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    Clinical Trial Results:
    PHASE IIIB, RANDOMIZED STUDY OF MULTIPLE ADMINISTRATION REGIMENS FOR NIVOLUMAB PLUS IPILIMUMAB IN SUBJECTS WITH PREVIOUSLY UNTREATED UNRESECTABLE OR METASTATIC MELANOMA

    Summary
    EudraCT number
    		 2016-001941-26
    Trial protocol
    		 ES   IT  
    Global end of trial date
    25 Oct 2019

    Results information
    Results version number
    		 v1(current)
    This version publication date
    07 Nov 2020
    First version publication date
    07 Nov 2020
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    CA209-742
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 -
    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
    Bristol-Myers Squibb Study Director, 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
    23 Dec 2019
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    25 Oct 2019
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To evaluate the difference in safety between co-administered BMS-986214 fixed ratio combination (FRC) (nivolumab 1 mg/kg and ipilimumab 3 mg/kg) relative to sequentially administered nivolumab (1 mg/kg) and ipilimumab (3 mg/kg) as measured by the incidence of AEs in the Broad Scope MedDRA Anaphylactic Reaction SMQ occurring within 2 days after dosing during the combination, Part 1 period in subjects with previously untreated, unresectable or metastatic melanoma.
    Protection of trial subjects
    The study was in compliance with the ethical principles derived from the Declaration of Helsinki and in compliance with all International Conference on Harmonization Good Clinical Practice Guidelines. All the local regulatory requirements pertinent to safety of trial subjects were followed.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    27 Oct 2016
    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: 28
    Country: Number of subjects enrolled
    France: 42
    Country: Number of subjects enrolled
    Italy: 16
    Country: Number of subjects enrolled
    Spain: 20
    Worldwide total number of subjects
    106
    EEA total number of subjects
    78
    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)
    67
    From 65 to 84 years
    38
    85 years and over
    1

    Subject disposition

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    Recruitment
    Recruitment details
    		 -

    Pre-assignment
    Screening details
    		 106 participants were randomized and treated.

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

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Arm A
    Arm description
    		 Concomitant administration of Nivolumab and Ipilimumab every 3 weeks for 4 doses followed by Nivolumab flat dose in the Maintenance Phase
    Arm type
    		 Experimental

    Investigational medicinal product name
    Nivolumab/Ipilimumab FRC
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Intravenous use
    Dosage and administration details
    40 mg Nivolumab/ 120 mg Ipilimumab - every 3 weeks for 4 doses

    Arm title
    		 Arm B
    Arm description
    		 Sequential administration of Nivolumab and Ipilimumab every 3 weeks for 4 doses followed by Nivolumab flat dose in the Maintenance Phase
    Arm type
    		 Experimental

    Investigational medicinal product name
    Ipilimumab
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Intravenous use
    Dosage and administration details
    3 mg/Kg every 3 weeks for 4 doses

    Investigational medicinal product name
    Nivolumab
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Intravenous use
    Dosage and administration details
    1 mg/kg very 3 weeks for 4 doses

    Number of subjects in period 1
    		Arm A Arm B
    Started
    53
    53
    Completed
    24
    30
    Not completed
    29
    23
         Study Drug Toxicity
    22
    16
         Participant Withdrew Consent
    1
    -
         Disease Progression
    6
    7
    Period 2
    Period 2 title
    Transition from Part 1 to Part 2
    Is this the baseline period?
    		 No
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Subject, Investigator, Monitor

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Arm A
    Arm description
    		 Concomitant administration of Nivolumab and Ipilimumab every 3 weeks for 4 doses followed by Nivolumab flat dose in the Maintenance Phase
    Arm type
    		 Experimental

    Investigational medicinal product name
    Nivolumab/Ipilimumab FRC
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Intravenous use
    Dosage and administration details
    40 mg Nivolumab/ 120 mg Ipilimumab every 3 weeks for 4 doses

    Arm title
    		 Arm B
    Arm description
    		 Sequential administration of Nivolumab and Ipilimumab every 3 weeks for 4 doses followed by Nivolumab flat dose in the Maintenance Phase
    Arm type
    		 Experimental

    Investigational medicinal product name
    Ipilimumab
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Intravenous use
    Dosage and administration details
    3 mg/Kg every 3 weeks for 4 doses

    Investigational medicinal product name
    Nivolumab
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Intravenous use
    Dosage and administration details
    1 mg/kg every 3 weeks for 4 doses

