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    Clinical Trial Results:
    A Phase II Study of Pembrolizumab (MK-3475) as Monotherapy in Subjects with Previously Treated Locally Advanced Unresectable or Metastatic (Stage IV) Mismatched Repair Deficient or Microsatellite Instability-High Colorectal Carcinoma (KEYNOTE-164)

    Summary
    EudraCT number
    		 2015-001852-32
    Trial protocol
    		 DE   BE   ES   FR  
    Global end of trial date
    19 Feb 2021

    Results information
    Results version number
    		 v1(current)
    This version publication date
    01 Mar 2022
    First version publication date
    01 Mar 2022
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    MK-3475-164
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT02460198
    WHO universal trial number (UTN)
    		 -
    Other trial identifiers
    		 JAPIC-CTI: 153046, Merck: KEYNOTE-164
    Sponsors
    Sponsor organisation name
    Merck Sharp & Dohme Corp.
    Sponsor organisation address
    2000 Galloping Hill Road, Kenilworth, NJ, United States, 07033
    Public contact
    Clinical Trials Disclosure, Merck Sharp & Dohme Corp., ClinicalTrialsDisclosure@merck.com
    Scientific contact
    Clinical Trials Disclosure, Merck Sharp & Dohme Corp., 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
    19 Feb 2021
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    09 Sep 2019
    Global end of trial reached?
    Yes
    Global end of trial date
    19 Feb 2021
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    Participants with previously-treated locally-advanced unresectable or metastatic mismatched repair (MMR) deficient or microsatellite instability-high (MSI-H) colorectal carcinoma (CRC) were treated with pembrolizumab (MK-3475, KEYTRUDA®) monotherapy. Cohort A participants were required to have been previously treated with standard therapies, which included fluoropyrimidine, oxaliplatin, and irinotecan. Cohort B, participants were required to have been previously treated with at least one line of systemic standard of care therapy: fluoropyrimidine + oxaliplatin or fluoropyrimidine + irinotecan +/ - anti-vascular endothelial growth factor (VEGF)/ epidermal growth factor regulator (EGFR) monoclonal antibody. The primary hypothesis is that Objective Response Rate (ORR) based on Response Evaluation Criteria in Solid Tumors v1.1 (RECIST 1.1) assessed by central imaging vendor in participants with locally advanced unresectable or metastatic MMR deficient or MSI high CRC is greater than 15%.
    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
    25 Aug 2015
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    No
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Australia: 6
    Country: Number of subjects enrolled
    Belgium: 9
    Country: Number of subjects enrolled
    Canada: 5
    Country: Number of subjects enrolled
    France: 11
    Country: Number of subjects enrolled
    Germany: 9
    Country: Number of subjects enrolled
    Israel: 8
    Country: Number of subjects enrolled
    Japan: 13
    Country: Number of subjects enrolled
    Korea, Republic of: 17
    Country: Number of subjects enrolled
    Spain: 9
    Country: Number of subjects enrolled
    United States: 37
    Worldwide total number of subjects
    124
    EEA total number of subjects
    38
    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)
    80
    From 65 to 84 years
    44
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 This study was conducted at 34 clinical sites in 10 countries.

    Pre-assignment
    Screening details
    		 Participant flow as per the database cutoff date of 19FEB2021.

    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 - Pembrolizumab 200 mg
    Arm description
    		 Participants were previously treated with standard therapies, which included fluoropyrimidine, oxaliplatin, and irinotecan. Cohort A participants received pembrolizumab 200 mg intravenously (IV) on Day 1 of every 3-week cycle (Q3W) for up to approximately 52 cycles (up to approximately 3 years), which included a first course of 35 cycles and second course treatment phase of 17 cycles after experiencing PD if criteria were met for re-treatment.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Pembrolizumab 200 mg
    Investigational medicinal product code
    Other name
    KEYTRUDA® MK-3475
    Pharmaceutical forms
    Infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    IV Infusion

    Arm title
    		 Cohort B - Pembrolizumab 200 mg
    Arm description
    		 Participants were previously treated with at least one line of systemic standard of care therapy: fluoropyrimidine + oxaliplatin or fluoropyrimidine + irinotecan +/ - anti vascular endothelial growth factor (VEGF)/ epidermal growth factor regulator (EGFR) monoclonal antibody. Cohort B participants received pembrolizumab 200 mg IV on Day 1 Q3W for up to approximately 52 cycles (up to approximately 3 years), which included a first course of 35 cycles and second course treatment phase of 17 cycles after experiencing PD if criteria were met for re-treatment.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Pembrolizumab 200 mg
    Investigational medicinal product code
    Other name
    KEYTRUDA® MK-3475
    Pharmaceutical forms
    Infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    IV Infusion

    Number of subjects in period 1
    		Cohort A - Pembrolizumab 200 mg Cohort B - Pembrolizumab 200 mg
    Started
    61
    63
    Completed
    0
    0
    Not completed
    61
    63
         Site Terminated By Sponsor
    -
    1
         Consent withdrawn by subject
    2
    4
         Adverse event, non-fatal
    1
    3
         Death
    36
    28
         Lost to follow-up
    1
    1
         Transferred to extension study
    15
    15
         Did Not Continue on Extension Study
    6
    11

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Cohort A - Pembrolizumab 200 mg
    Reporting group description
    		 Participants were previously treated with standard therapies, which included fluoropyrimidine, oxaliplatin, and irinotecan. Cohort A participants received pembrolizumab 200 mg intravenously (IV) on Day 1 of every 3-week cycle (Q3W) for up to approximately 52 cycles (up to approximately 3 years), which included a first course of 35 cycles and second course treatment phase of 17 cycles after experiencing PD if criteria were met for re-treatment.

    Reporting group title
    Cohort B - Pembrolizumab 200 mg
    Reporting group description
    		 Participants were previously treated with at least one line of systemic standard of care therapy: fluoropyrimidine + oxaliplatin or fluoropyrimidine + irinotecan +/ - anti vascular endothelial growth factor (VEGF)/ epidermal growth factor regulator (EGFR) monoclonal antibody. Cohort B participants received pembrolizumab 200 mg IV on Day 1 Q3W for up to approximately 52 cycles (up to approximately 3 years), which included a first course of 35 cycles and second course treatment phase of 17 cycles after experiencing PD if criteria were met for re-treatment.

    Reporting group values
    		 Cohort A - Pembrolizumab 200 mg Cohort B - Pembrolizumab 200 mg Total
    Number of subjects
    		 61 63 124
    Age categorical
    Units: Participants
        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)
    		 42 38 80
        From 65-84 years
    		 19 25 44
        85 years and over
    		 0 0 0
    Age Continuous
    Units: Years
        arithmetic mean (standard deviation)
    		 54.3 ( 14.5 ) 57.8 ( 15.2 ) -
    Sex: Female, Male
    Units: Participants
        Female
    		 25 30 55
        Male
    		 36 33 69
    Race (NIH/OMB)
    Units: Subjects
        American Indian or Alaska Native
    		 0 0 0
        Asian
    		 19 14 33
        Native Hawaiian or Other Pacific Islander
    		 0 0 0
        Black or African American
    		 0 7 7
        White
    		 42 42 84
        More than one race
    		 0 0 0
        Unknown or Not Reported
    		 0 0 0
    Ethnicity (NIH/OMB)
    Units: Subjects
        Hispanic or Latino
    		 1 3 4
        Not Hispanic or Latino
    		 59 60 119
        Unknown or Not Reported
    		 1 0 1

    End points

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    End points reporting groups
    Reporting group title
    Cohort A - Pembrolizumab 200 mg
    Reporting group description
    		 Participants were previously treated with standard therapies, which included fluoropyrimidine, oxaliplatin, and irinotecan. Cohort A participants received pembrolizumab 200 mg intravenously (IV) on Day 1 of every 3-week cycle (Q3W) for up to approximately 52 cycles (up to approximately 3 years), which included a first course of 35 cycles and second course treatment phase of 17 cycles after experiencing PD if criteria were met for re-treatment.

