (0.00%)
    0 / 17 (0.00%)
    1 / 10 (10.00%)
         occurrences all number
    0
    0
    0
    1
    Amnesia
         subjects affected / exposed
    0 / 16 (0.00%)
    0 / 26 (0.00%)
    0 / 17 (0.00%)
    1 / 10 (10.00%)
         occurrences all number
    0
    0
    0
    1
    Dizziness
         subjects affected / exposed
    0 / 16 (0.00%)
    3 / 26 (11.54%)
    1 / 17 (5.88%)
    0 / 10 (0.00%)
         occurrences all number
    0
    4
    1
    0
    Headache
         subjects affected / exposed
    1 / 16 (6.25%)
    0 / 26 (0.00%)
    1 / 17 (5.88%)
    0 / 10 (0.00%)
         occurrences all number
    1
    0
    1
    0
    Sinus headache
         subjects affected / exposed
    1 / 16 (6.25%)
    0 / 26 (0.00%)
    0 / 17 (0.00%)
    0 / 10 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Blood and lymphatic system disorders
    Leukocytosis
         subjects affected / exposed
    1 / 16 (6.25%)
    0 / 26 (0.00%)
    0 / 17 (0.00%)
    2 / 10 (20.00%)
         occurrences all number
    1
    0
    0
    3
    Anaemia
         subjects affected / exposed
    3 / 16 (18.75%)
    0 / 26 (0.00%)
    2 / 17 (11.76%)
    1 / 10 (10.00%)
         occurrences all number
    3
    0
    2
    1
    Thrombocytopenia
         subjects affected / exposed
    0 / 16 (0.00%)
    0 / 26 (0.00%)
    1 / 17 (5.88%)
    0 / 10 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Neutropenia
         subjects affected / exposed
    0 / 16 (0.00%)
    0 / 26 (0.00%)
    0 / 17 (0.00%)
    1 / 10 (10.00%)
         occurrences all number
    0
    0
    0
    1
    Eye disorders
    Diplopia
         subjects affected / exposed
    0 / 16 (0.00%)
    0 / 26 (0.00%)
    0 / 17 (0.00%)
    1 / 10 (10.00%)
         occurrences all number
    0
    0
    0
    2
    Metamorphopsia
         subjects affected / exposed
    0 / 16 (0.00%)
    0 / 26 (0.00%)
    0 / 17 (0.00%)
    1 / 10 (10.00%)
         occurrences all number
    0
    0
    0
    1
    Vision blurred
         subjects affected / exposed
    0 / 16 (0.00%)
    2 / 26 (7.69%)
    0 / 17 (0.00%)
    1 / 10 (10.00%)
         occurrences all number
    0
    2
    0
    1
    Gastrointestinal disorders
    Abdominal distension
         subjects affected / exposed
    1 / 16 (6.25%)
    1 / 26 (3.85%)
    1 / 17 (5.88%)
    0 / 10 (0.00%)
         occurrences all number
    1
    1
    1
    0
    Abdominal discomfort
         subjects affected / exposed
    0 / 16 (0.00%)
    0 / 26 (0.00%)
    0 / 17 (0.00%)
    1 / 10 (10.00%)
         occurrences all number
    0
    0
    0
    1
    Abdominal pain
         subjects affected / exposed
    0 / 16 (0.00%)
    0 / 26 (0.00%)
    1 / 17 (5.88%)
    2 / 10 (20.00%)
         occurrences all number
    0
    0
    1
    2
    Constipation
         subjects affected / exposed
    2 / 16 (12.50%)
    2 / 26 (7.69%)
    3 / 17 (17.65%)
    2 / 10 (20.00%)
         occurrences all number
    2
    2
    3
    2
    Diarrhoea
         subjects affected / exposed
    3 / 16 (18.75%)
    4 / 26 (15.38%)
    4 / 17 (23.53%)
    2 / 10 (20.00%)
         occurrences all number
    3
    4
    4
    4
    Dry mouth
         subjects affected / exposed
    0 / 16 (0.00%)
    3 / 26 (11.54%)
    0 / 17 (0.00%)
    2 / 10 (20.00%)
         occurrences all number
    0
    3
    0
    2
    Ileus
         subjects affected / exposed
    1 / 16 (6.25%)
    0 / 26 (0.00%)
    0 / 17 (0.00%)
