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    Clinical Trial Results:
    An Open-label, Randomized, Phase 3 Study of Nivolumab or Chemotherapy in Subjects with Relapsed Small-cell Lung Cancer after Platinum-based First Line Chemotherapy (CheckMate 331: CHECKpoint pathway and nivoluMAb clinical Trial Evaluation 331)

    Summary
    EudraCT number
    		 2015-001097-18
    Trial protocol
    		 CZ   AT   DE   BE   GB   DK   HU   GR   PL   ES   FR   RO   IT  
    Global end of trial date
    22 Aug 2022

    Results information
    Results version number
    		 v1(current)
    This version publication date
    05 Aug 2023
    First version publication date
    05 Aug 2023
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    CA209-331
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 -
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Bristol-Myers Squibb
    Sponsor organisation address
    Chaussee de la Hulpe 185, Brussels, Belgium, 1170
    Public contact
    Bristol-Myers Squibb International Corporation, EU Study Start-Up Unit, Clinical.Trials@bms.com
    Scientific contact
    Bristol-Myers Squibb Study Director, Bristol-Myers Squibb, Clinical.Trials@bms.com
    Paediatric regulatory details
    Is trial part of an agreed paediatric investigation plan (PIP)
    No
    Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Results analysis stage
    Analysis stage
    Final
    Date of interim/final analysis
    11 Oct 2022
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    22 Aug 2022
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    Compare efficacy of Nivolumab versus chemotherapy in subjects with relapsed small-cell lung cancer (SCLC) after platinum-based, first-line chemotherapy.
    Protection of trial subjects
    The study was in compliance with the ethical principles derived from the Declaration of Helsinki and in compliance with all International Conference on Harmonization Good Clinical Practice Guidelines. All the local regulatory requirements pertinent to safety of trial participants were followed.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    14 Sep 2015
    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
    Austria: 5
    Country: Number of subjects enrolled
    Australia: 15
    Country: Number of subjects enrolled
    Belgium: 18
    Country: Number of subjects enrolled
    Brazil: 11
    Country: Number of subjects enrolled
    Chile: 2
    Country: Number of subjects enrolled
    China: 82
    Country: Number of subjects enrolled
    Czechia: 4
    Country: Number of subjects enrolled
    Denmark: 8
    Country: Number of subjects enrolled
    France: 36
    Country: Number of subjects enrolled
    Germany: 62
    Country: Number of subjects enrolled
    Greece: 13
    Country: Number of subjects enrolled
    Hungary: 4
    Country: Number of subjects enrolled
    Israel: 7
    Country: Number of subjects enrolled
    Italy: 24
    Country: Number of subjects enrolled
    Japan: 46
    Country: Number of subjects enrolled
    Korea, Democratic People's Republic of: 13
    Country: Number of subjects enrolled
    Norway: 10
    Country: Number of subjects enrolled
    Poland: 26
    Country: Number of subjects enrolled
    Romania: 32
    Country: Number of subjects enrolled
    Russian Federation: 15
    Country: Number of subjects enrolled
    Spain: 57
    Country: Number of subjects enrolled
    Switzerland: 11
    Country: Number of subjects enrolled
    United Kingdom: 17
    Country: Number of subjects enrolled
    United States: 51
    Worldwide total number of subjects
    569
    EEA total number of subjects
    299
    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)
    347
    From 65 to 84 years
    221
    85 years and over
    1

    Subject disposition

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    Recruitment
    Recruitment details
    		 -

    Pre-assignment
    Screening details
    		 569 randomized and 547 treated

    Period 1
    Period 1 title
    Pre-treatment
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Not blinded

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Group A
    Arm description
    		 Nivolumab 240mg IV on Day 1 of a 14-day cycle
    Arm type
    		 Experimental

    Investigational medicinal product name
    Nivolumab
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    240mg on Day 1 of a 14-day cycle

    Arm title
    		 Group B
    Arm description
    		 Chemotherapy (Topotecan 1.5 mg/m^2 IV or 2.3 mg/m^2 Oral once daily on Days 1 to 5 of a 21-day cycle / Amrubicin 40 mg/m^2 IV once daily on Days 1 to 3 of a 21-day cycle)
    Arm type
    		 Active comparator

    Investigational medicinal product name
    Amrubicin
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    40 mg/m^2 once daily on Days 1 to 3 of a 21-day cycle

    Investigational medicinal product name
    Topotecan
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Infusion, Capsule
    Routes of administration
    Intravenous use, Oral use
    Dosage and administration details
    1.5 mg/m^2 IV OR 2.3 mg/m^2 oral once daily on Days 1 to 5 of a 21-day cycle

    Number of subjects in period 1
    		Group A Group B
    Started
    284
    285
    Completed
    282
    265
    Not completed
    2
    20
         Consent withdrawn by subject
    -
    10
         subject request to discontinue study treatment
    -
    4
         Other reasons
    1
    1
         Participant no longer meets Study Criteria
    -
    4
         Disease Progression
    1
    1
    Period 2
    Period 2 title
    Treatment
    Is this the baseline period?
    		 No
    Allocation method
    Randomised - controlled
    Blinding used
    		 Not blinded

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Group A
    Arm description
    		 Nivolumab 240mg IV on Day 1 of a 14-day cycle
    Arm type
    		 Experimental

    Investigational medicinal product name
    Nivolumab
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    240mg on Day 1 of a 14-day cycle

    Arm title
    		 Group B
    Arm description
    		 Chemotherapy (Topotecan 1.5 mg/m^2 IV or 2.3 mg/m^2 Oral once daily on Days 1 to 5 of a 21-day cycle / Amrubicin 40 mg/m^2 IV once daily on Days 1 to 3 of a 21-day cycle)
    Arm type
    		 Active comparator

    Investigational medicinal product name
    Amrubicin
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    40 mg/m^2 once daily on Days 1 to 3 of a 21-day cycle

