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    Clinical Trial Results:
    PHASE 1 STUDY TO COMPARE BEMPEGALDESLEUKIN COMBINED WITH NIVOLUMAB AND TYROSINE KINASE INHIBITOR (TKI) TO NIVOLUMAB AND TKI ALONE IN PARTICIPANTS WITH PREVIOUSLY UNTREATED ADVANCED OR METASTATIC RENAL CELL CARCINOMA (MRCC) (PIVOT IO 011)

    Summary
    EudraCT number
    		 2018-003200-39
    Trial protocol
    		 FR   ES   DE  
    Global end of trial date
    18 Jan 2024

    Results information
    Results version number
    		 v1(current)
    This version publication date
    18 Jan 2025
    First version publication date
    18 Jan 2025
    Other versions

    Trial information

    		 Close Top of page
    Trial identification
    Sponsor protocol code
    CA045-011
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 -
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Bristol-Myers Squibb International Corporation
    Sponsor organisation address
    Chaussée 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
    EU Study Start-Up Unit, 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
    18 Jan 2024
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    18 Jan 2024
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To evaluate safety, tolerability, DLTs, and RP2D of nivolumab, bempegaldesleukin, and axitinib combination. To evaluate safety, tolerability, DLTs, and RP2D of nivolumab, bempegaldesleukin, and cabozantinib combination.
    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
    01 Sep 2020
    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
    Canada: 2
    Country: Number of subjects enrolled
    United States: 28
    Worldwide total number of subjects
    30
    EEA total number of subjects
    0
    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)
    23
    From 65 to 84 years
    7
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 -

    Pre-assignment
    Screening details
    		 30 subjects enrolled and treated

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

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Part 1A: Treatment 1
    Arm description
    		 Nivolumab 360 mg IV Q3W + bempegaldesleukin 0.006 mg/kg IV Q3W combined with Axitinib 5 mg Oral BID
    Arm type
    		 Experimental

    Investigational medicinal product name
    nivolumab
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Intravascular use
    Dosage and administration details
    100 mg (10 mg/mL)

    Investigational medicinal product name
    bempegaldesleukin
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Intravascular use
    Dosage and administration details
    1 mg of rhIL-2 per vial

    Investigational medicinal product name
    axitinib
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    1 mg, 5 mg or various strengths

    Arm title
    		 Part 1A: Treatment 2
    Arm description
    		 Nivolumab 360 mg IV Q3W + bempegaldesleukin 0.006 mg/kg IV Q3W combined with Axitinib 3 mg Oral BID
    Arm type
    		 Experimental

    Investigational medicinal product name
    nivolumab
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Intravascular use
    Dosage and administration details
    100 mg (10 mg/mL)

    Investigational medicinal product name
    axitinib
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    1 mg, 5 mg or various strengths

    Investigational medicinal product name
    bempegaldesleukin
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Intravascular use
    Dosage and administration details
    1 mg of rhIL-2 per vial

    Arm title
    		 Part 1B: Treatment 1
    Arm description
    		 Nivolumab 360 mg IV Q3W + bempegaldesleukin 0.006 mg/kg IV Q3W combined with Cabozantinib 40mg Oral QD
    Arm type
    		 Experimental

    Investigational medicinal product name
    cabozantinib
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    20 mg, 40 mg or various strengths

    Investigational medicinal product name
    bempegaldesleukin
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Intravascular use
    Dosage and administration details
    1 mg of rhIL-2 per vial

    Investigational medicinal product name
    nivolumab
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Intravascular use
    Dosage and administration details
    100 mg (10 mg/mL)

    Arm title
    		 Part 1B: Treatment 2
    Arm description
    		 Nivolumab 360 mg IV Q3W + bempegaldesleukin 0.006 mg/kg IV Q3W combined with Cabozantinib 20mg Oral QD
    Arm type
    		 Experimental

    Investigational medicinal product name
    nivolumab
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Intravascular use
    Dosage and administration details
    100 mg (10 mg/mL)

    Investigational medicinal product name
    cabozantinib
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    20 mg, 40 mg or various strengths

    Investigational medicinal product name
    bempegaldesleukin
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Intravascular use
    Dosage and administration details
    1 mg of rhIL-2 per vial

    Number of subjects in period 1
    		Part 1A: Treatment 1 Part 1A: Treatment 2 Part 1B: Treatment 1 Part 1B: Treatment 2
    Started
    7
    8
    7
    8
    Completed
    0
    0
    0
    0
    Not completed
    7
    8
    7
    8
         Consent withdrawn by subject
    -
    -
    -
    1
         Other Reasons
    -
    -
    7
    1
         Death
    1
    3
    -
    -
         Follow-up no longer required per protocol
    6
    5
    -
    6

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Part 1A: Treatment 1
    Reporting group description
    		 Nivolumab 360 mg IV Q3W + bempegaldesleukin 0.006 mg/kg IV Q3W combined with Axitinib 5 mg Oral BID

    Reporting group title
    Part 1A: Treatment 2
    Reporting group description
    		 Nivolumab 360 mg IV Q3W + bempegaldesleukin 0.006 mg/kg IV Q3W combined with Axitinib 3 mg Oral BID

    Reporting group title
    Part 1B: Treatment 1
    Reporting group description
    		 Nivolumab 360 mg IV Q3W + bempegaldesleukin 0.006 mg/kg IV Q3W combined with Cabozantinib 40mg Oral QD

    Reporting group title
    Part 1B: Treatment 2
    Reporting group description
    		 Nivolumab 360 mg IV Q3W + bempegaldesleukin 0.006 mg/kg IV Q3W combined with Cabozantinib 20mg Oral QD

    Reporting group values
    		 Part 1A: Treatment 1 Part 1A: Treatment 2 Part 1B: Treatment 1 Part 1B: Treatment 2 Total
    Number of subjects
    		 7 8 7 8 30
    Age Categorical
    Units: Participants
        Adults (18-64 years)
    		 5 7 4 7 23
        From 65-84 years
    		 2 1 3 1 7
    Age Continuous
    Units: years
        arithmetic mean (standard deviation)
    		 58.7 ( 16.16 ) 57.0 ( 7.67 ) 63.4 ( 6.58 ) 59.5 ( 6.50 ) -
    Sex: Female, Male
    Units: Participants
        Female
    		 1 2 2 1 6
        Male
    		 6 6 5 7 24
    Race
    Units: Subjects
        White
    		 6 8 7 7 28
        Black or African American
    		 1 0 0 0 1
        Other
    		 0 0 0 1 1
    Ethnicity
    Units: Subjects
        Hispanic or Latino
    		 1 0 0 0 1
        Not Hispanic or Latino
    		 6 8 7 7 28
        Not Reported
    		 0 0 0 1 1

    End points

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    End points reporting groups
    Reporting group title
    Part 1A: Treatment 1
    Reporting group description
    		 Nivolumab 360 mg IV Q3W + bempegaldesleukin 0.006 mg/kg IV Q3W combined with Axitinib 5 mg Oral BID

    Reporting group title
    Part 1A: Treatment 2
    Reporting group description
    		 Nivolumab 360 mg IV Q3W + bempegaldesleukin 0.006 mg/kg IV Q3W combined with Axitinib 3 mg Oral BID

    Reporting group title
    Part 1B: Treatment 1
    Reporting group description
    		 Nivolumab 360 mg IV Q3W + bempegaldesleukin 0.006 mg/kg IV Q3W combined with Cabozantinib 40mg Oral QD

