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    Clinical Trial Results:
    A Phase II Single-arm, Open-label Monotherapy Clinical Trial of Pembrolizumab (MK-3475) in Locally Advanced/Metastatic Renal Cell Carcinoma (mRCC) (KEYNOTE-427)

    Summary
    EudraCT number
    		 2016-000589-47
    Trial protocol
    		 DE   DK   GB   ES   CZ   PL  
    Global end of trial date
    01 Apr 2022

    Results information
    Results version number
    		 v1(current)
    This version publication date
    06 Apr 2023
    First version publication date
    06 Apr 2023
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    3475-427
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT02853344
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Merck Sharp & Dohme LLC
    Sponsor organisation address
    126 East Lincoln Avenue, P.O. Box 2000, Rahway, NJ, United States, 07065
    Public contact
    Clinical Trials Disclosure, Merck Sharp & Dohme LLC, ClinicalTrialsDisclosure@merck.com
    Scientific contact
    Clinical Trials Disclosure, Merck Sharp & Dohme LLC, ClinicalTrialsDisclosure@merck.com
    Paediatric regulatory details
    Is trial part of an agreed paediatric investigation plan (PIP)
    No
    Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Results analysis stage
    Analysis stage
    Final
    Date of interim/final analysis
    01 Apr 2022
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    05 Feb 2021
    Global end of trial reached?
    Yes
    Global end of trial date
    01 Apr 2022
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The purpose of this study is to assess the safety and efficacy of monotherapy pembrolizumab (MK-3475) in participants with renal cell carcinoma (RCC). There will be two cohorts in this study: Cohort A will consist of participants with clear cell (cc) RCC and Cohort B will consist of participants with non-clear cell (ncc) RCC.
    Protection of trial subjects
    This study was conducted in conformance with Good Clinical Practice standards and applicable country and/or local statutes and regulations regarding ethical committee review, informed consent, and the protection of human subjects participating in biomedical research.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    30 Sep 2016
    Long term follow-up planned
    Yes
    Long term follow-up rationale
    		 Safety, Efficacy
    Long term follow-up duration
    		 63 Months
    Independent data monitoring committee (IDMC) involvement?
    No
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Canada: 28
    Country: Number of subjects enrolled
    Czechia: 13
    Country: Number of subjects enrolled
    Denmark: 26
    Country: Number of subjects enrolled
    Germany: 6
    Country: Number of subjects enrolled
    Korea, Republic of: 23
    Country: Number of subjects enrolled
    Poland: 42
    Country: Number of subjects enrolled
    Russian Federation: 27
    Country: Number of subjects enrolled
    Spain: 24
    Country: Number of subjects enrolled
    United Kingdom: 27
    Country: Number of subjects enrolled
    United States: 59
    Worldwide total number of subjects
    275
    EEA total number of subjects
    111
    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)
    164
    From 65 to 84 years
    107
    85 years and over
    4

    Subject disposition

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    Recruitment
    Recruitment details
    		 -

    Pre-assignment
    Screening details
    		 Participants who met the following key criteria at screening were eligible for enrollment: 1. Histologically confirmed diagnosis of ccRCC or nccRCC. 2. Had locally advanced/metastatic disease. 3. Had measurable disease per RECIST 1.1 as assessed by BICR. 4. Had received no prior systemic therapy for advanced RCC.

    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
    		 Cohort A: Clear Cell RCC
    Arm description
    		 Participants with clear cell RCC received pembrolizumab 200 mg intravenously (IV) every 3 weeks (Q3W) for up to 35 doses (approximately 24 months).
    Arm type
    		 Experimental

    Investigational medicinal product name
    Pembrolizumab
    Investigational medicinal product code
    Other name
    MK-3475 Keytruda
    Pharmaceutical forms
    Concentrate for solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    200 mg intravenously (IV) every 3 weeks (Q3W)

    Arm title
    		 Cohort B: Non-clear Cell RCC
    Arm description
    		 Participants with non-clear cell RCC received pembrolizumab 200 mg IV Q3W for up to 35 doses (approximately 24 months).
    Arm type
    		 Experimental

    Investigational medicinal product name
    Pembrolizumab
    Investigational medicinal product code
    Other name
    MK-3475 Keytruda
    Pharmaceutical forms
    Concentrate for solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    200 mg intravenously (IV) every 3 weeks (Q3W)

    Number of subjects in period 1
    		Cohort A: Clear Cell RCC Cohort B: Non-clear Cell RCC
    Started
    110
    165
    Received Second Course of Pembrolizumab
    3
    5
    Completed
    0
    0
    Not completed
    110
    165
         Consent withdrawn by subject
    2
    4
         Death
    70
    112
         Participation in Study Terminated by Sponsor
    37
    48
         Lost to follow-up
    1
    1

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Cohort A: Clear Cell RCC
    Reporting group description
    		 Participants with clear cell RCC received pembrolizumab 200 mg intravenously (IV) every 3 weeks (Q3W) for up to 35 doses (approximately 24 months).

    Reporting group title
    Cohort B: Non-clear Cell RCC
    Reporting group description
    		 Participants with non-clear cell RCC received pembrolizumab 200 mg IV Q3W for up to 35 doses (approximately 24 months).

    Reporting group values
    		 Cohort A: Clear Cell RCC Cohort B: Non-clear Cell RCC Total
    Number of subjects
    		 110 165 275
    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)
    		 58 106 164
        From 65-84 years
    		 49 58 107
        85 years and over
    		 3 1 4
    Age Continuous
    Units: Years
        arithmetic mean (standard deviation)
    		 62.9 ± 11.0 60.0 ± 12.3 -
    Sex: Female, Male
    Units: Participants
        Female
    		 24 56 80
        Male
    		 86 109 195
    Race (NIH/OMB)
    Units: Subjects
        American Indian or Alaska Native
    		 1 1 2
        Asian
    		 11 17 28
        Native Hawaiian or Other Pacific Islander
    		 0 0 0
        Black or African American
    		 0 1 1
        White
    		 98 145 243
        More than one race
    		 0 0 0
        Unknown or Not Reported
    		 0 1 1
    Ethnicity (NIH/OMB)
    Units: Subjects
        Hispanic or Latino
    		 2 1 3
        Not Hispanic or Latino
    		 104 156 260
        Unknown or Not Reported
    		 4 8 12

    End points

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    End points reporting groups
    Reporting group title
    Cohort A: Clear Cell RCC
    Reporting group description
    		 Participants with clear cell RCC received pembrolizumab 200 mg intravenously (IV) every 3 weeks (Q3W) for up to 35 doses (approximately 24 months).