    Investigational medicinal product name
    Topotecan
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Infusion, Capsule
    Routes of administration
    Intravenous use, Oral use
    Dosage and administration details
    1.5 mg/m^2 IV OR 2.3 mg/m^2 oral once daily on Days 1 to 5 of a 21-day cycle

    Number of subjects in period 2
    		Group A Group B
    Started
    282
    265
    Completed
    0
    0
    Not completed
    282
    265
         Adverse event, serious fatal
    1
    1
         Consent withdrawn by subject
    2
    3
         Study drug toxicity
    18
    38
         Adverse Event unrelated to Study drug
    14
    11
         Maximum Clinical Benefit
    -
    5
         subject request to discontinue study treatment
    6
    34
         Other reasons
    6
    1
         Lost to follow-up
    1
    -
         Disease Progression
    233
    171
         Administrative reason by sponsor
    1
    1

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Group A
    Reporting group description
    		 Nivolumab 240mg IV on Day 1 of a 14-day cycle

    Reporting group title
    Group B
    Reporting group description
    		 Chemotherapy (Topotecan 1.5 mg/m^2 IV or 2.3 mg/m^2 Oral once daily on Days 1 to 5 of a 21-day cycle / Amrubicin 40 mg/m^2 IV once daily on Days 1 to 3 of a 21-day cycle)

    Reporting group values
    		 Group A Group B Total
    Number of subjects
    		 284 285 569
    Age categorical
    Units:
    Age Continuous
    Units: years
        arithmetic mean (standard deviation)
    		 61.5 ( 9.2 ) 61.6 ( 8.4 ) -
    Sex: Female, Male
    Units: Participants
        Female
    		 110 108 218
        Male
    		 174 177 351
    Race (NIH/OMB)
    Units: Subjects
        American Indian or Alaska Native
    		 0 1 1
        Asian
    		 70 71 141
        Native Hawaiian or Other Pacific Islander
    		 0 0 0
        Black or African American
    		 1 2 3
        White
    		 211 211 422
        More than one race
    		 0 0 0
        Unknown or Not Reported
    		 2 0 2
    Ethnicity (NIH/OMB)
    Units: Subjects
        Hispanic or Latino
    		 4 6 10
        Not Hispanic or Latino
    		 125 142 267
        Unknown or Not Reported
    		 155 137 292

    End points

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    End points reporting groups
    Reporting group title
    Group A
    Reporting group description
    		 Nivolumab 240mg IV on Day 1 of a 14-day cycle

    Reporting group title
    Group B
    Reporting group description
    		 Chemotherapy (Topotecan 1.5 mg/m^2 IV or 2.3 mg/m^2 Oral once daily on Days 1 to 5 of a 21-day cycle / Amrubicin 40 mg/m^2 IV once daily on Days 1 to 3 of a 21-day cycle)
    Reporting group title
    Group A
    Reporting group description
    		 Nivolumab 240mg IV on Day 1 of a 14-day cycle

    Reporting group title
    Group B
    Reporting group description
    		 Chemotherapy (Topotecan 1.5 mg/m^2 IV or 2.3 mg/m^2 Oral once daily on Days 1 to 5 of a 21-day cycle / Amrubicin 40 mg/m^2 IV once daily on Days 1 to 3 of a 21-day cycle)

    Primary: Overall Survival (OS)

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    End point title
    		 Overall Survival (OS)
    End point description
    The time from randomization to the date of death, data was based on Kaplan-Meier Estimates. A participant who has not died will be censored at last known date alive.
    End point type
    Primary
    End point timeframe
    OS was followed continuously while participants were on the study drug and every 3 months, minimum follow up for overall survival was 15.8 months
    End point values
    		 Group A Group B
    Number of subjects analysed
    284
    285
    Units: Months
        median (confidence interval 95%)
    7.46 (5.65 to 9.20)
    8.38 (7.03 to 10.02)
    Statistical analysis title
    		 Hazard Ratio (HR)
    Comparison groups
    Group A v Group B
    Number of subjects included in analysis
    569
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    		 = 0.1144
    Method
    		 Logrank
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.86
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.72
         upper limit
    		 1.04

    Secondary: Progression Free Survival (PFS)

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    End point title
    		 Progression Free Survival (PFS)
    End point description
    PFS is defined as the time from randomization to the date of the first documented tumor progression based on investigator assessment (per RECIST 1.1), or death due to any cause. Participants who die without a reported prior progression will be considered to have progressed on the date of their death. Participants who did not progress or die will be censored on the date of their last evaluable tumor assessment. Participants who did not have any on study tumor assessments and did not die will be censored on the date they were randomized. Participants who started any subsequent anti-cancer therapy without a prior reported progression will be censored at the last evaluable tumor assessment prior to initiation of the subsequent anti-cancer therapy. Progressive disease (PD)= At least a 20% increase in the sum of diameters of target lesions, taking as reference the smallest sum on study. The sum must demonstrate an absolute increase of at least 5 mm.
    End point type
    Secondary
    End point timeframe
    From randomization to the date of first documented tumor progression, or death due to any cause. Tumor response assessed every 6 weeks from first dose until week 30, and every 12 weeks (Up to approximately 80 months)
    End point values
    		 Group A Group B
    Number of subjects analysed
    284
    285
    Units: Months
        median (confidence interval 95%)
    1.45 (1.41 to 1.51)
    3.71 (2.96 to 4.24)
    Statistical analysis title
    		 Hazard Ratio (HR)
    Comparison groups
    Group A v Group B
    Number of subjects included in analysis
    569
    Analysis specification
    Pre-specified
    Analysis type
    Method
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    1.39
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 1.16
         upper limit
    		 1.66

    Secondary: Objective Response Rate (ORR)