    Reporting group title
    Part 1B: Treatment 2
    Reporting group description
    		 Nivolumab 360 mg IV Q3W + bempegaldesleukin 0.006 mg/kg IV Q3W combined with Cabozantinib 20mg Oral QD

    Primary: Number of Subjects with Adverse Events

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    End point title
    		 Number of Subjects with Adverse Events [1]
    End point description
    Number of Subjects with Adverse Events. 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. Here "99999" represents NA
    End point type
    Primary
    End point timeframe
    From first dose to 100 days post last dose (Approximately 27 months)
    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: No Statistical Analysis for this endpoint
    End point values
    		 Part 1A: Treatment 1 Part 1A: Treatment 2 Part 1B: Treatment 1 Part 1B: Treatment 2
    Number of subjects analysed
    7
    8
    7
    8
    Units: Subjects
        Any Grade
    7
    8
    7
    8
        Grade 3 to 4
    99999
    99999
    99999
    99999
    No statistical analyses for this end point

    Primary: Number of Subjects with Serious Adverse Events

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    End point title
    		 Number of Subjects with Serious Adverse Events [2]
    End point description
    Is life-threatening (defined as an event in which the participant was at risk of death at the time of the event; it does not refer to an event which might have caused death if it were more severe).
    End point type
    Primary
    End point timeframe
    From first dose to 100 days post last dose (Approximately 27 months)
    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: No Statistical Analysis for this endpoint
    End point values
    		 Part 1A: Treatment 1 Part 1A: Treatment 2 Part 1B: Treatment 1 Part 1B: Treatment 2
    Number of subjects analysed
    7
    8
    7
    8
    Units: Subjects
        Any Grade
    4
    3
    1
    5
        Grade 3 to 4
    4
    3
    1
    4
    No statistical analyses for this end point

    Primary: Number of Subjects with DLTs

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    End point title
    		 Number of Subjects with DLTs [3]
    End point description
    DLTs will be defined based on the incidence, severity, and duration of AEs, for which no clear alternative cause is identified and that occur within the DLT window of 21 days from initiation of study drug(s). AEs will be graded according to the NCI CTCAE v5. For the purpose of participant management, potential DLTs that occur at any time, whether during dose escalation or after, will result in all study drug(s) being held pending evaluation of the event’s relatedness to study drug, severity and duration.
    End point type
    Primary
    End point timeframe
    From first dose to 100 days post last dose (Approximately 25 months)
    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: No Statistical Analysis for this endpoint
    End point values
    		 Part 1A: Treatment 1 Part 1A: Treatment 2 Part 1B: Treatment 1 Part 1B: Treatment 2
    Number of subjects analysed
    7
    8
    7
    8
    Units: Subjects
    0
    0
    0
    0
    No statistical analyses for this end point

    Primary: Number of Subjects with AEs leading to discontinuation

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    End point title
    		 Number of Subjects with AEs leading to discontinuation [4]
    End point description
    Number of Subjects with AEs leading to discontinuation
    End point type
    Primary
    End point timeframe
    From first dose to 100 days post last dose (Approximately 27 months)
    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: No Statistical Analysis for this endpoint
    End point values
    		 Part 1A: Treatment 1 Part 1A: Treatment 2 Part 1B: Treatment 1 Part 1B: Treatment 2
    Number of subjects analysed
    7
    8
    7
    8
    Units: Subjects
        Any Grade
    2
    3
    1
    4
        Grade 3 to 4
    1
    2
    0
    3
    No statistical analyses for this end point

    Primary: Number of subjects with immune-mediated AEs

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    End point title
    		 Number of subjects with immune-mediated AEs [5]
    End point description
    Number of subjects with immune-mediated AEs
    End point type
    Primary
    End point timeframe
    From first dose to 100 days post last dose (Approximately 27 months)
    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: No Statistical Analysis for this endpoint
    End point values
    		 Part 1A: Treatment 1 Part 1A: Treatment 2 Part 1B: Treatment 1 Part 1B: Treatment 2
    Number of subjects analysed
    7
    8
    7
    8
    Units: Subjects
        Any Grade
    0
    2
    0
    0
        Grade 3 to 4
    0
    0
    0
    0
        Grade 5
    0
    0
    0
    0
    No statistical analyses for this end point