    Reporting group title
    Cohort B - Pembrolizumab 200 mg
    Reporting group description
    		 Participants were previously treated with at least one line of systemic standard of care therapy: fluoropyrimidine + oxaliplatin or fluoropyrimidine + irinotecan +/ - anti vascular endothelial growth factor (VEGF)/ epidermal growth factor regulator (EGFR) monoclonal antibody. Cohort B participants received pembrolizumab 200 mg IV on Day 1 Q3W for up to approximately 52 cycles (up to approximately 3 years), which included a first course of 35 cycles and second course treatment phase of 17 cycles after experiencing PD if criteria were met for re-treatment.

    Primary: Objective Response Rate (ORR) - Response Evaluation Criteria in Solid Tumors 1.1 (RECIST 1.1) Assessed by Central Imaging Vendor

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    End point title
    		 Objective Response Rate (ORR) - Response Evaluation Criteria in Solid Tumors 1.1 (RECIST 1.1) Assessed by Central Imaging Vendor [1]
    End point description
    Objective response rate was defined as the percentage of the participants in the analysis population who had a complete response (CR) or partial response (PR). Complete Response: disappearance of all target lesions. Partial Response: at least a 30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum diameters. Responses were based upon blinded central imaging vendor per RECIST 1.1. The point estimate and 95% confidence interval for the ORR, were provided using an exact binomial distribution (Clopper and Pearson method). Participants without response data were counted as nonresponders. The analysis population consisted of all participants who received at least one dose of study treatment. The data cutoff date was 09-SEPT-2019.
    End point type
    Primary
    End point timeframe
    Up to approximately 48 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 - Pembrolizumab 200 mg Cohort B - Pembrolizumab 200 mg
    Number of subjects analysed
    61
    63
    Units: Percentage of participants
        number (confidence interval 95%)
    32.8 (21.3 to 46.0)
    34.9 (23.3 to 48.0)
    No statistical analyses for this end point

    Secondary: Disease Control Rate (DCR) per RECIST 1.1 Assessed by Central Imaging Vendor.

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    End point title
    		 Disease Control Rate (DCR) per RECIST 1.1 Assessed by Central Imaging Vendor.
    End point description
    Disease Control Rate was defined as the percentage of participants who achieved confirmed CR or PR or had demonstrated stable disease (SD) for at least 24 weeks prior to any evidence of progression. Complete Response: disappearance of all target lesions. Partial Response: at least a 30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum diameters. Stable Disease: neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for progressive disease (PD), taking as reference the smallest sum diameters while on study. Progressive Disease: at least a 20% increase in the sum of diameters of target lesions and an absolute increase of at least 5 mm. or the appearance of new lesion(s). Participants in the analysis population with missing DCR were considered as disease not under control. The analysis population consisted of all participants who received at least one dose of study treatment. The data cutoff date was 19-Feb-2021.
    End point type
    Secondary
    End point timeframe
    Up to approximately 66 months
    End point values
    		 Cohort A - Pembrolizumab 200 mg Cohort B - Pembrolizumab 200 mg
    Number of subjects analysed
    61
    63
    Units: Percentage of participants
        number (confidence interval 95%)
    50.8 (37.7 to 63.9)
    55.6 (42.5 to 68.1)
    No statistical analyses for this end point

    Secondary: Progression-Free Survival (PFS) per RECIST 1.1 Assessed by Central Imaging Vendor.

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    End point title
    		 Progression-Free Survival (PFS) per RECIST 1.1 Assessed by Central Imaging Vendor.
    End point description
    PFS is defined as the time from first day of study treatment to the first documented disease progression or death due to any cause, whichever occurs first. Progressive Disease: at least a 20% increase in the sum of diameters of target lesions, taking as reference the smallest sum on study (this includes the baseline sum if that is the smallest on study). In addition to the relative increase of 20%, the sum must have also demonstrated an absolute increase of at least 5 mm. (Note: the appearance of one or more new lesions was also considered progression). PFS was summarized by Kaplan-Meier (KM) methods. The analysis population consisted of all participants who received at least one dose of study treatment. The data cutoff date was 19-FEB-2021.
    End point type
    Secondary
    End point timeframe
    Up to approximately 66 months
    End point values
    		 Cohort A - Pembrolizumab 200 mg Cohort B - Pembrolizumab 200 mg
    Number of subjects analysed
    61
    63
    Units: Months
        median (confidence interval 95%)
    2.3 (2.1 to 8.1)
    4.1 (2.1 to 18.9)
    No statistical analyses for this end point

    Secondary: Overall Survival (OS)

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    End point title
    		 Overall Survival (OS)
    End point description
    OS is defined as the time from first day of study treatment to death due to any cause. Participants without documented death at the time of analysis are censored at the date of the last follow-up. OS was summarized by Kaplan-Meier (KM) methods. The analysis population consisted of all participants who received at least one dose of study treatment. "9999" indicates OS upper limit was not reached for Cohort B. The data cutoff date was 19-FEB-2021.
    End point type
    Secondary
    End point timeframe
    Up to approximately 66 months
    End point values
    		 Cohort A - Pembrolizumab 200 mg Cohort B - Pembrolizumab 200 mg
    Number of subjects analysed
    61
    63
    Units: Months
        median (confidence interval 95%)
    31.4 (21.4 to 58)
    47 (19.2 to 9999)
    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 (AE) was defined as any unfavorable and unintended sign including an abnormal laboratory finding, symptom or disease associated with the use of a medical treatment or procedure, regardless of whether it was considered related to the medical treatment or procedure, that occurred during the course of the study. The analysis population consisted of all 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 - Pembrolizumab 200 mg Cohort B - Pembrolizumab 200 mg
    Number of subjects analysed
    61
    63
    Units: Participants
    60
    63
    No statistical analyses for this end point

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

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    End point title
    		 Number of Participants Who Discontinued Study Treatment Due to an AE.
    End point description
    An adverse event (AE) was defined as any unfavorable and unintended sign including an abnormal laboratory finding, symptom or disease associated with the use of a medical treatment or procedure, regardless of whether it was considered related to the medical treatment or procedure, that occurred during the course of the study. The analysis population consisted of all participants who received at least one dose of study treatment.
    End point type
    Secondary
    End point timeframe
    Up to approximately 36 months
    End point values
    		 Cohort A - Pembrolizumab 200 mg Cohort B - Pembrolizumab 200 mg
    Number of subjects analysed
    61
    63
    Units: Participants
    5
    5
    No statistical analyses for this end point