    0 / 10 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Flatulence
         subjects affected / exposed
    0 / 16 (0.00%)
    0 / 26 (0.00%)
    1 / 17 (5.88%)
    0 / 10 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Frequent bowel movements
         subjects affected / exposed
    0 / 16 (0.00%)
    0 / 26 (0.00%)
    0 / 17 (0.00%)
    1 / 10 (10.00%)
         occurrences all number
    0
    0
    0
    1
    Haemorrhoids
         subjects affected / exposed
    0 / 16 (0.00%)
    0 / 26 (0.00%)
    1 / 17 (5.88%)
    1 / 10 (10.00%)
         occurrences all number
    0
    0
    1
    1
    Haematochezia
         subjects affected / exposed
    0 / 16 (0.00%)
    0 / 26 (0.00%)
    1 / 17 (5.88%)
    0 / 10 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Dyspepsia
         subjects affected / exposed
    0 / 16 (0.00%)
    1 / 26 (3.85%)
    1 / 17 (5.88%)
    0 / 10 (0.00%)
         occurrences all number
    0
    1
    1
    0
    Immune-mediated enterocolitis
         subjects affected / exposed
    0 / 16 (0.00%)
    0 / 26 (0.00%)
    0 / 17 (0.00%)
    1 / 10 (10.00%)
         occurrences all number
    0
    0
    0
    1
    Vomiting
         subjects affected / exposed
    1 / 16 (6.25%)
    1 / 26 (3.85%)
    2 / 17 (11.76%)
    0 / 10 (0.00%)
         occurrences all number
    1
    1
    2
    0
    Stomatitis
         subjects affected / exposed
    0 / 16 (0.00%)
    0 / 26 (0.00%)
    1 / 17 (5.88%)
    0 / 10 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Proctitis
         subjects affected / exposed
    0 / 16 (0.00%)
    0 / 26 (0.00%)
    1 / 17 (5.88%)
    0 / 10 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Pancreatitis
         subjects affected / exposed
    0 / 16 (0.00%)
    0 / 26 (0.00%)
    0 / 17 (0.00%)
    1 / 10 (10.00%)
         occurrences all number
    0
    0
    0
    1
    Nausea
         subjects affected / exposed
    2 / 16 (12.50%)
    3 / 26 (11.54%)
    2 / 17 (11.76%)
    3 / 10 (30.00%)
         occurrences all number
    3
    3
    2
    4
    Inguinal hernia
         subjects affected / exposed
    0 / 16 (0.00%)
    0 / 26 (0.00%)
    1 / 17 (5.88%)
    0 / 10 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Hepatobiliary disorders
    Hepatitis
         subjects affected / exposed
    0 / 16 (0.00%)
    0 / 26 (0.00%)
    2 / 17 (11.76%)
    0 / 10 (0.00%)
         occurrences all number
    0
    0
    2
    0
    Hepatic function abnormal
         subjects affected / exposed
    1 / 16 (6.25%)
    0 / 26 (0.00%)
    0 / 17 (0.00%)
    0 / 10 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Drug-induced liver injury
         subjects affected / exposed
    0 / 16 (0.00%)
    0 / 26 (0.00%)
    1 / 17 (5.88%)
    0 / 10 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Hyperbilirubinaemia
         subjects affected / exposed
    0 / 16 (0.00%)
    0 / 26 (0.00%)
    1 / 17 (5.88%)
    0 / 10 (0.00%)
         occurrences all number
    0
    0
    2
    0
    Skin and subcutaneous tissue disorders
    Hyperhidrosis
         subjects affected / exposed
    0 / 16 (0.00%)
    0 / 26 (0.00%)
    0 / 17 (0.00%)
    1 / 10 (10.00%)
         occurrences all number
    0
    0
    0
    1
    Dermatitis
         subjects affected / exposed
    0 / 16 (0.00%)
    2 / 26 (7.69%)
    0 / 17 (0.00%)
    0 / 10 (0.00%)
         occurrences all number
    0
    2
    0
    0
