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    Clinical Trial Results:
    A Double-Blind, Placebo-Controlled Pivotal Phase III Study Evaluating Xilonix in Symptomatic Colorectal Cancer Patients Refractory to Standard Therapy

    Summary
    EudraCT number
    		 2014-000550-12
    Trial protocol
    		 HU   GB   PL   DE   CZ   BG  
    Global end of trial date
    03 Nov 2015

    Results information
    Results version number
    		 v2(current)
    This version publication date
    31 Mar 2022
    First version publication date
    18 Apr 2021
    Other versions
    		 v1
    Version creation reason

    Trial information

    		 Close Top of page
    Trial identification
    Sponsor protocol code
    2014-PT026
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT02138422
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Janssen Research & Development, LLC
    Sponsor organisation address
    920 Route 202, Raritan, United States, NJ 08869
    Public contact
    Clinical Registry Group, Janssen Research & Development, LLC, ClinicalTrialsEU@its.jnj.com
    Scientific contact
    Clinical Registry Group, Janssen Research & Development, LLC, ClinicalTrialsEU@its.jnj.com
    Paediatric regulatory details
    Is trial part of an agreed paediatric investigation plan (PIP)
    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
    03 Nov 2015
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    03 Nov 2015
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The primary purpose of the study was to evaluate objective response rate (ORR), a composite measure assessing change in Lean Body Mass (LBM), fatigue, pain, and appetite from baseline to week 8.
    Protection of trial subjects
    The study was performed in accordance with the current version of the declaration of Helsinki (64th world medical association [WMA] General Assembly, Fortaleza, Brazil, October 2013). Safety assessment included Adverse events, hematology, and chemistry labs.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    20 Mar 2014
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Bulgaria: 14
    Country: Number of subjects enrolled
    Czechia: 32
    Country: Number of subjects enrolled
    France: 12
    Country: Number of subjects enrolled
    Georgia: 19
    Country: Number of subjects enrolled
    Hungary: 28
    Country: Number of subjects enrolled
    Poland: 164
    Country: Number of subjects enrolled
    Russian Federation: 23
    Country: Number of subjects enrolled
    United Kingdom: 17
    Worldwide total number of subjects
    309
    EEA total number of subjects
    250
    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)
    172
    From 65 to 84 years
    137
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 -

    Pre-assignment
    Screening details
    		 A total of 458 subjects were screened and 333 were randomized.

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

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Placebo Controlled Period (CP) plus BSC
    Arm description
    		 Subjects received matching Placebo via intravenous (IV) injection once every 2 weeks (one cycle) for a total of 4 infusions (four cycles). Best supportive care (BSC) is defined as those measures intended to provide palliation of symptoms and improve quality of life. This included, but is not limited to, psychological support, dietary advice, exercise advice, antibiotics, anti-emetics, and analgesia.
    Arm type
    		 Placebo

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Injection
    Routes of administration
    Intravenous use
    Dosage and administration details
    Subjects received IV injection of matching Placebo.

    Arm title
    		 Bermekimab (Xilonix) plus BSC
    Arm description
    		 Subjects received an intravenous (IV) injection of Bermekimab 7.5 milligrams per kilograms (mg/kg) once every 2 weeks (Cycle 1) for a total of 4 infusions (four cycles). BSC is defined as those measures intended to provide palliation of symptoms and improve quality of life. This included, but is not limited to, psychological support, dietary advice, exercise advice, antibiotics, anti-emetics, and analgesia.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Bermekimab
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Injection
    Routes of administration
    Intravenous use
    Dosage and administration details
    Subjects received IV injection of Bermekimab 7.5 mg/kg.

    Number of subjects in period 1
    		Placebo Controlled Period (CP) plus BSC Bermekimab (Xilonix) plus BSC
    Started
    102
    207
    Completed
    83
    167
    Not completed
    19
    40
         Adverse event, serious fatal
    5
    9
         Physician decision
    3
    6
         Consent withdrawn by subject
    1
    5
         Adverse event, non-fatal
    3
    3
         Other
    3
    10
         Lost to follow-up
    -
    3
    Period 2
    Period 2 title
    Open Label Extension
    Is this the baseline period?
    		 No
    Allocation method
    Not applicable
    Blinding used
    		 Not blinded

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Placebo to Bermekimab (after CP)
    Arm description
    		 Subjects who received Placebo at Week 0, 2, 4, and 6 in CP received Bermekimab 7.5 mg/kg IV injection at Week 8 and every two weeks onwards.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Bermekimab
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Injection
    Routes of administration
    Intravenous use
    Dosage and administration details
    Subjects received Bermekimab 7.5 mg/kg IV injection.

