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    Clinical Trial Results:
    A Phase 3, Multicenter, Randomized, Double-Blind, Placebo-Controlled, 3-Arm Study of SAR302503 in Patients with Intermediate-2 or High-Risk Primary Myelofibrosis, Post-Polycythemia Vera Myelofibrosis, or Post-Essential Thrombocythemia Myelofibrosis with Splenomegaly

    Summary
    EudraCT number
    2011-001897-25
    Trial protocol
    BE   GB   HU   LT   PT   ES   DE   SE   AT   IT   IE  
    Global end of trial date
    09 Jun 2014

    Results information
    Results version number
    v1(current)
    This version publication date
    23 May 2016
    First version publication date
    06 Aug 2015
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    EFC12153
    Additional study identifiers
    ISRCTN number
    -
    US NCT number
    NCT01437787
    WHO universal trial number (UTN)
    U1111-1121-7170
    Sponsors
    Sponsor organisation name
    Sanofi aventis recherche & développement
    Sponsor organisation address
    1 avenue Pierre Brossolette, Chilly-Mazarin, France, 91380
    Public contact
    Trial Transparency Team, Sanofi aventis recherche & développement, Contact-US@sanofi.com
    Scientific contact
    Trial Transparency Team, Sanofi aventis recherche & développement, Contact-US@sanofi.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
    24 Jul 2014
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    09 Jun 2014
    Was the trial ended prematurely?
    Yes
    General information about the trial
    Main objective of the trial
    To evaluate the efficacy of daily oral doses of 400 mg or 500 mg of SAR302503 compared to placebo in the reduction of spleen volume as determined by magnetic resonance imaging (MRI) (or computed tomography scan in subjects with contraindications for MRI).
    Protection of trial subjects
    Subjects were fully informed of all pertinent aspects of the clinical trial as well as the possibility to discontinue at any time in language and terms appropriate for the subject and considering the local culture. During the course of the trial, subjects were provided with individual subject cards indicating the nature of the trial the subject is participating, contact details and any information needed in the event of a medical emergency. Collected personal data and human biological samples were processed in compliance with the Sanofi-Aventis Group Personal Data Protection Charter ensuring that the Group abides by the laws governing personal data protection in force in all countries in which it operates.
    Background therapy
    -
    Evidence for comparator
    -
    Actual start date of recruitment
    22 Dec 2011
    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
    Australia: 12
    Country: Number of subjects enrolled
    Austria: 2
    Country: Number of subjects enrolled
    Belgium: 5
    Country: Number of subjects enrolled
    Brazil: 4
    Country: Number of subjects enrolled
    Canada: 8
    Country: Number of subjects enrolled
    France: 27
    Country: Number of subjects enrolled
    Germany: 7
    Country: Number of subjects enrolled
    Hungary: 17
    Country: Number of subjects enrolled
    Ireland: 3
    Country: Number of subjects enrolled
    Israel: 12
    Country: Number of subjects enrolled
    Italy: 27
    Country: Number of subjects enrolled
    Lithuania: 9
    Country: Number of subjects enrolled
    Poland: 17
    Country: Number of subjects enrolled
    Portugal: 11
    Country: Number of subjects enrolled
    Korea, Democratic People's Republic of: 11
    Country: Number of subjects enrolled
    Romania: 15
    Country: Number of subjects enrolled
    Russian Federation: 17
    Country: Number of subjects enrolled
    Singapore: 9
    Country: Number of subjects enrolled
    South Africa: 3
    Country: Number of subjects enrolled
    Spain: 4
    Country: Number of subjects enrolled
    Sweden: 5
    Country: Number of subjects enrolled
    Taiwan: 4
    Country: Number of subjects enrolled
    United Kingdom: 36
    Country: Number of subjects enrolled
    United States: 24
    Worldwide total number of subjects
    289
    EEA total number of subjects
    185
    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)
    140
    From 65 to 84 years
    147
    85 years and over
    2

    Subject disposition

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    Recruitment
    Recruitment details
    The study was conducted at 101 sites in 25 countries. A total of 351 subjects were screened between 22 December 2011 and 24 August 2012.

    Pre-assignment
    Screening details
    Of 351 screened subjects, 62 were screen failures and 289 were randomized.

    Period 1
    Period 1 title
    Overall trial (overall period)
    Is this the baseline period?
    Yes
    Allocation method
    Randomised - controlled
    Blinding used
    Double blind
    Roles blinded
    Subject, Investigator

    Arms
    Are arms mutually exclusive
    No

    Arm title
    Placebo
    Arm description
    Placebo up to 6 cycles (1 cycle=28 days - median exposure= 24 weeks). At the end of cycle 6, subjects were crossed-over to SAR302503 400 or 500 mg until disease progression or unacceptable toxicity.
    Arm type
    Placebo

    Investigational medicinal product name
    Placebo (for SAR302503)
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule, hard
    Routes of administration
    Oral use
    Dosage and administration details
    Placebo matched to SAR302503 once daily on an empty stomach.

    Arm title
    SAR302503 400 mg
    Arm description
    SAR302503 400 mg until disease progression and/or unacceptable toxicity (median exposure= 62.1 weeks).
    Arm type
    Experimental

    Investigational medicinal product name
    Fedratinib
    Investigational medicinal product code
    SAR302503
    Other name
    Pharmaceutical forms
    Capsule, hard
    Routes of administration
    Oral use
    Dosage and administration details
    SAR302503 400 mg once daily on an empty stomach.