    Dermatitis acneiform
         subjects affected / exposed
    0 / 16 (0.00%)
    0 / 26 (0.00%)
    1 / 17 (5.88%)
    1 / 10 (10.00%)
         occurrences all number
    0
    0
    1
    3
    Dry skin
         subjects affected / exposed
    0 / 16 (0.00%)
    1 / 26 (3.85%)
    1 / 17 (5.88%)
    1 / 10 (10.00%)
         occurrences all number
    0
    1
    1
    1
    Intertrigo
         subjects affected / exposed
    0 / 16 (0.00%)
    0 / 26 (0.00%)
    1 / 17 (5.88%)
    0 / 10 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Lichenoid keratosis
         subjects affected / exposed
    0 / 16 (0.00%)
    0 / 26 (0.00%)
    0 / 17 (0.00%)
    1 / 10 (10.00%)
         occurrences all number
    0
    0
    0
    1
    Onychoclasis
         subjects affected / exposed
    1 / 16 (6.25%)
    0 / 26 (0.00%)
    0 / 17 (0.00%)
    0 / 10 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Pruritus
         subjects affected / exposed
    3 / 16 (18.75%)
    6 / 26 (23.08%)
    3 / 17 (17.65%)
    1 / 10 (10.00%)
         occurrences all number
    3
    7
    4
    1
    Rash
         subjects affected / exposed
    1 / 16 (6.25%)
    3 / 26 (11.54%)
    1 / 17 (5.88%)
    2 / 10 (20.00%)
         occurrences all number
    1
    3
    1
    2
    Rash maculo-papular
         subjects affected / exposed
    0 / 16 (0.00%)
    2 / 26 (7.69%)
    1 / 17 (5.88%)
    1 / 10 (10.00%)
         occurrences all number
    0
    3
    2
    1
    Skin ulcer
         subjects affected / exposed
    0 / 16 (0.00%)
    0 / 26 (0.00%)
    0 / 17 (0.00%)
    1 / 10 (10.00%)
         occurrences all number
    0
    0
    0
    2
    Urticaria
         subjects affected / exposed
    0 / 16 (0.00%)
    1 / 26 (3.85%)
    1 / 17 (5.88%)
    0 / 10 (0.00%)
         occurrences all number
    0
    1
    1
    0
    Skin hyperpigmentation
         subjects affected / exposed
    1 / 16 (6.25%)
    0 / 26 (0.00%)
    0 / 17 (0.00%)
    0 / 10 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Renal and urinary disorders
    Acute kidney injury
         subjects affected / exposed
    1 / 16 (6.25%)
    1 / 26 (3.85%)
    0 / 17 (0.00%)
    2 / 10 (20.00%)
         occurrences all number
    1
    1
    0
    2
    Pollakiuria
         subjects affected / exposed
    2 / 16 (12.50%)
    8 / 26 (30.77%)
    1 / 17 (5.88%)
    7 / 10 (70.00%)
         occurrences all number
    2
    9
    1
    15
    Dysuria
         subjects affected / exposed
    0 / 16 (0.00%)
    10 / 26 (38.46%)
    1 / 17 (5.88%)
    4 / 10 (40.00%)
         occurrences all number
    0
    12
    1
    7
    Haematuria
         subjects affected / exposed
    4 / 16 (25.00%)
    11 / 26 (42.31%)
    4 / 17 (23.53%)
    5 / 10 (50.00%)
         occurrences all number
    4
    16
    7
    10
    Hypertonic bladder
         subjects affected / exposed
    1 / 16 (6.25%)
    0 / 26 (0.00%)
    0 / 17 (0.00%)
    0 / 10 (0.00%)
         occurrences all number
    2
    0
    0
    0
    Leukocyturia
         subjects affected / exposed
    0 / 16 (0.00%)
    0 / 26 (0.00%)
    0 / 17 (0.00%)
    1 / 10 (10.00%)
         occurrences all number
    0
    0
    0
    3
    Micturition urgency
         subjects affected / exposed
    0 / 16 (0.00%)
    7 / 26 (26.92%)
    0 / 17 (0.00%)
    4 / 10 (40.00%)
         occurrences all number
    0
    7
    0
    10
    Nocturia
         subjects affected / exposed
    0 / 16 (0.00%)