    Reporting group title
    Cohort B: Non-clear Cell RCC
    Reporting group description
    		 Participants with non-clear cell RCC received pembrolizumab 200 mg IV Q3W for up to 35 doses (approximately 24 months).

    Primary: Objective Response Rate (ORR)

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    End point title
    		 Objective Response Rate (ORR) [1]
    End point description
    ORR was defined as the percentage of participants who had a Complete Response (CR: Disappearance of all target lesions) or a Partial Response (PR: At least a 30% decrease in the sum of diameters of target lesions) as assessed by Blinded Independent Central Review (BICR) per Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST 1.1). The population analyzed included all allocated participants who received at least one dose of study treatment.
    End point type
    Primary
    End point timeframe
    Up to approximately 66 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 analyses were planned for this endpoint.
    End point values
    		 Cohort A: Clear Cell RCC Cohort B: Non-clear Cell RCC
    Number of subjects analysed
    110
    165
    Units: Percentage of Participants
        number (confidence interval 95%)
    36.4 (27.4 to 46.1)
    26.7 (20.1 to 34.1)
    No statistical analyses for this end point

    Secondary: Duration of Response (DOR)

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    End point title
    		 Duration of Response (DOR)
    End point description
    For participants who demonstrated a confirmed Complete Response (CR: disappearance of all target lesions) or Partial Response (PR: At least a 30% decrease in the sum of diameters of target lesions) per RECIST 1.1, DOR was defined as the time from first documented evidence of a CR or PR until progressive disease (PD) or death. DOR for participants who had not progressed or died at the time of analysis was censored at the date of their last tumor assessment. Per RECIST 1.1, PD was defined as at least a 20% increase in the sum of diameters of target lesions as well as an absolute increase of at least 5 mm in the sum of diameters. The appearance of one or more new lesions was also considered PD. DOR assessments were based on BICR. The DOR as assessed using RECIST 1.1 for all participants who experienced a confirmed CR or PR is presented. The population analyzed included all allocated participants who received at least one dose of study treatment and had confirmed CR or PR.
    End point type
    Secondary
    End point timeframe
    Up to approximately 66 months
    End point values
    		 Cohort A: Clear Cell RCC Cohort B: Non-clear Cell RCC
    Number of subjects analysed
    110 [2]
    165 [3]
    Units: Months
        median (confidence interval 95%)
    18.9 (2.3 to 9999)
    29.0 (2.8 to 9999)
    Notes
    [2] - 9999 = upper limit not reached due to insufficient number of responding participants with PD.
    [3] - 9999 = upper limit not reached due to insufficient number of responding participants with PD.
    No statistical analyses for this end point

    Secondary: Disease Control Rate (DCR)

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    End point title
    		 Disease Control Rate (DCR)
    End point description
    DCR is defined as the percentage of participants who have achieved CR, PR, or Stable Disease (SD) for at least 6 months based on assessments by the BICR per RECIST 1.1. CR is defined as disappearance of all target lesions, PR is defined as at least a 30% decrease in the sum of diameters of target lesions, SD is defined as neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for progressive disease (PD): At least a 20% increase in the sum of diameters of target lesions and an absolute increase of at least 5 mm. The appearance of one or more new lesions is also considered PD. The population analyzed included all allocated participants who received at least one dose of study treatment.
    End point type
    Secondary
    End point timeframe
    Up to approximately 66 months
    End point values
    		 Cohort A: Clear Cell RCC Cohort B: Non-clear Cell RCC
    Number of subjects analysed
    110
    165
    Units: Percentage of Participants
        number (confidence interval 95%)
    58.2 (48.4 to 67.5)
    43.0 (35.4 to 51.0)
    No statistical analyses for this end point

    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 from first dose of study treatment to the first documented progressive disease (PD) per RECIST 1.1 based on BICR, or death due to any cause, whichever occurs first. Per RECIST 1.1, PD is defined as ≥20% increase in the sum of diameters of target lesions. In addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of ≥5 mm. The appearance of one or more new lesions is also considered PD. The population analyzed included all allocated participants who received at least one dose of study treatment.
    End point type
    Secondary
    End point timeframe
    Up to approximately 66 months
    End point values
    		 Cohort A: Clear Cell RCC Cohort B: Non-clear Cell RCC
    Number of subjects analysed
    110
    165
    Units: Months
        median (confidence interval 95%)
    7.1 (5.6 to 11.0)
    4.2 (2.9 to 5.6)
    No statistical analyses for this end point

    Secondary: Overall Survival

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    End point title
    		 Overall Survival
    End point description
    OS was defined as the time from first dose of study treatment to death due to any cause. The population analyzed included all allocated participants who received at least one dose of study treatment.
    End point type
    Secondary
    End point timeframe
    Up to approximately 66 months
    End point values
    		 Cohort A: Clear Cell RCC Cohort B: Non-clear Cell RCC
    Number of subjects analysed
    110
    165
    Units: Months
        median (confidence interval 95%)
    40.7 (31.1 to 52.6)
    29.9 (24.3 to 37.4)
    No statistical analyses for this end point

    Secondary: Number of Participants Who Experienced an Adverse Event (AE)

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    End point title
    		 Number of Participants Who Experienced an Adverse Event (AE)
    End point description
    An adverse event is defined as any untoward medical occurrence in a participant administered a pharmaceutical product and which does not necessarily have to have a causal relationship with this treatment. An adverse event can therefore be any unfavorable and unintended sign (including an abnormal laboratory finding, for example), symptom, or disease temporally associated with the use of a medicinal product or protocol-specified procedure, whether or not considered related to the medicinal product or protocol-specified procedure. The population analyzed included all allocated participants who received at least one dose of study treatment.
    End point type
    Secondary
    End point timeframe
    Up to approximately 27 months
    End point values
    		 Cohort A: Clear Cell RCC Cohort B: Non-clear Cell RCC
    Number of subjects analysed
    110
    165
    Units: Participants
    109
    155
    No statistical analyses for this end point