    Arm title
    		 Bermekimab (after CP)
    Arm description
    		 Subjects who received Bermekimab in CP were randomized to the control arm received IV placebo at 7.5 mg/kg via IV injection once every 2 weeks (one cycle) for a total of 4 infusions (four cycles).
    Arm type
    		 Experimental

    Investigational medicinal product name
    Bermekimab
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Injection
    Routes of administration
    Intravenous use
    Dosage and administration details
    Subjects received Bermekimab 7.5 mg/kg IV injection.

    Number of subjects in period 2 [1]
    		Placebo to Bermekimab (after CP) Bermekimab (after CP)
    Started
    62
    138
    Completed
    1
    2
    Not completed
    61
    136
         Adverse event, serious fatal
    9
    22
         Physician decision
    14
    31
         Consent withdrawn by subject
    17
    34
         Adverse event, non-fatal
    2
    10
         Other
    16
    32
         Protocol terminated
    2
    -
         Lost to follow-up
    -
    2
    Notes
    [1] - The number of subjects starting the period is not consistent with the number completing the preceding period. It is expected the number of subjects starting the subsequent period will be the same as the number completing the preceding period.
    Justification: Subjects who completed treatment period and opted to continue treatment entered in to the open label extension phase.

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Placebo Controlled Period (CP) plus BSC
    Reporting group description
    		 Subjects received matching Placebo via intravenous (IV) injection once every 2 weeks (one cycle) for a total of 4 infusions (four cycles). Best supportive care (BSC) is defined as those measures intended to provide palliation of symptoms and improve quality of life. This included, but is not limited to, psychological support, dietary advice, exercise advice, antibiotics, anti-emetics, and analgesia.

    Reporting group title
    Bermekimab (Xilonix) plus BSC
    Reporting group description
    		 Subjects received an intravenous (IV) injection of Bermekimab 7.5 milligrams per kilograms (mg/kg) once every 2 weeks (Cycle 1) for a total of 4 infusions (four cycles). BSC is defined as those measures intended to provide palliation of symptoms and improve quality of life. This included, but is not limited to, psychological support, dietary advice, exercise advice, antibiotics, anti-emetics, and analgesia.

    Reporting group values
    		 Placebo Controlled Period (CP) plus BSC Bermekimab (Xilonix) plus BSC Total
    Number of subjects
    		 102 207 309
    Title for AgeCategorical
    Units: subjects
        Children (2-11 years)
    		 0 0 0
        Adolescents (12-17 years)
    		 0 0 0
        Adults (18-64 years)
    		 60 112 172
        From 65 to 84 years
    		 42 95 137
        85 years and over
    		 0 0 0
    Title for AgeContinuous
    Units: years
        arithmetic mean (standard deviation)
    		 62.6 ( 9.21 ) 63.3 ( 10.08 ) -
    Title for Gender
    Units: subjects
        Female
    		 43 79 122
        Male
    		 59 128 187

    End points

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    End points reporting groups
    Reporting group title
    Placebo Controlled Period (CP) plus BSC
    Reporting group description
    		 Subjects received matching Placebo via intravenous (IV) injection once every 2 weeks (one cycle) for a total of 4 infusions (four cycles). Best supportive care (BSC) is defined as those measures intended to provide palliation of symptoms and improve quality of life. This included, but is not limited to, psychological support, dietary advice, exercise advice, antibiotics, anti-emetics, and analgesia.

    Reporting group title
    Bermekimab (Xilonix) plus BSC
    Reporting group description
    		 Subjects received an intravenous (IV) injection of Bermekimab 7.5 milligrams per kilograms (mg/kg) once every 2 weeks (Cycle 1) for a total of 4 infusions (four cycles). BSC is defined as those measures intended to provide palliation of symptoms and improve quality of life. This included, but is not limited to, psychological support, dietary advice, exercise advice, antibiotics, anti-emetics, and analgesia.
    Reporting group title
    Placebo to Bermekimab (after CP)
    Reporting group description
    		 Subjects who received Placebo at Week 0, 2, 4, and 6 in CP received Bermekimab 7.5 mg/kg IV injection at Week 8 and every two weeks onwards.

    Reporting group title
    Bermekimab (after CP)
    Reporting group description
    		 Subjects who received Bermekimab in CP were randomized to the control arm received IV placebo at 7.5 mg/kg via IV injection once every 2 weeks (one cycle) for a total of 4 infusions (four cycles).