    1 / 26 (3.85%)
    0 / 17 (0.00%)
    1 / 10 (10.00%)
         occurrences all number
    0
    1
    0
    1
    Bladder spasm
         subjects affected / exposed
    0 / 16 (0.00%)
    3 / 26 (11.54%)
    0 / 17 (0.00%)
    1 / 10 (10.00%)
         occurrences all number
    0
    3
    0
    1
    Proteinuria
         subjects affected / exposed
    0 / 16 (0.00%)
    1 / 26 (3.85%)
    0 / 17 (0.00%)
    1 / 10 (10.00%)
         occurrences all number
    0
    1
    0
    2
    Renal mass
         subjects affected / exposed
    0 / 16 (0.00%)
    0 / 26 (0.00%)
    1 / 17 (5.88%)
    0 / 10 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Renal pain
         subjects affected / exposed
    0 / 16 (0.00%)
    0 / 26 (0.00%)
    0 / 17 (0.00%)
    1 / 10 (10.00%)
         occurrences all number
    0
    0
    0
    1
    Strangury
         subjects affected / exposed
    0 / 16 (0.00%)
    2 / 26 (7.69%)
    0 / 17 (0.00%)
    0 / 10 (0.00%)
         occurrences all number
    0
    2
    0
    0
    Urethral pain
         subjects affected / exposed
    1 / 16 (6.25%)
    0 / 26 (0.00%)
    1 / 17 (5.88%)
    0 / 10 (0.00%)
         occurrences all number
    1
    0
    1
    0
    Urinary incontinence
         subjects affected / exposed
    1 / 16 (6.25%)
    3 / 26 (11.54%)
    1 / 17 (5.88%)
    2 / 10 (20.00%)
         occurrences all number
    1
    6
    1
    2
    Urinary retention
         subjects affected / exposed
    0 / 16 (0.00%)
    0 / 26 (0.00%)
    1 / 17 (5.88%)
    0 / 10 (0.00%)
         occurrences all number
    0
    0
    2
    0
    Urinary tract obstruction
         subjects affected / exposed
    1 / 16 (6.25%)
    0 / 26 (0.00%)
    0 / 17 (0.00%)
    0 / 10 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Urinary tract pain
         subjects affected / exposed
    0 / 16 (0.00%)
    1 / 26 (3.85%)
    1 / 17 (5.88%)
    2 / 10 (20.00%)
         occurrences all number
    0
    1
    1
    3
    Renal failure
         subjects affected / exposed
    1 / 16 (6.25%)
    0 / 26 (0.00%)
    0 / 17 (0.00%)
    0 / 10 (0.00%)
         occurrences all number
    3
    0
    0
    0
    Endocrine disorders
    Hypothyroidism
         subjects affected / exposed
    1 / 16 (6.25%)
    3 / 26 (11.54%)
    2 / 17 (11.76%)
    0 / 10 (0.00%)
         occurrences all number
    1
    5
    2
    0
    Hyperthyroidism
         subjects affected / exposed
    1 / 16 (6.25%)
    0 / 26 (0.00%)
    1 / 17 (5.88%)
    1 / 10 (10.00%)
         occurrences all number
    1
    0
    1
    1
    Glucocorticoid deficiency
         subjects affected / exposed
    0 / 16 (0.00%)
    0 / 26 (0.00%)
    0 / 17 (0.00%)
    1 / 10 (10.00%)
         occurrences all number
    0
    0
    0
    1
    Musculoskeletal and connective tissue disorders
    Flank pain
         subjects affected / exposed
    0 / 16 (0.00%)
    0 / 26 (0.00%)
    1 / 17 (5.88%)
    0 / 10 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Arthralgia
         subjects affected / exposed
    1 / 16 (6.25%)
    6 / 26 (23.08%)
    1 / 17 (5.88%)
    2 / 10 (20.00%)
         occurrences all number
    1
    9
    1
    2
    Arthritis
         subjects affected / exposed
    1 / 16 (6.25%)
    0 / 26 (0.00%)
    1 / 17 (5.88%)
    1 / 10 (10.00%)
         occurrences all number
    1
    0
    1
    1
    Back pain
         subjects affected / exposed
    0 / 16 (0.00%)