    Secondary: Number of Participants Who Discontinued Study Drug Due to an AE

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    End point title
    		 Number of Participants Who Discontinued Study Drug Due to an AE
    End point description
    An adverse event is defined as any untoward medical occurrence in a participant administered a pharmaceutical product and which does not necessarily have to have a causal relationship with this treatment. An adverse event can therefore be any unfavorable and unintended sign (including an abnormal laboratory finding, for example), symptom, or disease temporally associated with the use of a medicinal product or protocol-specified procedure, whether or not considered related to the medicinal product or protocol-specified procedure. The population analyzed included all allocated participants who received at least one dose of study treatment.
    End point type
    Secondary
    End point timeframe
    Up to approximately 24 months
    End point values
    		 Cohort A: Clear Cell RCC Cohort B: Non-clear Cell RCC
    Number of subjects analysed
    110
    165
    Units: Participants
    23
    25
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Up to approximately 66 months
    Adverse event reporting additional description
    Safety analysis population includes all participants who received at least one dose of study treatment. Progression of cancer under study was not an AE unless considered related to study treatment. Therefore, MedDRA preferred terms "Neoplasm Progression", "Malignant Neoplasm Progression" and "Disease Progression" unrelated to the drug are excluded.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    24.1
    Reporting groups
    Reporting group title
    Cohort B: nccRCC First Course
    Reporting group description
    		 Participants with non-clear cell RCC received pembrolizumab 200 mg IV Q3W for up to 35 doses (approximately 24 months)

    Reporting group title
    Cohort B: nccRCC Second Course
    Reporting group description
    		 Participants with non-clear cell RCC received pembrolizumab 200 mg IV Q3W for up to 35 doses (approximately 24 months). Eligible participants with nccRCC who experienced disease progression received up to 17 additional doses of pembrolizumab.

    Reporting group title
    Cohort A: ccRCC First Course
    Reporting group description
    		 Participants with clear cell RCC received pembrolizumab 200 mg intravenously (IV) every 3 weeks (Q3W) for up to 35 doses (approximately 24 months).

    Reporting group title
    Cohort A: ccRCC Second Course
    Reporting group description
    		 Participants with clear cell RCC received pembrolizumab 200 mg IV Q3W for up to 35 doses (approximately 24 months). Eligible participants with ccRCC who experienced disease progression received up to 17 additional doses of pembrolizumab.