    Secondary: Duration of Response (DOR) per RECIST 1.1 as Assessed by the Central Imaging Vendor

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    End point title
    		 Duration of Response (DOR) per RECIST 1.1 as Assessed by the Central Imaging Vendor
    End point description
    For participants who demonstrated a CR or PR, duration of response was defined as the time from first documented evidence of CR or PR until disease progression or death due to any cause, whichever occurred first. Complete Response: disappearance of all target lesions. Partial Response: at least a 30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum diameters. Responses were based upon blinded central imaging vendor per RECIST 1.1. Duration of Response was based on independent radiologist review (IRC) review using RECIST 1.1 and was summarized by Kaplan-Meier (KM) methods for censored data. Nonresponders were excluded from the analysis of DOR. The analysis population consisted of all participants who received at least one dose of study treatment and demonstrated a CR or PR. "9999" indicates median DOR and DOR upper limit for both cohorts A and B were not reached by the time of last disease assessment.
    End point type
    Secondary
    End point timeframe
    Up to approximately 66 months
    End point values
    		 Cohort A - Pembrolizumab 200 mg Cohort B - Pembrolizumab 200 mg
    Number of subjects analysed
    20
    22
    Units: Months
        median (full range (min-max))
    9999 (6.2 to 9999)
    9999 (4.4 to 9999)
    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
    Adverse events were collected for a minimum of 30 days after the end of treatment and every 12 weeks during follow-up. The analysis population for AEs included all randomized participants who received at least one dose of study medication whereas the analysis population for deaths included all randomized participants.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    23.1
    Reporting groups
    Reporting group title
    Cohort A First Course
    Reporting group description
    		 Participants were previously treated with standard therapies, which must include fluoropyrimidine, oxaliplatin, and irinotecan. Cohort A participants received pembrolizumab 200 mg intravenously (IV) on Day 1 of every 3-week cycle (Q3W) for up to approximately 35 cycles (up to approximately 2 years).

    Reporting group title
    Cohort A Second Course
    Reporting group description
    		 Participants who completed first course of treatment were treated with pembrolizumab 200 mg intravenously (IV) on Day 1 of every 3-week cycle (Q3W) for up to 17 cycles (approximately 1 year) after experiencing PD if criteria were met for re-treatment.

    Reporting group title
    Cohort B Second Course
    Reporting group description
    		 Participants who completed first course of treatment were treated with pembrolizumab 200 mg intravenously (IV) on Day 1 of every 3-week cycle (Q3W) for up to 17 cycles (approximately 1 year) after experiencing PD if criteria were met for re-treatment.

    Reporting group title
    Cohort B First Course
    Reporting group description
    		 Participants were previously treated with at least one line of systemic standard of care therapy: fluoropyrimidine + oxaliplatin or fluoropyrimidine + irinotecan +/ - anti vascular endothelial growth factor (VEGF)/ epidermal growth factor regulator (EGFR) monoclonal antibody. Cohort B participants received pembrolizumab 200 mg IV on Day 1 Q3W for up to approximately 35 cycles (up to approximately 2 years).