    Number of subjects in period 2
    		Arm A Arm B
    Started
    24
    30
    Completed
    20
    22
    Not completed
    4
    8
         Adverse event, serious fatal
    -
    1
         Adverse event, non-fatal
    1
    1
         Adverse event unrelated to study drug
    1
    -
         Study Drug Toxicity
    -
    4
         Participant Withdrew Consent
    -
    1
         Disease Progression
    2
    1
    Period 3
    Period 3 title
    Maintenance Phase Part 2
    Is this the baseline period?
    		 No
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Subject, Investigator, Monitor

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Arm A
    Arm description
    		 Concomitant administration of Nivolumab and Ipilimumab every 3 weeks for 4 doses followed by Nivolumab flat dose in the Maintenance Phase
    Arm type
    		 Experimental

    Investigational medicinal product name
    Nivolumab
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Intravenous use
    Dosage and administration details
    480 mg every 4 weeks

    Arm title
    		 Arm B
    Arm description
    		 Sequential administration of Nivolumab and Ipilimumab every 3 weeks for 4 doses followed by Nivolumab flat dose in the Maintenance Phase
    Arm type
    		 Experimental

    Investigational medicinal product name
    Nivolumab
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Intravenous use
    Dosage and administration details
    480 mg every 4 weeks

    Number of subjects in period 3
    		Arm A Arm B
    Started
    20
    22
    Completed
    8
    14
    Not completed
    12
    8
         Maximum Clinical Benefit
    -
    2
         Study Drug Toxicity
    3
    4
         Disease Progression
    9
    2

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Arm A
    Reporting group description
    		 Concomitant administration of Nivolumab and Ipilimumab every 3 weeks for 4 doses followed by Nivolumab flat dose in the Maintenance Phase

    Reporting group title
    Arm B
    Reporting group description
    		 Sequential administration of Nivolumab and Ipilimumab every 3 weeks for 4 doses followed by Nivolumab flat dose in the Maintenance Phase

    Reporting group values
    		 Arm A Arm B Total
    Number of subjects
    		 53 53 106
    Age categorical
    Units: Subjects
        In utero
    		 0 0 0
        Preterm newborn infants (gestational age < 37 wks)
    		 0 0 0
        Newborns (0-27 days)
    		 0 0 0
        Infants and toddlers (28 days-23 months)
    		 0 0 0
        Children (2-11 years)
    		 0 0 0
        Adolescents (12-17 years)
    		 0 0 0
        Adults (18-64 years)
    		 32 35 67
        From 65-84 years
    		 20 18 38
        85 years and over
    		 1 0 1
    Age Continuous
    Units: years
        arithmetic mean (standard deviation)
    		 58.1 ( 14.5 ) 56.3 ( 14.6 ) -
    Sex: Female, Male
    Units: Participants
        Female
    		 18 26 44
        Male
    		 35 27 62
    Race (NIH/OMB)
    Units: Subjects
        American Indian or Alaska Native
    		 0 0 0
        Asian
    		 0 0 0
        Native Hawaiian or Other Pacific Islander
    		 0 0 0
        Black or African American
    		 1 0 1
        White
    		 48 50 98
        More than one race
    		 0 0 0
        Unknown or Not Reported
    		 4 3 7
    Ethnicity (NIH/OMB)
    Units: Subjects
        Hispanic or Latino
    		 1 1 2
        Not Hispanic or Latino
    		 26 28 54
        Unknown or Not Reported
    		 26 24 50

    End points

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    End points reporting groups
    Reporting group title
    Arm A
    Reporting group description
    		 Concomitant administration of Nivolumab and Ipilimumab every 3 weeks for 4 doses followed by Nivolumab flat dose in the Maintenance Phase

    Reporting group title
    Arm B
    Reporting group description
    		 Sequential administration of Nivolumab and Ipilimumab every 3 weeks for 4 doses followed by Nivolumab flat dose in the Maintenance Phase
    Reporting group title
    Arm A
    Reporting group description
    		 Concomitant administration of Nivolumab and Ipilimumab every 3 weeks for 4 doses followed by Nivolumab flat dose in the Maintenance Phase

    Reporting group title
    Arm B
    Reporting group description
    		 Sequential administration of Nivolumab and Ipilimumab every 3 weeks for 4 doses followed by Nivolumab flat dose in the Maintenance Phase
    Reporting group title
    Arm A
    Reporting group description
    		 Concomitant administration of Nivolumab and Ipilimumab every 3 weeks for 4 doses followed by Nivolumab flat dose in the Maintenance Phase

    Reporting group title
    Arm B
    Reporting group description
    		 Sequential administration of Nivolumab and Ipilimumab every 3 weeks for 4 doses followed by Nivolumab flat dose in the Maintenance Phase

    Primary: Percentage of participants affected by Adverse Events (AEs) in the Broad Scope MedDRA Anaphylactic Reaction standardized MedDRA queries (SMQ)