    Serious adverse events
    		 Cohort B: nccRCC First Course Cohort B: nccRCC Second Course Cohort A: ccRCC First Course Cohort A: ccRCC Second Course
    Total subjects affected by serious adverse events
         subjects affected / exposed
    47 / 165 (28.48%)
    0 / 5 (0.00%)
    52 / 110 (47.27%)
    0 / 3 (0.00%)
         number of deaths (all causes)
    113
    0
    71
    0
         number of deaths resulting from adverse events
    2
    0
    1
    0
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    B-cell small lymphocytic lymphoma
         subjects affected / exposed
    0 / 165 (0.00%)
    0 / 5 (0.00%)
    1 / 110 (0.91%)
    0 / 3 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Renal cell carcinoma
         subjects affected / exposed
    0 / 165 (0.00%)
    0 / 5 (0.00%)
    1 / 110 (0.91%)
    0 / 3 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Transitional cell carcinoma
         subjects affected / exposed
    1 / 165 (0.61%)
    0 / 5 (0.00%)
    0 / 110 (0.00%)
    0 / 3 (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
    Vascular disorders
    Peripheral artery aneurysm
         subjects affected / exposed
    1 / 165 (0.61%)
    0 / 5 (0.00%)
    0 / 110 (0.00%)
    0 / 3 (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
    Hypotension
         subjects affected / exposed
    1 / 165 (0.61%)
    0 / 5 (0.00%)
    0 / 110 (0.00%)
    0 / 3 (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
    Peripheral artery stenosis
         subjects affected / exposed
    1 / 165 (0.61%)
    0 / 5 (0.00%)
    0 / 110 (0.00%)
    0 / 3 (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
    General disorders and administration site conditions
    General physical health deterioration
         subjects affected / exposed
    1 / 165 (0.61%)
    0 / 5 (0.00%)
    0 / 110 (0.00%)
    0 / 3 (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
    Chest pain
         subjects affected / exposed
    1 / 165 (0.61%)
    0 / 5 (0.00%)
    0 / 110 (0.00%)
    0 / 3 (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
    Asthenia
         subjects affected / exposed
    1 / 165 (0.61%)
    0 / 5 (0.00%)
    1 / 110 (0.91%)
    0 / 3 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pyrexia
         subjects affected / exposed
    1 / 165 (0.61%)
    0 / 5 (0.00%)
    2 / 110 (1.82%)
    0 / 3 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    1 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Multiple organ dysfunction syndrome
         subjects affected / exposed
    1 / 165 (0.61%)
    0 / 5 (0.00%)
    0 / 110 (0.00%)
    0 / 3 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    Stent-graft endoleak
         subjects affected / exposed
    0 / 165 (0.00%)
    0 / 5 (0.00%)
    1 / 110 (0.91%)
    0 / 3 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Immune system disorders
    Contrast media allergy
         subjects affected / exposed
    0 / 165 (0.00%)
    0 / 5 (0.00%)
    1 / 110 (0.91%)
    0 / 3 (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
    Respiratory, thoracic and mediastinal disorders
    Chronic obstructive pulmonary disease
         subjects affected / exposed
    2 / 165 (1.21%)
    0 / 5 (0.00%)
    1 / 110 (0.91%)
    0 / 3 (0.00%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 0
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Atelectasis
         subjects affected / exposed
    0 / 165 (0.00%)
    0 / 5 (0.00%)
    1 / 110 (0.91%)
    0 / 3 (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
    Dyspnoea
         subjects affected / exposed
    3 / 165 (1.82%)
    0 / 5 (0.00%)
    1 / 110 (0.91%)
    0 / 3 (0.00%)
         occurrences causally related to treatment / all
    1 / 3
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pleural effusion
         subjects affected / exposed
    2 / 165 (1.21%)
    0 / 5 (0.00%)
    1 / 110 (0.91%)
    0 / 3 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pneumonitis
         subjects affected / exposed
    0 / 165 (0.00%)
    0 / 5 (0.00%)
    2 / 110 (1.82%)
    0 / 3 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    2 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    0 / 0
    Pulmonary embolism
         subjects affected / exposed
    0 / 165 (0.00%)
    0 / 5 (0.00%)
    1 / 110 (0.91%)
    0 / 3 (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
    Respiratory failure
         subjects affected / exposed
    1 / 165 (0.61%)
    0 / 5 (0.00%)
    0 / 110 (0.00%)
    0 / 3 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    Psychiatric disorders
    Anxiety
         subjects affected / exposed
    1 / 165 (0.61%)
    0 / 5 (0.00%)
    0 / 110 (0.00%)
    0 / 3 (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
    Delirium
         subjects affected / exposed
    1 / 165 (0.61%)
    0 / 5 (0.00%)
    0 / 110 (0.00%)
    0 / 3 (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
    Product issues
    Device dislocation
         subjects affected / exposed
    1 / 165 (0.61%)
    0 / 5 (0.00%)
    0 / 110 (0.00%)
    0 / 3 (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
    Injury, poisoning and procedural complications
    Acetabulum fracture
         subjects affected / exposed
    0 / 165 (0.00%)
    0 / 5 (0.00%)
    1 / 110 (0.91%)
    0 / 3 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Joint dislocation
         subjects affected / exposed
    1 / 165 (0.61%)
    0 / 5 (0.00%)
    0 / 110 (0.00%)
    0 / 3 (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
    Spinal compression fracture
         subjects affected / exposed
    0 / 165 (0.00%)
    0 / 5 (0.00%)
    1 / 110 (0.91%)
    0 / 3 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cardiac disorders
    Acute myocardial infarction
         subjects affected / exposed
    1 / 165 (0.61%)
    0 / 5 (0.00%)
    0 / 110 (0.00%)
    0 / 3 (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
    Acute coronary syndrome
         subjects affected / exposed
    1 / 165 (0.61%)
    0 / 5 (0.00%)
    2 / 110 (1.82%)
    0 / 3 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Atrial fibrillation
         subjects affected / exposed
    0 / 165 (0.00%)
    0 / 5 (0.00%)
    1 / 110 (0.91%)
    0 / 3 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Coronary artery stenosis
         subjects affected / exposed
    0 / 165 (0.00%)
    0 / 5 (0.00%)
    1 / 110 (0.91%)
    0 / 3 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Coronary artery disease