    Serious adverse events
    		 Cohort A First Course Cohort A Second Course Cohort B Second Course Cohort B First Course
    Total subjects affected by serious adverse events
         subjects affected / exposed
    31 / 61 (50.82%)
    1 / 6 (16.67%)
    1 / 3 (33.33%)
    25 / 63 (39.68%)
         number of deaths (all causes)
    38
    0
    0
    31
         number of deaths resulting from adverse events
    0
    0
    0
    0
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Acute myeloid leukaemia
    alternative dictionary used: MedDRA 23.1
         subjects affected / exposed
    0 / 61 (0.00%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    1 / 63 (1.59%)
         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 / 1
    Basal cell carcinoma
    alternative dictionary used: MedDRA 23.1
         subjects affected / exposed
    0 / 61 (0.00%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    1 / 63 (1.59%)
         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
    Metastases to skin
    alternative dictionary used: MedDRA 23.1
         subjects affected / exposed
    0 / 61 (0.00%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    1 / 63 (1.59%)
         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
    Squamous cell carcinoma
    alternative dictionary used: MedDRA 23.1
         subjects affected / exposed
    1 / 61 (1.64%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    0 / 63 (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
    Tumour associated fever
    alternative dictionary used: MedDRA 23.1
         subjects affected / exposed
    0 / 61 (0.00%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    1 / 63 (1.59%)
         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
    Tumour pain
    alternative dictionary used: MedDRA 23.1
         subjects affected / exposed
    1 / 61 (1.64%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    0 / 63 (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
    Embolism
    alternative dictionary used: MedDRA 23.1
         subjects affected / exposed
    0 / 61 (0.00%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    1 / 63 (1.59%)
         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
    Iliac artery occlusion
    alternative dictionary used: MedDRA 23.1
         subjects affected / exposed
    1 / 61 (1.64%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    0 / 63 (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
    Euthanasia
    alternative dictionary used: MedDRA 23.1
         subjects affected / exposed
    1 / 61 (1.64%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    0 / 63 (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
    General physical health deterioration
    alternative dictionary used: MedDRA 23.1
         subjects affected / exposed
    0 / 61 (0.00%)
    0 / 6 (0.00%)
    1 / 3 (33.33%)
    1 / 63 (1.59%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Generalised oedema
    alternative dictionary used: MedDRA 23.1
         subjects affected / exposed
    0 / 61 (0.00%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    1 / 63 (1.59%)
         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
    Pyrexia
    alternative dictionary used: MedDRA 23.1
         subjects affected / exposed
    2 / 61 (3.28%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    0 / 63 (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
    Reproductive system and breast disorders
    Female genital tract fistula
    alternative dictionary used: MedDRA 23.1
         subjects affected / exposed
    1 / 61 (1.64%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    0 / 63 (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
    Vaginal haemorrhage
    alternative dictionary used: MedDRA 23.1
         subjects affected / exposed
    1 / 61 (1.64%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    0 / 63 (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
    Respiratory, thoracic and mediastinal disorders
    Aspiration
    alternative dictionary used: MedDRA 23.1
         subjects affected / exposed
    1 / 61 (1.64%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    0 / 63 (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
    Dyspnoea
    alternative dictionary used: MedDRA 23.1
         subjects affected / exposed
    1 / 61 (1.64%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    4 / 63 (6.35%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pleural effusion
    alternative dictionary used: MedDRA 23.1
         subjects affected / exposed
    0 / 61 (0.00%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    1 / 63 (1.59%)
         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
    Pneumonitis
    alternative dictionary used: MedDRA 23.1
         subjects affected / exposed
    1 / 61 (1.64%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    1 / 63 (1.59%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pulmonary embolism
    alternative dictionary used: MedDRA 23.1
         subjects affected / exposed
    2 / 61 (3.28%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    0 / 63 (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
    Psychiatric disorders
    Suicide attempt
    alternative dictionary used: MedDRA 23.1
         subjects affected / exposed
    1 / 61 (1.64%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    0 / 63 (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 breakage
    alternative dictionary used: MedDRA 23.1
         subjects affected / exposed
    0 / 61 (0.00%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    1 / 63 (1.59%)
         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
    Investigations
    Blood bilirubin increased
    alternative dictionary used: MedDRA 23.1
         subjects affected / exposed
    1 / 61 (1.64%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    0 / 63 (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
    Incisional hernia
    alternative dictionary used: MedDRA 23.1
         subjects affected / exposed
    1 / 61 (1.64%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    0 / 63 (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
    Wrist fracture
    alternative dictionary used: MedDRA 23.1
         subjects affected / exposed
    1 / 61 (1.64%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    0 / 63 (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 disorders
    Acute myocardial infarction
    alternative dictionary used: MedDRA 23.1
         subjects affected / exposed
    1 / 61 (1.64%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    0 / 63 (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
    Sinus bradycardia
    alternative dictionary used: MedDRA 23.1
         subjects affected / exposed
    1 / 61 (1.64%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    0 / 63 (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
    Nervous system disorders
    Headache
    alternative dictionary used: MedDRA 23.1
         subjects affected / exposed
    1 / 61 (1.64%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    0 / 63 (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
    Paralysis
    alternative dictionary used: MedDRA 23.1
         subjects affected / exposed
    1 / 61 (1.64%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    0 / 63 (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
    Syncope
    alternative dictionary used: MedDRA 23.1
         subjects affected / exposed
    0 / 61 (0.00%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    1 / 63 (1.59%)
         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
    Blood and lymphatic system disorders
    Anaemia
    alternative dictionary used: MedDRA 23.1
         subjects affected / exposed
    0 / 61 (0.00%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    1 / 63 (1.59%)
         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
    Thrombocytopenia
    alternative dictionary used: MedDRA 23.1
         subjects affected / exposed
    0 / 61 (0.00%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    1 / 63 (1.59%)
         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
    Eye disorders
    Cataract
    alternative dictionary used: MedDRA 23.1
         subjects affected / exposed
    0 / 61 (0.00%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    1 / 63 (1.59%)
         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
    Corneal decompensation
    alternative dictionary used: MedDRA 23.1
         subjects affected / exposed
    0 / 61 (0.00%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    1 / 63 (1.59%)
         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
    Rhegmatogenous retinal detachment
    alternative dictionary used: MedDRA 23.1
         subjects affected / exposed
    0 / 61 (0.00%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    1 / 63 (1.59%)
         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
    Gastrointestinal disorders
    Abdominal pain
    alternative dictionary used: MedDRA 23.1
         subjects affected / exposed
    3 / 61 (4.92%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    1 / 63 (1.59%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Abdominal pain upper
    alternative dictionary used: MedDRA 23.1
         subjects affected / exposed
    1 / 61 (1.64%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    0 / 63 (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
    alternative dictionary used: MedDRA 23.1
         subjects affected / exposed
    1 / 61 (1.64%)
    1 / 6 (16.67%)
    0 / 3 (0.00%)
    0 / 63 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Diarrhoea
    alternative dictionary used: MedDRA 23.1
         subjects affected / exposed
    0 / 61 (0.00%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    2 / 63 (3.17%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Duodenal ulcer
    alternative dictionary used: MedDRA 23.1
         subjects affected / exposed
    1 / 61 (1.64%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    0 / 63 (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
    Enteritis
    alternative dictionary used: MedDRA 23.1
         subjects affected / exposed
    1 / 61 (1.64%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    0 / 63 (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
    Enterocolitis
    alternative dictionary used: MedDRA 23.1
         subjects affected / exposed
    0 / 61 (0.00%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    1 / 63 (1.59%)