    5 / 26 (19.23%)
    2 / 17 (11.76%)
    3 / 10 (30.00%)
         occurrences all number
    0
    5
    2
    6
    Joint range of motion decreased
         subjects affected / exposed
    0 / 16 (0.00%)
    0 / 26 (0.00%)
    0 / 17 (0.00%)
    1 / 10 (10.00%)
         occurrences all number
    0
    0
    0
    1
    Joint swelling
         subjects affected / exposed
    0 / 16 (0.00%)
    0 / 26 (0.00%)
    0 / 17 (0.00%)
    1 / 10 (10.00%)
         occurrences all number
    0
    0
    0
    1
    Muscular weakness
         subjects affected / exposed
    0 / 16 (0.00%)
    1 / 26 (3.85%)
    1 / 17 (5.88%)
    2 / 10 (20.00%)
         occurrences all number
    0
    1
    1
    3
    Myalgia
         subjects affected / exposed
    1 / 16 (6.25%)
    5 / 26 (19.23%)
    0 / 17 (0.00%)
    1 / 10 (10.00%)
         occurrences all number
    1
    8
    0
    1
    Myopathy
         subjects affected / exposed
    0 / 16 (0.00%)
    0 / 26 (0.00%)
    1 / 17 (5.88%)
    0 / 10 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Neck pain
         subjects affected / exposed
    0 / 16 (0.00%)
    0 / 26 (0.00%)
    0 / 17 (0.00%)
    1 / 10 (10.00%)
         occurrences all number
    0
    0
    0
    2
    Tendon disorder
         subjects affected / exposed
    0 / 16 (0.00%)
    0 / 26 (0.00%)
    0 / 17 (0.00%)
    1 / 10 (10.00%)
         occurrences all number
    0
    0
    0
    1
    Tenosynovitis
         subjects affected / exposed
    0 / 16 (0.00%)
    0 / 26 (0.00%)
    1 / 17 (5.88%)
    0 / 10 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Pain in extremity
         subjects affected / exposed
    1 / 16 (6.25%)
    2 / 26 (7.69%)
    1 / 17 (5.88%)
    0 / 10 (0.00%)
         occurrences all number
    1
    3
    1
    0
    Infections and infestations
    Conjunctivitis
         subjects affected / exposed
    1 / 16 (6.25%)
    1 / 26 (3.85%)
    0 / 17 (0.00%)
    0 / 10 (0.00%)
         occurrences all number
    1
    1
    0
    0
    Candida infection
         subjects affected / exposed
    0 / 16 (0.00%)
    0 / 26 (0.00%)
    1 / 17 (5.88%)
    0 / 10 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Bacterial disease carrier
         subjects affected / exposed
    0 / 16 (0.00%)
    1 / 26 (3.85%)
    0 / 17 (0.00%)
    1 / 10 (10.00%)
         occurrences all number
    0
    1
    0
    1
    Cystitis
         subjects affected / exposed
    0 / 16 (0.00%)
    2 / 26 (7.69%)
    0 / 17 (0.00%)
    0 / 10 (0.00%)
         occurrences all number
    0
    2
    0
    0
    Sinusitis
         subjects affected / exposed
    1 / 16 (6.25%)
    0 / 26 (0.00%)
    0 / 17 (0.00%)
    0 / 10 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Tooth infection
         subjects affected / exposed
    0 / 16 (0.00%)
    0 / 26 (0.00%)
    1 / 17 (5.88%)
    0 / 10 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Device related infection
         subjects affected / exposed
    0 / 16 (0.00%)
    0 / 26 (0.00%)
    1 / 17 (5.88%)
    0 / 10 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Ear infection
         subjects affected / exposed
    1 / 16 (6.25%)
    0 / 26 (0.00%)
    0 / 17 (0.00%)
    0 / 10 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Groin infection
         subjects affected / exposed
    1 / 16 (6.25%)
    0 / 26 (0.00%)
    0 / 17 (0.00%)
    0 / 10 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Herpes zoster