    Arm title
    SAR302503 500 mg
    Arm description
    SAR302503 500 mg until disease progression and/or unacceptable toxicity (median exposure =59.7 weeks).
    Arm type
    Experimental

    Investigational medicinal product name
    Fedratinib
    Investigational medicinal product code
    SAR302503
    Other name
    Pharmaceutical forms
    Capsule, hard
    Routes of administration
    Oral use
    Dosage and administration details
    SAR302503 500 mg once daily on an empty stomach.

    Number of subjects in period 1
    Placebo SAR302503 400 mg SAR302503 500 mg
    Started
    96
    96
    97
    Treated
    95
    96
    97
    Completed
    61
    0
    0
    Not completed
    35
    96
    97
         Other than specified
             12
             10
             7
         Adverse event
             8
             26
             35
         Study termination by sponsor
             -
             51
             45
         Poor compliance
             -
             1
             1
         Early crossover
             10
             -
             -
         'Randomized, but not treated '
             1
             -
             -
         Consent withdrawn by subject
             -
             -
             3
         Disease progression
             4
             6
             3
         Subject request
             -
             2
             3

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Placebo
    Reporting group description
    Placebo up to 6 cycles (1 cycle=28 days - median exposure= 24 weeks). At the end of cycle 6, subjects were crossed-over to SAR302503 400 or 500 mg until disease progression or unacceptable toxicity.

    Reporting group title
    SAR302503 400 mg
    Reporting group description
    SAR302503 400 mg until disease progression and/or unacceptable toxicity (median exposure= 62.1 weeks).

    Reporting group title
    SAR302503 500 mg
    Reporting group description
    SAR302503 500 mg until disease progression and/or unacceptable toxicity (median exposure =59.7 weeks).

    Reporting group values
    Placebo SAR302503 400 mg SAR302503 500 mg Total
    Number of subjects
    96 96 97 289
    Age categorical
    Units: Subjects
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    64.9 ± 9.5 62.9 ± 9.6 64.7 ± 9.3 -
    Gender categorical
    Units: Subjects
        Female
    41 42 36 119
        Male
    55 54 61 170
    Re-randomization
    Subjects in placebo group were re-randomized to SAR302503 400 mg or 500 mg after cycle 6 or earlier (if a subject experienced progressive disease PD prior to completing the first 6 cycles).
    Units: Subjects
        SAR302503 400 mg
    35 0 0 35
        SAR302503 500 mg
    36 0 0 36
        Not applicable
    25 96 97 218

    End points

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    End points reporting groups
    Reporting group title
    Placebo
    Reporting group description
    Placebo up to 6 cycles (1 cycle=28 days - median exposure= 24 weeks). At the end of cycle 6, subjects were crossed-over to SAR302503 400 or 500 mg until disease progression or unacceptable toxicity.

    Reporting group title
    SAR302503 400 mg
    Reporting group description
    SAR302503 400 mg until disease progression and/or unacceptable toxicity (median exposure= 62.1 weeks).

    Reporting group title
    SAR302503 500 mg
    Reporting group description
    SAR302503 500 mg until disease progression and/or unacceptable toxicity (median exposure =59.7 weeks).

    Primary: Response Rate (RR): Percentage of Subjects Who Had a >=35% Reduction From Baseline in Volume of Spleen Size at The End Cycle 6

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    End point title
    Response Rate (RR): Percentage of Subjects Who Had a >=35% Reduction From Baseline in Volume of Spleen Size at The End Cycle 6
    End point description
    Spleen volume was determined by magnetic resonance imaging (MRI) (or computed tomography scan in subjects with contraindications for MRI) at baseline and at the end of cycle 6 with a confirmatory scan approximately 4 weeks after the end of Cycle 6. The MRI or CT imaging results reviewed in a blinded manner by an Independent Review Committee (IRC). Analysis was performed on intent-to-treat (ITT) population defined as all randomized subjects who signed ICF.
    End point type
    Primary
    End point timeframe
    Baseline, Week 24
    End point values
    Placebo SAR302503 400 mg SAR302503 500 mg
    Number of subjects analysed
    96
    96
    97
    Units: percentage of subjects
        number (confidence interval 95%)
    1 (0 to 3.1)
    36.5 (26.8 to 46.1)
    40.2 (30.4 to 50)
    Statistical analysis title
    SAR302503 400 mg vs placebo
    Statistical analysis description
    A Chi-squared test was performed to compare the response rate at each dose to the placebo.
    Comparison groups
    SAR302503 400 mg v Placebo
    Number of subjects included in analysis
    192
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    < 0.0001 [1]
    Method
    Chi-squared
    Confidence interval
         level
    97.5%
         sides
    2-sided
         lower limit
    0.2416
         upper limit
    0.4667
    Notes
    [1] - Threshold for significance was 0.025.
    Statistical analysis title
    SAR302503 500 mg vs placebo
    Statistical analysis description
    A Chi-squared test was performed to compare the response rate at each dose to the placebo.
    Comparison groups
    SAR302503 500 mg v Placebo
    Number of subjects included in analysis
    193
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    < 0.0001 [2]
    Method
    Chi-squared
    Confidence interval
         level
    97.5%
         sides
    2-sided
         lower limit
    0.2777
         upper limit
    0.5056
    Notes
    [2] - Threshold for significance was 0.025.