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    End point title
    		 Percentage of participants affected by Adverse Events (AEs) in the Broad Scope MedDRA Anaphylactic Reaction standardized MedDRA queries (SMQ)
    End point description
    This outcome describes the proportion of participants experiencing at least 1 AE in the MedDRA Anaphylactic Reaction broad scope SMQ. Such AEs include any acute systemic reaction characterized by a large list of terms, including (but not limited to) pruritus, urticaria, flushing, hypotension, respiratory distress, and vascular insufficiency. It also includes other signs and symptoms such as asthma, choking sensation, coughing, sneezing, and difficulty breathing due to laryngeal spasm and/or bronchospasm. Less frequent clinical presentations are also captured and include hyperventilation, sensation of foreign body, and ocular edema.
    End point type
    Primary
    End point timeframe
    Within 2 days of dose in part 1 period (assessed up to June 2018, approximately 19 months)
    End point values
    		 Arm A Arm B
    Number of subjects analysed
    53
    53
    Units: Percent of Participants
        number (confidence interval 95%)
    15.1 (6.7 to 27.6)
    18.9 (9.4 to 32.0)
    Statistical analysis title
    		 AEs in the Broad Scope Anaphylactic Reaction SMQ
    Comparison groups
    Arm A v Arm B
    Number of subjects included in analysis
    106
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    Method
    Parameter type
    		 Cochran-Mantel-Haenszel Odds Ratio
    Point estimate
    0.76
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.27
         upper limit
    		 2.13
    Statistical analysis title
    		 AEs in the Broad Scope Anaphylactic Reaction SMQ
    Comparison groups
    Arm A v Arm B
    Number of subjects included in analysis
    106
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    Method
    Parameter type
    		 Percent difference in incidence rates
    Point estimate
    -3.8
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -18.3
         upper limit
    		 10.7

    Secondary: Percentage of participants affected by AEs in the Narrow Scope MedDRA Anaphylactic Reaction SMQ

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    End point title
    		 Percentage of participants affected by AEs in the Narrow Scope MedDRA Anaphylactic Reaction SMQ
    End point description
    This outcome describes the proportion of participants experiencing at least 1 AE in the MedDRA Anaphylactic Reaction narrow scope SMQ. The narrow scope SMQ is composed of a large list of terms, including (but not limited to) anaphylactic shock and reaction, shock and shock symptoms, and circulatory collapse, among the others.
    End point type
    Secondary
    End point timeframe
    Within 2 days of dose in Part 1 period (assessed up to June 2018, approximately 19 months)
    End point values
    		 Arm A Arm B
    Number of subjects analysed
    53
    53
    Units: Percent of Participants
        number (confidence interval 95%)
    0.0 (0.0 to 6.7)
    0.0 (0.0 to 6.7)
    Statistical analysis title
    		 AEs in the Narrow Scope Anaphylactic Reaction SMQ
    Comparison groups
    Arm A v Arm B
    Number of subjects included in analysis
    106
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    Method
    Parameter type
    		 Percent Difference in incidence rates
    Point estimate
    0
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0
         upper limit
    		 0

    Secondary: Percentage of Participants Affected by Hypersensitivity/Infusion Reaction Select AEs

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    End point title
    		 Percentage of Participants Affected by Hypersensitivity/Infusion Reaction Select AEs
    End point description
    This outcome describes the proportion of participants experiencing at least 1 AE in the Hypersensitivity/Infusion select AEs category. The select AEs consist of a list of preferred terms defined by the Sponsor and represent AEs with a potential immune-mediated etiology. The following 5 MedDRA preferred terms are included in the hypersensitivity/infusion reaction select AE category: Anaphylactic Reaction, Anaphylactic Shock, Bronchospasm, Hypersensitivity, and Infusion Related Reaction
    End point type
    Secondary
    End point timeframe
    Within 2 days of dose in part 1 period (assessed up to December 2019, approximately 37 months)
    End point values
    		 Arm A Arm B
    Number of subjects analysed
    53
    53
    Units: Percent of Participants
        number (not applicable)
    7.5
    9.4
    No statistical analyses for this end point

    Secondary: Percentage of participants affected by All Causality Grade 3 - 5 AEs

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    End point title
    		 Percentage of participants affected by All Causality Grade 3 - 5 AEs
    End point description
    This outcome describes the proportion of participants who experienced at least 1 AE of Grade 3 or higher defined using National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) version 4.0 criteria
    End point type
    Secondary
    End point timeframe
    From initial dose of study treatment and within 30 days of the last dose of study treatment (assessed up to December 2019, approximately 37 months)
    End point values
    		 Arm A Arm B
    Number of subjects analysed
    53
    53
    Units: Percent of participants
        number (not applicable)
    69.8
    56.6
    No statistical analyses for this end point