         subjects affected / exposed
    1 / 165 (0.61%)
    0 / 5 (0.00%)
    0 / 110 (0.00%)
    0 / 3 (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
    Cardiac failure
         subjects affected / exposed
    0 / 165 (0.00%)
    0 / 5 (0.00%)
    1 / 110 (0.91%)
    0 / 3 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cardiac arrest
         subjects affected / exposed
    1 / 165 (0.61%)
    0 / 5 (0.00%)
    0 / 110 (0.00%)
    0 / 3 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    0 / 0
    Atrial thrombosis
         subjects affected / exposed
    1 / 165 (0.61%)
    0 / 5 (0.00%)
    0 / 110 (0.00%)
    0 / 3 (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
    Left ventricular failure
         subjects affected / exposed
    1 / 165 (0.61%)
    0 / 5 (0.00%)
    0 / 110 (0.00%)
    0 / 3 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    Myocarditis
         subjects affected / exposed
    2 / 165 (1.21%)
    0 / 5 (0.00%)
    0 / 110 (0.00%)
    0 / 3 (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
    Pericardial effusion
         subjects affected / exposed
    0 / 165 (0.00%)
    0 / 5 (0.00%)
    1 / 110 (0.91%)
    0 / 3 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pericarditis
         subjects affected / exposed
    0 / 165 (0.00%)
    0 / 5 (0.00%)
    1 / 110 (0.91%)
    0 / 3 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Nervous system disorders
    Aphasia
         subjects affected / exposed
    1 / 165 (0.61%)
    0 / 5 (0.00%)
    0 / 110 (0.00%)
    0 / 3 (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
    Bell's palsy
         subjects affected / exposed
    0 / 165 (0.00%)
    0 / 5 (0.00%)
    1 / 110 (0.91%)
    0 / 3 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cerebral infarction
         subjects affected / exposed
    0 / 165 (0.00%)
    0 / 5 (0.00%)
    2 / 110 (1.82%)
    0 / 3 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    Haemorrhage intracranial
         subjects affected / exposed
    0 / 165 (0.00%)
    0 / 5 (0.00%)
    1 / 110 (0.91%)
    0 / 3 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    Encephalopathy
         subjects affected / exposed
    0 / 165 (0.00%)
    0 / 5 (0.00%)
    1 / 110 (0.91%)
    0 / 3 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Haemorrhagic stroke
         subjects affected / exposed
    1 / 165 (0.61%)
    0 / 5 (0.00%)
    0 / 110 (0.00%)
    0 / 3 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Myasthenic syndrome
         subjects affected / exposed
    0 / 165 (0.00%)
    0 / 5 (0.00%)
    1 / 110 (0.91%)
    0 / 3 (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
    Lacunar infarction
         subjects affected / exposed
    0 / 165 (0.00%)
    0 / 5 (0.00%)
    1 / 110 (0.91%)
    0 / 3 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Ischaemic stroke
         subjects affected / exposed
    1 / 165 (0.61%)
    0 / 5 (0.00%)
    0 / 110 (0.00%)
    0 / 3 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    Neuropathy peripheral
         subjects affected / exposed
    0 / 165 (0.00%)
    0 / 5 (0.00%)
    1 / 110 (0.91%)
    0 / 3 (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
    Neuritis
         subjects affected / exposed
    1 / 165 (0.61%)
    0 / 5 (0.00%)
    0 / 110 (0.00%)
    0 / 3 (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
    Myelopathy
         subjects affected / exposed
    0 / 165 (0.00%)
    0 / 5 (0.00%)
    1 / 110 (0.91%)
    0 / 3 (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
    Seizure
         subjects affected / exposed
    0 / 165 (0.00%)
    0 / 5 (0.00%)
    1 / 110 (0.91%)
    0 / 3 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Spinal cord compression
         subjects affected / exposed
    1 / 165 (0.61%)
    0 / 5 (0.00%)
    0 / 110 (0.00%)
    0 / 3 (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
    Blood and lymphatic system disorders
    Thrombocytopenia
         subjects affected / exposed
    1 / 165 (0.61%)
    0 / 5 (0.00%)
    0 / 110 (0.00%)
    0 / 3 (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
    Lymphadenopathy
         subjects affected / exposed
    0 / 165 (0.00%)
    0 / 5 (0.00%)
    1 / 110 (0.91%)
    0 / 3 (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
    Febrile neutropenia
         subjects affected / exposed
    0 / 165 (0.00%)
    0 / 5 (0.00%)
    1 / 110 (0.91%)
    0 / 3 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Abdominal pain upper
         subjects affected / exposed
    1 / 165 (0.61%)
    0 / 5 (0.00%)
    1 / 110 (0.91%)
    0 / 3 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Constipation
         subjects affected / exposed
    1 / 165 (0.61%)
    0 / 5 (0.00%)
    0 / 110 (0.00%)
    0 / 3 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Colitis
         subjects affected / exposed
    3 / 165 (1.82%)
    0 / 5 (0.00%)
    4 / 110 (3.64%)
    0 / 3 (0.00%)
         occurrences causally related to treatment / all
    3 / 3
    0 / 0
    4 / 4
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Diarrhoea
         subjects affected / exposed
    0 / 165 (0.00%)
    0 / 5 (0.00%)
    4 / 110 (3.64%)
    0 / 3 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    5 / 6
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Ileus
         subjects affected / exposed
    0 / 165 (0.00%)
    0 / 5 (0.00%)
    1 / 110 (0.91%)
    0 / 3 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gastric ulcer
         subjects affected / exposed
    0 / 165 (0.00%)
    0 / 5 (0.00%)
    1 / 110 (0.91%)
    0 / 3 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Oesophageal varices haemorrhage
         subjects affected / exposed
    1 / 165 (0.61%)
    0 / 5 (0.00%)
    0 / 110 (0.00%)
    0 / 3 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    Pancreatitis acute
         subjects affected / exposed
    0 / 165 (0.00%)
    0 / 5 (0.00%)
    1 / 110 (0.91%)
    0 / 3 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Rectal haemorrhage
         subjects affected / exposed
    0 / 165 (0.00%)
    0 / 5 (0.00%)
    1 / 110 (0.91%)
    0 / 3 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hepatobiliary disorders
    Autoimmune hepatitis
         subjects affected / exposed
    2 / 165 (1.21%)
    0 / 5 (0.00%)
    0 / 110 (0.00%)
    0 / 3 (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
    Cholecystitis
         subjects affected / exposed
    0 / 165 (0.00%)