    Secondary: Symptom Response Rate (SRR): Percentage of Subjects with >=50% Reduction From Baseline in the Total Symptom Score at End of Cycle 6

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    End point title
    Symptom Response Rate (SRR): Percentage of Subjects with >=50% Reduction From Baseline in the Total Symptom Score at End of Cycle 6
    End point description
    Total symptom score is the averaged value of the daily scores for each of 6 key Myelofibrosis (MF) associated Symptom items (night sweats, pruritus, abdominal discomfort, early satiety [filling up quickly when you eat], pain under ribs on left side, and bone or muscle pain), each item measured on a scale from 0 (absent) to 10 (worst imaginable). A higher score indicates worse symptoms. Analysis was performed on ITT population. Number of subjects analysed= subjects with available data at end of cycle 6.
    End point type
    Secondary
    End point timeframe
    Baseline, Week 24
    End point values
    Placebo SAR302503 400 mg SAR302503 500 mg
    Number of subjects analysed
    85
    91
    91
    Units: percentage of subjects
        number (confidence interval 95%)
    7.1 (1.6 to 12.5)
    36.3 (26.4 to 46.1)
    34.1 (24.3 to 43.8)
    No statistical analyses for this end point

    Secondary: Overall Survival (OS)

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    End point title
    Overall Survival (OS)
    End point description
    Overall survival was defined as the time interval from the date of randomization to the date of death due to any cause.
    End point type
    Secondary
    End point timeframe
    Week 92
    End point values
    Placebo SAR302503 400 mg SAR302503 500 mg
    Number of subjects analysed
    0 [3]
    0 [4]
    0 [5]
    Units: months
        number (not applicable)
    Notes
    [3] - Overall survival analysis was not performed due to short follow-up period.
    [4] - Overall survival analysis was not performed due to short follow-up period.
    [5] - Overall survival analysis was not performed due to short follow-up period.
    No statistical analyses for this end point

    Secondary: Progression Free Survival (PFS)

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    End point title
    Progression Free Survival (PFS)
    End point description
    Disease progression was defined as: - Progressive splenomegaly, defined as enlargement of spleen volume confirmed by MRI (or CT scan in subjects with contraindications for MRI) of >=25% compared to baseline value. - Leukemic transformation, confirmed by a bone marrow blast count of >=20% or the occurrence of a granulocytic sarcoma (chloroma). - An increase in peripheral blood blast percentage of >=20% that persists for at least 1 week. PFS was defined as the time interval from the date of randomization to the date of the first Investigator-assessed disease progression or the date of death due to any cause, whichever came first.
    End point type
    Secondary
    End point timeframe
    Week 24
    End point values
    Placebo SAR302503 400 mg SAR302503 500 mg
    Number of subjects analysed
    0 [6]
    0 [7]
    0 [8]
    Units: months
        number (not applicable)
    Notes
    [6] - PFS analysis was not performed due to short follow-up period.
    [7] - PFS analysis was not performed due to short follow-up period.
    [8] - PFS analysis was not performed due to short follow-up period.
    No statistical analyses for this end point

    Secondary: Percentage of Subjects who had >=25% Reduction From Baseline in Volume of Spleen Size at End of Cycle 6

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    End point title
    Percentage of Subjects who had >=25% Reduction From Baseline in Volume of Spleen Size at End of Cycle 6
    End point description
    Spleen volume was determined by magnetic resonance imaging (MRI) (or computed tomography scan in subjects with contraindications for MRI) at baseline and at the end of cycle 6 with a confirmatory scan approximately 4 weeks after the end of Cycle 6. Analysis was performed on ITT population.
    End point type
    Secondary
    End point timeframe
    Baseline, Week 24
    End point values
    Placebo SAR302503 400 mg SAR302503 500 mg
    Number of subjects analysed
    96
    96
    97
    Units: percentage of subjects
        number (confidence interval 95%)
    2.1 (0 to 4.9)
    49 (39 to 59)
    51.5 (41.6 to 61.5)
    No statistical analyses for this end point

    Secondary: Duration of Response in Spleen Volume by Central Imaging MRI/CT Scan

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    End point title
    Duration of Response in Spleen Volume by Central Imaging MRI/CT Scan
    End point description
    Response was measured by MRI (or CT scan). The duration of response was defined as the time from the date of the first response by independent review committee (IRC) to the date of the subsequent progressive disease by IRC or death, whichever was earlier. Data for this endpoint was analysed up to study completion. Analysis was performed on ITT population.
    End point type
    Secondary
    End point timeframe
    From the first response up to disease progression or death ( Up to Week 92)
    End point values
    Placebo SAR302503 400 mg SAR302503 500 mg
    Number of subjects analysed
    1
    54
    57
    Units: month
        median (full range (min-max))
    16.7 (16.7 to 16.7)
    10.4 (0 to 18.2)
    10.4 (0 to 19.7)
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    All Adverse Events (AE) were collected from signature of the informed consent form up to the final visit (Up to 92 Weeks) regardless of seriousness or relationship to investigational product.
    Adverse event reporting additional description
    Reported adverse events and deaths are treatment-emergent that is AEs that developed/worsened or deaths that occurred during the ‘on treatment period’ (from the first dose of IMP up to 30 days after the last dose).
    Assessment type
    Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    MedDRA
    Dictionary version
    17.0
    Reporting groups
    Reporting group title
    Placebo
    Reporting group description
    Placebo up to 6 cycles (1 cycle=28 days) (median duration of exposure= 24 weeks).