    Secondary: Percentage of participants affected by Drug-related Grade 3 - 5 AEs

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    End point title
    		 Percentage of participants affected by Drug-related Grade 3 - 5 AEs
    End point description
    This outcome describes the proportion of participants who experienced at least 1 Drug-related AE of Grade 3 or higher defined using National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) version 4.0 criteria
    End point type
    Secondary
    End point timeframe
    From initial dose of study treatment and within 30 days of the last dose of study treatment (assessed up to December 2019, approximately 37 months)
    End point values
    		 Arm A Arm B
    Number of subjects analysed
    53
    53
    Units: Percent of participants
        number (not applicable)
    58.5
    47.2
    No statistical analyses for this end point

    Secondary: Geometric Mean Concentration of Ipilimumab at End of Infusion (EOI)

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    End point title
    		 Geometric Mean Concentration of Ipilimumab at End of Infusion (EOI)
    End point description
    End point type
    Secondary
    End point timeframe
    From Cycle 1, Day 1 to Cycle 4, Day 1 (approximately 9 weeks). Each cycle lasts 3 weeks. Cycle 1 day 1, Cycle 2 day 1 and Cycle 4 day 1 values reported.
    End point values
    		 Arm A Arm B
    Number of subjects analysed
    53
    53
    Units: micrograms per milliliter (ug/mL)
    geometric mean (geometric coefficient of variation)
        Cycle 1 Day 1
    60.4 ( 93.0 )
    61.5 ( 72.3 )
        Cycle 2 Day 1
    66.8 ( 134 )
    72.1 ( 71.8 )
        Cycle 4 Day 1
    77.9 ( 94.2 )
    84.6 ( 104 )
    No statistical analyses for this end point

    Secondary: Geometric Mean Concentration of Nivolumab at End of Infusion (EOI)

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    End point title
    		 Geometric Mean Concentration of Nivolumab at End of Infusion (EOI)
    End point description
    End point type
    Secondary
    End point timeframe
    From Cycle 1, Day 1 to Cycle 4, Day 1 (approximately 9 weeks). Each cycle lasts 3 weeks. Cycle 1 day 1, Cycle 2 day 1 and Cycle 4 day 1 values reported
    End point values
    		 Arm A Arm B
    Number of subjects analysed
    53
    53
    Units: micrograms per milliliter (ug/mL)
    geometric mean (geometric coefficient of variation)
        Cycle 1 Day 1
    20.9 ( 77.3 )
    21.8 ( 117 )
        Cycle 2 Day 1
    24.2 ( 122 )
    22.4 ( 101 )
        Cycle 4 Day 1
    27.9 ( 79.8 )
    27.4 ( 79.9 )
    No statistical analyses for this end point

    Secondary: Geometric Mean Trough Concentration of Ipilimumab

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    End point title
    		 Geometric Mean Trough Concentration of Ipilimumab
    End point description
    End point type
    Secondary
    End point timeframe
    From Cycle 2, Day 1 to Cycle 4, Day 1 (approximately 6 weeks). Each cycle lasts 3 weeks.
    End point values
    		 Arm A Arm B
    Number of subjects analysed
    53
    53
    Units: micrograms per milliliter (ug/mL)
    geometric mean (geometric coefficient of variation)
        Cycle 2 Day 1
    10.8 ( 30.2 )
    9.94 ( 38.9 )
        Cycle 4 Day 1
    16.5 ( 36.9 )
    13.7 ( 46.0 )
    No statistical analyses for this end point

    Secondary: Geometric Mean Trough Concentration of Nivolumab

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    End point title
    		 Geometric Mean Trough Concentration of Nivolumab
    End point description
    End point type
    Secondary
    End point timeframe
    From Cycle 2, Day 1 to Cycle 4, Day 1 (approximately 6 weeks). Each cycle lasts 3 weeks.
    End point values
    		 Arm A Arm B
    Number of subjects analysed
    53
    53
    Units: micrograms per milliliter (ug/mL)
    geometric mean (geometric coefficient of variation)
        Cycle 2 Day 1
    3.94 ( 56.6 )
    2.75 ( 65.9 )
        Cycle 4 Day 1
    6.50 ( 44.6 )
    4.05 ( 75.3 )
    No statistical analyses for this end point

    Secondary: Objective Response Rate (ORR)