    0 / 5 (0.00%)
    2 / 110 (1.82%)
    0 / 3 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cholecystitis acute
         subjects affected / exposed
    0 / 165 (0.00%)
    0 / 5 (0.00%)
    1 / 110 (0.91%)
    0 / 3 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cholelithiasis
         subjects affected / exposed
    1 / 165 (0.61%)
    0 / 5 (0.00%)
    0 / 110 (0.00%)
    0 / 3 (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
    Hepatitis
         subjects affected / exposed
    0 / 165 (0.00%)
    0 / 5 (0.00%)
    2 / 110 (1.82%)
    0 / 3 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    3 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hepatotoxicity
         subjects affected / exposed
    1 / 165 (0.61%)
    0 / 5 (0.00%)
    0 / 110 (0.00%)
    0 / 3 (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
    Hepatitis cholestatic
         subjects affected / exposed
    0 / 165 (0.00%)
    0 / 5 (0.00%)
    1 / 110 (0.91%)
    0 / 3 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Renal and urinary disorders
    Nephritis
         subjects affected / exposed
    1 / 165 (0.61%)
    0 / 5 (0.00%)
    0 / 110 (0.00%)
    0 / 3 (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
    Acute kidney injury
         subjects affected / exposed
    2 / 165 (1.21%)
    0 / 5 (0.00%)
    2 / 110 (1.82%)
    0 / 3 (0.00%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 0
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Urinary retention
         subjects affected / exposed
    1 / 165 (0.61%)
    0 / 5 (0.00%)
    0 / 110 (0.00%)
    0 / 3 (0.00%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Endocrine disorders
    Adrenal insufficiency
         subjects affected / exposed
    1 / 165 (0.61%)
    0 / 5 (0.00%)
    1 / 110 (0.91%)
    0 / 3 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Secondary adrenocortical insufficiency
         subjects affected / exposed
    0 / 165 (0.00%)
    0 / 5 (0.00%)
    1 / 110 (0.91%)
    0 / 3 (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
    Musculoskeletal and connective tissue disorders
    Intervertebral disc protrusion
         subjects affected / exposed
    0 / 165 (0.00%)
    0 / 5 (0.00%)
    1 / 110 (0.91%)
    0 / 3 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Muscular weakness
         subjects affected / exposed
    1 / 165 (0.61%)
    0 / 5 (0.00%)
    0 / 110 (0.00%)
    0 / 3 (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
    Myositis
         subjects affected / exposed
    1 / 165 (0.61%)
    0 / 5 (0.00%)
    0 / 110 (0.00%)
    0 / 3 (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
    Pathological fracture
         subjects affected / exposed
    1 / 165 (0.61%)
    0 / 5 (0.00%)
    0 / 110 (0.00%)
    0 / 3 (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
    Polyarthritis
         subjects affected / exposed
    1 / 165 (0.61%)
    0 / 5 (0.00%)
    0 / 110 (0.00%)
    0 / 3 (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
    Abdominal abscess
         subjects affected / exposed
    1 / 165 (0.61%)
    0 / 5 (0.00%)
    0 / 110 (0.00%)
    0 / 3 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal bacterial infection
         subjects affected / exposed
    1 / 165 (0.61%)
    0 / 5 (0.00%)
    0 / 110 (0.00%)
    0 / 3 (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
    Encephalitis
         subjects affected / exposed
    0 / 165 (0.00%)
    0 / 5 (0.00%)
    1 / 110 (0.91%)
    0 / 3 (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
    Cellulitis
         subjects affected / exposed
    0 / 165 (0.00%)
    0 / 5 (0.00%)
    1 / 110 (0.91%)
    0 / 3 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Escherichia sepsis
         subjects affected / exposed
    1 / 165 (0.61%)
    0 / 5 (0.00%)
    0 / 110 (0.00%)
    0 / 3 (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
    Bronchitis
         subjects affected / exposed
    0 / 165 (0.00%)
    0 / 5 (0.00%)
    1 / 110 (0.91%)
    0 / 3 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Influenza
         subjects affected / exposed
    0 / 165 (0.00%)
    0 / 5 (0.00%)
    1 / 110 (0.91%)
    0 / 3 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pneumonia
         subjects affected / exposed
    2 / 165 (1.21%)
    0 / 5 (0.00%)
    2 / 110 (1.82%)
    0 / 3 (0.00%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 0
    0 / 3
    0 / 0
         deaths causally related to treatment / all
    1 / 2
    0 / 0
    0 / 0
    0 / 0
    Urinary tract infection
         subjects affected / exposed
    1 / 165 (0.61%)
    0 / 5 (0.00%)
    2 / 110 (1.82%)
    0 / 3 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Sepsis
         subjects affected / exposed
    1 / 165 (0.61%)
    0 / 5 (0.00%)
    0 / 110 (0.00%)
    0 / 3 (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
    Urosepsis
         subjects affected / exposed
    1 / 165 (0.61%)
    0 / 5 (0.00%)
    0 / 110 (0.00%)
    0 / 3 (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
    Vascular device infection
         subjects affected / exposed
    1 / 165 (0.61%)
    0 / 5 (0.00%)
    0 / 110 (0.00%)
    0 / 3 (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
    Metabolism and nutrition disorders
    Hypercalcaemia
         subjects affected / exposed
    0 / 165 (0.00%)
    0 / 5 (0.00%)
    1 / 110 (0.91%)
    0 / 3 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Diabetic ketoacidosis
         subjects affected / exposed
    1 / 165 (0.61%)
    0 / 5 (0.00%)
    0 / 110 (0.00%)
    0 / 3 (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
    Diabetes mellitus
         subjects affected / exposed
    0 / 165 (0.00%)
    0 / 5 (0.00%)
    1 / 110 (0.91%)
    0 / 3 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Adult failure to thrive
         subjects affected / exposed
    0 / 165 (0.00%)
    0 / 5 (0.00%)
    1 / 110 (0.91%)
    0 / 3 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Dehydration
         subjects affected / exposed
    1 / 165 (0.61%)
    0 / 5 (0.00%)
    2 / 110 (1.82%)
    0 / 3 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Type 2 diabetes mellitus
         subjects affected / exposed
    0 / 165 (0.00%)
    0 / 5 (0.00%)
    1 / 110 (0.91%)
    0 / 3 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Type 1 diabetes mellitus
         subjects affected / exposed
    2 / 165 (1.21%)
    0 / 5 (0.00%)
    1 / 110 (0.91%)
    0 / 3 (0.00%)