    Primary: Objective Response Rate (ORR) for mITT population

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    End point title
    		 Objective Response Rate (ORR) for mITT population
    End point description
    Objective response was defined as improvement or stabilization (greater than or equal to [>=] 0 kilograms [kg] change) of Lean Body Mass (LBM) as assessed by Dual-energy X-ray Absorptiometry (DEXA) scan; and improvement or no worsening (>=0 score point change) on any two of the three symptom scale measures (fatigue, pain, appetite) of European Organization for Research and Treatment of Cancer – Quality of Life Questionnaire (EORTC QLQ-C30). Modified intent-to-treat (mITT) population was defined as all randomized subjects who received at least one infusion of the study drug.
    End point type
    Primary
    End point timeframe
    Up to 8 weeks
    End point values
    		 Placebo Controlled Period (CP) plus BSC Bermekimab (Xilonix) plus BSC
    Number of subjects analysed
    102
    207
    Units: Subjects
        number (not applicable)
    19
    33
    Statistical analysis title
    		 Statistical analysis 1
    Comparison groups
    Placebo Controlled Period (CP) plus BSC v Bermekimab (Xilonix) plus BSC
    Number of subjects included in analysis
    309
    Analysis specification
    Pre-specified
    Analysis type
    		 non-inferiority
    P-value
    		 = 0.004
    Method
    		 Pearson Chi-Square test
    Parameter type
    		 Unadjusted Odds Ratio
    Point estimate
    2.14
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 1.21
         upper limit
    		 3.78

    Primary: ORR for per Protocol Population

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    End point title
    		 ORR for per Protocol Population
    End point description
    Objective response was defined as improvement or stabilization (>= 0 kg change) of LBM as assessed by DEXA scan; and improvement or no worsening (>=0 score point change) on any two of the three symptom scale measures (fatigue, pain, appetite) of EORTC QLQ-C30. Per protocol population set excluded the 24 subjects who were randomized but not dosed and the 17 placebo subjects from mITT population who showed significant level of MABp1 concentration at PK assessment.
    End point type
    Primary
    End point timeframe
    Up to 8 weeks
    End point values
    		 Placebo Controlled Period (CP) plus BSC Bermekimab (Xilonix) plus BSC
    Number of subjects analysed
    85
    207
    Units: Subjects
        number (not applicable)
    19
    68
    Statistical analysis title
    		 Statistical analysis 1
    Comparison groups
    Placebo Controlled Period (CP) plus BSC v Bermekimab (Xilonix) plus BSC
    Number of subjects included in analysis
    292
    Analysis specification
    Pre-specified
    Analysis type
    		 non-inferiority
    P-value
    		 = 0.037
    Method
    		 Pearson Chi-Square test
    Parameter type
    		 Unadjusted Odds Ratio
    Point estimate
    1.7
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.94
         upper limit
    		 3.06

    Secondary: Change from Baseline in Interleukin-6 (IL-6) up to 8 Weeks

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    End point title
    		 Change from Baseline in Interleukin-6 (IL-6) up to 8 Weeks
    End point description
    Change in IL-6 up to 8 weeks was analyzed. mITT population was defined as all randomized subjects who received at least one infusion of the study drug.
    End point type
    Secondary
    End point timeframe
    Baseline up to 8 weeks
    End point values
    		 Placebo Controlled Period (CP) plus BSC Bermekimab (Xilonix) plus BSC
    Number of subjects analysed
    102
    207
    Units: picograms per milliliter (pg/mL)
        arithmetic mean (standard deviation)
    9.9 ( 2.7 )
    1.6 ( 1.9 )
    No statistical analyses for this end point

    Secondary: Change from Baseline in Platelet Count up to 8 Weeks

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    End point title
    		 Change from Baseline in Platelet Count up to 8 Weeks
    End point description
    Change in platelet count up to 8 weeks was reported. mITT population was defined as all randomized subjects who received at least one infusion of the study drug.
    End point type
    Secondary
    End point timeframe
    Baseline up to 8 Weeks
    End point values
    		 Placebo Controlled Period (CP) plus BSC Bermekimab (Xilonix) plus BSC
    Number of subjects analysed
    102
    207
    Units: 1000 per cubic millimeter (mm^-3)
        arithmetic mean (standard deviation)
    39.53 ( 7.56 )
    13.45 ( 5.33 )
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Up to 8 weeks
    Adverse event reporting additional description
    Safety analysis set included enrolled subjects receiving at least one dose of the study drug.
    Assessment type
    		 Non-systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    18.0
    Reporting groups
    Reporting group title
    Placebo (CP) plus BSC
    Reporting group description
    		 Subjects received matching Placebo via intravenous (IV) injection once every 2 weeks (one cycle) for a total of 4 infusions (four cycles). Best supportive care (BSC) is defined as those measures intended to provide palliation of symptoms and improve quality of life. This included, but is not limited to, psychological support, dietary advice, exercise advice, antibiotics, anti-emetics, and analgesia.