         subjects affected / exposed
    1 / 16 (6.25%)
    0 / 26 (0.00%)
    0 / 17 (0.00%)
    0 / 10 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Infected skin ulcer
         subjects affected / exposed
    0 / 16 (0.00%)
    0 / 26 (0.00%)
    1 / 17 (5.88%)
    0 / 10 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Nail infection
         subjects affected / exposed
    0 / 16 (0.00%)
    0 / 26 (0.00%)
    0 / 17 (0.00%)
    1 / 10 (10.00%)
         occurrences all number
    0
    0
    0
    1
    Orchitis
         subjects affected / exposed
    1 / 16 (6.25%)
    0 / 26 (0.00%)
    0 / 17 (0.00%)
    0 / 10 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Oropharyngeal candidiasis
         subjects affected / exposed
    0 / 16 (0.00%)
    0 / 26 (0.00%)
    0 / 17 (0.00%)
    1 / 10 (10.00%)
         occurrences all number
    0
    0
    0
    2
    Pneumonia
         subjects affected / exposed
    1 / 16 (6.25%)
    0 / 26 (0.00%)
    0 / 17 (0.00%)
    0 / 10 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Pneumonia klebsiella
         subjects affected / exposed
    0 / 16 (0.00%)
    0 / 26 (0.00%)
    1 / 17 (5.88%)
    0 / 10 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Pseudomonas infection
         subjects affected / exposed
    0 / 16 (0.00%)
    0 / 26 (0.00%)
    1 / 17 (5.88%)
    0 / 10 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Pyelonephritis
         subjects affected / exposed
    0 / 16 (0.00%)
    0 / 26 (0.00%)
    2 / 17 (11.76%)
    0 / 10 (0.00%)
         occurrences all number
    0
    0
    4
    0
    Upper respiratory tract infection
         subjects affected / exposed
    1 / 16 (6.25%)
    0 / 26 (0.00%)
    0 / 17 (0.00%)
    0 / 10 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Urinary tract infection
         subjects affected / exposed
    1 / 16 (6.25%)
    9 / 26 (34.62%)
    2 / 17 (11.76%)
    3 / 10 (30.00%)
         occurrences all number
    1
    9
    2
    4
    Wound infection
         subjects affected / exposed
    1 / 16 (6.25%)
    1 / 26 (3.85%)
    0 / 17 (0.00%)
    0 / 10 (0.00%)
         occurrences all number
    1
    1
    0
    0
    Metabolism and nutrition disorders
    Decreased appetite
         subjects affected / exposed
    0 / 16 (0.00%)
    1 / 26 (3.85%)
    1 / 17 (5.88%)
    1 / 10 (10.00%)
         occurrences all number
    0
    1
    1
    1
    Dehydration
         subjects affected / exposed
    0 / 16 (0.00%)
    0 / 26 (0.00%)
    0 / 17 (0.00%)
    1 / 10 (10.00%)
         occurrences all number
    0
    0
    0
    1
    Diabetes mellitus
         subjects affected / exposed
    1 / 16 (6.25%)
    1 / 26 (3.85%)
    0 / 17 (0.00%)
    0 / 10 (0.00%)
         occurrences all number
    1
    1
    0
    0
    Hypercalcaemia
         subjects affected / exposed
    2 / 16 (12.50%)
    0 / 26 (0.00%)
    0 / 17 (0.00%)
    1 / 10 (10.00%)
         occurrences all number
    4
    0
    0
    1
    Hyperglycaemia
         subjects affected / exposed
    5 / 16 (31.25%)
    1 / 26 (3.85%)
    2 / 17 (11.76%)
    1 / 10 (10.00%)
         occurrences all number
    8
    1
    2
    1
    Hyperkalaemia
         subjects affected / exposed
    0 / 16 (0.00%)
    2 / 26 (7.69%)
    0 / 17 (0.00%)
    0 / 10 (0.00%)
         occurrences all number
    0
    2
    0
    0
    Hyperuricaemia
         subjects affected / exposed
    1 / 16 (6.25%)