    Primary: Number of Subjects with Clinical Laboratory Abnormalities

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    End point title
    		 Number of Subjects with Clinical Laboratory Abnormalities [6]
    End point description
    Number of Subjects with Clinical Laboratory Abnormalities
    End point type
    Primary
    End point timeframe
    From first dose to 100 days post last dose (Approximately 27 months)
    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: No Statistical Analysis for this endpoint
    End point values
    		 Part 1A: Treatment 1 Part 1A: Treatment 2 Part 1B: Treatment 1 Part 1B: Treatment 2
    Number of subjects analysed
    7
    8
    7
    8
    Units: Subjects
        Hemoglobin|Grade 0
    1
    4
    0
    4
        Platelet Count|Grade 0
    7
    7
    7
    6
        Leukocytes|Grade 0
    7
    8
    6
    6
        Lymphocytes (Absolute)|Grade 0
    6
    5
    3
    8
        Absolute Neutrophil Count|Grade 0
    6
    7
    5
    4
        Alakaline Phosphatase|Grade 0
    4
    5
    4
    5
        Aspartate Aminotransferase|Grade 0
    4
    7
    3
    4
        Alanine Amino Transferase|Grade 0
    4
    5
    0
    2
        Bilirubin Total|Grade 0
    4
    7
    7
    6
        Creatine|Grade 0
    1
    1
    1
    1
        Hypernatremia|Grade 0
    6
    8
    7
    8
        Hyopnatremia|Grade 0
    2
    3
    3
    4
        Hyperkalemia|Grade 0
    5
    6
    6
    7
        Hypokalemia|Grade 0
    6
    7
    7
    8
        Hypercalcemia|Grade 0
    5
    7
    6
    6
        Hypocalcemia|Grade 0
    6
    6
    7
    7
        Hypermagnesemia|Grade 0
    7
    8
    6
    8
        Hypomagnesemia|Grade 0
    6
    7
    5
    8
        Hypoglycemia|Grade 0
    7
    7
    7
    6
        Hemoglobin|Grade 1
    5
    2
    6
    4
        Platelet Count|Grade 1
    0
    1
    0
    2
        Leukocytes|Grade 1
    0
    0
    1
    2
        Lymphocytes (Absolute)|Grade 1
    1
    2
    2
    0
        Absolute Neutrophil Count|Grade 1
    1
    0
    2
    2
        Alakaline Phosphatase|Grade 1
    3
    3
    3
    3
        Aspartate Aminotransferase|Grade 1
    3
    0
    4
    4
        Alanine Amino Transferase|Grade 1
    3
    2
    7
    5
        Bilirubin Total|Grade 1
    2
    1
    0
    2
        Creatine|Grade 1
    4
    5
    5
    7
        Hypernatremia|Grade 1
    1
    0
    0
    0
        Hyopnatremia|Grade 1
    5
    5
    4
    4
        Hyperkalemia|Grade 1
    2
    1
    1
    1
        Hypokalemia|Grade 1
    1
    1
    0
    0
        Hypercalcemia|Grade 1
    1
    1
    1
    2
        Hypocalcemia|Grade 1
    1
    2
    0
    1
        Hypermagnesemia|Grade 1
    0
    0
    1
    0
        Hypomagnesemia|Grade 1
    1
    1
    2
    0
        Hypoglycemia|Grade 1
    0
    1
    0
    2
        Hemoglobin|Grade 2
    1
    2
    1
    0
        Platelet Count|Grade 2
    0
    0
    0
    0
        Leukocytes|Grade 2
    0
    0
    0
    0
        Lymphocytes (Absolute)|Grade 2
    0
    0
    1
    0
        Absolute Neutrophil Count|Grade 2
    0
    0
    0
    1
        Alakaline Phosphatase|Grade 2
    0
    0
    0
    0
        Aspartate Aminotransferase|Grade 2
    0
    1
    0
    0
        Alanine Amino Transferase|Grade 2
    0
    0
    0
    1
        Bilirubin Total|Grade 2
    1
    0
    0
    0
        Creatine|Grade 2
    2
    2
    1
    0
        Hypernatremia|Grade 2
    0
    0
    0
    0
        Hyopnatremia|Grade 2
    0
    0
    0
    0
        Hyperkalemia|Grade 2
    0
    1
    0
    0
        Hypokalemia|Grade 2
    0
    0
    0
    0
        Hypercalcemia|Grade 2
    1
    0
    0
    0
        Hypocalcemia|Grade 2
    0
    0
    0
    0
        Hypermagnesemia|Grade 2
    0
    0
    0
    0
        Hypomagnesemia|Grade 2
    0
    0
    0
    0
        Hypoglycemia|Grade 2
    0
    0
    0
    0
        Hemoglobin|Grade 3
    0
    0
    0
    0
        Platelet Count|Grade 3
    0
    0
    0
    0
        Leukocytes|Grade 3
    0
    0
    0
    0
        Lymphocytes (Absolute)|Grade 3
    0
    1
    1
    0
        Absolute Neutrophil Count|Grade 3
    0
    1
    0
    1
        Alakaline Phosphatase|Grade 3
    0
    0
    0
    0
        Aspartate Aminotransferase|Grade 3
    0
    0
    0
    0
        Alanine Amino Transferase|Grade 3
    0
    1
    0
    0
        Bilirubin Total|Grade 3
    0
    0
    0
    0
        Creatine|Grade 3
    0
    0
    0
    0
        Hypernatremia|Grade 3
    0
    0
    0
    0
        Hyopnatremia|Grade 3
    0
    0
    0
    0
        Hyperkalemia|Grade 3
    0
    0
    0
    0
        Hypokalemia|Grade 3
    0
    0
    0
    0
        Hypercalcemia|Grade 3
    0
    0
    0
    0
        Hypocalcemia|Grade 3
    0
    0
    0
    0
        Hypermagnesemia|Grade 3
    0
    0
    0
    0
        Hypomagnesemia|Grade 3
    0
    0
    0
    0
        Hypoglycemia|Grade 3
    0
    0
    0
    0
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Adverse Events and Serious Adverse Events: (From first dose to last dose + 100 days): Approximately 27 Months All-Cause mortality (From randomization to end of study): Approximately 40 Months
    Adverse event reporting additional description
    The number at Risk for All-Cause Mortality represents all Randomized Participants. The number at Risk for Serious Adverse Events and Other (Not Including Serious) Adverse Events 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
    MedDRA26.1
    Reporting groups
    Reporting group title
    Part 1A: Treatment 1
    Reporting group description
    		 Nivolumab 360 mg IV Q3W + bempegaldesleukin 0.006 mg/kg IV Q3W combined with Axitinib 5 mg Oral BID

    Reporting group title
    Part 1B: Treatment 2
    Reporting group description
    		 Nivolumab 360 mg IV Q3W + bempegaldesleukin 0.006 mg/kg IV Q3W combined with Cabozantinib 20mg Oral QD

    Reporting group title
    Part 1B: Treatment 1
    Reporting group description
    		 Nivolumab 360 mg IV Q3W + bempegaldesleukin 0.006 mg/kg IV Q3W combined with Cabozantinib 40mg Oral QD

    Reporting group title
    Part 1A: Treatment 2
    Reporting group description
    		 Nivolumab 360 mg IV Q3W + bempegaldesleukin 0.006 mg/kg IV Q3W combined with Axitinib 3 mg Oral BID