    Reporting group title
    SAR302503 400 mg
    Reporting group description
    SAR302503 400 mg (from first dose after initial randomization to the end of study, median duration of exposure= 62.1 weeks).

    Reporting group title
    SAR302503 500 mg
    Reporting group description
    SAR302503 500 mg (from first dose after intial randomization to the end of study, median duration of exposure= 59.7 weeks).

    Reporting group title
    SAR302503 400 mg after cross-over
    Reporting group description
    SAR302503 400 mg (from first dose after re-randomization to the end of study, median duration of exposure= 43.9 weeks).

    Reporting group title
    SAR302503 500 mg after cross-over
    Reporting group description
    SAR302503 500 mg (from first dose after re-randomization to the end of study, median duration of exposure= 44.2 weeks).

    Serious adverse events
    Placebo SAR302503 400 mg SAR302503 500 mg SAR302503 400 mg after cross-over SAR302503 500 mg after cross-over
    Total subjects affected by serious adverse events
         subjects affected / exposed
    22 / 95 (23.16%)
    37 / 96 (38.54%)
    43 / 97 (44.33%)
    13 / 35 (37.14%)
    13 / 36 (36.11%)
         number of deaths (all causes)
    6
    5
    6
    0
    1
         number of deaths resulting from adverse events
    Vascular disorders
    Aortic Stenosis
         subjects affected / exposed
    0 / 95 (0.00%)
    0 / 96 (0.00%)
    0 / 97 (0.00%)
    1 / 35 (2.86%)
    0 / 36 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Haematoma
         subjects affected / exposed
    0 / 95 (0.00%)
    0 / 96 (0.00%)
    1 / 97 (1.03%)
    0 / 35 (0.00%)
    0 / 36 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Peripheral Artery Thrombosis
         subjects affected / exposed
    0 / 95 (0.00%)
    0 / 96 (0.00%)
    1 / 97 (1.03%)
    0 / 35 (0.00%)
    0 / 36 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Shock Haemorrhagic
         subjects affected / exposed
    0 / 95 (0.00%)
    1 / 96 (1.04%)
    0 / 97 (0.00%)
    1 / 35 (2.86%)
    0 / 36 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Acute Leukaemia
         subjects affected / exposed
    0 / 95 (0.00%)
    1 / 96 (1.04%)
    0 / 97 (0.00%)
    0 / 35 (0.00%)
    0 / 36 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    0 / 0
    0 / 0
    Acute Myeloid Leukaemia
         subjects affected / exposed
    2 / 95 (2.11%)
    2 / 96 (2.08%)
    0 / 97 (0.00%)
    0 / 35 (0.00%)
    0 / 36 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 2
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    Adenocarcinoma Of Colon
         subjects affected / exposed
    0 / 95 (0.00%)
    1 / 96 (1.04%)
    1 / 97 (1.03%)
    0 / 35 (0.00%)
    0 / 36 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Basal Cell Carcinoma
         subjects affected / exposed
    1 / 95 (1.05%)
    0 / 96 (0.00%)
    0 / 97 (0.00%)
    1 / 35 (2.86%)
    0 / 36 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Chronic Lymphocytic Leukaemia
         subjects affected / exposed
    0 / 95 (0.00%)
    0 / 96 (0.00%)
    0 / 97 (0.00%)
    0 / 35 (0.00%)
    1 / 36 (2.78%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Leukaemia
         subjects affected / exposed
    0 / 95 (0.00%)
    0 / 96 (0.00%)
    1 / 97 (1.03%)
    0 / 35 (0.00%)
    0 / 36 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Lung Neoplasm Malignant
         subjects affected / exposed
    0 / 95 (0.00%)
    0 / 96 (0.00%)
    1 / 97 (1.03%)
    0 / 35 (0.00%)
    0 / 36 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Prostate Cancer
         subjects affected / exposed
    0 / 95 (0.00%)
    1 / 96 (1.04%)
    1 / 97 (1.03%)
    0 / 35 (0.00%)
    0 / 36 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Rectal Adenocarcinoma
         subjects affected / exposed
    0 / 95 (0.00%)
    0 / 96 (0.00%)
    1 / 97 (1.03%)
    0 / 35 (0.00%)
    0 / 36 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Squamous Cell Carcinoma
         subjects affected / exposed
    1 / 95 (1.05%)
    0 / 96 (0.00%)
    0 / 97 (0.00%)
    0 / 35 (0.00%)
    0 / 36 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Disease Progression
         subjects affected / exposed
    1 / 95 (1.05%)
    2 / 96 (2.08%)
    1 / 97 (1.03%)
    0 / 35 (0.00%)
    0 / 36 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 1
    0 / 1
    0 / 0
    0 / 0
    Localised Oedema
         subjects affected / exposed
    0 / 95 (0.00%)
    1 / 96 (1.04%)
    0 / 97 (0.00%)
    0 / 35 (0.00%)
    0 / 36 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Multi-Organ Failure
         subjects affected / exposed
    0 / 95 (0.00%)
    1 / 96 (1.04%)
    1 / 97 (1.03%)
    1 / 35 (2.86%)
    0 / 36 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 1
    0 / 0
    Pyrexia
         subjects affected / exposed
    1 / 95 (1.05%)
    0 / 96 (0.00%)
    1 / 97 (1.03%)
    0 / 35 (0.00%)