    2 / 26 (7.69%)
    0 / 17 (0.00%)
    0 / 10 (0.00%)
         occurrences all number
    1
    2
    0
    0
    Hypocalcaemia
         subjects affected / exposed
    0 / 16 (0.00%)
    0 / 26 (0.00%)
    1 / 17 (5.88%)
    0 / 10 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Hypokalaemia
         subjects affected / exposed
    3 / 16 (18.75%)
    2 / 26 (7.69%)
    1 / 17 (5.88%)
    1 / 10 (10.00%)
         occurrences all number
    4
    2
    1
    1
    Hypomagnesaemia
         subjects affected / exposed
    0 / 16 (0.00%)
    0 / 26 (0.00%)
    1 / 17 (5.88%)
    1 / 10 (10.00%)
         occurrences all number
    0
    0
    1
    1
    Hyponatraemia
         subjects affected / exposed
    2 / 16 (12.50%)
    0 / 26 (0.00%)
    2 / 17 (11.76%)
    1 / 10 (10.00%)
         occurrences all number
    3
    0
    2
    1
    Polydipsia
         subjects affected / exposed
    0 / 16 (0.00%)
    0 / 26 (0.00%)
    0 / 17 (0.00%)
    1 / 10 (10.00%)
         occurrences all number
    0
    0
    0
    1
    Steroid diabetes
         subjects affected / exposed
    0 / 16 (0.00%)
    0 / 26 (0.00%)
    1 / 17 (5.88%)
    0 / 10 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Hypophosphataemia
         subjects affected / exposed
    1 / 16 (6.25%)
    1 / 26 (3.85%)
    1 / 17 (5.88%)
    0 / 10 (0.00%)
         occurrences all number
    1
    2
    1
    0

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    10 May 2019
    Increased the window for screening procedures, decreased the number of required slides for biomarker analysis from 20 to 15, made random bladder biopsies at screening optional, allowed for urine cytology to be tested on a voided specimen, and increased the window for repeat TURBT for participants with stage T1 disease from 4 to 8 weeks to be consistent with professional society guidelines.
    01 Nov 2019
    Revised study design to pause enrollment into Arm D once the safety lead-in was completed. Introduced modified randomization to account for BCG availability. Removed eligibility for non-CIS participants. Deleted the endpoint of event free survival (EFS) in non-CIS participants.
    22 Sep 2021
    Details of closure of the study, with provision for participants currently on treatment to continue. Removal of pharmacokinetic (except for immunogenicity), biomarker, healthcare resource utilization, and patient-reported outcome (PRO) assessments. Details of closure of the study, with provision for participants currently on treatment to continue. Removal of pharmacokinetic (except for immunogenicity), biomarker, healthcare resource utilization, and patient-reported outcome (PRO) assessments. Removal of study-related efficacy assessment and Pathology Review Committee. Sites should continue efficacy assessment as per the local standard of care. Removal of study-related efficacy assessment and Pathology Review Committee. Sites should continue efficacy assessment as per the local standard of care.

    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.
    As of early April 2021, study enrollment was significantly behind (number enrolled 142; target 480). Since the study would be unable to meet the scientific objectives within a projected timeline, it was decided in May 2021 to close the study.
    For support, Contact us.
    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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