    Serious adverse events
    		 Part 1A: Treatment 1 Part 1B: Treatment 2 Part 1B: Treatment 1 Part 1A: Treatment 2
    Total subjects affected by serious adverse events
         subjects affected / exposed
    4 / 7 (57.14%)
    5 / 8 (62.50%)
    1 / 7 (14.29%)
    3 / 8 (37.50%)
         number of deaths (all causes)
    3
    1
    0
    3
         number of deaths resulting from adverse events
    Injury, poisoning and procedural complications
    Infusion related reaction
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 8 (0.00%)
    0 / 7 (0.00%)
    1 / 8 (12.50%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Vascular disorders
    Capillary leak syndrome
         subjects affected / exposed
    0 / 7 (0.00%)
    2 / 8 (25.00%)
    0 / 7 (0.00%)
    0 / 8 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    2 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hypertension
         subjects affected / exposed
    1 / 7 (14.29%)
    0 / 8 (0.00%)
    0 / 7 (0.00%)
    0 / 8 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cardiac disorders
    Myocardial infarction
         subjects affected / exposed
    0 / 7 (0.00%)
    1 / 8 (12.50%)
    0 / 7 (0.00%)
    0 / 8 (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
    Nervous system disorders
    Cerebrovascular accident
         subjects affected / exposed
    0 / 7 (0.00%)
    1 / 8 (12.50%)
    0 / 7 (0.00%)
    0 / 8 (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
    Syncope
         subjects affected / exposed
    1 / 7 (14.29%)
    0 / 8 (0.00%)
    0 / 7 (0.00%)
    0 / 8 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Gastrointestinal fistula
         subjects affected / exposed
    0 / 7 (0.00%)
    1 / 8 (12.50%)
    0 / 7 (0.00%)
    0 / 8 (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
    Diarrhoea
         subjects affected / exposed
    1 / 7 (14.29%)
    0 / 8 (0.00%)
    0 / 7 (0.00%)
    0 / 8 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Abdominal pain
         subjects affected / exposed
    0 / 7 (0.00%)
    1 / 8 (12.50%)
    0 / 7 (0.00%)
    0 / 8 (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
    Haematochezia
         subjects affected / exposed
    1 / 7 (14.29%)
    0 / 8 (0.00%)
    0 / 7 (0.00%)
    0 / 8 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Asthma
         subjects affected / exposed
    1 / 7 (14.29%)
    0 / 8 (0.00%)
    0 / 7 (0.00%)
    0 / 8 (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
    Haemoptysis
         subjects affected / exposed
    1 / 7 (14.29%)
    0 / 8 (0.00%)
    0 / 7 (0.00%)
    0 / 8 (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
    Hypoxia
         subjects affected / exposed
    0 / 7 (0.00%)
    1 / 8 (12.50%)
    0 / 7 (0.00%)
    0 / 8 (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
    Pulmonary embolism
         subjects affected / exposed
    2 / 7 (28.57%)
    0 / 8 (0.00%)
    0 / 7 (0.00%)
    0 / 8 (0.00%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Respiratory failure
         subjects affected / exposed
    1 / 7 (14.29%)
    0 / 8 (0.00%)
    0 / 7 (0.00%)
    0 / 8 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Renal and urinary disorders
    Acute kidney injury
         subjects affected / exposed
    1 / 7 (14.29%)
    0 / 8 (0.00%)
    0 / 7 (0.00%)
    1 / 8 (12.50%)
         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
    Musculoskeletal and connective tissue disorders
    Muscular weakness
         subjects affected / exposed
    1 / 7 (14.29%)
    0 / 8 (0.00%)
    0 / 7 (0.00%)
    0 / 8 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Neck pain
         subjects affected / exposed
    1 / 7 (14.29%)
    0 / 8 (0.00%)
    0 / 7 (0.00%)
    0 / 8 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Infections and infestations
    Clostridium difficile infection
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 8 (0.00%)
    0 / 7 (0.00%)
    1 / 8 (12.50%)
         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
    Sepsis
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 8 (0.00%)
    0 / 7 (0.00%)
    1 / 8 (12.50%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Urinary tract infection
         subjects affected / exposed
    1 / 7 (14.29%)
    0 / 8 (0.00%)
    0 / 7 (0.00%)
    1 / 8 (12.50%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Dehydration
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 8 (0.00%)
    1 / 7 (14.29%)
    0 / 8 (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
    Decreased appetite
         subjects affected / exposed
    1 / 7 (14.29%)
    0 / 8 (0.00%)
    0 / 7 (0.00%)
    0 / 8 (0.00%)
         occurrences causally related to treatment / all
    2 / 2
    0 / 0
    0 / 0
    0 / 0
         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
    		 Part 1A: Treatment 1 Part 1B: Treatment 2 Part 1B: Treatment 1 Part 1A: Treatment 2
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    7 / 7 (100.00%)
    8 / 8 (100.00%)
    7 / 7 (100.00%)
    8 / 8 (100.00%)
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Lipoma
         subjects affected / exposed
    1 / 7 (14.29%)
    0 / 8 (0.00%)
    0 / 7 (0.00%)
    0 / 8 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Breast neoplasm
         subjects affected / exposed
    1 / 7 (14.29%)
    0 / 8 (0.00%)
    0 / 7 (0.00%)
    0 / 8 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Vascular disorders
    Hypertension
         subjects affected / exposed
    2 / 7 (28.57%)
    4 / 8 (50.00%)
    3 / 7 (42.86%)
    4 / 8 (50.00%)
         occurrences all number
    5
    4
    4
    11
    Hot flush
         subjects affected / exposed
    1 / 7 (14.29%)
    1 / 8 (12.50%)
    0 / 7 (0.00%)
    2 / 8 (25.00%)
         occurrences all number
    1
    1
    0
    2
    Flushing
         subjects affected / exposed
    0 / 7 (0.00%)
    1 / 8 (12.50%)
    0 / 7 (0.00%)
    0 / 8 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Embolism
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 8 (0.00%)
    0 / 7 (0.00%)
    1 / 8 (12.50%)
         occurrences all number
    0
    0
    0
    1
    Pallor
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 8 (0.00%)
    0 / 7 (0.00%)
    1 / 8 (12.50%)
         occurrences all number
    0
    0
    0
    1
    Hypotension
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 8 (0.00%)
    1 / 7 (14.29%)
    1 / 8 (12.50%)
         occurrences all number
    0
    0
    1
    4
    General disorders and administration site conditions
    Chills
         subjects affected / exposed
    2 / 7 (28.57%)
    7 / 8 (87.50%)
    2 / 7 (28.57%)
    5 / 8 (62.50%)
         occurrences all number
    3
    17
    2
    21
    Chest discomfort
         subjects affected / exposed
    1 / 7 (14.29%)
    0 / 8 (0.00%)
    0 / 7 (0.00%)
    0 / 8 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Face oedema
         subjects affected / exposed
    1 / 7 (14.29%)
    1 / 8 (12.50%)
    0 / 7 (0.00%)
    1 / 8 (12.50%)
         occurrences all number
    1
    1
    0
    5
    Fatigue
         subjects affected / exposed
    6 / 7 (85.71%)
    6 / 8 (75.00%)
    2 / 7 (28.57%)
    8 / 8 (100.00%)
         occurrences all number
    7
    10
    2
    29
    Feeling of body temperature change
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 8 (0.00%)
    0 / 7 (0.00%)
    1 / 8 (12.50%)
         occurrences all number
    0
    0
    0
    1
    Influenza like illness
         subjects affected / exposed