    1 / 36 (2.78%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Reproductive system and breast disorders
    Benign Prostatic Hyperplasia
         subjects affected / exposed
    0 / 95 (0.00%)
    0 / 96 (0.00%)
    1 / 97 (1.03%)
    0 / 35 (0.00%)
    0 / 36 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Vaginal Haemorrhage
         subjects affected / exposed
    0 / 95 (0.00%)
    0 / 96 (0.00%)
    0 / 97 (0.00%)
    1 / 35 (2.86%)
    0 / 36 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Adrenal Haematoma
         subjects affected / exposed
    0 / 95 (0.00%)
    1 / 96 (1.04%)
    0 / 97 (0.00%)
    0 / 35 (0.00%)
    0 / 36 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Contusion
         subjects affected / exposed
    1 / 95 (1.05%)
    0 / 96 (0.00%)
    0 / 97 (0.00%)
    0 / 35 (0.00%)
    0 / 36 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Femur Fracture
         subjects affected / exposed
    1 / 95 (1.05%)
    0 / 96 (0.00%)
    0 / 97 (0.00%)
    0 / 35 (0.00%)
    0 / 36 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Muscle Rupture
         subjects affected / exposed
    0 / 95 (0.00%)
    1 / 96 (1.04%)
    0 / 97 (0.00%)
    0 / 35 (0.00%)
    0 / 36 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    Post Procedural Haemorrhage
         subjects affected / exposed
    0 / 95 (0.00%)
    1 / 96 (1.04%)
    0 / 97 (0.00%)
    0 / 35 (0.00%)
    0 / 36 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Procedural Intestinal Perforation
         subjects affected / exposed
    0 / 95 (0.00%)
    0 / 96 (0.00%)
    1 / 97 (1.03%)
    0 / 35 (0.00%)
    0 / 36 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Transfusion-Related Acute Lung Injury
         subjects affected / exposed
    1 / 95 (1.05%)
    0 / 96 (0.00%)
    0 / 97 (0.00%)
    0 / 35 (0.00%)
    0 / 36 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Investigations
    Alanine Aminotransferase Increased
         subjects affected / exposed
    0 / 95 (0.00%)
    0 / 96 (0.00%)
    2 / 97 (2.06%)
    0 / 35 (0.00%)
    0 / 36 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Amylase Increased
         subjects affected / exposed
    0 / 95 (0.00%)
    1 / 96 (1.04%)
    1 / 97 (1.03%)
    0 / 35 (0.00%)
    0 / 36 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Aspartate Aminotransferase Increased
         subjects affected / exposed
    0 / 95 (0.00%)
    0 / 96 (0.00%)
    2 / 97 (2.06%)
    0 / 35 (0.00%)
    0 / 36 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Lipase Increased
         subjects affected / exposed
    0 / 95 (0.00%)
    1 / 96 (1.04%)
    1 / 97 (1.03%)
    0 / 35 (0.00%)
    0 / 36 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Liver Function Test Abnormal
         subjects affected / exposed
    0 / 95 (0.00%)
    0 / 96 (0.00%)
    1 / 97 (1.03%)
    0 / 35 (0.00%)
    0 / 36 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Occult Blood
         subjects affected / exposed
    0 / 95 (0.00%)
    0 / 96 (0.00%)
    1 / 97 (1.03%)
    0 / 35 (0.00%)
    0 / 36 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cardiac disorders
    Acute Coronary Syndrome
         subjects affected / exposed
    0 / 95 (0.00%)
    1 / 96 (1.04%)
    0 / 97 (0.00%)
    1 / 35 (2.86%)
    0 / 36 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Acute Left Ventricular Failure
         subjects affected / exposed
    0 / 95 (0.00%)
    1 / 96 (1.04%)
    0 / 97 (0.00%)
    0 / 35 (0.00%)
    0 / 36 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Acute Myocardial Infarction
         subjects affected / exposed
    1 / 95 (1.05%)
    0 / 96 (0.00%)
    2 / 97 (2.06%)
    0 / 35 (0.00%)
    0 / 36 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    1 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Angina Unstable
         subjects affected / exposed
    0 / 95 (0.00%)
    1 / 96 (1.04%)
    0 / 97 (0.00%)
    0 / 35 (0.00%)
    0 / 36 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Atrial Fibrillation
         subjects affected / exposed
    0 / 95 (0.00%)
    2 / 96 (2.08%)
    1 / 97 (1.03%)
    0 / 35 (0.00%)
    0 / 36 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 3
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cardiac Arrest
         subjects affected / exposed
    0 / 95 (0.00%)
    0 / 96 (0.00%)
    1 / 97 (1.03%)
    0 / 35 (0.00%)
    0 / 36 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    Cardiac Disorder
         subjects affected / exposed
    0 / 95 (0.00%)
    0 / 96 (0.00%)
    0 / 97 (0.00%)
    1 / 35 (2.86%)
    0 / 36 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cardiac Failure
         subjects affected / exposed
    3 / 95 (3.16%)
    5 / 96 (5.21%)
    3 / 97 (3.09%)
    0 / 35 (0.00%)
    1 / 36 (2.78%)
         occurrences causally related to treatment / all
    0 / 3
    1 / 6
    0 / 3
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    Cardiac Failure Congestive