         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
    Enterocutaneous fistula
    alternative dictionary used: MedDRA 23.1
         subjects affected / exposed
    0 / 61 (0.00%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    1 / 63 (1.59%)
         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
    Gastric fistula
    alternative dictionary used: MedDRA 23.1
         subjects affected / exposed
    0 / 61 (0.00%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    1 / 63 (1.59%)
         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
    Gastrointestinal fistula
    alternative dictionary used: MedDRA 23.1
         subjects affected / exposed
    0 / 61 (0.00%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    1 / 63 (1.59%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Ileus
    alternative dictionary used: MedDRA 23.1
         subjects affected / exposed
    3 / 61 (4.92%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    0 / 63 (0.00%)
         occurrences causally related to treatment / all
    0 / 7
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Incarcerated umbilical hernia
    alternative dictionary used: MedDRA 23.1
         subjects affected / exposed
    0 / 61 (0.00%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    1 / 63 (1.59%)
         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
    Intestinal obstruction
    alternative dictionary used: MedDRA 23.1
         subjects affected / exposed
    1 / 61 (1.64%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    0 / 63 (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
    Lower gastrointestinal haemorrhage
    alternative dictionary used: MedDRA 23.1
         subjects affected / exposed
    0 / 61 (0.00%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    1 / 63 (1.59%)
         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
    Nausea
    alternative dictionary used: MedDRA 23.1
         subjects affected / exposed
    1 / 61 (1.64%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    1 / 63 (1.59%)
         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
    Pancreatitis
    alternative dictionary used: MedDRA 23.1
         subjects affected / exposed
    1 / 61 (1.64%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    0 / 63 (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
    Pneumatosis intestinalis
    alternative dictionary used: MedDRA 23.1
         subjects affected / exposed
    0 / 61 (0.00%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    1 / 63 (1.59%)
         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
    Small intestinal obstruction
    alternative dictionary used: MedDRA 23.1
         subjects affected / exposed
    1 / 61 (1.64%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    3 / 63 (4.76%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 5
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Subileus
    alternative dictionary used: MedDRA 23.1
         subjects affected / exposed
    1 / 61 (1.64%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    0 / 63 (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
    Upper gastrointestinal haemorrhage
    alternative dictionary used: MedDRA 23.1
         subjects affected / exposed
    1 / 61 (1.64%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    0 / 63 (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
    Vomiting
    alternative dictionary used: MedDRA 23.1
         subjects affected / exposed
    0 / 61 (0.00%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    1 / 63 (1.59%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hepatobiliary disorders
    Biloma
    alternative dictionary used: MedDRA 23.1
         subjects affected / exposed
    1 / 61 (1.64%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    0 / 63 (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
    Cholecystitis acute
    alternative dictionary used: MedDRA 23.1
         subjects affected / exposed
    1 / 61 (1.64%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    0 / 63 (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
    Cholelithiasis
    alternative dictionary used: MedDRA 23.1
         subjects affected / exposed
    1 / 61 (1.64%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    0 / 63 (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
    Hyperbilirubinaemia
    alternative dictionary used: MedDRA 23.1
         subjects affected / exposed
    0 / 61 (0.00%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    1 / 63 (1.59%)
         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
    Skin and subcutaneous tissue disorders
    Erythema multiforme
    alternative dictionary used: MedDRA 23.1
         subjects affected / exposed
    1 / 61 (1.64%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    0 / 63 (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
    Renal and urinary disorders
    Acute kidney injury
    alternative dictionary used: MedDRA 23.1
         subjects affected / exposed
    1 / 61 (1.64%)
    1 / 6 (16.67%)
    0 / 3 (0.00%)
    0 / 63 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Renal failure
    alternative dictionary used: MedDRA 23.1
         subjects affected / exposed
    0 / 61 (0.00%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    1 / 63 (1.59%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Urinary tract obstruction
    alternative dictionary used: MedDRA 23.1
         subjects affected / exposed
    1 / 61 (1.64%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    0 / 63 (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
    Musculoskeletal and connective tissue disorders
    Autoimmune arthritis
    alternative dictionary used: MedDRA 23.1
         subjects affected / exposed
    0 / 61 (0.00%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    1 / 63 (1.59%)
         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
    Flank pain
    alternative dictionary used: MedDRA 23.1
         subjects affected / exposed
    1 / 61 (1.64%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    1 / 63 (1.59%)
         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
    Muscle swelling
    alternative dictionary used: MedDRA 23.1
         subjects affected / exposed
    1 / 61 (1.64%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    0 / 63 (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
    Infections and infestations
    Abdominal infection
    alternative dictionary used: MedDRA 23.1
         subjects affected / exposed
    0 / 61 (0.00%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    1 / 63 (1.59%)
         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
    Abdominal wall abscess
    alternative dictionary used: MedDRA 23.1
         subjects affected / exposed
    0 / 61 (0.00%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    1 / 63 (1.59%)
         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
    Bacteraemia
    alternative dictionary used: MedDRA 23.1
         subjects affected / exposed
    0 / 61 (0.00%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    1 / 63 (1.59%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Bacterial pyelonephritis
    alternative dictionary used: MedDRA 23.1
         subjects affected / exposed
    0 / 61 (0.00%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    1 / 63 (1.59%)
         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
    Bronchitis
    alternative dictionary used: MedDRA 23.1
         subjects affected / exposed
    0 / 61 (0.00%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    1 / 63 (1.59%)
         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
    Device related infection
    alternative dictionary used: MedDRA 23.1
         subjects affected / exposed
    0 / 61 (0.00%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    1 / 63 (1.59%)
         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
    Influenza
    alternative dictionary used: MedDRA 23.1
         subjects affected / exposed
    1 / 61 (1.64%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    0 / 63 (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
    Klebsiella sepsis
    alternative dictionary used: MedDRA 23.1
         subjects affected / exposed
    0 / 61 (0.00%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    1 / 63 (1.59%)
         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
    Pneumonia
    alternative dictionary used: MedDRA 23.1
         subjects affected / exposed
    1 / 61 (1.64%)
    1 / 6 (16.67%)
    0 / 3 (0.00%)
    1 / 63 (1.59%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Sepsis
    alternative dictionary used: MedDRA 23.1
         subjects affected / exposed
    1 / 61 (1.64%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    4 / 63 (6.35%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    Urinary tract infection
    alternative dictionary used: MedDRA 23.1
         subjects affected / exposed
    2 / 61 (3.28%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    2 / 63 (3.17%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 0
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Urinary tract infection bacterial
    alternative dictionary used: MedDRA 23.1
         subjects affected / exposed
    0 / 61 (0.00%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    1 / 63 (1.59%)
         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
    Urosepsis
    alternative dictionary used: MedDRA 23.1
         subjects affected / exposed
    0 / 61 (0.00%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    2 / 63 (3.17%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Alkalosis hypochloraemic
    alternative dictionary used: MedDRA 23.1
         subjects affected / exposed
    0 / 61 (0.00%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    1 / 63 (1.59%)
         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
    Dehydration
    alternative dictionary used: MedDRA 23.1
         subjects affected / exposed
    1 / 61 (1.64%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    1 / 63 (1.59%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hyponatraemia
    alternative dictionary used: MedDRA 23.1
         subjects affected / exposed
    1 / 61 (1.64%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    0 / 63 (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
    Malnutrition
    alternative dictionary used: MedDRA 23.1