    2 / 7 (28.57%)
    3 / 8 (37.50%)
    0 / 7 (0.00%)
    3 / 8 (37.50%)
         occurrences all number
    3
    9
    0
    3
    Localised oedema
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 8 (0.00%)
    0 / 7 (0.00%)
    1 / 8 (12.50%)
         occurrences all number
    0
    0
    0
    1
    Non-cardiac chest pain
         subjects affected / exposed
    1 / 7 (14.29%)
    0 / 8 (0.00%)
    0 / 7 (0.00%)
    0 / 8 (0.00%)
         occurrences all number
    2
    0
    0
    0
    Oedema peripheral
         subjects affected / exposed
    2 / 7 (28.57%)
    1 / 8 (12.50%)
    1 / 7 (14.29%)
    4 / 8 (50.00%)
         occurrences all number
    3
    1
    1
    6
    Pain
         subjects affected / exposed
    1 / 7 (14.29%)
    1 / 8 (12.50%)
    0 / 7 (0.00%)
    2 / 8 (25.00%)
         occurrences all number
    1
    1
    0
    2
    Pyrexia
         subjects affected / exposed
    3 / 7 (42.86%)
    4 / 8 (50.00%)
    0 / 7 (0.00%)
    5 / 8 (62.50%)
         occurrences all number
    10
    16
    0
    29
    Mucosal inflammation
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 8 (0.00%)
    0 / 7 (0.00%)
    1 / 8 (12.50%)
         occurrences all number
    0
    0
    0
    1
    Immune system disorders
    Hypersensitivity
         subjects affected / exposed
    0 / 7 (0.00%)
    1 / 8 (12.50%)
    0 / 7 (0.00%)
    0 / 8 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Reproductive system and breast disorders
    Vulval disorder
         subjects affected / exposed
    1 / 7 (14.29%)
    0 / 8 (0.00%)
    0 / 7 (0.00%)
    0 / 8 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Pelvic pain
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 8 (0.00%)
    0 / 7 (0.00%)
    1 / 8 (12.50%)
         occurrences all number
    0
    0
    0
    1
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    2 / 7 (28.57%)
    3 / 8 (37.50%)
    0 / 7 (0.00%)
    6 / 8 (75.00%)
         occurrences all number
    2
    3
    0
    10
    Asthma
         subjects affected / exposed
    1 / 7 (14.29%)
    0 / 8 (0.00%)
    0 / 7 (0.00%)
    0 / 8 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Dysphonia
         subjects affected / exposed
    3 / 7 (42.86%)
    2 / 8 (25.00%)
    0 / 7 (0.00%)
    4 / 8 (50.00%)
         occurrences all number
    4
    2
    0
    7
    Upper-airway cough syndrome
         subjects affected / exposed
    1 / 7 (14.29%)
    0 / 8 (0.00%)
    0 / 7 (0.00%)
    0 / 8 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Rhinorrhoea
         subjects affected / exposed
    1 / 7 (14.29%)
    1 / 8 (12.50%)
    0 / 7 (0.00%)
    1 / 8 (12.50%)
         occurrences all number
    2
    1
    0
    1
    Productive cough
         subjects affected / exposed
    1 / 7 (14.29%)
    1 / 8 (12.50%)
    0 / 7 (0.00%)
    0 / 8 (0.00%)
         occurrences all number
    1
    1
    0
    0
    Pharyngeal ulceration
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 8 (0.00%)
    0 / 7 (0.00%)
    1 / 8 (12.50%)
         occurrences all number
    0
    0
    0
    1
    Paranasal sinus hypersecretion
         subjects affected / exposed
    0 / 7 (0.00%)
    1 / 8 (12.50%)
    0 / 7 (0.00%)
    1 / 8 (12.50%)
         occurrences all number
    0
    1
    0
    1
    Nasal congestion
         subjects affected / exposed
    1 / 7 (14.29%)
    0 / 8 (0.00%)
    0 / 7 (0.00%)
    1 / 8 (12.50%)
         occurrences all number
    1
    0
    0
    1
    Hiccups
         subjects affected / exposed
    1 / 7 (14.29%)
    0 / 8 (0.00%)
    0 / 7 (0.00%)
    0 / 8 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Haemoptysis
         subjects affected / exposed
    1 / 7 (14.29%)
    0 / 8 (0.00%)
    0 / 7 (0.00%)
    0 / 8 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Epistaxis
         subjects affected / exposed
    3 / 7 (42.86%)
    0 / 8 (0.00%)
    0 / 7 (0.00%)
    0 / 8 (0.00%)
         occurrences all number
    4
    0
    0
    0
    Dyspnoea
         subjects affected / exposed
    4 / 7 (57.14%)
    2 / 8 (25.00%)
    1 / 7 (14.29%)
    4 / 8 (50.00%)
         occurrences all number
    6
    2
    1
    6
    Vocal cord thickening
         subjects affected / exposed
    1 / 7 (14.29%)
    0 / 8 (0.00%)
    0 / 7 (0.00%)
    0 / 8 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Psychiatric disorders
    Anxiety
         subjects affected / exposed
    2 / 7 (28.57%)
    2 / 8 (25.00%)
    0 / 7 (0.00%)
    1 / 8 (12.50%)
         occurrences all number
    2
    2
    0
    1
    Insomnia
         subjects affected / exposed
    2 / 7 (28.57%)
    1 / 8 (12.50%)
    0 / 7 (0.00%)
    6 / 8 (75.00%)
         occurrences all number
    3
    4
    0
    14
    Depression
         subjects affected / exposed
    2 / 7 (28.57%)
    0 / 8 (0.00%)
    0 / 7 (0.00%)
    0 / 8 (0.00%)
         occurrences all number
    3
    0
    0
    0
    Investigations
    Blood cholesterol increased
         subjects affected / exposed
    1 / 7 (14.29%)
    0 / 8 (0.00%)
    0 / 7 (0.00%)
    0 / 8 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Alanine aminotransferase increased
         subjects affected / exposed
    1 / 7 (14.29%)
    1 / 8 (12.50%)
    5 / 7 (71.43%)
    1 / 8 (12.50%)
         occurrences all number
    1
    1
    5
    1
    Amylase increased
         subjects affected / exposed
    0 / 7 (0.00%)
    1 / 8 (12.50%)
    0 / 7 (0.00%)
    1 / 8 (12.50%)
         occurrences all number
    0
    2
    0
    1
    Aspartate aminotransferase increased
         subjects affected / exposed
    1 / 7 (14.29%)
    1 / 8 (12.50%)
    3 / 7 (42.86%)
    1 / 8 (12.50%)
         occurrences all number
    1
    1
    3
    1
    Blood alkaline phosphatase increased
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 8 (0.00%)
    1 / 7 (14.29%)
    0 / 8 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Blood creatinine increased
         subjects affected / exposed
    1 / 7 (14.29%)
    0 / 8 (0.00%)
    2 / 7 (28.57%)
    0 / 8 (0.00%)
         occurrences all number
    1
    0
    2
    0
    Blood lactate dehydrogenase increased
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 8 (0.00%)
    4 / 7 (57.14%)
    0 / 8 (0.00%)
         occurrences all number
    0
    0
    4
    0
    Blood phosphorus decreased
         subjects affected / exposed
    0 / 7 (0.00%)
    1 / 8 (12.50%)
    0 / 7 (0.00%)
    0 / 8 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Blood thyroid stimulating hormone decreased
         subjects affected / exposed
    0 / 7 (0.00%)
    1 / 8 (12.50%)
    0 / 7 (0.00%)
    0 / 8 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Blood thyroid stimulating hormone increased
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 8 (0.00%)
    1 / 7 (14.29%)
    0 / 8 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Ejection fraction decreased
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 8 (0.00%)
    0 / 7 (0.00%)
    2 / 8 (25.00%)
         occurrences all number
    0
    0
    0
    2
    Lipase increased
         subjects affected / exposed
    1 / 7 (14.29%)
    1 / 8 (12.50%)
    1 / 7 (14.29%)
    1 / 8 (12.50%)
         occurrences all number
    1
    1
    1
    1
    Lymphocyte count decreased
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 8 (0.00%)
    1 / 7 (14.29%)
    0 / 8 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Weight decreased
         subjects affected / exposed
    3 / 7 (42.86%)
    0 / 8 (0.00%)
    1 / 7 (14.29%)
    3 / 8 (37.50%)