    Reporting group title
    Bermekimab plus BSC
    Reporting group description
    		 Subjects received an intravenous (IV) injection of Bermekimab 7.5 milligrams per kilograms (mg/kg) once every 2 weeks (Cycle 1) for a total of 4 infusions (four cycles). BSC is defined as those measures intended to provide palliation of symptoms and improve quality of life. This included, but is not limited to, psychological support, dietary advice, exercise advice, antibiotics, anti-emetics, and analgesia.

    Reporting group title
    Placebo to Bermekimab (after CP)
    Reporting group description
    		 Subjects who received Placebo at Week 0, 2, 4, and 6 in CP received Bermekimab 7.5 mg/kg IV injection at Week 8 and every two weeks onwards.

    Reporting group title
    Bermekimab (after CP)
    Reporting group description
    		 Subjects who received Bermekimab in CP were randomized to the control arm received IV placebo at 7.5 mg/kg via IV injection once every 2 weeks (one cycle) for a total of 4 infusions (four cycles).

    Serious adverse events
    		 Placebo (CP) plus BSC Bermekimab plus BSC Placebo to Bermekimab (after CP) Bermekimab (after CP)
    Total subjects affected by serious adverse events
         subjects affected / exposed
    27 / 102 (26.47%)
    45 / 207 (21.74%)
    15 / 62 (24.19%)
    50 / 138 (36.23%)
         number of deaths (all causes)
    14
    23
    11
    31
         number of deaths resulting from adverse events
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Colorectal Cancer
         subjects affected / exposed
    0 / 102 (0.00%)
    4 / 207 (1.93%)
    1 / 62 (1.61%)
    7 / 138 (5.07%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 4
    0 / 1
    0 / 8
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Malignant Neoplasm Progression
         subjects affected / exposed
    0 / 102 (0.00%)
    0 / 207 (0.00%)
    0 / 62 (0.00%)
    1 / 138 (0.72%)
         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 Central Nervous System
         subjects affected / exposed
    2 / 102 (1.96%)
    1 / 207 (0.48%)
    0 / 62 (0.00%)
    0 / 138 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Metastases to Liver
         subjects affected / exposed
    0 / 102 (0.00%)
    0 / 207 (0.00%)
    0 / 62 (0.00%)
    1 / 138 (0.72%)
         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
    Metastasis
         subjects affected / exposed
    0 / 102 (0.00%)
    1 / 207 (0.48%)
    0 / 62 (0.00%)
    1 / 138 (0.72%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Metastatic Neoplasm
         subjects affected / exposed
    0 / 102 (0.00%)
    0 / 207 (0.00%)
    0 / 62 (0.00%)
    1 / 138 (0.72%)
         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
    Vascular disorders
    Deep Vein Thrombosis
         subjects affected / exposed
    0 / 102 (0.00%)
    2 / 207 (0.97%)
    0 / 62 (0.00%)
    0 / 138 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 3
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Embolism
         subjects affected / exposed
    1 / 102 (0.98%)
    0 / 207 (0.00%)
    0 / 62 (0.00%)
    0 / 138 (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
    Surgical and medical procedures
    Chemotherapy
         subjects affected / exposed
    1 / 102 (0.98%)
    0 / 207 (0.00%)
    0 / 62 (0.00%)
    0 / 138 (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
    Asthenia
         subjects affected / exposed
    1 / 102 (0.98%)
    1 / 207 (0.48%)
    2 / 62 (3.23%)
    0 / 138 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Death
         subjects affected / exposed
    0 / 102 (0.00%)
    1 / 207 (0.48%)
    0 / 62 (0.00%)
    2 / 138 (1.45%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 2
    Disease Progression
         subjects affected / exposed
    4 / 102 (3.92%)
    7 / 207 (3.38%)
    5 / 62 (8.06%)
    12 / 138 (8.70%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 8
    0 / 5
    0 / 12
         deaths causally related to treatment / all
    0 / 2
    0 / 2
    0 / 1
    0 / 2
    Fatigue
         subjects affected / exposed
    1 / 102 (0.98%)
    0 / 207 (0.00%)
    1 / 62 (1.61%)
    0 / 138 (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
    General Physical Health Deterioration
         subjects affected / exposed
    2 / 102 (1.96%)
    3 / 207 (1.45%)
    1 / 62 (1.61%)