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    End point title
    		 Objective Response Rate (ORR)
    End point description
    ORR is defined as the percentage of randomized participants whose best overall response (BOR) from baseline is either a complete response (CR) or partial response (PR) based on investigator assessment per RECIST 1.1 criteria. For participants without documented progression or subsequent anti-cancer therapy, all available response designations will contribute to the BOR determination. For participants who continue nivolumab beyond progression, the BOR should be determined based on tumor assessments before initial RECIST 1.1 defined progression. CR= Disappearance of all target lesions. Any pathological lymph nodes must have reduction in short axis to <10 mm. PR= At least a 30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum diameters. Progressive disease (PD)= At least a 20% increase in the sum of diameters of target lesions, taking as reference the smallest sum on study. The sum must demonstrate an absolute increase of at least 5 mm.
    End point type
    Secondary
    End point timeframe
    From randomization to the date of objectively documented progression or the date of subsequent anti-cancer therapy, whichever occurs first (Up to approximately 80 months)
    End point values
    		 Group A Group B
    Number of subjects analysed
    284
    285
    Units: Percentage of Participants
        number (confidence interval 95%)
    13.7 (10.0 to 18.3)
    16.8 (12.7 to 21.7)
    Statistical analysis title
    		 Estimate of Odds Ratio (OR)
    Comparison groups
    Group A v Group B
    Number of subjects included in analysis
    569
    Analysis specification
    Pre-specified
    Analysis type
    Method
    Parameter type
    		 Estimate of Odds Ratio (OR)
    Point estimate
    0.78
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.49
         upper limit
    		 1.24

    Post-hoc: Overall Survival (OS) - Extended Collection

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    End point title
    		 Overall Survival (OS) - Extended Collection
    End point description
    The time from randomization to the date of death, data was based on Kaplan-Meier Estimates. A participant who has not died will be censored at last known date alive.
    End point type
    Post-hoc
    End point timeframe
    OS was followed continuously while participants were on the study drug and every 3 months, minimum follow up for overall survival was 64 months (Up to approximately 80 months)
    End point values
    		 Group A Group B
    Number of subjects analysed
    284
    285
    Units: Months
        median (confidence interval 95%)
    7.46 (5.65 to 9.20)
    8.38 (7.03 to 10.02)
    Statistical analysis title
    		 Hazard Ratio (HR)
    Comparison groups
    Group A v Group B
    Number of subjects included in analysis
    569
    Analysis specification
    Post-hoc
    Analysis type
    		 superiority
    Method
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.87
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.73
         upper limit
    		 1.04

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    SAEs and NSAEs are assessed from first dose to 100 days post last dose (Up to approximately 72 months). Participants were assessed for deaths (all causes) from their first dose to study completion (Up to approximately 80 months).
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    25.0
    Reporting groups
    Reporting group title
    Group B
    Reporting group description
    		 Chemotherapy (Topotecan 1.5 mg/m^2 IV or 2.3 mg/m^2 oral once daily on Days 1 to 5 of a 21-day cycle / Amrubicin 40 mg/m^2 IV once daily on Days 1 to 3 of a 21-day cycle)

    Reporting group title
    Group A
    Reporting group description
    		 Nivolumab 240mg IV on Day 1 of a 14-day cycle