         occurrences all number
    3
    0
    1
    5
    Weight increased
         subjects affected / exposed
    1 / 7 (14.29%)
    0 / 8 (0.00%)
    0 / 7 (0.00%)
    0 / 8 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Injury, poisoning and procedural complications
    Contusion
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 8 (0.00%)
    0 / 7 (0.00%)
    1 / 8 (12.50%)
         occurrences all number
    0
    0
    0
    1
    Fall
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 8 (0.00%)
    0 / 7 (0.00%)
    1 / 8 (12.50%)
         occurrences all number
    0
    0
    0
    2
    Infusion related reaction
         subjects affected / exposed
    1 / 7 (14.29%)
    0 / 8 (0.00%)
    0 / 7 (0.00%)
    2 / 8 (25.00%)
         occurrences all number
    2
    0
    0
    5
    Procedural pain
         subjects affected / exposed
    1 / 7 (14.29%)
    0 / 8 (0.00%)
    0 / 7 (0.00%)
    0 / 8 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Thermal burn
         subjects affected / exposed
    0 / 7 (0.00%)
    1 / 8 (12.50%)
    0 / 7 (0.00%)
    0 / 8 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Cardiac disorders
    Aortic valve disease
         subjects affected / exposed
    1 / 7 (14.29%)
    0 / 8 (0.00%)
    0 / 7 (0.00%)
    0 / 8 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Supraventricular extrasystoles
         subjects affected / exposed
    0 / 7 (0.00%)
    1 / 8 (12.50%)
    0 / 7 (0.00%)
    0 / 8 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Coronary artery disease
         subjects affected / exposed
    1 / 7 (14.29%)
    0 / 8 (0.00%)
    0 / 7 (0.00%)
    0 / 8 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Sinus tachycardia
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 8 (0.00%)
    1 / 7 (14.29%)
    2 / 8 (25.00%)
         occurrences all number
    0
    0
    1
    2
    Bundle branch block right
         subjects affected / exposed
    1 / 7 (14.29%)
    0 / 8 (0.00%)
    0 / 7 (0.00%)
    0 / 8 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Tachycardia
         subjects affected / exposed
    0 / 7 (0.00%)
    1 / 8 (12.50%)
    0 / 7 (0.00%)
    0 / 8 (0.00%)
         occurrences all number
    0
    2
    0
    0
    Nervous system disorders
    Brain fog
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 8 (0.00%)
    0 / 7 (0.00%)
    1 / 8 (12.50%)
         occurrences all number
    0
    0
    0
    1
    Aphasia
         subjects affected / exposed
    0 / 7 (0.00%)
    1 / 8 (12.50%)
    0 / 7 (0.00%)
    0 / 8 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Disturbance in attention
         subjects affected / exposed
    1 / 7 (14.29%)
    0 / 8 (0.00%)
    0 / 7 (0.00%)
    0 / 8 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Dizziness
         subjects affected / exposed
    2 / 7 (28.57%)
    4 / 8 (50.00%)
    0 / 7 (0.00%)
    2 / 8 (25.00%)
         occurrences all number
    3
    6
    0
    3
    Dizziness postural
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 8 (0.00%)
    0 / 7 (0.00%)
    1 / 8 (12.50%)
         occurrences all number
    0
    0
    0
    1
    Dysgeusia
         subjects affected / exposed
    1 / 7 (14.29%)
    2 / 8 (25.00%)
    0 / 7 (0.00%)
    1 / 8 (12.50%)
         occurrences all number
    1
    2
    0
    1
    Peripheral sensory neuropathy
         subjects affected / exposed
    1 / 7 (14.29%)
    2 / 8 (25.00%)
    0 / 7 (0.00%)
    3 / 8 (37.50%)
         occurrences all number
    2
    2
    0
    3
    Neuropathy peripheral
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 8 (0.00%)
    0 / 7 (0.00%)
    1 / 8 (12.50%)
         occurrences all number
    0
    0
    0
    1
    Migraine
         subjects affected / exposed
    0 / 7 (0.00%)
    1 / 8 (12.50%)
    0 / 7 (0.00%)
    0 / 8 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Hypoaesthesia
         subjects affected / exposed
    1 / 7 (14.29%)
    0 / 8 (0.00%)
    0 / 7 (0.00%)
    0 / 8 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Headache
         subjects affected / exposed
    5 / 7 (71.43%)
    3 / 8 (37.50%)
    1 / 7 (14.29%)
    6 / 8 (75.00%)
         occurrences all number
    12
    3
    1
    20
    Peripheral motor neuropathy
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 8 (0.00%)
    0 / 7 (0.00%)
    1 / 8 (12.50%)
         occurrences all number
    0
    0
    0
    1
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 8 (0.00%)
    1 / 7 (14.29%)
    0 / 8 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Lymphadenopathy
         subjects affected / exposed
    1 / 7 (14.29%)
    0 / 8 (0.00%)
    0 / 7 (0.00%)
    0 / 8 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Eosinophilia
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 8 (0.00%)
    2 / 7 (28.57%)
    0 / 8 (0.00%)
         occurrences all number
    0
    0
    2
    0
    Neutropenia
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 8 (0.00%)
    0 / 7 (0.00%)
    1 / 8 (12.50%)
         occurrences all number
    0
    0
    0
    1
    Ear and labyrinth disorders
    Deafness
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 8 (0.00%)
    0 / 7 (0.00%)
    1 / 8 (12.50%)
         occurrences all number
    0
    0
    0
    1
    Ear congestion
         subjects affected / exposed
    1 / 7 (14.29%)
    0 / 8 (0.00%)
    0 / 7 (0.00%)
    0 / 8 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Ear pain
         subjects affected / exposed
    1 / 7 (14.29%)
    0 / 8 (0.00%)
    0 / 7 (0.00%)
    1 / 8 (12.50%)
         occurrences all number
    1
    0
    0
    1
    Tinnitus
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 8 (0.00%)
    1 / 7 (14.29%)
    0 / 8 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Vertigo
         subjects affected / exposed
    0 / 7 (0.00%)
    1 / 8 (12.50%)
    0 / 7 (0.00%)
    0 / 8 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Ear pruritus
         subjects affected / exposed
    1 / 7 (14.29%)
    0 / 8 (0.00%)
    0 / 7 (0.00%)
    0 / 8 (0.00%)
         occurrences all number
    2
    0
    0
    0
    Eye disorders
    Dry eye
         subjects affected / exposed
    1 / 7 (14.29%)
    0 / 8 (0.00%)
    0 / 7 (0.00%)
    1 / 8 (12.50%)
         occurrences all number
    1
    0
    0
    1
    Lacrimation increased
         subjects affected / exposed
    1 / 7 (14.29%)
    0 / 8 (0.00%)
    0 / 7 (0.00%)
    0 / 8 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Periorbital oedema
         subjects affected / exposed
    0 / 7 (0.00%)
    1 / 8 (12.50%)
    0 / 7 (0.00%)
    1 / 8 (12.50%)
         occurrences all number
    0
    1
    0
    2
    Periorbital swelling
         subjects affected / exposed
    0 / 7 (0.00%)
    1 / 8 (12.50%)
    0 / 7 (0.00%)
    0 / 8 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Vision blurred
         subjects affected / exposed
    0 / 7 (0.00%)
    1 / 8 (12.50%)
    0 / 7 (0.00%)
    0 / 8 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Visual impairment
         subjects affected / exposed
    1 / 7 (14.29%)
    0 / 8 (0.00%)
    0 / 7 (0.00%)
    0 / 8 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Gastrointestinal disorders
    Diverticulum
         subjects affected / exposed
    1 / 7 (14.29%)
    0 / 8 (0.00%)
    0 / 7 (0.00%)
    0 / 8 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Abdominal pain
         subjects affected / exposed
    1 / 7 (14.29%)
    0 / 8 (0.00%)
    0 / 7 (0.00%)
    4 / 8 (50.00%)