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    End point title
    		 Objective Response Rate (ORR)
    End point description
    The ORR is defined as the proportion of participants with a Best Overall Response (BOR) of Complete Response (CR) or Partial Response (PR). The BOR is defined as the best response designation, as determined by the investigator, recorded between the date of randomization and the date of objectively documented progression per RECIST 1.1 or the date of subsequent anti-cancer therapy, whichever occurs first.
    End point type
    Secondary
    End point timeframe
    Week 12 following randomization, every 8 weeks for the first 12 months and then every 12 weeks until disease progression
    End point values
    		 Arm A Arm B
    Number of subjects analysed
    53
    53
    Units: Percentage of Participants
        number (confidence interval 95%)
    52.8 (38.6 to 66.7)
    60.4 (46.0 to 73.5)
    Statistical analysis title
    		 ORR
    Comparison groups
    Arm A v Arm B
    Number of subjects included in analysis
    106
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    Method
    Parameter type
    		 Difference of ORRs
    Point estimate
    -7.5
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -26.1
         upper limit
    		 11
    Statistical analysis title
    		 ORR
    Comparison groups
    Arm A v Arm B
    Number of subjects included in analysis
    106
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    Method
    Parameter type
    		 Odds ratio (OR)
    Point estimate
    0.75
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.35
         upper limit
    		 1.58

    Secondary: Progression Free Survival (PFS)

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    End point title
    		 Progression Free Survival (PFS)
    End point description
    PFS is defined as the time between the date of randomization and the first date of documented progression, as determined by the investigator, or death due to any cause, whichever occurs first.
    End point type
    Secondary
    End point timeframe
    From the date of randomization to the first date of documented progression (assessed up to December 2019, approximately 37 months)
    End point values
    		 Arm A Arm B
    Number of subjects analysed
    53
    53
    Units: Months
        median (confidence interval 95%)
    10.25 (2.96 to 9999)
    9999 (4.96 to 9999)
    Statistical analysis title
    		 PFS
    Comparison groups
    Arm A v Arm B
    Number of subjects included in analysis
    106
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    Method
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    1.36
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.78
         upper limit
    		 2.37

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Adverse events were reported from start of treatment up to 30 days after last treatment.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    22.1
    Reporting groups
    Reporting group title
    Fixed Ratio Combination
    Reporting group description
    		 Subjects were infused with a fixed dose of BMS-986214 for 60 minutes for 6 weeks in Part 1 followed by nivolumab flat dose (480 mg, 30 minute infusion) in Part 2 until progression or unacceptable toxicity.

    Reporting group title
    Sequential Combination
    Reporting group description
    		 Subjects were administered nivolumab and ipilimumab sequentially, as two separate infusions, one 60 minute nivolumab infusion and one 90 minute ipilimumab infusion with a 30 minute break between each infusion for 6 weeks in Part 1 followed by nivolumab flat dose (480 mg, 30 minute infusion) in Part 2 until progression or unacceptable toxicity.