    Serious adverse events
    		 Group B Group A
    Total subjects affected by serious adverse events
         subjects affected / exposed
    171 / 265 (64.53%)
    183 / 282 (64.89%)
         number of deaths (all causes)
    246
    249
         number of deaths resulting from adverse events
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Tongue neoplasm
         subjects affected / exposed
    0 / 265 (0.00%)
    1 / 282 (0.35%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Adenocarcinoma
         subjects affected / exposed
    1 / 265 (0.38%)
    0 / 282 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Basal cell carcinoma
         subjects affected / exposed
    0 / 265 (0.00%)
    1 / 282 (0.35%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cancer pain
         subjects affected / exposed
    0 / 265 (0.00%)
    1 / 282 (0.35%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Epiglottic cancer
         subjects affected / exposed
    0 / 265 (0.00%)
    1 / 282 (0.35%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lung neoplasm malignant
         subjects affected / exposed
    1 / 265 (0.38%)
    0 / 282 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Malignant neoplasm progression
         subjects affected / exposed
    85 / 265 (32.08%)
    108 / 282 (38.30%)
         occurrences causally related to treatment / all
    0 / 89
    0 / 116
         deaths causally related to treatment / all
    0 / 79
    0 / 96
    Pericardial effusion malignant
         subjects affected / exposed
    0 / 265 (0.00%)
    1 / 282 (0.35%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Second primary malignancy
         subjects affected / exposed
    1 / 265 (0.38%)
    0 / 282 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Squamous cell carcinoma of lung
         subjects affected / exposed
    0 / 265 (0.00%)
    1 / 282 (0.35%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Squamous cell carcinoma of the tongue
         subjects affected / exposed
    0 / 265 (0.00%)
    1 / 282 (0.35%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Tumour invasion
         subjects affected / exposed
    0 / 265 (0.00%)
    1 / 282 (0.35%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Tumour pain
         subjects affected / exposed
    1 / 265 (0.38%)
    0 / 282 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vascular disorders
    Poor venous access
         subjects affected / exposed
    1 / 265 (0.38%)
    0 / 282 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Deep vein thrombosis
         subjects affected / exposed
    0 / 265 (0.00%)
    1 / 282 (0.35%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Superior vena cava syndrome
         subjects affected / exposed
    2 / 265 (0.75%)
    0 / 282 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Shock
         subjects affected / exposed
    1 / 265 (0.38%)
    0 / 282 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    General disorders and administration site conditions
    Performance status decreased
         subjects affected / exposed
    1 / 265 (0.38%)
    0 / 282 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pain
         subjects affected / exposed
    2 / 265 (0.75%)
    1 / 282 (0.35%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Oedema peripheral
         subjects affected / exposed
    0 / 265 (0.00%)
    1 / 282 (0.35%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Non-cardiac chest pain
         subjects affected / exposed
    1 / 265 (0.38%)
    1 / 282 (0.35%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Multiple organ dysfunction syndrome
         subjects affected / exposed
    1 / 265 (0.38%)
    0 / 282 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Mucosal inflammation
         subjects affected / exposed
    0 / 265 (0.00%)
    1 / 282 (0.35%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Sudden death
         subjects affected / exposed
    1 / 265 (0.38%)
    0 / 282 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    General physical health deterioration
         subjects affected / exposed
    6 / 265 (2.26%)
    8 / 282 (2.84%)
         occurrences causally related to treatment / all
    1 / 8
    1 / 8
         deaths causally related to treatment / all
    0 / 1
    0 / 4
    Fatigue
         subjects affected / exposed
    1 / 265 (0.38%)
    0 / 282 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Death
         subjects affected / exposed
    1 / 265 (0.38%)
    0 / 282 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Chest pain
         subjects affected / exposed
    0 / 265 (0.00%)
    1 / 282 (0.35%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Asthenia
         subjects affected / exposed
    5 / 265 (1.89%)
    0 / 282 (0.00%)
         occurrences causally related to treatment / all
    1 / 5
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Pyrexia
         subjects affected / exposed
    3 / 265 (1.13%)
    4 / 282 (1.42%)
         occurrences causally related to treatment / all
    1 / 3
    1 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Malaise
         subjects affected / exposed
    1 / 265 (0.38%)
    1 / 282 (0.35%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Interstitial lung disease
         subjects affected / exposed
    0 / 265 (0.00%)
    2 / 282 (0.71%)
         occurrences causally related to treatment / all
    0 / 0
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Acute pulmonary oedema
         subjects affected / exposed
    0 / 265 (0.00%)
    1 / 282 (0.35%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Acute respiratory failure
         subjects affected / exposed
    0 / 265 (0.00%)
    1 / 282 (0.35%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Atelectasis
         subjects affected / exposed
    1 / 265 (0.38%)
    0 / 282 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bronchial obstruction
         subjects affected / exposed
    1 / 265 (0.38%)
    0 / 282 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Chronic obstructive pulmonary disease
         subjects affected / exposed
    2 / 265 (0.75%)
    1 / 282 (0.35%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cough
         subjects affected / exposed
    0 / 265 (0.00%)
    1 / 282 (0.35%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Dyspnoea
         subjects affected / exposed
    8 / 265 (3.02%)
    9 / 282 (3.19%)
         occurrences causally related to treatment / all
    1 / 8
    1 / 9
         deaths causally related to treatment / all
    0 / 1
    0 / 1
    Epistaxis
         subjects affected / exposed
    1 / 265 (0.38%)
    0 / 282 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Haemoptysis
         subjects affected / exposed
    3 / 265 (1.13%)
    1 / 282 (0.35%)
         occurrences causally related to treatment / all
    1 / 3
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypoxia
         subjects affected / exposed
    0 / 265 (0.00%)
    1 / 282 (0.35%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lung infiltration
         subjects affected / exposed
    1 / 265 (0.38%)
    0 / 282 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Oesophagobronchial fistula
         subjects affected / exposed
    0 / 265 (0.00%)
    1 / 282 (0.35%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Pleural effusion
         subjects affected / exposed
    2 / 265 (0.75%)
    2 / 282 (0.71%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pleurisy
         subjects affected / exposed
    0 / 265 (0.00%)