         occurrences all number
    1
    0
    0
    4
    Abdominal pain upper
         subjects affected / exposed
    2 / 7 (28.57%)
    0 / 8 (0.00%)
    0 / 7 (0.00%)
    1 / 8 (12.50%)
         occurrences all number
    2
    0
    0
    1
    Constipation
         subjects affected / exposed
    4 / 7 (57.14%)
    1 / 8 (12.50%)
    1 / 7 (14.29%)
    4 / 8 (50.00%)
         occurrences all number
    7
    1
    1
    5
    Diarrhoea
         subjects affected / exposed
    6 / 7 (85.71%)
    5 / 8 (62.50%)
    2 / 7 (28.57%)
    8 / 8 (100.00%)
         occurrences all number
    33
    18
    2
    53
    Abdominal discomfort
         subjects affected / exposed
    1 / 7 (14.29%)
    0 / 8 (0.00%)
    0 / 7 (0.00%)
    0 / 8 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Dry mouth
         subjects affected / exposed
    1 / 7 (14.29%)
    2 / 8 (25.00%)
    0 / 7 (0.00%)
    0 / 8 (0.00%)
         occurrences all number
    1
    2
    0
    0
    Dyspepsia
         subjects affected / exposed
    2 / 7 (28.57%)
    1 / 8 (12.50%)
    0 / 7 (0.00%)
    4 / 8 (50.00%)
         occurrences all number
    3
    1
    0
    12
    Enterocolitis
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 8 (0.00%)
    0 / 7 (0.00%)
    1 / 8 (12.50%)
         occurrences all number
    0
    0
    0
    1
    Flatulence
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 8 (0.00%)
    0 / 7 (0.00%)
    1 / 8 (12.50%)
         occurrences all number
    0
    0
    0
    1
    Haemorrhoids
         subjects affected / exposed
    1 / 7 (14.29%)
    0 / 8 (0.00%)
    0 / 7 (0.00%)
    0 / 8 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Gastrooesophageal reflux disease
         subjects affected / exposed
    1 / 7 (14.29%)
    0 / 8 (0.00%)
    0 / 7 (0.00%)
    1 / 8 (12.50%)
         occurrences all number
    1
    0
    0
    1
    Gingival bleeding
         subjects affected / exposed
    0 / 7 (0.00%)
    1 / 8 (12.50%)
    0 / 7 (0.00%)
    0 / 8 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Glossitis
         subjects affected / exposed
    1 / 7 (14.29%)
    0 / 8 (0.00%)
    0 / 7 (0.00%)
    0 / 8 (0.00%)
         occurrences all number
    2
    0
    0
    0
    Haematochezia
         subjects affected / exposed
    1 / 7 (14.29%)
    0 / 8 (0.00%)
    0 / 7 (0.00%)
    0 / 8 (0.00%)
         occurrences all number
    2
    0
    0
    0
    Gastritis
         subjects affected / exposed
    0 / 7 (0.00%)
    1 / 8 (12.50%)
    0 / 7 (0.00%)
    0 / 8 (0.00%)
         occurrences all number
    0
    2
    0
    0
    Hiatus hernia
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 8 (0.00%)
    0 / 7 (0.00%)
    1 / 8 (12.50%)
         occurrences all number
    0
    0
    0
    1
    Lip dry
         subjects affected / exposed
    1 / 7 (14.29%)
    0 / 8 (0.00%)
    0 / 7 (0.00%)
    0 / 8 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Mouth swelling
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 8 (0.00%)
    0 / 7 (0.00%)
    1 / 8 (12.50%)
         occurrences all number
    0
    0
    0
    1
    Nausea
         subjects affected / exposed
    5 / 7 (71.43%)
    6 / 8 (75.00%)
    2 / 7 (28.57%)
    7 / 8 (87.50%)
         occurrences all number
    19
    12
    2
    27
    Oral pain
         subjects affected / exposed
    1 / 7 (14.29%)
    3 / 8 (37.50%)
    0 / 7 (0.00%)
    0 / 8 (0.00%)
         occurrences all number
    1
    4
    0
    0
    Stomatitis
         subjects affected / exposed
    5 / 7 (71.43%)
    3 / 8 (37.50%)
    2 / 7 (28.57%)
    4 / 8 (50.00%)
         occurrences all number
    13
    5
    2
    8
    Toothache
         subjects affected / exposed
    0 / 7 (0.00%)
    1 / 8 (12.50%)
    0 / 7 (0.00%)
    0 / 8 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Vomiting
         subjects affected / exposed
    4 / 7 (57.14%)
    5 / 8 (62.50%)
    0 / 7 (0.00%)
    5 / 8 (62.50%)
         occurrences all number
    16
    11
    0
    11
    Proctalgia
         subjects affected / exposed
    1 / 7 (14.29%)
    0 / 8 (0.00%)
    0 / 7 (0.00%)
    0 / 8 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Skin and subcutaneous tissue disorders
    Acne
         subjects affected / exposed
    0 / 7 (0.00%)
    1 / 8 (12.50%)
    0 / 7 (0.00%)
    0 / 8 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Alopecia
         subjects affected / exposed
    1 / 7 (14.29%)
    2 / 8 (25.00%)
    0 / 7 (0.00%)
    2 / 8 (25.00%)
         occurrences all number
    1
    2
    0
    2
    Blister
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 8 (0.00%)
    0 / 7 (0.00%)
    1 / 8 (12.50%)
         occurrences all number
    0
    0
    0
    1
    Rash
         subjects affected / exposed
    3 / 7 (42.86%)
    3 / 8 (37.50%)
    0 / 7 (0.00%)
    4 / 8 (50.00%)
         occurrences all number
    7
    5
    0
    9
    Pruritus
         subjects affected / exposed
    1 / 7 (14.29%)
    5 / 8 (62.50%)
    1 / 7 (14.29%)
    6 / 8 (75.00%)
         occurrences all number
    1
    9
    1
    12
    Palmar-plantar erythrodysaesthesia syndrome
         subjects affected / exposed
    3 / 7 (42.86%)
    2 / 8 (25.00%)
    1 / 7 (14.29%)
    5 / 8 (62.50%)
         occurrences all number
    5
    2
    2
    5
    Night sweats
         subjects affected / exposed
    2 / 7 (28.57%)
    0 / 8 (0.00%)
    0 / 7 (0.00%)
    0 / 8 (0.00%)
         occurrences all number
    2
    0
    0
    0
    Nail disorder
         subjects affected / exposed
    1 / 7 (14.29%)
    0 / 8 (0.00%)
    0 / 7 (0.00%)
    0 / 8 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Hyperhidrosis
         subjects affected / exposed
    1 / 7 (14.29%)
    3 / 8 (37.50%)
    0 / 7 (0.00%)
    4 / 8 (50.00%)
         occurrences all number
    2
    12
    0
    11
    Eczema
         subjects affected / exposed
    0 / 7 (0.00%)
    1 / 8 (12.50%)
    0 / 7 (0.00%)
    0 / 8 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Dry skin
         subjects affected / exposed
    1 / 7 (14.29%)
    1 / 8 (12.50%)
    0 / 7 (0.00%)
    4 / 8 (50.00%)
         occurrences all number
    1
    1
    0
    6
    Dermatitis acneiform
         subjects affected / exposed
    0 / 7 (0.00%)
    1 / 8 (12.50%)
    0 / 7 (0.00%)
    0 / 8 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Sensitive skin
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 8 (0.00%)
    0 / 7 (0.00%)
    1 / 8 (12.50%)
         occurrences all number
    0
    0
    0
    1
    Rash maculo-papular
         subjects affected / exposed
    2 / 7 (28.57%)
    1 / 8 (12.50%)
    2 / 7 (28.57%)
    3 / 8 (37.50%)
         occurrences all number
    2
    1
    2
    3
    Skin exfoliation
         subjects affected / exposed
    0 / 7 (0.00%)
    1 / 8 (12.50%)
    0 / 7 (0.00%)
    1 / 8 (12.50%)
         occurrences all number
    0
    1
    0
    1
    Renal and urinary disorders
    Urine abnormality
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 8 (0.00%)
    0 / 7 (0.00%)
    1 / 8 (12.50%)
         occurrences all number
    0
    0
    0
    1
    Pollakiuria
         subjects affected / exposed
    1 / 7 (14.29%)
    0 / 8 (0.00%)
    1 / 7 (14.29%)
    0 / 8 (0.00%)
         occurrences all number
    1
    0
    1
    0
    Nocturia
         subjects affected / exposed
    1 / 7 (14.29%)
    1 / 8 (12.50%)
    0 / 7 (0.00%)
    0 / 8 (0.00%)
         occurrences all number
    1
    1
    0
    0
    Proteinuria
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 8 (0.00%)