         occurrences causally related to treatment / all
    2 / 2
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hypophosphataemia
         subjects affected / exposed
    0 / 165 (0.00%)
    0 / 5 (0.00%)
    1 / 110 (0.91%)
    0 / 3 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    2 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hyponatraemia
         subjects affected / exposed
    2 / 165 (1.21%)
    0 / 5 (0.00%)
    1 / 110 (0.91%)
    0 / 3 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hyperglycaemia
         subjects affected / exposed
    0 / 165 (0.00%)
    0 / 5 (0.00%)
    3 / 110 (2.73%)
    0 / 3 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 3
    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
    		 Cohort B: nccRCC First Course Cohort B: nccRCC Second Course Cohort A: ccRCC First Course Cohort A: ccRCC Second Course
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    142 / 165 (86.06%)
    3 / 5 (60.00%)
    105 / 110 (95.45%)
    3 / 3 (100.00%)
    Vascular disorders
    Hypertension
         subjects affected / exposed
    11 / 165 (6.67%)
    0 / 5 (0.00%)
    9 / 110 (8.18%)
    0 / 3 (0.00%)
         occurrences all number
    12
    0
    11
    0
    General disorders and administration site conditions
    Asthenia
         subjects affected / exposed
    19 / 165 (11.52%)
    1 / 5 (20.00%)
    13 / 110 (11.82%)
    0 / 3 (0.00%)
         occurrences all number
    22
    1
    23
    0
    Catheter site pain
         subjects affected / exposed
    2 / 165 (1.21%)
    0 / 5 (0.00%)
    0 / 110 (0.00%)
    1 / 3 (33.33%)
         occurrences all number
    2
    0
    0
    1
    Chest pain
         subjects affected / exposed
    9 / 165 (5.45%)
    0 / 5 (0.00%)
    7 / 110 (6.36%)
    0 / 3 (0.00%)
         occurrences all number
    10
    0
    7
    0
    Fatigue
         subjects affected / exposed
    42 / 165 (25.45%)
    0 / 5 (0.00%)
    43 / 110 (39.09%)
    0 / 3 (0.00%)
         occurrences all number
    48
    0
    51
    0
    Influenza like illness
         subjects affected / exposed
    7 / 165 (4.24%)
    0 / 5 (0.00%)
    10 / 110 (9.09%)
    0 / 3 (0.00%)
         occurrences all number
    13
    0
    24
    0
    Oedema peripheral
         subjects affected / exposed
    14 / 165 (8.48%)
    0 / 5 (0.00%)
    8 / 110 (7.27%)
    0 / 3 (0.00%)
         occurrences all number
    16
    0
    9
    0
    Pyrexia
         subjects affected / exposed
    17 / 165 (10.30%)
    1 / 5 (20.00%)
    8 / 110 (7.27%)
    0 / 3 (0.00%)
         occurrences all number
    21
    1
    8
    0
    Immune system disorders
    Hypersensitivity
         subjects affected / exposed
    0 / 165 (0.00%)
    0 / 5 (0.00%)
    0 / 110 (0.00%)
    1 / 3 (33.33%)
         occurrences all number
    0
    0
    0
    1
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    26 / 165 (15.76%)
    0 / 5 (0.00%)
    25 / 110 (22.73%)
    0 / 3 (0.00%)
         occurrences all number
    30
    0
    30
    0
    Dyspnoea
         subjects affected / exposed
    15 / 165 (9.09%)
    0 / 5 (0.00%)
    16 / 110 (14.55%)
    0 / 3 (0.00%)
         occurrences all number
    19
    0
    19
    0
    Productive cough
         subjects affected / exposed
    9 / 165 (5.45%)
    0 / 5 (0.00%)
    2 / 110 (1.82%)
    0 / 3 (0.00%)
         occurrences all number
    11
    0
    2
    0
    Wheezing
         subjects affected / exposed
    1 / 165 (0.61%)
    0 / 5 (0.00%)
    2 / 110 (1.82%)
    1 / 3 (33.33%)
         occurrences all number
    1
    0
    2
    1
    Psychiatric disorders
    Depression
         subjects affected / exposed
    6 / 165 (3.64%)
    0 / 5 (0.00%)
    8 / 110 (7.27%)
    0 / 3 (0.00%)
         occurrences all number
    7
    0
    8
    0
    Insomnia
         subjects affected / exposed
    13 / 165 (7.88%)
    0 / 5 (0.00%)
    10 / 110 (9.09%)
    0 / 3 (0.00%)
         occurrences all number
    14
    0
    13
    0
    Investigations
    Alanine aminotransferase increased
         subjects affected / exposed
    15 / 165 (9.09%)
    0 / 5 (0.00%)
    15 / 110 (13.64%)
    0 / 3 (0.00%)
         occurrences all number
    17
    0
    15
    0
    Aspartate aminotransferase increased
         subjects affected / exposed
    12 / 165 (7.27%)
    0 / 5 (0.00%)
    12 / 110 (10.91%)
    0 / 3 (0.00%)
         occurrences all number
    13
    0
    15
    0
    Blood alkaline phosphatase increased
         subjects affected / exposed
    13 / 165 (7.88%)
    0 / 5 (0.00%)
    8 / 110 (7.27%)
    0 / 3 (0.00%)
         occurrences all number
    15
    0
    8
    0
    Weight decreased
         subjects affected / exposed
    10 / 165 (6.06%)
    0 / 5 (0.00%)
    4 / 110 (3.64%)
    0 / 3 (0.00%)
         occurrences all number
    10
    0
    4
    0
    Neutrophil count decreased
         subjects affected / exposed
    3 / 165 (1.82%)
    0 / 5 (0.00%)
    1 / 110 (0.91%)
    1 / 3 (33.33%)
         occurrences all number
    9
    0
    1
    1
    Lymphocyte count decreased
         subjects affected / exposed
    5 / 165 (3.03%)
    0 / 5 (0.00%)
    7 / 110 (6.36%)
    0 / 3 (0.00%)
         occurrences all number
    11
    0
    9
    0
    Blood creatinine increased
         subjects affected / exposed
    12 / 165 (7.27%)
    0 / 5 (0.00%)
    19 / 110 (17.27%)
    0 / 3 (0.00%)
         occurrences all number
    15
    0
    23
    0
    Cardiac disorders
    Tachycardia
         subjects affected / exposed
    1 / 165 (0.61%)
    1 / 5 (20.00%)
    1 / 110 (0.91%)
    0 / 3 (0.00%)
         occurrences all number
    1
    1
    2
    0
    Nervous system disorders
    Headache
         subjects affected / exposed
    18 / 165 (10.91%)
    0 / 5 (0.00%)
    13 / 110 (11.82%)
    0 / 3 (0.00%)
         occurrences all number
    24
    0
    17
    0
    Dizziness
         subjects affected / exposed
    6 / 165 (3.64%)
    0 / 5 (0.00%)
    10 / 110 (9.09%)
    0 / 3 (0.00%)
         occurrences all number
    9
    0
    13
    0
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    19 / 165 (11.52%)
    0 / 5 (0.00%)
    15 / 110 (13.64%)
    0 / 3 (0.00%)
         occurrences all number
    24
    0
    16
    0
    Gastrointestinal disorders
    Constipation
         subjects affected / exposed
    18 / 165 (10.91%)
    0 / 5 (0.00%)
    23 / 110 (20.91%)
    1 / 3 (33.33%)
         occurrences all number
    23
    0
    23
    1
    Abdominal pain
         subjects affected / exposed