    1 / 282 (0.35%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonitis
         subjects affected / exposed
    0 / 265 (0.00%)
    10 / 282 (3.55%)
         occurrences causally related to treatment / all
    0 / 0
    9 / 11
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Pneumothorax
         subjects affected / exposed
    1 / 265 (0.38%)
    1 / 282 (0.35%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pulmonary embolism
         subjects affected / exposed
    4 / 265 (1.51%)
    1 / 282 (0.35%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pulmonary haemorrhage
         subjects affected / exposed
    1 / 265 (0.38%)
    0 / 282 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory distress
         subjects affected / exposed
    1 / 265 (0.38%)
    0 / 282 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory failure
         subjects affected / exposed
    2 / 265 (0.75%)
    2 / 282 (0.71%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 2
    Mediastinal disorder
         subjects affected / exposed
    0 / 265 (0.00%)
    1 / 282 (0.35%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Psychiatric disorders
    Confusional state
         subjects affected / exposed
    2 / 265 (0.75%)
    2 / 282 (0.71%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Delirium
         subjects affected / exposed
    1 / 265 (0.38%)
    0 / 282 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Disorientation
         subjects affected / exposed
    1 / 265 (0.38%)
    0 / 282 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Investigations
    Amylase increased
         subjects affected / exposed
    0 / 265 (0.00%)
    1 / 282 (0.35%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Aspartate aminotransferase increased
         subjects affected / exposed
    0 / 265 (0.00%)
    1 / 282 (0.35%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Blood creatinine increased
         subjects affected / exposed
    0 / 265 (0.00%)
    1 / 282 (0.35%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Blood electrolytes abnormal
         subjects affected / exposed
    1 / 265 (0.38%)
    0 / 282 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    C-reactive protein increased
         subjects affected / exposed
    2 / 265 (0.75%)
    0 / 282 (0.00%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gamma-glutamyltransferase increased
         subjects affected / exposed
    0 / 265 (0.00%)
    1 / 282 (0.35%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lipase increased
         subjects affected / exposed
    0 / 265 (0.00%)
    2 / 282 (0.71%)
         occurrences causally related to treatment / all
    0 / 0
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Platelet count decreased
         subjects affected / exposed
    10 / 265 (3.77%)
    4 / 282 (1.42%)
         occurrences causally related to treatment / all
    12 / 12
    1 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    White blood cell count decreased
         subjects affected / exposed
    2 / 265 (0.75%)
    1 / 282 (0.35%)
         occurrences causally related to treatment / all
    2 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Neutrophil count decreased
         subjects affected / exposed
    4 / 265 (1.51%)
    2 / 282 (0.71%)
         occurrences causally related to treatment / all
    3 / 4
    0 / 2
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Injury, poisoning and procedural complications
    Bone contusion
         subjects affected / exposed
    1 / 265 (0.38%)
    0 / 282 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Contusion
         subjects affected / exposed
    0 / 265 (0.00%)
    1 / 282 (0.35%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Femoral neck fracture
         subjects affected / exposed
    1 / 265 (0.38%)
    1 / 282 (0.35%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infusion related reaction
         subjects affected / exposed
    1 / 265 (0.38%)
    1 / 282 (0.35%)
         occurrences causally related to treatment / all
    1 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Injection related reaction
         subjects affected / exposed
    0 / 265 (0.00%)
    1 / 282 (0.35%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Subdural haematoma
         subjects affected / exposed
    0 / 265 (0.00%)
    1 / 282 (0.35%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Synovial rupture
         subjects affected / exposed
    1 / 265 (0.38%)
    0 / 282 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Toxicity to various agents
         subjects affected / exposed
    0 / 265 (0.00%)
    1 / 282 (0.35%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Cardiac disorders
    Cardiac arrest
         subjects affected / exposed
    0 / 265 (0.00%)
    1 / 282 (0.35%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Atrial flutter
         subjects affected / exposed
    1 / 265 (0.38%)
    0 / 282 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Atrial fibrillation
         subjects affected / exposed
    1 / 265 (0.38%)
    1 / 282 (0.35%)
         occurrences causally related to treatment / all
    0 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    1 / 1
    Acute myocardial infarction
         subjects affected / exposed
    1 / 265 (0.38%)
    0 / 282 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac failure
         subjects affected / exposed
    1 / 265 (0.38%)
    2 / 282 (0.71%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pericardial effusion
         subjects affected / exposed
    0 / 265 (0.00%)
    1 / 282 (0.35%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardio-respiratory arrest
         subjects affected / exposed
    1 / 265 (0.38%)
    0 / 282 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Cardiac tamponade
         subjects affected / exposed
    0 / 265 (0.00%)
    1 / 282 (0.35%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac failure acute
         subjects affected / exposed
    0 / 265 (0.00%)
    1 / 282 (0.35%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    1 / 1
    Nervous system disorders
    Brain oedema
         subjects affected / exposed
    0 / 265 (0.00%)
    1 / 282 (0.35%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cerebellar ataxia
         subjects affected / exposed
    0 / 265 (0.00%)
    1 / 282 (0.35%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cerebrovascular accident
         subjects affected / exposed
    2 / 265 (0.75%)
    0 / 282 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Epilepsy
         subjects affected / exposed
    0 / 265 (0.00%)
    1 / 282 (0.35%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Haemorrhage intracranial
         subjects affected / exposed
    0 / 265 (0.00%)
    1 / 282 (0.35%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Headache
         subjects affected / exposed
    1 / 265 (0.38%)
    1 / 282 (0.35%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hemiparesis
         subjects affected / exposed
    1 / 265 (0.38%)
    0 / 282 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Lacunar infarction
         subjects affected / exposed
    0 / 265 (0.00%)
    1 / 282 (0.35%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Neurological symptom
         subjects affected / exposed
    1 / 265 (0.38%)
    0 / 282 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Paraneoplastic neurological syndrome
         subjects affected / exposed
    0 / 265 (0.00%)
    1 / 282 (0.35%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    1 / 1
    Seizure
         subjects affected / exposed