    0 / 7 (0.00%)
    1 / 8 (12.50%)
         occurrences all number
    0
    0
    0
    1
    Endocrine disorders
    Hyperthyroidism
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 8 (0.00%)
    1 / 7 (14.29%)
    1 / 8 (12.50%)
         occurrences all number
    0
    0
    1
    1
    Hypothyroidism
         subjects affected / exposed
    1 / 7 (14.29%)
    0 / 8 (0.00%)
    1 / 7 (14.29%)
    2 / 8 (25.00%)
         occurrences all number
    1
    0
    1
    2
    Musculoskeletal and connective tissue disorders
    Flank pain
         subjects affected / exposed
    1 / 7 (14.29%)
    0 / 8 (0.00%)
    0 / 7 (0.00%)
    1 / 8 (12.50%)
         occurrences all number
    1
    0
    0
    1
    Arthralgia
         subjects affected / exposed
    5 / 7 (71.43%)
    3 / 8 (37.50%)
    0 / 7 (0.00%)
    4 / 8 (50.00%)
         occurrences all number
    6
    5
    0
    8
    Back pain
         subjects affected / exposed
    2 / 7 (28.57%)
    2 / 8 (25.00%)
    1 / 7 (14.29%)
    2 / 8 (25.00%)
         occurrences all number
    4
    4
    1
    2
    Musculoskeletal discomfort
         subjects affected / exposed
    1 / 7 (14.29%)
    0 / 8 (0.00%)
    0 / 7 (0.00%)
    0 / 8 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Musculoskeletal chest pain
         subjects affected / exposed
    2 / 7 (28.57%)
    0 / 8 (0.00%)
    0 / 7 (0.00%)
    0 / 8 (0.00%)
         occurrences all number
    2
    0
    0
    0
    Muscular weakness
         subjects affected / exposed
    2 / 7 (28.57%)
    0 / 8 (0.00%)
    0 / 7 (0.00%)
    0 / 8 (0.00%)
         occurrences all number
    2
    0
    0
    0
    Muscle tightness
         subjects affected / exposed
    1 / 7 (14.29%)
    0 / 8 (0.00%)
    0 / 7 (0.00%)
    0 / 8 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Muscle spasms
         subjects affected / exposed
    1 / 7 (14.29%)
    0 / 8 (0.00%)
    0 / 7 (0.00%)
    1 / 8 (12.50%)
         occurrences all number
    1
    0
    0
    1
    Myalgia
         subjects affected / exposed
    1 / 7 (14.29%)
    2 / 8 (25.00%)
    1 / 7 (14.29%)
    5 / 8 (62.50%)
         occurrences all number
    1
    2
    1
    7
    Pain in extremity
         subjects affected / exposed
    1 / 7 (14.29%)
    0 / 8 (0.00%)
    0 / 7 (0.00%)
    3 / 8 (37.50%)
         occurrences all number
    1
    0
    0
    3
    Neck pain
         subjects affected / exposed
    1 / 7 (14.29%)
    1 / 8 (12.50%)
    0 / 7 (0.00%)
    0 / 8 (0.00%)
         occurrences all number
    2
    2
    0
    0
    Infections and infestations
    Arthritis infective
         subjects affected / exposed
    0 / 7 (0.00%)
    1 / 8 (12.50%)
    0 / 7 (0.00%)
    0 / 8 (0.00%)
         occurrences all number
    0
    1
    0
    0
    COVID-19
         subjects affected / exposed
    1 / 7 (14.29%)
    1 / 8 (12.50%)
    0 / 7 (0.00%)
    2 / 8 (25.00%)
         occurrences all number
    1
    1
    0
    2
    Diverticulitis
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 8 (0.00%)
    0 / 7 (0.00%)
    1 / 8 (12.50%)
         occurrences all number
    0
    0
    0
    1
    Furuncle
         subjects affected / exposed
    1 / 7 (14.29%)
    1 / 8 (12.50%)
    0 / 7 (0.00%)
    0 / 8 (0.00%)
         occurrences all number
    1
    2
    0
    0
    Gingivitis
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 8 (0.00%)
    0 / 7 (0.00%)
    1 / 8 (12.50%)
         occurrences all number
    0
    0
    0
    1
    Urinary tract infection
         subjects affected / exposed
    0 / 7 (0.00%)
    1 / 8 (12.50%)
    1 / 7 (14.29%)
    1 / 8 (12.50%)
         occurrences all number
    0
    1
    1
    1
    Lower respiratory tract infection
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 8 (0.00%)
    0 / 7 (0.00%)
    1 / 8 (12.50%)
         occurrences all number
    0
    0
    0
    1
    Nasopharyngitis
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 8 (0.00%)
    0 / 7 (0.00%)
    1 / 8 (12.50%)
         occurrences all number
    0
    0
    0
    1
    Pneumonia
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 8 (0.00%)
    0 / 7 (0.00%)
    1 / 8 (12.50%)
         occurrences all number
    0
    0
    0
    1
    Sinusitis
         subjects affected / exposed
    1 / 7 (14.29%)
    0 / 8 (0.00%)
    0 / 7 (0.00%)
    1 / 8 (12.50%)
         occurrences all number
    1
    0
    0
    1
    Tooth infection
         subjects affected / exposed
    0 / 7 (0.00%)
    1 / 8 (12.50%)
    0 / 7 (0.00%)
    0 / 8 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Laryngitis
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 8 (0.00%)
    0 / 7 (0.00%)
    1 / 8 (12.50%)
         occurrences all number
    0
    0
    0
    1
    Metabolism and nutrition disorders
    Hyperlipidaemia
         subjects affected / exposed
    0 / 7 (0.00%)
    1 / 8 (12.50%)
    0 / 7 (0.00%)
    0 / 8 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Hyperglycaemia
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 8 (0.00%)
    1 / 7 (14.29%)
    0 / 8 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Hypercalcaemia
         subjects affected / exposed
    2 / 7 (28.57%)
    0 / 8 (0.00%)
    0 / 7 (0.00%)
    0 / 8 (0.00%)
         occurrences all number
    2
    0
    0
    0
    Dehydration
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 8 (0.00%)
    1 / 7 (14.29%)
    1 / 8 (12.50%)
         occurrences all number
    0
    0
    1
    1
    Decreased appetite
         subjects affected / exposed
    4 / 7 (57.14%)
    2 / 8 (25.00%)
    1 / 7 (14.29%)
    6 / 8 (75.00%)
         occurrences all number
    9
    4
    1
    13
    Hyponatraemia
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 8 (0.00%)
    2 / 7 (28.57%)
    0 / 8 (0.00%)
         occurrences all number
    0
    0
    2
    0
    Hypophosphataemia
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 8 (0.00%)
    1 / 7 (14.29%)
    0 / 8 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Hypomagnesaemia
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 8 (0.00%)
    1 / 7 (14.29%)
    0 / 8 (0.00%)
         occurrences all number
    0
    0
    1
    0

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    09 Dec 2020
     Revision to align with study design modification that incorporated cabozantinib  Modifications made to bridge bempegaldesleukin and nivolumab program updates to align with Common Terminology Criteria for Adverse Event (CTCAE) version 5  Incorporates Administrative Letter 01  Revision to inclusion criteria 2)h, 2)i, 3)h)iv through 3)h)vii; added exclusion criteria 1)x and 2)g  Added SARS-CoV-2 language  Updated Appendix 11 management algorithms
    28 Jun 2022
     Text was updated to discontinue treatment with bempegaldesleukin and may continue to receive nivolumab plus a tyrosine kinase inhibitor.  The maximum study duration was shortened to the nivolumab treatment period (2 years) plus 100 days for safety follow-up.  Imaging will be performed per standard of care. All study treatment decisions including progression and recurrence will be based on the Investigator’s assessment of tumor images.  All enrollment to the CA045011 study has stopped. As the Phase 2 enrollment will not be initiated, with this amendment the Part 2 (Phase 2) activities are not applicable.

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

    Limitations and caveats
    Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.
    None reported
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