         subjects affected / exposed
    0 / 95 (0.00%)
    0 / 96 (0.00%)
    2 / 97 (2.06%)
    1 / 35 (2.86%)
    0 / 36 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 2
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cardio-Respiratory Arrest
         subjects affected / exposed
    0 / 95 (0.00%)
    1 / 96 (1.04%)
    0 / 97 (0.00%)
    0 / 35 (0.00%)
    0 / 36 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    Cardiogenic Shock
         subjects affected / exposed
    0 / 95 (0.00%)
    1 / 96 (1.04%)
    0 / 97 (0.00%)
    0 / 35 (0.00%)
    0 / 36 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    0 / 0
    0 / 0
    Left Ventricular Dysfunction
         subjects affected / exposed
    0 / 95 (0.00%)
    0 / 96 (0.00%)
    1 / 97 (1.03%)
    0 / 35 (0.00%)
    0 / 36 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Myocardial Ischaemia
         subjects affected / exposed
    1 / 95 (1.05%)
    1 / 96 (1.04%)
    0 / 97 (0.00%)
    0 / 35 (0.00%)
    0 / 36 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Right Ventricular Failure
         subjects affected / exposed
    0 / 95 (0.00%)
    1 / 96 (1.04%)
    0 / 97 (0.00%)
    0 / 35 (0.00%)
    0 / 36 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Acute Pulmonary Oedema
         subjects affected / exposed
    0 / 95 (0.00%)
    1 / 96 (1.04%)
    1 / 97 (1.03%)
    0 / 35 (0.00%)
    0 / 36 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Dyspnoea
         subjects affected / exposed
    1 / 95 (1.05%)
    0 / 96 (0.00%)
    0 / 97 (0.00%)
    0 / 35 (0.00%)
    0 / 36 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Epistaxis
         subjects affected / exposed
    1 / 95 (1.05%)
    0 / 96 (0.00%)
    0 / 97 (0.00%)
    0 / 35 (0.00%)
    0 / 36 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Lung Disorder
         subjects affected / exposed
    0 / 95 (0.00%)
    0 / 96 (0.00%)
    0 / 97 (0.00%)
    0 / 35 (0.00%)
    1 / 36 (2.78%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pleural Effusion
         subjects affected / exposed
    1 / 95 (1.05%)
    0 / 96 (0.00%)
    0 / 97 (0.00%)
    0 / 35 (0.00%)
    0 / 36 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pneumonitis
         subjects affected / exposed
    0 / 95 (0.00%)
    0 / 96 (0.00%)
    1 / 97 (1.03%)
    0 / 35 (0.00%)
    0 / 36 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    Productive Cough
         subjects affected / exposed
    0 / 95 (0.00%)
    1 / 96 (1.04%)
    0 / 97 (0.00%)
    0 / 35 (0.00%)
    0 / 36 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pulmonary Embolism
         subjects affected / exposed
    0 / 95 (0.00%)
    0 / 96 (0.00%)
    1 / 97 (1.03%)
    0 / 35 (0.00%)
    0 / 36 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    Pulmonary Hypertension
         subjects affected / exposed
    0 / 95 (0.00%)
    1 / 96 (1.04%)
    0 / 97 (0.00%)
    0 / 35 (0.00%)
    0 / 36 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pulmonary Oedema
         subjects affected / exposed
    0 / 95 (0.00%)
    0 / 96 (0.00%)
    1 / 97 (1.03%)
    0 / 35 (0.00%)
    1 / 36 (2.78%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Respiratory Distress
         subjects affected / exposed
    0 / 95 (0.00%)
    0 / 96 (0.00%)
    0 / 97 (0.00%)
    0 / 35 (0.00%)
    1 / 36 (2.78%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    Respiratory Failure
         subjects affected / exposed
    0 / 95 (0.00%)
    0 / 96 (0.00%)
    1 / 97 (1.03%)
    1 / 35 (2.86%)
    0 / 36 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    1 / 95 (1.05%)
    4 / 96 (4.17%)
    5 / 97 (5.15%)
    3 / 35 (8.57%)
    2 / 36 (5.56%)
         occurrences causally related to treatment / all
    0 / 4
    2 / 5
    19 / 23
    5 / 6
    3 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Disseminated Intravascular Coagulation
         subjects affected / exposed
    0 / 95 (0.00%)
    2 / 96 (2.08%)
    0 / 97 (0.00%)
    0 / 35 (0.00%)
    0 / 36 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    Haemorrhagic Anaemia
         subjects affected / exposed
    0 / 95 (0.00%)
    0 / 96 (0.00%)
    0 / 97 (0.00%)
    1 / 35 (2.86%)
    0 / 36 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Leukocytosis
         subjects affected / exposed
    1 / 95 (1.05%)
    1 / 96 (1.04%)
    1 / 97 (1.03%)
    0 / 35 (0.00%)
    0 / 36 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    Neutropenia
         subjects affected / exposed
    0 / 95 (0.00%)
    0 / 96 (0.00%)
    0 / 97 (0.00%)
    1 / 35 (2.86%)
    0 / 36 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Splenic Haemorrhage
         subjects affected / exposed
    0 / 95 (0.00%)
    0 / 96 (0.00%)
    1 / 97 (1.03%)
    0 / 35 (0.00%)
    0 / 36 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Splenic Infarction
         subjects affected / exposed
    2 / 95 (2.11%)
    0 / 96 (0.00%)