    0 / 265 (0.00%)
    1 / 282 (0.35%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Spinal cord compression
         subjects affected / exposed
    0 / 265 (0.00%)
    1 / 282 (0.35%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Syncope
         subjects affected / exposed
    0 / 265 (0.00%)
    1 / 282 (0.35%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Toxic encephalopathy
         subjects affected / exposed
    0 / 265 (0.00%)
    1 / 282 (0.35%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    Lymphadenopathy
         subjects affected / exposed
    1 / 265 (0.38%)
    0 / 282 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Leukopenia
         subjects affected / exposed
    3 / 265 (1.13%)
    1 / 282 (0.35%)
         occurrences causally related to treatment / all
    2 / 3
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Febrile neutropenia
         subjects affected / exposed
    23 / 265 (8.68%)
    7 / 282 (2.48%)
         occurrences causally related to treatment / all
    25 / 25
    0 / 7
         deaths causally related to treatment / all
    3 / 3
    0 / 1
    Bone marrow failure
         subjects affected / exposed
    1 / 265 (0.38%)
    0 / 282 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Anaemia
         subjects affected / exposed
    14 / 265 (5.28%)
    3 / 282 (1.06%)
         occurrences causally related to treatment / all
    13 / 14
    0 / 5
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Myelosuppression
         subjects affected / exposed
    10 / 265 (3.77%)
    0 / 282 (0.00%)
         occurrences causally related to treatment / all
    10 / 10
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Neutropenia
         subjects affected / exposed
    11 / 265 (4.15%)
    0 / 282 (0.00%)
         occurrences causally related to treatment / all
    11 / 12
    0 / 0
         deaths causally related to treatment / all
    1 / 1
    0 / 0
    Pancytopenia
         subjects affected / exposed
    8 / 265 (3.02%)
    0 / 282 (0.00%)
         occurrences causally related to treatment / all
    9 / 9
    0 / 0
         deaths causally related to treatment / all
    1 / 1
    0 / 0
    Thrombocytopenia
         subjects affected / exposed
    15 / 265 (5.66%)
    1 / 282 (0.35%)
         occurrences causally related to treatment / all
    15 / 15
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ear and labyrinth disorders
    Vertigo
         subjects affected / exposed
    1 / 265 (0.38%)
    0 / 282 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Abdominal pain upper
         subjects affected / exposed
    1 / 265 (0.38%)
    0 / 282 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ascites
         subjects affected / exposed
    0 / 265 (0.00%)
    1 / 282 (0.35%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Abdominal hernia obstructive
         subjects affected / exposed
    0 / 265 (0.00%)
    1 / 282 (0.35%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Abdominal pain
         subjects affected / exposed
    4 / 265 (1.51%)
    4 / 282 (1.42%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Colitis
         subjects affected / exposed
    1 / 265 (0.38%)
    2 / 282 (0.71%)
         occurrences causally related to treatment / all
    0 / 1
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vomiting
         subjects affected / exposed
    1 / 265 (0.38%)
    2 / 282 (0.71%)
         occurrences causally related to treatment / all
    0 / 1
    1 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Small intestinal haemorrhage
         subjects affected / exposed
    0 / 265 (0.00%)
    1 / 282 (0.35%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Oral disorder
         subjects affected / exposed
    0 / 265 (0.00%)
    1 / 282 (0.35%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nausea
         subjects affected / exposed
    2 / 265 (0.75%)
    2 / 282 (0.71%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Intestinal obstruction
         subjects affected / exposed
    0 / 265 (0.00%)
    1 / 282 (0.35%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Intestinal haemorrhage
         subjects affected / exposed
    1 / 265 (0.38%)
    0 / 282 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Immune-mediated enterocolitis
         subjects affected / exposed
    0 / 265 (0.00%)
    1 / 282 (0.35%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrooesophageal reflux disease
         subjects affected / exposed
    0 / 265 (0.00%)
    1 / 282 (0.35%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastritis
         subjects affected / exposed
    1 / 265 (0.38%)
    0 / 282 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastric haemorrhage
         subjects affected / exposed
    0 / 265 (0.00%)
    1 / 282 (0.35%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Dysphagia
         subjects affected / exposed
    0 / 265 (0.00%)
    1 / 282 (0.35%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Duodenal ulcer
         subjects affected / exposed
    0 / 265 (0.00%)
    1 / 282 (0.35%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Diarrhoea
         subjects affected / exposed
    1 / 265 (0.38%)
    4 / 282 (1.42%)
         occurrences causally related to treatment / all
    1 / 1
    2 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Constipation
         subjects affected / exposed
    1 / 265 (0.38%)
    0 / 282 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatobiliary disorders
    Drug-induced liver injury
         subjects affected / exposed
    0 / 265 (0.00%)
    1 / 282 (0.35%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatic failure
         subjects affected / exposed
    0 / 265 (0.00%)
    1 / 282 (0.35%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatitis
         subjects affected / exposed
    0 / 265 (0.00%)
    1 / 282 (0.35%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Jaundice cholestatic
         subjects affected / exposed
    0 / 265 (0.00%)
    1 / 282 (0.35%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Skin and subcutaneous tissue disorders
    Dermatitis
         subjects affected / exposed
    0 / 265 (0.00%)
    1 / 282 (0.35%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Paraneoplastic pemphigus
         subjects affected / exposed
    0 / 265 (0.00%)
    1 / 282 (0.35%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pruritus
         subjects affected / exposed
    0 / 265 (0.00%)
    1 / 282 (0.35%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Stevens-Johnson syndrome
         subjects affected / exposed
    0 / 265 (0.00%)
    1 / 282 (0.35%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal and urinary disorders
    Bladder dilatation
         subjects affected / exposed
    1 / 265 (0.38%)
    0 / 282 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Haematuria
         subjects affected / exposed
    0 / 265 (0.00%)
    1 / 282 (0.35%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal failure
         subjects affected / exposed
    2 / 265 (0.75%)
    0 / 282 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Endocrine disorders
    Adrenocorticotropic hormone deficiency
         subjects affected / exposed
    0 / 265 (0.00%)
    1 / 282 (0.35%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cushing's syndrome
         subjects affected / exposed
    0 / 265 (0.00%)
    1 / 282 (0.35%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hyperthyroidism
         subjects affected / exposed
    0 / 265 (0.00%)
    2 / 282 (0.71%)