    Serious adverse events
    		 Fixed Ratio Combination Sequential Combination
    Total subjects affected by serious adverse events
         subjects affected / exposed
    29 / 53 (54.72%)
    26 / 53 (49.06%)
         number of deaths (all causes)
    14
    14
         number of deaths resulting from adverse events
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Basal cell carcinoma
         subjects affected / exposed
    1 / 53 (1.89%)
    0 / 53 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Malignant neoplasm progression
         subjects affected / exposed
    2 / 53 (3.77%)
    1 / 53 (1.89%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Vascular disorders
    Thrombosis
         subjects affected / exposed
    0 / 53 (0.00%)
    1 / 53 (1.89%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Adverse drug reaction
         subjects affected / exposed
    1 / 53 (1.89%)
    0 / 53 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Chest pain
         subjects affected / exposed
    1 / 53 (1.89%)
    0 / 53 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    General physical health deterioration
         subjects affected / exposed
    1 / 53 (1.89%)
    0 / 53 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Oedema peripheral
         subjects affected / exposed
    1 / 53 (1.89%)
    0 / 53 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pyrexia
         subjects affected / exposed
    7 / 53 (13.21%)
    0 / 53 (0.00%)
         occurrences causally related to treatment / all
    5 / 7
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Immune system disorders
    Autoimmune disorder
         subjects affected / exposed
    0 / 53 (0.00%)
    1 / 53 (1.89%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    1 / 53 (1.89%)
    0 / 53 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Dyspnoea
         subjects affected / exposed
    0 / 53 (0.00%)
    3 / 53 (5.66%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonitis
         subjects affected / exposed
    1 / 53 (1.89%)
    1 / 53 (1.89%)
         occurrences causally related to treatment / all
    1 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pulmonary embolism
         subjects affected / exposed
    0 / 53 (0.00%)
    1 / 53 (1.89%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Investigations
    Alanine aminotransferase increased
         subjects affected / exposed
    1 / 53 (1.89%)
    1 / 53 (1.89%)
         occurrences causally related to treatment / all
    2 / 2
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Aspartate aminotransferase increased
         subjects affected / exposed
    0 / 53 (0.00%)
    1 / 53 (1.89%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pancreatic enzymes increased
         subjects affected / exposed
    1 / 53 (1.89%)
    0 / 53 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Transaminases increased
         subjects affected / exposed
    0 / 53 (0.00%)
    1 / 53 (1.89%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Infusion related reaction
         subjects affected / exposed
    0 / 53 (0.00%)
    1 / 53 (1.89%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac disorders
    Angina pectoris
         subjects affected / exposed
    1 / 53 (1.89%)
    0 / 53 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Atrial fibrillation
         subjects affected / exposed
    0 / 53 (0.00%)
    1 / 53 (1.89%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nervous system disorders
    Facial paralysis
         subjects affected / exposed
    0 / 53 (0.00%)
    1 / 53 (1.89%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Headache
         subjects affected / exposed
    1 / 53 (1.89%)
    0 / 53 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Spinal cord compression
         subjects affected / exposed
    1 / 53 (1.89%)
    0 / 53 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Guillain-Barre syndrome
         subjects affected / exposed
    1 / 53 (1.89%)
    0 / 53 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Motor neurone disease
         subjects affected / exposed
    1 / 53 (1.89%)
    0 / 53 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Eye disorders
    Iridocyclitis
         subjects affected / exposed
    1 / 53 (1.89%)
    0 / 53 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Abdominal pain upper
         subjects affected / exposed
    1 / 53 (1.89%)
    1 / 53 (1.89%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Autoimmune colitis
         subjects affected / exposed
    2 / 53 (3.77%)
    1 / 53 (1.89%)
         occurrences causally related to treatment / all
    2 / 2
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Colitis
         subjects affected / exposed
    3 / 53 (5.66%)
    3 / 53 (5.66%)
         occurrences causally related to treatment / all
    3 / 3
    4 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cyclic vomiting syndrome
         subjects affected / exposed
    1 / 53 (1.89%)
    0 / 53 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Diarrhoea
         subjects affected / exposed
    1 / 53 (1.89%)
    1 / 53 (1.89%)
         occurrences causally related to treatment / all
    1 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Duodenitis
         subjects affected / exposed
    0 / 53 (0.00%)
    1 / 53 (1.89%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Enteritis
         subjects affected / exposed
    0 / 53 (0.00%)
    1 / 53 (1.89%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Erosive duodenitis
         subjects affected / exposed
    1 / 53 (1.89%)
    0 / 53 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Intestinal perforation
         subjects affected / exposed