    1 / 138 (0.72%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 3
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Multi-Organ Failure
         subjects affected / exposed
    0 / 102 (0.00%)
    0 / 207 (0.00%)
    0 / 62 (0.00%)
    1 / 138 (0.72%)
         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
    Obstruction
         subjects affected / exposed
    0 / 102 (0.00%)
    1 / 207 (0.48%)
    0 / 62 (0.00%)
    0 / 138 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pain
         subjects affected / exposed
    0 / 102 (0.00%)
    0 / 207 (0.00%)
    0 / 62 (0.00%)
    1 / 138 (0.72%)
         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
         subjects affected / exposed
    0 / 102 (0.00%)
    0 / 207 (0.00%)
    1 / 62 (1.61%)
    1 / 138 (0.72%)
         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
    Immune system disorders
    Hypersensitivity
         subjects affected / exposed
    0 / 102 (0.00%)
    0 / 207 (0.00%)
    0 / 62 (0.00%)
    1 / 138 (0.72%)
         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
    Respiratory, thoracic and mediastinal disorders
    Dyspnoea
         subjects affected / exposed
    1 / 102 (0.98%)
    2 / 207 (0.97%)
    0 / 62 (0.00%)
    1 / 138 (0.72%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 4
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hypoxia
         subjects affected / exposed
    0 / 102 (0.00%)
    1 / 207 (0.48%)
    0 / 62 (0.00%)
    0 / 138 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pleural Effusion
         subjects affected / exposed
    0 / 102 (0.00%)
    0 / 207 (0.00%)
    0 / 62 (0.00%)
    2 / 138 (1.45%)
         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
    Pneumonitis
         subjects affected / exposed
    0 / 102 (0.00%)
    1 / 207 (0.48%)
    0 / 62 (0.00%)
    0 / 138 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pulmonary Embolism
         subjects affected / exposed
    1 / 102 (0.98%)
    0 / 207 (0.00%)
    0 / 62 (0.00%)
    0 / 138 (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 Failure
         subjects affected / exposed
    1 / 102 (0.98%)
    1 / 207 (0.48%)
    0 / 62 (0.00%)
    1 / 138 (0.72%)
         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
    Investigations
    Alanine Aminotransferase Increased
         subjects affected / exposed
    0 / 102 (0.00%)
    1 / 207 (0.48%)
    0 / 62 (0.00%)
    0 / 138 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Platelet Count Decreased
         subjects affected / exposed
    0 / 102 (0.00%)
    0 / 207 (0.00%)
    0 / 62 (0.00%)
    1 / 138 (0.72%)
         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
    Injury, poisoning and procedural complications
    Cervical Vertebral Fracture
         subjects affected / exposed
    0 / 102 (0.00%)
    0 / 207 (0.00%)
    0 / 62 (0.00%)
    1 / 138 (0.72%)
         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
    Hip Fracture
         subjects affected / exposed
    0 / 102 (0.00%)
    1 / 207 (0.48%)
    0 / 62 (0.00%)
    0 / 138 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Incisional Hernia
         subjects affected / exposed
    0 / 102 (0.00%)
    0 / 207 (0.00%)
    0 / 62 (0.00%)
    1 / 138 (0.72%)
         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
    Lumbar Vertebral Fracture
         subjects affected / exposed
    0 / 102 (0.00%)
    0 / 207 (0.00%)
    0 / 62 (0.00%)
    1 / 138 (0.72%)
         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
    Stoma Site Haemorrhage
         subjects affected / exposed
    0 / 102 (0.00%)
    0 / 207 (0.00%)
    0 / 62 (0.00%)
    1 / 138 (0.72%)
         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
    Congenital, familial and genetic disorders
    Hydrocele
         subjects affected / exposed
    0 / 102 (0.00%)
    0 / 207 (0.00%)
    0 / 62 (0.00%)
    1 / 138 (0.72%)
         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
    Cardiac disorders
    Cardiopulmonary Failure
         subjects affected / exposed
    0 / 102 (0.00%)
    1 / 207 (0.48%)
    0 / 62 (0.00%)
    0 / 138 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Coronary Artery Disease
         subjects affected / exposed
    0 / 102 (0.00%)
    0 / 207 (0.00%)
    0 / 62 (0.00%)
    1 / 138 (0.72%)
         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