    2 / 97 (2.06%)
    0 / 35 (0.00%)
    0 / 36 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Splenomegaly
         subjects affected / exposed
    0 / 95 (0.00%)
    1 / 96 (1.04%)
    0 / 97 (0.00%)
    0 / 35 (0.00%)
    0 / 36 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Thrombocytopenia
         subjects affected / exposed
    0 / 95 (0.00%)
    1 / 96 (1.04%)
    2 / 97 (2.06%)
    1 / 35 (2.86%)
    1 / 36 (2.78%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 2
    0 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Nervous system disorders
    Cerebrovascular Accident
         subjects affected / exposed
    0 / 95 (0.00%)
    0 / 96 (0.00%)
    1 / 97 (1.03%)
    0 / 35 (0.00%)
    0 / 36 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Convulsion
         subjects affected / exposed
    0 / 95 (0.00%)
    0 / 96 (0.00%)
    1 / 97 (1.03%)
    0 / 35 (0.00%)
    0 / 36 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Dizziness
         subjects affected / exposed
    0 / 95 (0.00%)
    1 / 96 (1.04%)
    0 / 97 (0.00%)
    0 / 35 (0.00%)
    0 / 36 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Encephalopathy
         subjects affected / exposed
    0 / 95 (0.00%)
    0 / 96 (0.00%)
    1 / 97 (1.03%)
    0 / 35 (0.00%)
    0 / 36 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Haemorrhage Intracranial
         subjects affected / exposed
    1 / 95 (1.05%)
    0 / 96 (0.00%)
    0 / 97 (0.00%)
    0 / 35 (0.00%)
    0 / 36 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Haemorrhagic Stroke
         subjects affected / exposed
    0 / 95 (0.00%)
    1 / 96 (1.04%)
    0 / 97 (0.00%)
    0 / 35 (0.00%)
    0 / 36 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Headache
         subjects affected / exposed
    0 / 95 (0.00%)
    1 / 96 (1.04%)
    0 / 97 (0.00%)
    0 / 35 (0.00%)
    0 / 36 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hypoglycaemic Coma
         subjects affected / exposed
    0 / 95 (0.00%)
    0 / 96 (0.00%)
    0 / 97 (0.00%)
    1 / 35 (2.86%)
    0 / 36 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Wernicke's Encephalopathy
         subjects affected / exposed
    0 / 95 (0.00%)
    0 / 96 (0.00%)
    1 / 97 (1.03%)
    0 / 35 (0.00%)
    2 / 36 (5.56%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    0 / 0
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Eye disorders
    Amaurosis Fugax
         subjects affected / exposed
    0 / 95 (0.00%)
    0 / 96 (0.00%)
    0 / 97 (0.00%)
    0 / 35 (0.00%)
    1 / 36 (2.78%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Periorbital Oedema
         subjects affected / exposed
    0 / 95 (0.00%)
    0 / 96 (0.00%)
    0 / 97 (0.00%)
    0 / 35 (0.00%)
    1 / 36 (2.78%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Vitreous Haemorrhage
         subjects affected / exposed
    0 / 95 (0.00%)
    1 / 96 (1.04%)
    0 / 97 (0.00%)
    0 / 35 (0.00%)
    0 / 36 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Abdominal Pain
         subjects affected / exposed
    0 / 95 (0.00%)
    0 / 96 (0.00%)
    0 / 97 (0.00%)
    1 / 35 (2.86%)
    0 / 36 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Abdominal Pain Upper
         subjects affected / exposed
    0 / 95 (0.00%)
    1 / 96 (1.04%)
    0 / 97 (0.00%)
    0 / 35 (0.00%)
    0 / 36 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Abdominal Wall Haematoma
         subjects affected / exposed
    1 / 95 (1.05%)
    0 / 96 (0.00%)
    0 / 97 (0.00%)
    0 / 35 (0.00%)
    0 / 36 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Ascites
         subjects affected / exposed
    3 / 95 (3.16%)
    0 / 96 (0.00%)
    2 / 97 (2.06%)
    0 / 35 (0.00%)
    0 / 36 (0.00%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 0
    1 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Colitis
         subjects affected / exposed
    0 / 95 (0.00%)
    0 / 96 (0.00%)
    1 / 97 (1.03%)
    0 / 35 (0.00%)
    0 / 36 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Diarrhoea
         subjects affected / exposed
    0 / 95 (0.00%)
    1 / 96 (1.04%)
    1 / 97 (1.03%)
    1 / 35 (2.86%)
    0 / 36 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    1 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gastritis
         subjects affected / exposed
    0 / 95 (0.00%)
    0 / 96 (0.00%)
    1 / 97 (1.03%)
    0 / 35 (0.00%)
    0 / 36 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal Haemorrhage
         subjects affected / exposed
    0 / 95 (0.00%)
    0 / 96 (0.00%)
    1 / 97 (1.03%)
    0 / 35 (0.00%)
    0 / 36 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal Polyp Haemorrhage
         subjects affected / exposed
    0 / 95 (0.00%)
    0 / 96 (0.00%)
    1 / 97 (1.03%)
    0 / 35 (0.00%)
    0 / 36 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Haematemesis
         subjects affected / exposed
    0 / 95 (0.00%)
    0 / 96 (0.00%)
    1 / 97 (1.03%)