    0 / 53 (0.00%)
    1 / 53 (1.89%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pancreatitis acute
         subjects affected / exposed
    1 / 53 (1.89%)
    0 / 53 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Rectal haemorrhage
         subjects affected / exposed
    1 / 53 (1.89%)
    0 / 53 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vomiting
         subjects affected / exposed
    3 / 53 (5.66%)
    1 / 53 (1.89%)
         occurrences causally related to treatment / all
    2 / 3
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Immune-Mediated enterocolitis
         subjects affected / exposed
    1 / 53 (1.89%)
    1 / 53 (1.89%)
         occurrences causally related to treatment / all
    1 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatobiliary disorders
    Acute hepatic failure
         subjects affected / exposed
    1 / 53 (1.89%)
    0 / 53 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Autoimmune hepatitis
         subjects affected / exposed
    1 / 53 (1.89%)
    0 / 53 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Hepatic function abnormal
         subjects affected / exposed
    0 / 53 (0.00%)
    1 / 53 (1.89%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatitis
         subjects affected / exposed
    2 / 53 (3.77%)
    0 / 53 (0.00%)
         occurrences causally related to treatment / all
    2 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatocellular injury
         subjects affected / exposed
    4 / 53 (7.55%)
    2 / 53 (3.77%)
         occurrences causally related to treatment / all
    5 / 5
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypertransaminasaemia
         subjects affected / exposed
    2 / 53 (3.77%)
    0 / 53 (0.00%)
         occurrences causally related to treatment / all
    3 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal and urinary disorders
    Dysuria
         subjects affected / exposed
    0 / 53 (0.00%)
    1 / 53 (1.89%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Urinary tract obstruction
         subjects affected / exposed
    1 / 53 (1.89%)
    0 / 53 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Endocrine disorders
    Hypophysitis
         subjects affected / exposed
    1 / 53 (1.89%)
    0 / 53 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Thyroiditis
         subjects affected / exposed
    1 / 53 (1.89%)
    1 / 53 (1.89%)
         occurrences causally related to treatment / all
    1 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    2 / 53 (3.77%)
    1 / 53 (1.89%)
         occurrences causally related to treatment / all
    2 / 3
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Haematoma muscle
         subjects affected / exposed
    1 / 53 (1.89%)
    0 / 53 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infections and infestations
    Lower respiratory tract infection
         subjects affected / exposed
    1 / 53 (1.89%)
    0 / 53 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Meningitis aseptic
         subjects affected / exposed
    0 / 53 (0.00%)
    1 / 53 (1.89%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Parotitis
         subjects affected / exposed
    1 / 53 (1.89%)
    0 / 53 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonia
         subjects affected / exposed
    1 / 53 (1.89%)
    0 / 53 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory tract infection
         subjects affected / exposed
    0 / 53 (0.00%)
    1 / 53 (1.89%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Urinary tract infection
         subjects affected / exposed
    1 / 53 (1.89%)
    1 / 53 (1.89%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Urosepsis
         subjects affected / exposed
    0 / 53 (0.00%)
    1 / 53 (1.89%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Dehydration
         subjects affected / exposed
    0 / 53 (0.00%)
    1 / 53 (1.89%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Fixed Ratio Combination Sequential Combination
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    46 / 53 (86.79%)
    50 / 53 (94.34%)
    General disorders and administration site conditions
    Asthenia
         subjects affected / exposed
    11 / 53 (20.75%)
    15 / 53 (28.30%)
         occurrences all number
    12
    17
    Chills
         subjects affected / exposed
    3 / 53 (5.66%)
    4 / 53 (7.55%)
         occurrences all number
    3
    4
    Fatigue
         subjects affected / exposed
    9 / 53 (16.98%)
    8 / 53 (15.09%)
         occurrences all number
    9
    9
    Influenza like illness
         subjects affected / exposed
    2 / 53 (3.77%)
    6 / 53 (11.32%)
         occurrences all number
    2
    6
    Pyrexia
         subjects affected / exposed
    14 / 53 (26.42%)
    15 / 53 (28.30%)
         occurrences all number
    16
    19
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    7 / 53 (13.21%)
    3 / 53 (5.66%)
         occurrences all number
    7
    3
    Dyspnoea
         subjects affected / exposed
    2 / 53 (3.77%)
    3 / 53 (5.66%)
         occurrences all number
    2
    3
    Psychiatric disorders
    Insomnia
         subjects affected / exposed
    2 / 53 (3.77%)
    3 / 53 (5.66%)
         occurrences all number
    2
    3
    Investigations
    Alanine aminotransferase increased
         subjects affected / exposed
    7 / 53 (13.21%)
    6 / 53 (11.32%)
         occurrences all number
    11
    7
    Amylase increased
         subjects affected / exposed
    4 / 53 (7.55%)
    2 / 53 (3.77%)
         occurrences all number
    4
    2
    Aspartate aminotransferase increased
         subjects affected / exposed
    5 / 53 (9.43%)
    4 / 53 (7.55%)
         occurrences all number