         subjects affected / exposed
    1 / 61 (1.64%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    0 / 63 (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
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Cohort A First Course Cohort A Second Course Cohort B Second Course Cohort B First Course
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    56 / 61 (91.80%)
    5 / 6 (83.33%)
    3 / 3 (100.00%)
    58 / 63 (92.06%)
    Vascular disorders
    Hypertension
    alternative dictionary used: MedDRA 23.1
         subjects affected / exposed
    4 / 61 (6.56%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    5 / 63 (7.94%)
         occurrences all number
    4
    0
    0
    9
    General disorders and administration site conditions
    Asthenia
    alternative dictionary used: MedDRA 23.1
         subjects affected / exposed
    14 / 61 (22.95%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    5 / 63 (7.94%)
         occurrences all number
    20
    0
    0
    6
    Chills
    alternative dictionary used: MedDRA 23.1
         subjects affected / exposed
    3 / 61 (4.92%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    4 / 63 (6.35%)
         occurrences all number
    4
    0
    0
    4
    Fatigue
    alternative dictionary used: MedDRA 23.1
         subjects affected / exposed
    19 / 61 (31.15%)
    1 / 6 (16.67%)
    0 / 3 (0.00%)
    24 / 63 (38.10%)
         occurrences all number
    24
    1
    0
    29
    Influenza like illness
    alternative dictionary used: MedDRA 23.1
         subjects affected / exposed
    4 / 61 (6.56%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    7 / 63 (11.11%)
         occurrences all number
    5
    0
    0
    11
    Malaise
    alternative dictionary used: MedDRA 23.1
         subjects affected / exposed
    2 / 61 (3.28%)
    1 / 6 (16.67%)
    0 / 3 (0.00%)
    3 / 63 (4.76%)
         occurrences all number
    2
    1
    0
    3
    Oedema peripheral
    alternative dictionary used: MedDRA 23.1
         subjects affected / exposed
    11 / 61 (18.03%)
    0 / 6 (0.00%)
    1 / 3 (33.33%)
    10 / 63 (15.87%)
         occurrences all number
    12
    0
    1
    10
    Pyrexia
    alternative dictionary used: MedDRA 23.1
         subjects affected / exposed
    13 / 61 (21.31%)
    2 / 6 (33.33%)
    0 / 3 (0.00%)
    11 / 63 (17.46%)
         occurrences all number
    22
    5
    0
    19
    Reproductive system and breast disorders
    Pelvic pain
    alternative dictionary used: MedDRA 23.1
         subjects affected / exposed
    2 / 61 (3.28%)
    1 / 6 (16.67%)
    0 / 3 (0.00%)
    0 / 63 (0.00%)
         occurrences all number
    2
    1
    0
    0
    Respiratory, thoracic and mediastinal disorders
    Cough
    alternative dictionary used: MedDRA 23.1
         subjects affected / exposed
    15 / 61 (24.59%)
    1 / 6 (16.67%)
    1 / 3 (33.33%)
    9 / 63 (14.29%)
         occurrences all number
    20
    1
    1
    9
    Dysphonia
    alternative dictionary used: MedDRA 23.1
         subjects affected / exposed
    1 / 61 (1.64%)
    0 / 6 (0.00%)
    1 / 3 (33.33%)
    2 / 63 (3.17%)
         occurrences all number
    1
    0
    1
    2
    Dyspnoea
    alternative dictionary used: MedDRA 23.1
         subjects affected / exposed
    9 / 61 (14.75%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    8 / 63 (12.70%)
         occurrences all number
    10
    0
    0
    9
    Epistaxis
    alternative dictionary used: MedDRA 23.1
         subjects affected / exposed
    1 / 61 (1.64%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    5 / 63 (7.94%)
         occurrences all number
    1
    0
    0
    5
    Oropharyngeal pain
    alternative dictionary used: MedDRA 23.1
         subjects affected / exposed
    3 / 61 (4.92%)
    0 / 6 (0.00%)
    1 / 3 (33.33%)
    4 / 63 (6.35%)
         occurrences all number
    3
    0
    1
    4
    Productive cough
    alternative dictionary used: MedDRA 23.1
         subjects affected / exposed
    4 / 61 (6.56%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    1 / 63 (1.59%)
         occurrences all number
    4
    0
    0
    1
    Psychiatric disorders
    Depression
    alternative dictionary used: MedDRA 23.1
         subjects affected / exposed
    2 / 61 (3.28%)
    1 / 6 (16.67%)
    0 / 3 (0.00%)
    5 / 63 (7.94%)
         occurrences all number
    3
    1
    0
    5
    Drug dependence
    alternative dictionary used: MedDRA 23.1
         subjects affected / exposed
    1 / 61 (1.64%)
    1 / 6 (16.67%)
    0 / 3 (0.00%)
    0 / 63 (0.00%)
         occurrences all number
    1
    1
    0
    0
    Insomnia
    alternative dictionary used: MedDRA 23.1
         subjects affected / exposed
    8 / 61 (13.11%)
    1 / 6 (16.67%)
    0 / 3 (0.00%)
    5 / 63 (7.94%)
         occurrences all number
    8
    1
    0
    6
    Investigations
    Alanine aminotransferase increased
    alternative dictionary used: MedDRA 23.1
         subjects affected / exposed
    8 / 61 (13.11%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    7 / 63 (11.11%)
         occurrences all number
    11
    0
    0
    10
    Aspartate aminotransferase increased
    alternative dictionary used: MedDRA 23.1
         subjects affected / exposed
    6 / 61 (9.84%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    5 / 63 (7.94%)
         occurrences all number
    9
    0
    0
    7
    Blood alkaline phosphatase increased
    alternative dictionary used: MedDRA 23.1
         subjects affected / exposed
    5 / 61 (8.20%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    3 / 63 (4.76%)
         occurrences all number
    5
    0
    0
    3
    Blood bilirubin increased
    alternative dictionary used: MedDRA 23.1
         subjects affected / exposed
    2 / 61 (3.28%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    4 / 63 (6.35%)
         occurrences all number
    2
    0
    0
    4
    Blood creatinine increased
    alternative dictionary used: MedDRA 23.1
         subjects affected / exposed
    5 / 61 (8.20%)
    0 / 6 (0.00%)
    1 / 3 (33.33%)
    3 / 63 (4.76%)
         occurrences all number
    7
    0
    1
    5
    Weight decreased
    alternative dictionary used: MedDRA 23.1
         subjects affected / exposed
    7 / 61 (11.48%)
    1 / 6 (16.67%)
    0 / 3 (0.00%)
    1 / 63 (1.59%)
         occurrences all number
    7
    1
    0
    1
    Injury, poisoning and procedural complications
    Fall
    alternative dictionary used: MedDRA 23.1
         subjects affected / exposed
    2 / 61 (3.28%)
    0 / 6 (0.00%)
    1 / 3 (33.33%)
    3 / 63 (4.76%)
         occurrences all number
    2
    0
    1
    3
    Limb injury
    alternative dictionary used: MedDRA 23.1
         subjects affected / exposed
    1 / 61 (1.64%)
    0 / 6 (0.00%)
    1 / 3 (33.33%)
    1 / 63 (1.59%)
         occurrences all number
    1
    0
    1
    1
    Stoma site pruritus
    alternative dictionary used: MedDRA 23.1
         subjects affected / exposed
    1 / 61 (1.64%)
    1 / 6 (16.67%)
    0 / 3 (0.00%)
    0 / 63 (0.00%)
         occurrences all number
    1
    1
    0
    0
    Nervous system disorders
    Amnesia
    alternative dictionary used: MedDRA 23.1
         subjects affected / exposed
    1 / 61 (1.64%)
    0 / 6 (0.00%)
    1 / 3 (33.33%)
    2 / 63 (3.17%)
         occurrences all number
    1
    0
    1
    2
    Dizziness
    alternative dictionary used: MedDRA 23.1
         subjects affected / exposed
    4 / 61 (6.56%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    3 / 63 (4.76%)
         occurrences all number
    5
    0
    0
    3
    Dysgeusia
    alternative dictionary used: MedDRA 23.1
         subjects affected / exposed
    1 / 61 (1.64%)
    0 / 6 (0.00%)
    1 / 3 (33.33%)
    1 / 63 (1.59%)
         occurrences all number
    1
    0
    1
    4
    Headache
    alternative dictionary used: MedDRA 23.1
         subjects affected / exposed
    9 / 61 (14.75%)
    1 / 6 (16.67%)
    0 / 3 (0.00%)
    8 / 63 (12.70%)
         occurrences all number
    11
    1
    0
    16
    Neuropathy peripheral
    alternative dictionary used: MedDRA 23.1
         subjects affected / exposed
    4 / 61 (6.56%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    2 / 63 (3.17%)
         occurrences all number
    6
    0
    0
    2
    Paraesthesia
    alternative dictionary used: MedDRA 23.1
         subjects affected / exposed
    2 / 61 (3.28%)
    1 / 6 (16.67%)
    0 / 3 (0.00%)
    1 / 63 (1.59%)
         occurrences all number
    4
    1
    0
    1
    Blood and lymphatic system disorders
    Anaemia
    alternative dictionary used: MedDRA 23.1
         subjects affected / exposed
    12 / 61 (19.67%)
    2 / 6 (33.33%)
    1 / 3 (33.33%)
    11 / 63 (17.46%)
         occurrences all number
    21
    4
    1
    13
    Ear and labyrinth disorders
    Tinnitus
    alternative dictionary used: MedDRA 23.1
         subjects affected / exposed
    1 / 61 (1.64%)
    0 / 6 (0.00%)
    1 / 3 (33.33%)
    2 / 63 (3.17%)
         occurrences all number
    1
    0
    1
    2
    Eye disorders
    Dry eye
    alternative dictionary used: MedDRA 23.1
         subjects affected / exposed
    4 / 61 (6.56%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    2 / 63 (3.17%)
         occurrences all number
    4
    0
    0
    2
    Ocular discomfort
    alternative dictionary used: MedDRA 23.1
         subjects affected / exposed
    0 / 61 (0.00%)
    0 / 6 (0.00%)
    1 / 3 (33.33%)
    1 / 63 (1.59%)
         occurrences all number
    0
    0
    1
    1
    Gastrointestinal disorders
    Abdominal discomfort
    alternative dictionary used: MedDRA 23.1
         subjects affected / exposed
    4 / 61 (6.56%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    1 / 63 (1.59%)
         occurrences all number
    5
    0
    0
    1
    Abdominal distension
    alternative dictionary used: MedDRA 23.1
         subjects affected / exposed
    4 / 61 (6.56%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    3 / 63 (4.76%)
         occurrences all number
    4
    0
    0
    3
    Abdominal pain
    alternative dictionary used: MedDRA 23.1
         subjects affected / exposed
    18 / 61 (29.51%)
    1 / 6 (16.67%)
    0 / 3 (0.00%)
    14 / 63 (22.22%)
         occurrences all number
    26
    1
    0
    18
    Angular cheilitis
    alternative dictionary used: MedDRA 23.1
         subjects affected / exposed
    0 / 61 (0.00%)
    0 / 6 (0.00%)
    1 / 3 (33.33%)
    1 / 63 (1.59%)
         occurrences all number