    Myocardial Infarction
         subjects affected / exposed
    1 / 102 (0.98%)
    0 / 207 (0.00%)
    0 / 62 (0.00%)
    0 / 138 (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
    Cerebrovascular Accident
         subjects affected / exposed
    0 / 102 (0.00%)
    1 / 207 (0.48%)
    0 / 62 (0.00%)
    0 / 138 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Headache
         subjects affected / exposed
    0 / 102 (0.00%)
    0 / 207 (0.00%)
    1 / 62 (1.61%)
    0 / 138 (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
    Lateral Medullary Syndrome
         subjects affected / exposed
    0 / 102 (0.00%)
    0 / 207 (0.00%)
    0 / 62 (0.00%)
    1 / 138 (0.72%)
         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
    Spinal Cord Compression
         subjects affected / exposed
    1 / 102 (0.98%)
    0 / 207 (0.00%)
    0 / 62 (0.00%)
    0 / 138 (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
    Syncope
         subjects affected / exposed
    0 / 102 (0.00%)
    0 / 207 (0.00%)
    0 / 62 (0.00%)
    1 / 138 (0.72%)
         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
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    4 / 102 (3.92%)
    3 / 207 (1.45%)
    2 / 62 (3.23%)
    3 / 138 (2.17%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 6
    0 / 3
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Ear and labyrinth disorders
    Vertigo
         subjects affected / exposed
    0 / 102 (0.00%)
    1 / 207 (0.48%)
    0 / 62 (0.00%)
    0 / 138 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Abdominal Pain
         subjects affected / exposed
    0 / 102 (0.00%)
    1 / 207 (0.48%)
    0 / 62 (0.00%)
    5 / 138 (3.62%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 5
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Anal Haemorrhage
         subjects affected / exposed
    0 / 102 (0.00%)
    1 / 207 (0.48%)
    0 / 62 (0.00%)
    0 / 138 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Ascites
         subjects affected / exposed
    1 / 102 (0.98%)
    0 / 207 (0.00%)
    0 / 62 (0.00%)
    0 / 138 (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
    Constipation
         subjects affected / exposed
    0 / 102 (0.00%)
    0 / 207 (0.00%)
    0 / 62 (0.00%)
    1 / 138 (0.72%)
         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
    Diarrhoea
         subjects affected / exposed
    0 / 102 (0.00%)
    0 / 207 (0.00%)
    1 / 62 (1.61%)
    0 / 138 (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 Haemorrhage
         subjects affected / exposed
    0 / 102 (0.00%)
    0 / 207 (0.00%)
    0 / 62 (0.00%)
    1 / 138 (0.72%)
         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 Obstruction
         subjects affected / exposed
    0 / 102 (0.00%)
    0 / 207 (0.00%)
    1 / 62 (1.61%)
    0 / 138 (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
    Ileal Stenosis
         subjects affected / exposed
    1 / 102 (0.98%)
    0 / 207 (0.00%)
    0 / 62 (0.00%)
    0 / 138 (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
    Ileus
         subjects affected / exposed
    2 / 102 (1.96%)
    0 / 207 (0.00%)
    1 / 62 (1.61%)
    0 / 138 (0.00%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Obstruction Gastric
         subjects affected / exposed
    0 / 102 (0.00%)
    0 / 207 (0.00%)
    1 / 62 (1.61%)
    0 / 138 (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
    Pancreatitis Acute
         subjects affected / exposed
    0 / 102 (0.00%)
    0 / 207 (0.00%)
    0 / 62 (0.00%)
    1 / 138 (0.72%)
         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
    Rectal Haemorrhage
         subjects affected / exposed
    0 / 102 (0.00%)
    1 / 207 (0.48%)
    0 / 62 (0.00%)
    0 / 138 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Small Intestinal Obstruction
         subjects affected / exposed
    0 / 102 (0.00%)
    1 / 207 (0.48%)
    0 / 62 (0.00%)
    1 / 138 (0.72%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Subileus
         subjects affected / exposed
    0 / 102 (0.00%)
    1 / 207 (0.48%)
    0 / 62 (0.00%)
    1 / 138 (0.72%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Vomiting
         subjects affected / exposed
    1 / 102 (0.98%)
    1 / 207 (0.48%)
    0 / 62 (0.00%)
    2 / 138 (1.45%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hepatobiliary disorders