         occurrences causally related to treatment / all
    0 / 0
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Secondary adrenocortical insufficiency
         subjects affected / exposed
    1 / 265 (0.38%)
    0 / 282 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Inappropriate antidiuretic hormone secretion
         subjects affected / exposed
    2 / 265 (0.75%)
    1 / 282 (0.35%)
         occurrences causally related to treatment / all
    0 / 2
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Back pain
         subjects affected / exposed
    1 / 265 (0.38%)
    1 / 282 (0.35%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Arthralgia
         subjects affected / exposed
    2 / 265 (0.75%)
    1 / 282 (0.35%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Arthritis
         subjects affected / exposed
    0 / 265 (0.00%)
    1 / 282 (0.35%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bone pain
         subjects affected / exposed
    0 / 265 (0.00%)
    1 / 282 (0.35%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Osteoporotic fracture
         subjects affected / exposed
    1 / 265 (0.38%)
    0 / 282 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pain in extremity
         subjects affected / exposed
    0 / 265 (0.00%)
    2 / 282 (0.71%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pathological fracture
         subjects affected / exposed
    1 / 265 (0.38%)
    0 / 282 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Osteonecrosis of jaw
         subjects affected / exposed
    0 / 265 (0.00%)
    1 / 282 (0.35%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infections and infestations
    Bronchitis bacterial
         subjects affected / exposed
    0 / 265 (0.00%)
    1 / 282 (0.35%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bullous erysipelas
         subjects affected / exposed
    0 / 265 (0.00%)
    1 / 282 (0.35%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cellulitis
         subjects affected / exposed
    1 / 265 (0.38%)
    0 / 282 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Chronic sinusitis
         subjects affected / exposed
    0 / 265 (0.00%)
    1 / 282 (0.35%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Device related infection
         subjects affected / exposed
    1 / 265 (0.38%)
    0 / 282 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Encephalitis
         subjects affected / exposed
    0 / 265 (0.00%)
    1 / 282 (0.35%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Enterocolitis infectious
         subjects affected / exposed
    1 / 265 (0.38%)
    0 / 282 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Erysipelas
         subjects affected / exposed
    1 / 265 (0.38%)
    0 / 282 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Herpes simplex
         subjects affected / exposed
    0 / 265 (0.00%)
    1 / 282 (0.35%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Appendicitis
         subjects affected / exposed
    0 / 265 (0.00%)
    1 / 282 (0.35%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bacteraemia
         subjects affected / exposed
    1 / 265 (0.38%)
    0 / 282 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bronchitis
         subjects affected / exposed
    0 / 265 (0.00%)
    2 / 282 (0.71%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infectious pleural effusion
         subjects affected / exposed
    0 / 265 (0.00%)
    1 / 282 (0.35%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infective exacerbation of chronic obstructive airways disease
         subjects affected / exposed
    0 / 265 (0.00%)
    1 / 282 (0.35%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Localised infection
         subjects affected / exposed
    1 / 265 (0.38%)
    0 / 282 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Neutropenic sepsis
         subjects affected / exposed
    4 / 265 (1.51%)
    0 / 282 (0.00%)
         occurrences causally related to treatment / all
    3 / 4
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ophthalmic herpes zoster
         subjects affected / exposed
    1 / 265 (0.38%)
    0 / 282 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Peritonsillar abscess
         subjects affected / exposed
    0 / 265 (0.00%)
    1 / 282 (0.35%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumocystis jirovecii pneumonia
         subjects affected / exposed
    1 / 265 (0.38%)
    0 / 282 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonia
         subjects affected / exposed
    9 / 265 (3.40%)
    15 / 282 (5.32%)
         occurrences causally related to treatment / all
    1 / 10
    0 / 17
         deaths causally related to treatment / all
    0 / 1
    0 / 3
    Pneumonia aspiration
         subjects affected / exposed
    0 / 265 (0.00%)
    1 / 282 (0.35%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonia bacterial
         subjects affected / exposed
    0 / 265 (0.00%)
    1 / 282 (0.35%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Post procedural infection
         subjects affected / exposed
    1 / 265 (0.38%)
    0 / 282 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pulmonary sepsis
         subjects affected / exposed
    1 / 265 (0.38%)
    0 / 282 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Respiratory tract infection
         subjects affected / exposed
    2 / 265 (0.75%)
    3 / 282 (1.06%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 3
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Sepsis
         subjects affected / exposed
    2 / 265 (0.75%)
    2 / 282 (0.71%)
         occurrences causally related to treatment / all
    2 / 2
    0 / 2
         deaths causally related to treatment / all
    2 / 2
    0 / 1
    Upper respiratory tract infection
         subjects affected / exposed
    0 / 265 (0.00%)
    1 / 282 (0.35%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Urinary tract infection
         subjects affected / exposed
    1 / 265 (0.38%)
    2 / 282 (0.71%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vascular device infection
         subjects affected / exposed
    2 / 265 (0.75%)
    0 / 282 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Dehydration
         subjects affected / exposed
    0 / 265 (0.00%)
    1 / 282 (0.35%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Electrolyte imbalance
         subjects affected / exposed
    1 / 265 (0.38%)
    0 / 282 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Glucose tolerance impaired
         subjects affected / exposed
    0 / 265 (0.00%)
    1 / 282 (0.35%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hyperglycaemia
         subjects affected / exposed
    0 / 265 (0.00%)
    2 / 282 (0.71%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Hyperkalaemia
         subjects affected / exposed
    1 / 265 (0.38%)
    0 / 282 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypokalaemia
         subjects affected / exposed
    1 / 265 (0.38%)
    0 / 282 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypomagnesaemia
         subjects affected / exposed
    0 / 265 (0.00%)
    1 / 282 (0.35%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hyponatraemia
         subjects affected / exposed
    3 / 265 (1.13%)
    5 / 282 (1.77%)
         occurrences causally related to treatment / all
    1 / 3
    2 / 7
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Type 1 diabetes mellitus
         subjects affected / exposed
    0 / 265 (0.00%)
    1 / 282 (0.35%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Group B Group A