    0
    0
    1
    1
    Colitis
    alternative dictionary used: MedDRA 23.1
         subjects affected / exposed
    2 / 61 (3.28%)
    1 / 6 (16.67%)
    0 / 3 (0.00%)
    0 / 63 (0.00%)
         occurrences all number
    2
    1
    0
    0
    Constipation
    alternative dictionary used: MedDRA 23.1
         subjects affected / exposed
    13 / 61 (21.31%)
    1 / 6 (16.67%)
    0 / 3 (0.00%)
    13 / 63 (20.63%)
         occurrences all number
    15
    1
    0
    14
    Diarrhoea
    alternative dictionary used: MedDRA 23.1
         subjects affected / exposed
    23 / 61 (37.70%)
    1 / 6 (16.67%)
    0 / 3 (0.00%)
    16 / 63 (25.40%)
         occurrences all number
    46
    2
    0
    28
    Dyspepsia
    alternative dictionary used: MedDRA 23.1
         subjects affected / exposed
    5 / 61 (8.20%)
    1 / 6 (16.67%)
    0 / 3 (0.00%)
    9 / 63 (14.29%)
         occurrences all number
    7
    1
    0
    9
    Nausea
    alternative dictionary used: MedDRA 23.1
         subjects affected / exposed
    22 / 61 (36.07%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    17 / 63 (26.98%)
         occurrences all number
    32
    0
    0
    26
    Proctalgia
    alternative dictionary used: MedDRA 23.1
         subjects affected / exposed
    2 / 61 (3.28%)
    0 / 6 (0.00%)
    1 / 3 (33.33%)
    2 / 63 (3.17%)
         occurrences all number
    3
    0
    1
    3
    Stomatitis
    alternative dictionary used: MedDRA 23.1
         subjects affected / exposed
    3 / 61 (4.92%)
    0 / 6 (0.00%)
    1 / 3 (33.33%)
    3 / 63 (4.76%)
         occurrences all number
    3
    0
    2
    5
    Toothache
    alternative dictionary used: MedDRA 23.1
         subjects affected / exposed
    2 / 61 (3.28%)
    1 / 6 (16.67%)
    0 / 3 (0.00%)
    2 / 63 (3.17%)
         occurrences all number
    2
    1
    0
    2
    Vomiting
    alternative dictionary used: MedDRA 23.1
         subjects affected / exposed
    18 / 61 (29.51%)
    1 / 6 (16.67%)
    0 / 3 (0.00%)
    14 / 63 (22.22%)
         occurrences all number
    37
    2
    0
    18
    Skin and subcutaneous tissue disorders
    Dermal cyst
    alternative dictionary used: MedDRA 23.1
         subjects affected / exposed
    0 / 61 (0.00%)
    0 / 6 (0.00%)
    1 / 3 (33.33%)
    1 / 63 (1.59%)
         occurrences all number
    0
    0
    1
    1
    Dry skin
    alternative dictionary used: MedDRA 23.1
         subjects affected / exposed
    4 / 61 (6.56%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    5 / 63 (7.94%)
         occurrences all number
    4
    0
    0
    8
    Night sweats
    alternative dictionary used: MedDRA 23.1
         subjects affected / exposed
    2 / 61 (3.28%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    5 / 63 (7.94%)
         occurrences all number
    2
    0
    0
    5
    Pruritus
    alternative dictionary used: MedDRA 23.1
         subjects affected / exposed
    11 / 61 (18.03%)
    1 / 6 (16.67%)
    0 / 3 (0.00%)
    8 / 63 (12.70%)
         occurrences all number
    15
    1
    0
    9
    Rash
    alternative dictionary used: MedDRA 23.1
         subjects affected / exposed
    8 / 61 (13.11%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    9 / 63 (14.29%)
         occurrences all number
    13
    0
    0
    18
    Rash maculo-papular
    alternative dictionary used: MedDRA 23.1
         subjects affected / exposed
    2 / 61 (3.28%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    4 / 63 (6.35%)
         occurrences all number
    2
    0
    0
    5
    Solar lentigo
    alternative dictionary used: MedDRA 23.1
         subjects affected / exposed
    0 / 61 (0.00%)
    0 / 6 (0.00%)
    1 / 3 (33.33%)
    1 / 63 (1.59%)
         occurrences all number
    0
    0
    1
    1
    Urticaria
    alternative dictionary used: MedDRA 23.1
         subjects affected / exposed
    2 / 61 (3.28%)
    1 / 6 (16.67%)
    0 / 3 (0.00%)
    2 / 63 (3.17%)
         occurrences all number
    2
    1
    0
    2
    Renal and urinary disorders
    Dysuria
    alternative dictionary used: MedDRA 23.1
         subjects affected / exposed
    4 / 61 (6.56%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    1 / 63 (1.59%)
         occurrences all number
    4
    0
    0
    1
    Haematuria
    alternative dictionary used: MedDRA 23.1
         subjects affected / exposed
    2 / 61 (3.28%)
    1 / 6 (16.67%)
    0 / 3 (0.00%)
    2 / 63 (3.17%)
         occurrences all number
    5
    2
    0
    2
    Urinary tract discomfort
    alternative dictionary used: MedDRA 23.1
         subjects affected / exposed
    0 / 61 (0.00%)
    0 / 6 (0.00%)
    1 / 3 (33.33%)
    1 / 63 (1.59%)
         occurrences all number
    0
    0
    1
    1
    Endocrine disorders
    Hyperthyroidism
    alternative dictionary used: MedDRA 23.1
         subjects affected / exposed
    4 / 61 (6.56%)
    1 / 6 (16.67%)
    0 / 3 (0.00%)
    7 / 63 (11.11%)
         occurrences all number
    5
    1
    0
    7
    Hypothyroidism
    alternative dictionary used: MedDRA 23.1
         subjects affected / exposed
    6 / 61 (9.84%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    13 / 63 (20.63%)
         occurrences all number
    6
    0
    0
    15
    Musculoskeletal and connective tissue disorders
    Arthralgia
    alternative dictionary used: MedDRA 23.1
         subjects affected / exposed
    15 / 61 (24.59%)
    0 / 6 (0.00%)
    1 / 3 (33.33%)
    16 / 63 (25.40%)
         occurrences all number
    26
    0
    1
    19
    Back pain
    alternative dictionary used: MedDRA 23.1
         subjects affected / exposed
    8 / 61 (13.11%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    14 / 63 (22.22%)
         occurrences all number
    8
    0
    0
    18
    Flank pain
    alternative dictionary used: MedDRA 23.1
         subjects affected / exposed
    3 / 61 (4.92%)
    1 / 6 (16.67%)
    1 / 3 (33.33%)
    3 / 63 (4.76%)
         occurrences all number
    9
    2
    1
    3
    Muscle spasms
    alternative dictionary used: MedDRA 23.1
         subjects affected / exposed
    4 / 61 (6.56%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    3 / 63 (4.76%)
         occurrences all number
    4
    0
    0
    3
    Myalgia
    alternative dictionary used: MedDRA 23.1
         subjects affected / exposed
    6 / 61 (9.84%)
    1 / 6 (16.67%)
    0 / 3 (0.00%)
    7 / 63 (11.11%)
         occurrences all number
    7
    1
    0
    7
    Pain in extremity
    alternative dictionary used: MedDRA 23.1
         subjects affected / exposed
    5 / 61 (8.20%)
    0 / 6 (0.00%)
    1 / 3 (33.33%)
    5 / 63 (7.94%)
         occurrences all number
    6
    0
    2
    8
    Infections and infestations
    Conjunctivitis
    alternative dictionary used: MedDRA 23.1
         subjects affected / exposed
    4 / 61 (6.56%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    0 / 63 (0.00%)
         occurrences all number
    6
    0
    0
    0
    Enterocolitis infectious
    alternative dictionary used: MedDRA 23.1
         subjects affected / exposed
    1 / 61 (1.64%)
    1 / 6 (16.67%)
    0 / 3 (0.00%)
    0 / 63 (0.00%)
         occurrences all number
    1
    1
    0
    0
    Folliculitis
    alternative dictionary used: MedDRA 23.1
         subjects affected / exposed
    1 / 61 (1.64%)
    1 / 6 (16.67%)
    0 / 3 (0.00%)
    0 / 63 (0.00%)
         occurrences all number
    1
    1
    0
    0
    Gingivitis
    alternative dictionary used: MedDRA 23.1
         subjects affected / exposed
    1 / 61 (1.64%)
    1 / 6 (16.67%)
    0 / 3 (0.00%)
    0 / 63 (0.00%)
         occurrences all number
    1
    1
    0
    0
    Groin abscess
    alternative dictionary used: MedDRA 23.1
         subjects affected / exposed
    1 / 61 (1.64%)
    1 / 6 (16.67%)
    0 / 3 (0.00%)
    0 / 63 (0.00%)
         occurrences all number
    1
    1
    0
    0
    Nasopharyngitis
    alternative dictionary used: MedDRA 23.1
         subjects affected / exposed
    7 / 61 (11.48%)
    0 / 6 (0.00%)
    1 / 3 (33.33%)
    2 / 63 (3.17%)
         occurrences all number
    9
    0
    1
    2
    Sinusitis
    alternative dictionary used: MedDRA 23.1
         subjects affected / exposed
    4 / 61 (6.56%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    2 / 63 (3.17%)
         occurrences all number
    8
    0
    0
    2
    Upper respiratory tract infection
    alternative dictionary used: MedDRA 23.1
         subjects affected / exposed
    8 / 61 (13.11%)
    1 / 6 (16.67%)
    0 / 3 (0.00%)
    8 / 63 (12.70%)
         occurrences all number
    13
    1
    0
    10
    Urinary tract infection
    alternative dictionary used: MedDRA 23.1
         subjects affected / exposed
    4 / 61 (6.56%)
    1 / 6 (16.67%)
    0 / 3 (0.00%)
    5 / 63 (7.94%)
         occurrences all number
    7
    1
    0
    7
    Wound infection
    alternative dictionary used: MedDRA 23.1
         subjects affected / exposed
    2 / 61 (3.28%)
    1 / 6 (16.67%)
    0 / 3 (0.00%)
    0 / 63 (0.00%)
         occurrences all number
    2
    1
    0
    0
    Metabolism and nutrition disorders
    Decreased appetite
    alternative dictionary used: MedDRA 23.1
         subjects affected / exposed
    14 / 61 (22.95%)
    2 / 6 (33.33%)
    0 / 3 (0.00%)
    11 / 63 (17.46%)
         occurrences all number
    16
    3
    0
    13
    Hypoalbuminaemia
    alternative dictionary used: MedDRA 23.1
         subjects affected / exposed
    5 / 61 (8.20%)
    1 / 6 (16.67%)
    0 / 3 (0.00%)
    1 / 63 (1.59%)
         occurrences all number
    5
    1
    0
    1
    Hypocalcaemia
    alternative dictionary used: MedDRA 23.1
         subjects affected / exposed
    1 / 61 (1.64%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    6 / 63 (9.52%)
         occurrences all number
    1
    0
    0
    7
    Hypokalaemia
    alternative dictionary used: MedDRA 23.1
         subjects affected / exposed
    3 / 61 (4.92%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    4 / 63 (6.35%)
         occurrences all number
    5
    0
    0
    14
    Hypomagnesaemia
    alternative dictionary used: MedDRA 23.1
         subjects affected / exposed
    2 / 61 (3.28%)
    1 / 6 (16.67%)
    0 / 3 (0.00%)
    3 / 63 (4.76%)
         occurrences all number
    12
    1
    0
    3
    Polydipsia
    alternative dictionary used: MedDRA 23.1
         subjects affected / exposed
    0 / 61 (0.00%)
    0 / 6 (0.00%)
    1 / 3 (33.33%)
    1 / 63 (1.59%)
         occurrences all number
    0
    0
    1
    1