    Hepatic Failure
         subjects affected / exposed
    3 / 102 (2.94%)
    2 / 207 (0.97%)
    0 / 62 (0.00%)
    1 / 138 (0.72%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 3
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Jaundice
         subjects affected / exposed
    0 / 102 (0.00%)
    1 / 207 (0.48%)
    0 / 62 (0.00%)
    2 / 138 (1.45%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Renal and urinary disorders
    Acute Kidney Injury
         subjects affected / exposed
    1 / 102 (0.98%)
    0 / 207 (0.00%)
    0 / 62 (0.00%)
    0 / 138 (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
    Haemorrhage Urinary Tract
         subjects affected / exposed
    0 / 102 (0.00%)
    0 / 207 (0.00%)
    0 / 62 (0.00%)
    1 / 138 (0.72%)
         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
    Hydronephrosis
         subjects affected / exposed
    0 / 102 (0.00%)
    0 / 207 (0.00%)
    1 / 62 (1.61%)
    0 / 138 (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 Failure
         subjects affected / exposed
    1 / 102 (0.98%)
    0 / 207 (0.00%)
    0 / 62 (0.00%)
    1 / 138 (0.72%)
         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
    Renal Impairment
         subjects affected / exposed
    0 / 102 (0.00%)
    1 / 207 (0.48%)
    0 / 62 (0.00%)
    0 / 138 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Urinary Retention
         subjects affected / exposed
    1 / 102 (0.98%)
    0 / 207 (0.00%)
    0 / 62 (0.00%)
    0 / 138 (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
    Endocrine disorders
    Hypopituitarism
         subjects affected / exposed
    0 / 102 (0.00%)
    0 / 207 (0.00%)
    1 / 62 (1.61%)
    0 / 138 (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
    Musculoskeletal and connective tissue disorders
    Muscular Weakness
         subjects affected / exposed
    0 / 102 (0.00%)
    0 / 207 (0.00%)
    1 / 62 (1.61%)
    0 / 138 (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
    Musculoskeletal Pain
         subjects affected / exposed
    0 / 102 (0.00%)
    1 / 207 (0.48%)
    0 / 62 (0.00%)
    0 / 138 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Spinal Pain
         subjects affected / exposed
    0 / 102 (0.00%)
    0 / 207 (0.00%)
    0 / 62 (0.00%)
    1 / 138 (0.72%)
         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
    Infections and infestations
    Abdominal Abscess
         subjects affected / exposed
    0 / 102 (0.00%)
    0 / 207 (0.00%)
    0 / 62 (0.00%)
    1 / 138 (0.72%)
         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
         subjects affected / exposed
    0 / 102 (0.00%)
    0 / 207 (0.00%)
    0 / 62 (0.00%)
    2 / 138 (1.45%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Bronchopneumonia
         subjects affected / exposed
    0 / 102 (0.00%)
    1 / 207 (0.48%)
    0 / 62 (0.00%)
    0 / 138 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cystitis
         subjects affected / exposed
    0 / 102 (0.00%)
    0 / 207 (0.00%)
    0 / 62 (0.00%)
    1 / 138 (0.72%)
         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
    Gastroenteritis
         subjects affected / exposed
    1 / 102 (0.98%)
    0 / 207 (0.00%)
    0 / 62 (0.00%)
    0 / 138 (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
    Infection
         subjects affected / exposed
    0 / 102 (0.00%)
    0 / 207 (0.00%)
    0 / 62 (0.00%)
    1 / 138 (0.72%)
         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
    Peritonitis
         subjects affected / exposed
    0 / 102 (0.00%)
    1 / 207 (0.48%)
    0 / 62 (0.00%)
    0 / 138 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pyonephrosis
         subjects affected / exposed
    0 / 102 (0.00%)
    1 / 207 (0.48%)
    0 / 62 (0.00%)
    0 / 138 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Respiratory Tract Infection
         subjects affected / exposed
    0 / 102 (0.00%)
    0 / 207 (0.00%)
    0 / 62 (0.00%)
    1 / 138 (0.72%)
         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
    Upper Respiratory Tract Infection
         subjects affected / exposed
    0 / 102 (0.00%)
    1 / 207 (0.48%)
    0 / 62 (0.00%)
    0 / 138 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Urosepsis
         subjects affected / exposed
    0 / 102 (0.00%)
    1 / 207 (0.48%)