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    248 / 265 (93.58%)
    249 / 282 (88.30%)
    General disorders and administration site conditions
    Asthenia
         subjects affected / exposed
    60 / 265 (22.64%)
    65 / 282 (23.05%)
         occurrences all number
    78
    76
    Fatigue
         subjects affected / exposed
    78 / 265 (29.43%)
    63 / 282 (22.34%)
         occurrences all number
    95
    76
    Pyrexia
         subjects affected / exposed
    37 / 265 (13.96%)
    28 / 282 (9.93%)
         occurrences all number
    37
    38
    Oedema peripheral
         subjects affected / exposed
    17 / 265 (6.42%)
    12 / 282 (4.26%)
         occurrences all number
    17
    12
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    52 / 265 (19.62%)
    63 / 282 (22.34%)
         occurrences all number
    60
    78
    Dyspnoea
         subjects affected / exposed
    45 / 265 (16.98%)
    63 / 282 (22.34%)
         occurrences all number
    51
    80
    Epistaxis
         subjects affected / exposed
    15 / 265 (5.66%)
    2 / 282 (0.71%)
         occurrences all number
    17
    2
    Productive cough
         subjects affected / exposed
    8 / 265 (3.02%)
    20 / 282 (7.09%)
         occurrences all number
    8
    23
    Psychiatric disorders
    Insomnia
         subjects affected / exposed
    17 / 265 (6.42%)
    23 / 282 (8.16%)
         occurrences all number
    25
    25
    Investigations
    Blood alkaline phosphatase increased
         subjects affected / exposed
    9 / 265 (3.40%)
    16 / 282 (5.67%)
         occurrences all number
    10
    25
    Aspartate aminotransferase increased
         subjects affected / exposed
    16 / 265 (6.04%)
    22 / 282 (7.80%)
         occurrences all number
    22
    28
    Alanine aminotransferase increased
         subjects affected / exposed
    13 / 265 (4.91%)
    22 / 282 (7.80%)
         occurrences all number
    14
    27
    Amylase increased
         subjects affected / exposed
    2 / 265 (0.75%)
    15 / 282 (5.32%)
         occurrences all number
    2
    19
    Gamma-glutamyltransferase increased
         subjects affected / exposed
    11 / 265 (4.15%)
    20 / 282 (7.09%)
         occurrences all number
    14
    22
    Lipase increased
         subjects affected / exposed
    4 / 265 (1.51%)
    27 / 282 (9.57%)
         occurrences all number
    6
    36
    Haemoglobin decreased
         subjects affected / exposed
    14 / 265 (5.28%)
    5 / 282 (1.77%)
         occurrences all number
    18
    8
    Neutrophil count decreased
         subjects affected / exposed
    60 / 265 (22.64%)
    28 / 282 (9.93%)
         occurrences all number
    137
    44
    Platelet count decreased
         subjects affected / exposed
    63 / 265 (23.77%)
    20 / 282 (7.09%)
         occurrences all number
    124
    30
    Weight decreased
         subjects affected / exposed
    16 / 265 (6.04%)
    26 / 282 (9.22%)
         occurrences all number
    16
    27
    White blood cell count decreased
         subjects affected / exposed
    46 / 265 (17.36%)
    26 / 282 (9.22%)
         occurrences all number
    123
    58
    Injury, poisoning and procedural complications
    Infusion related reaction
         subjects affected / exposed
    16 / 265 (6.04%)
    8 / 282 (2.84%)
         occurrences all number
    22
    8
    Nervous system disorders
    Dizziness
         subjects affected / exposed
    17 / 265 (6.42%)
    20 / 282 (7.09%)
         occurrences all number
    17
    21
    Headache
         subjects affected / exposed
    21 / 265 (7.92%)
    30 / 282 (10.64%)
         occurrences all number
    26
    35
    Blood and lymphatic system disorders
    Leukopenia
         subjects affected / exposed
    41 / 265 (15.47%)
    12 / 282 (4.26%)
         occurrences all number
    114
    17
    Anaemia
         subjects affected / exposed
    163 / 265 (61.51%)
    68 / 282 (24.11%)
         occurrences all number
    275
    95
    Neutropenia
         subjects affected / exposed
    93 / 265 (35.09%)
    17 / 282 (6.03%)
         occurrences all number
    182
    25
    Thrombocytopenia
         subjects affected / exposed
    78 / 265 (29.43%)
    19 / 282 (6.74%)
         occurrences all number
    188
    21
    Gastrointestinal disorders
    Abdominal pain
         subjects affected / exposed
    14 / 265 (5.28%)
    19 / 282 (6.74%)
         occurrences all number
    16
    21
    Abdominal pain upper
         subjects affected / exposed
    11 / 265 (4.15%)
    16 / 282 (5.67%)
         occurrences all number
    12
    17
    Stomatitis
         subjects affected / exposed
    17 / 265 (6.42%)
    12 / 282 (4.26%)
         occurrences all number
    24
    13
    Nausea
         subjects affected / exposed
    59 / 265 (22.26%)
    48 / 282 (17.02%)
         occurrences all number
    85
    61
    Diarrhoea
         subjects affected / exposed
    44 / 265 (16.60%)
    34 / 282 (12.06%)
         occurrences all number
    56
    48
    Vomiting
         subjects affected / exposed
    41 / 265 (15.47%)
    33 / 282 (11.70%)
         occurrences all number
    59
    48
    Constipation
         subjects affected / exposed
    49 / 265 (18.49%)
    45 / 282 (15.96%)
         occurrences all number
    59
    56
    Skin and subcutaneous tissue disorders
    Alopecia
         subjects affected / exposed
    26 / 265 (9.81%)
    4 / 282 (1.42%)
         occurrences all number
    26
    4
    Pruritus
         subjects affected / exposed
    4 / 265 (1.51%)
    27 / 282 (9.57%)
         occurrences all number
    4
    43
    Rash
         subjects affected / exposed
    11 / 265 (4.15%)
    21 / 282 (7.45%)
         occurrences all number
    11
    26
    Endocrine disorders
    Hypothyroidism
         subjects affected / exposed
    1 / 265 (0.38%)
    23 / 282 (8.16%)
         occurrences all number
    1
    23
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    17 / 265 (6.42%)
    27 / 282 (9.57%)
         occurrences all number
    20
    32
    Back pain
         subjects affected / exposed
    25 / 265 (9.43%)
    30 / 282 (10.64%)
         occurrences all number
    27
    31
    Pain in extremity
         subjects affected / exposed
    11 / 265 (4.15%)
    16 / 282 (5.67%)
         occurrences all number
    11
    19
    Infections and infestations
    Upper respiratory tract infection
         subjects affected / exposed
    13 / 265 (4.91%)
    15 / 282 (5.32%)
         occurrences all number
    16
    21
    Pneumonia
         subjects affected / exposed
    22 / 265 (8.30%)
    16 / 282 (5.67%)
         occurrences all number
    24
    18
    Metabolism and nutrition disorders
    Decreased appetite
         subjects affected / exposed
    70 / 265 (26.42%)
    79 / 282 (28.01%)
         occurrences all number
    86
    93
    Hyperglycaemia
         subjects affected / exposed
    8 / 265 (3.02%)
    15 / 282 (5.32%)
         occurrences all number
    10
    21
    Hypokalaemia
         subjects affected / exposed
    18 / 265 (6.79%)
    19 / 282 (6.74%)
         occurrences all number
    22
    27
    Hyponatraemia
         subjects affected / exposed
    25 / 265 (9.43%)
    24 / 282 (8.51%)
         occurrences all number
    30
    43

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    15 Dec 2015
    Study Director and Medical Monitor Updated
    07 Sep 2016
    Analysis timeline and exploratory objectives updated
    20 Mar 2018
    Study personnel updated

    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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