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    24 Aug 2015
    Amendment 1: The protocol was updated to reflect routine clinical practice and to allow enrollment flexibility when defining previous treatments.
    27 Nov 2015
    Amendment 2: The protocol was updated to further clarify prior treatments a subject should have received in order to be eligible for participation in the study.
    06 May 2016
    Amendment 3: The protocol was updated to include a second cohort of 60 subjects added to evaluate pembrolizumab 200 mg 3QW in subjects with CRC who have undergone 1 line of systemic treatment (fluoropyrimidine + oxaliplatin or fluoropyrimidine + irinotecan +/- anti-VEGF/EGFR monoclonal antibody). The first cohort was designated Cohort A, the second, Cohort B.
    10 Feb 2017
    Amendment 4: The protocol was amended to allow additional follow-up analysis to be performed. For Cohort A, the planned interim analysis was to be performed after the first 40 treated subjects have been followed up for at least 18 weeks. However, due to the rapid enrollment of the remaining subjects in Cohort A, it was decided to be conducted after all 61 subject enrolled in Cohort A had been followed up for at least 18 weeks. With this change, the group sequential approach based on the first 40 subjects as originally planned was no longer applicable.
    13 Feb 2018
    Amendment 7: The protocol was updated to add guidelines in the event of dose modification and toxicity management. Guidelines for pembrolizumab were modified to add guidelines in the event of myocarditis and updated guidelines for several other conditions.
    21 Jan 2020
    Amendment 8: The protocol was updated to allow participants access to an extension study.

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

    Limitations and caveats
    Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.
    None reported
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    The status and protocol content of GB trials is no longer updated since 1 January 2021. For the UK, as of 31 January 2021, EU Law applies only to the territory of Northern Ireland (NI) to the extent foreseen in the Protocol on Ireland/NI. Legal notice
    As of 31 January 2023, all EU/EEA initial clinical trial applications must be submitted through CTIS . Updated EudraCT trials information and information on PIP/Art 46 trials conducted exclusively in third countries continues to be submitted through EudraCT and published on this website.

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