    0 / 62 (0.00%)
    0 / 138 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Dehydration
         subjects affected / exposed
    0 / 102 (0.00%)
    2 / 207 (0.97%)
    0 / 62 (0.00%)
    0 / 138 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hyperkalaemia
         subjects affected / exposed
    0 / 102 (0.00%)
    0 / 207 (0.00%)
    0 / 62 (0.00%)
    1 / 138 (0.72%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Placebo (CP) plus BSC Bermekimab plus BSC Placebo to Bermekimab (after CP) Bermekimab (after CP)
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    54 / 102 (52.94%)
    122 / 207 (58.94%)
    39 / 62 (62.90%)
    87 / 138 (63.04%)
    Investigations
    Weight Decreased
         subjects affected / exposed
    7 / 102 (6.86%)
    20 / 207 (9.66%)
    7 / 62 (11.29%)
    16 / 138 (11.59%)
         occurrences all number
    8
    21
    8
    21
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    6 / 102 (5.88%)
    16 / 207 (7.73%)
    5 / 62 (8.06%)
    11 / 138 (7.97%)
         occurrences all number
    6
    27
    8
    21
    General disorders and administration site conditions
    Fatigue
         subjects affected / exposed
    11 / 102 (10.78%)
    24 / 207 (11.59%)
    8 / 62 (12.90%)
    20 / 138 (14.49%)
         occurrences all number
    15
    29
    8
    23
    Asthenia
         subjects affected / exposed
    9 / 102 (8.82%)
    18 / 207 (8.70%)
    11 / 62 (17.74%)
    17 / 138 (12.32%)
         occurrences all number
    9
    21
    15
    27
    Oedema Peripheral
         subjects affected / exposed
    8 / 102 (7.84%)
    21 / 207 (10.14%)
    3 / 62 (4.84%)
    9 / 138 (6.52%)
         occurrences all number
    8
    26
    3
    9
    Pyrexia
         subjects affected / exposed
    5 / 102 (4.90%)
    9 / 207 (4.35%)
    2 / 62 (3.23%)
    12 / 138 (8.70%)
         occurrences all number
    5
    9
    2
    14
    Gastrointestinal disorders
    Constipation
         subjects affected / exposed
    7 / 102 (6.86%)
    19 / 207 (9.18%)
    4 / 62 (6.45%)
    11 / 138 (7.97%)
         occurrences all number
    7
    22
    4
    11
    Ascites
         subjects affected / exposed
    8 / 102 (7.84%)
    11 / 207 (5.31%)
    3 / 62 (4.84%)
    9 / 138 (6.52%)
         occurrences all number
    8
    13
    3
    10
    Diarrhoea
         subjects affected / exposed
    2 / 102 (1.96%)
    9 / 207 (4.35%)
    3 / 62 (4.84%)
    7 / 138 (5.07%)
         occurrences all number
    4
    10
    4
    7
    Vomiting
         subjects affected / exposed
    5 / 102 (4.90%)
    13 / 207 (6.28%)
    2 / 62 (3.23%)
    5 / 138 (3.62%)
         occurrences all number
    5
    18
    2
    7
    Nausea
         subjects affected / exposed
    12 / 102 (11.76%)
    18 / 207 (8.70%)
    2 / 62 (3.23%)
    8 / 138 (5.80%)
         occurrences all number
    12
    26
    2
    10
    Abdominal Pain
         subjects affected / exposed
    14 / 102 (13.73%)
    32 / 207 (15.46%)
    6 / 62 (9.68%)
    22 / 138 (15.94%)
         occurrences all number
    16
    32
    6
    28
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    3 / 102 (2.94%)
    4 / 207 (1.93%)
    1 / 62 (1.61%)
    8 / 138 (5.80%)
         occurrences all number
    4
    4
    1
    9
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    4 / 102 (3.92%)
    3 / 207 (1.45%)
    4 / 62 (6.45%)
    1 / 138 (0.72%)
         occurrences all number
    4
    5
    4
    1
    Pain in Extremity
         subjects affected / exposed
    2 / 102 (1.96%)
    8 / 207 (3.86%)
    4 / 62 (6.45%)
    4 / 138 (2.90%)
         occurrences all number
    2
    8
    4
    4
    Infections and infestations
    Urinary Tract Infection
         subjects affected / exposed
    3 / 102 (2.94%)
    9 / 207 (4.35%)
    2 / 62 (3.23%)
    8 / 138 (5.80%)
         occurrences all number
    4
    10
    2
    8
    Metabolism and nutrition disorders
    Decreased Appetite
         subjects affected / exposed
    9 / 102 (8.82%)
    17 / 207 (8.21%)
    4 / 62 (6.45%)
    15 / 138 (10.87%)
         occurrences all number
    9
    17
    4
    17

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? No

    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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    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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