    22 / 165 (13.33%)
    0 / 5 (0.00%)
    10 / 110 (9.09%)
    0 / 3 (0.00%)
         occurrences all number
    28
    0
    11
    0
    Vomiting
         subjects affected / exposed
    27 / 165 (16.36%)
    0 / 5 (0.00%)
    8 / 110 (7.27%)
    0 / 3 (0.00%)
         occurrences all number
    37
    0
    9
    0
    Nausea
         subjects affected / exposed
    28 / 165 (16.97%)
    0 / 5 (0.00%)
    22 / 110 (20.00%)
    0 / 3 (0.00%)
         occurrences all number
    38
    0
    26
    0
    Haemorrhoids
         subjects affected / exposed
    1 / 165 (0.61%)
    1 / 5 (20.00%)
    0 / 110 (0.00%)
    0 / 3 (0.00%)
         occurrences all number
    1
    1
    0
    0
    Dyspepsia
         subjects affected / exposed
    6 / 165 (3.64%)
    0 / 5 (0.00%)
    8 / 110 (7.27%)
    0 / 3 (0.00%)
         occurrences all number
    6
    0
    8
    0
    Dry mouth
         subjects affected / exposed
    15 / 165 (9.09%)
    0 / 5 (0.00%)
    13 / 110 (11.82%)
    0 / 3 (0.00%)
         occurrences all number
    18
    0
    16
    0
    Diarrhoea
         subjects affected / exposed
    40 / 165 (24.24%)
    0 / 5 (0.00%)
    35 / 110 (31.82%)
    0 / 3 (0.00%)
         occurrences all number
    65
    0
    58
    0
    Skin and subcutaneous tissue disorders
    Rash maculo-papular
         subjects affected / exposed
    10 / 165 (6.06%)
    0 / 5 (0.00%)
    8 / 110 (7.27%)
    0 / 3 (0.00%)
         occurrences all number
    11
    0
    8
    0
    Dry skin
         subjects affected / exposed
    10 / 165 (6.06%)
    0 / 5 (0.00%)
    7 / 110 (6.36%)
    0 / 3 (0.00%)
         occurrences all number
    11
    0
    9
    0
    Pruritus
         subjects affected / exposed
    37 / 165 (22.42%)
    1 / 5 (20.00%)
    41 / 110 (37.27%)
    0 / 3 (0.00%)
         occurrences all number
    48
    1
    54
    0
    Rash
         subjects affected / exposed
    19 / 165 (11.52%)
    0 / 5 (0.00%)
    17 / 110 (15.45%)
    1 / 3 (33.33%)
         occurrences all number
    24
    0
    23
    1
    Renal and urinary disorders
    Haematuria
         subjects affected / exposed
    6 / 165 (3.64%)
    0 / 5 (0.00%)
    6 / 110 (5.45%)
    0 / 3 (0.00%)
         occurrences all number
    9
    0
    6
    0
    Endocrine disorders
    Hypothyroidism
         subjects affected / exposed
    26 / 165 (15.76%)
    0 / 5 (0.00%)
    16 / 110 (14.55%)
    0 / 3 (0.00%)
         occurrences all number
    27
    0
    17
    0
    Hyperthyroidism
         subjects affected / exposed
    11 / 165 (6.67%)
    0 / 5 (0.00%)
    6 / 110 (5.45%)
    0 / 3 (0.00%)
         occurrences all number
    11
    0
    6
    0
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    29 / 165 (17.58%)
    0 / 5 (0.00%)
    37 / 110 (33.64%)
    1 / 3 (33.33%)
         occurrences all number
    40
    0
    54
    1
    Back pain
         subjects affected / exposed
    22 / 165 (13.33%)
    0 / 5 (0.00%)
    12 / 110 (10.91%)
    0 / 3 (0.00%)
         occurrences all number
    28
    0
    13
    0
    Groin pain
         subjects affected / exposed
    1 / 165 (0.61%)
    0 / 5 (0.00%)
    1 / 110 (0.91%)
    1 / 3 (33.33%)
         occurrences all number
    1
    0
    1
    1
    Pain in extremity
         subjects affected / exposed
    15 / 165 (9.09%)
    0 / 5 (0.00%)
    7 / 110 (6.36%)
    0 / 3 (0.00%)
         occurrences all number
    15
    0
    7
    0
    Myalgia
         subjects affected / exposed
    10 / 165 (6.06%)
    0 / 5 (0.00%)
    11 / 110 (10.00%)
    0 / 3 (0.00%)
         occurrences all number
    15
    0
    12
    0
    Infections and infestations
    Nasopharyngitis
         subjects affected / exposed
    11 / 165 (6.67%)
    0 / 5 (0.00%)
    8 / 110 (7.27%)
    0 / 3 (0.00%)
         occurrences all number
    16
    0
    9
    0
    Sinusitis
         subjects affected / exposed
    3 / 165 (1.82%)
    0 / 5 (0.00%)
    6 / 110 (5.45%)
    1 / 3 (33.33%)
         occurrences all number
    3
    0
    7
    1
    Upper respiratory tract infection
         subjects affected / exposed
    9 / 165 (5.45%)
    1 / 5 (20.00%)
    9 / 110 (8.18%)
    0 / 3 (0.00%)
         occurrences all number
    10
    1
    9
    0
    Urinary tract infection
         subjects affected / exposed
    14 / 165 (8.48%)
    1 / 5 (20.00%)
    5 / 110 (4.55%)
    0 / 3 (0.00%)
         occurrences all number
    15
    1
    15
    0
    Metabolism and nutrition disorders
    Hyperkalaemia
         subjects affected / exposed
    7 / 165 (4.24%)
    0 / 5 (0.00%)
    8 / 110 (7.27%)
    0 / 3 (0.00%)
         occurrences all number
    10
    0
    18
    0
    Hyperglycaemia
         subjects affected / exposed
    3 / 165 (1.82%)
    0 / 5 (0.00%)
    7 / 110 (6.36%)
    0 / 3 (0.00%)
         occurrences all number
    3
    0
    9
    0
    Hypercalcaemia
         subjects affected / exposed
    3 / 165 (1.82%)
    0 / 5 (0.00%)
    7 / 110 (6.36%)
    0 / 3 (0.00%)
         occurrences all number
    3
    0
    9
    0
    Decreased appetite
         subjects affected / exposed
    25 / 165 (15.15%)
    0 / 5 (0.00%)
    22 / 110 (20.00%)
    0 / 3 (0.00%)
         occurrences all number
    29
    0
    24
    0

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    18 Apr 2017
    Amendment 1 clarified eligibility so that inclusion and exclusion criteria were not overly restrictive, and provided a clear and concise guide to investigators on management of AEs associated with pembrolizumab. Additionally, the amendment allowed enrollment in Cohort B upon local laboratory confirmation of diagnosis, and central laboratory confirmation that the submitted tissue is adequate for central review (previously, central laboratory diagnosis confirmation was required before allocation).
    20 Nov 2017
    Amendment 2 updated the dose modification and toxicity management guidelines for pembrolizumab in order to be in alignment with the most current label and safety information for pembrolizumab. The amendment also changed the timing of bone scans at screening (accepting scans that have been performed within 42 days of screening).
    02 Dec 2020
    Amendment 3 removed reference to “sub-trial” in the Future Biomarker Research (FBR) sections of the protocol.
    09 Jul 2021
    Amendment 4 updated the dose modification and toxicity management guidelines for immune-related adverse events (irAEs).

    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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