    7
    4
    Blood lactate dehydrogenase increased
         subjects affected / exposed
    4 / 53 (7.55%)
    3 / 53 (5.66%)
         occurrences all number
    5
    3
    Lipase increased
         subjects affected / exposed
    6 / 53 (11.32%)
    3 / 53 (5.66%)
         occurrences all number
    6
    4
    Gamma-Glutamyltransferase increased
         subjects affected / exposed
    3 / 53 (5.66%)
    1 / 53 (1.89%)
         occurrences all number
    4
    1
    Injury, poisoning and procedural complications
    Infusion related reaction
         subjects affected / exposed
    4 / 53 (7.55%)
    3 / 53 (5.66%)
         occurrences all number
    7
    3
    Nervous system disorders
    Dizziness
         subjects affected / exposed
    2 / 53 (3.77%)
    3 / 53 (5.66%)
         occurrences all number
    2
    4
    Headache
         subjects affected / exposed
    8 / 53 (15.09%)
    10 / 53 (18.87%)
         occurrences all number
    9
    12
    Paraesthesia
         subjects affected / exposed
    2 / 53 (3.77%)
    4 / 53 (7.55%)
         occurrences all number
    2
    4
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    2 / 53 (3.77%)
    4 / 53 (7.55%)
         occurrences all number
    2
    4
    Gastrointestinal disorders
    Abdominal pain
         subjects affected / exposed
    4 / 53 (7.55%)
    3 / 53 (5.66%)
         occurrences all number
    4
    3
    Abdominal pain upper
         subjects affected / exposed
    2 / 53 (3.77%)
    3 / 53 (5.66%)
         occurrences all number
    2
    3
    Constipation
         subjects affected / exposed
    8 / 53 (15.09%)
    6 / 53 (11.32%)
         occurrences all number
    8
    6
    Diarrhoea
         subjects affected / exposed
    12 / 53 (22.64%)
    22 / 53 (41.51%)
         occurrences all number
    17
    28
    Dry mouth
         subjects affected / exposed
    5 / 53 (9.43%)
    1 / 53 (1.89%)
         occurrences all number
    5
    1
    Nausea
         subjects affected / exposed
    9 / 53 (16.98%)
    11 / 53 (20.75%)
         occurrences all number
    12
    11
    Vomiting
         subjects affected / exposed
    6 / 53 (11.32%)
    8 / 53 (15.09%)
         occurrences all number
    7
    11
    Abdominal distension
         subjects affected / exposed
    3 / 53 (5.66%)
    1 / 53 (1.89%)
         occurrences all number
    3
    1
    Colitis
         subjects affected / exposed
    1 / 53 (1.89%)
    3 / 53 (5.66%)
         occurrences all number
    1
    3
    Hepatobiliary disorders
    Hepatitis
         subjects affected / exposed
    4 / 53 (7.55%)
    2 / 53 (3.77%)
         occurrences all number
    5
    2
    Hepatocellular injury
         subjects affected / exposed
    5 / 53 (9.43%)
    1 / 53 (1.89%)
         occurrences all number
    5
    1
    Skin and subcutaneous tissue disorders
    Erythema
         subjects affected / exposed
    3 / 53 (5.66%)
    4 / 53 (7.55%)
         occurrences all number
    3
    4
    Hyperhidrosis
         subjects affected / exposed
    1 / 53 (1.89%)
    3 / 53 (5.66%)
         occurrences all number
    1
    3
    Lichenoid keratosis
         subjects affected / exposed
    1 / 53 (1.89%)
    3 / 53 (5.66%)
         occurrences all number
    1
    3
    Night sweats
         subjects affected / exposed
    2 / 53 (3.77%)
    5 / 53 (9.43%)
         occurrences all number
    2
    6
    Pruritus
         subjects affected / exposed
    5 / 53 (9.43%)
    11 / 53 (20.75%)
         occurrences all number
    5
    11
    Rash
         subjects affected / exposed
    13 / 53 (24.53%)
    10 / 53 (18.87%)
         occurrences all number
    13
    11
    Rash pruritic
         subjects affected / exposed
    9 / 53 (16.98%)
    6 / 53 (11.32%)
         occurrences all number
    10
    7
    Vitiligo
         subjects affected / exposed
    4 / 53 (7.55%)
    3 / 53 (5.66%)
         occurrences all number
    4
    3
    Endocrine disorders
    Hyperthyroidism
         subjects affected / exposed
    8 / 53 (15.09%)
    6 / 53 (11.32%)
         occurrences all number
    8
    6
    Hypothyroidism
         subjects affected / exposed
    8 / 53 (15.09%)
    3 / 53 (5.66%)
         occurrences all number
    8
    3
    Thyroiditis
         subjects affected / exposed
    2 / 53 (3.77%)
    3 / 53 (5.66%)
         occurrences all number
    2
    3
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    7 / 53 (13.21%)
    3 / 53 (5.66%)
         occurrences all number
    8
    4
    Back pain
         subjects affected / exposed
    3 / 53 (5.66%)
    1 / 53 (1.89%)
         occurrences all number
    3
    1
    Musculoskeletal pain
         subjects affected / exposed
    3 / 53 (5.66%)
    1 / 53 (1.89%)
         occurrences all number
    3
    2
    Myalgia
         subjects affected / exposed
    6 / 53 (11.32%)
    7 / 53 (13.21%)
         occurrences all number
    6
    7
    Infections and infestations
    Urinary tract infection
         subjects affected / exposed
    3 / 53 (5.66%)
    2 / 53 (3.77%)
         occurrences all number
    4
    2
    Metabolism and nutrition disorders
    Decreased appetite
         subjects affected / exposed
    9 / 53 (16.98%)
    6 / 53 (11.32%)
         occurrences all number
    9
    7
    Hypokalaemia
         subjects affected / exposed
    3 / 53 (5.66%)
    2 / 53 (3.77%)
         occurrences all number
    3
    2

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    25 Aug 2017
    - changed the timing of primary endpoint analysis - study duration revised - other minor changes

    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
    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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