    0 / 35 (0.00%)
    0 / 36 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    Ileus Paralytic
         subjects affected / exposed
    0 / 95 (0.00%)
    0 / 96 (0.00%)
    1 / 97 (1.03%)
    0 / 35 (0.00%)
    0 / 36 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Nausea
         subjects affected / exposed
    0 / 95 (0.00%)
    0 / 96 (0.00%)
    0 / 97 (0.00%)
    1 / 35 (2.86%)
    0 / 36 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pancreatitis
         subjects affected / exposed
    0 / 95 (0.00%)
    1 / 96 (1.04%)
    0 / 97 (0.00%)
    0 / 35 (0.00%)
    0 / 36 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Rectal Haemorrhage
         subjects affected / exposed
    0 / 95 (0.00%)
    1 / 96 (1.04%)
    0 / 97 (0.00%)
    0 / 35 (0.00%)
    0 / 36 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Small Intestinal Perforation
         subjects affected / exposed
    0 / 95 (0.00%)
    0 / 96 (0.00%)
    1 / 97 (1.03%)
    0 / 35 (0.00%)
    0 / 36 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Umbilical Hernia
         subjects affected / exposed
    0 / 95 (0.00%)
    1 / 96 (1.04%)
    0 / 97 (0.00%)
    0 / 35 (0.00%)
    0 / 36 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Volvulus
         subjects affected / exposed
    0 / 95 (0.00%)
    1 / 96 (1.04%)
    0 / 97 (0.00%)
    0 / 35 (0.00%)
    0 / 36 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Vomiting
         subjects affected / exposed
    0 / 95 (0.00%)
    0 / 96 (0.00%)
    1 / 97 (1.03%)
    1 / 35 (2.86%)
    2 / 36 (5.56%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    1 / 1
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Renal and urinary disorders
    Renal Colic
         subjects affected / exposed
    1 / 95 (1.05%)
    0 / 96 (0.00%)
    0 / 97 (0.00%)
    0 / 35 (0.00%)
    0 / 36 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Renal Cyst
         subjects affected / exposed
    0 / 95 (0.00%)
    0 / 96 (0.00%)
    1 / 97 (1.03%)
    0 / 35 (0.00%)
    0 / 36 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Renal Failure Acute
         subjects affected / exposed
    0 / 95 (0.00%)
    1 / 96 (1.04%)
    1 / 97 (1.03%)
    0 / 35 (0.00%)
    0 / 36 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Renal Failure Chronic
         subjects affected / exposed
    0 / 95 (0.00%)
    0 / 96 (0.00%)
    1 / 97 (1.03%)
    0 / 35 (0.00%)
    0 / 36 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Urinary Retention
         subjects affected / exposed
    0 / 95 (0.00%)
    0 / 96 (0.00%)
    1 / 97 (1.03%)
    0 / 35 (0.00%)
    0 / 36 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hepatobiliary disorders
    Cholecystitis
         subjects affected / exposed
    0 / 95 (0.00%)
    0 / 96 (0.00%)
    1 / 97 (1.03%)
    0 / 35 (0.00%)
    0 / 36 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cholelithiasis
         subjects affected / exposed
    0 / 95 (0.00%)
    1 / 96 (1.04%)
    1 / 97 (1.03%)
    0 / 35 (0.00%)
    0 / 36 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hydrocholecystis
         subjects affected / exposed
    0 / 95 (0.00%)
    0 / 96 (0.00%)
    1 / 97 (1.03%)
    0 / 35 (0.00%)
    0 / 36 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hypertransaminasaemia
         subjects affected / exposed
    0 / 95 (0.00%)
    0 / 96 (0.00%)
    0 / 97 (0.00%)
    0 / 35 (0.00%)
    1 / 36 (2.78%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Back Pain
         subjects affected / exposed
    0 / 95 (0.00%)
    1 / 96 (1.04%)
    0 / 97 (0.00%)
    0 / 35 (0.00%)
    0 / 36 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Musculoskeletal Pain
         subjects affected / exposed
    0 / 95 (0.00%)
    0 / 96 (0.00%)
    0 / 97 (0.00%)
    1 / 35 (2.86%)
    0 / 36 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pathological Fracture
         subjects affected / exposed
    0 / 95 (0.00%)
    1 / 96 (1.04%)
    0 / 97 (0.00%)
    0 / 35 (0.00%)
    0 / 36 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Endocrine disorders
    Adrenal Haemorrhage
         subjects affected / exposed
    0 / 95 (0.00%)
    0 / 96 (0.00%)
    0 / 97 (0.00%)
    1 / 35 (2.86%)
    0 / 36 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Cachexia
         subjects affected / exposed
    1 / 95 (1.05%)
    0 / 96 (0.00%)
    0 / 97 (0.00%)
    0 / 35 (0.00%)
    0 / 36 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hyperkalaemia
         subjects affected / exposed
    1 / 95 (1.05%)
    1 / 96 (1.04%)
    2 / 97 (2.06%)
    0 / 35 (0.00%)
    0 / 36 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    1 / 1
    0 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hypocalcaemia
         subjects affected / exposed
    0 / 95 (0.00%)
    1 / 96 (1.04%)
    0 / 97 (0.00%)
    0 / 35 (0.00%)
    0 / 36 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hyponatraemia
         subjects affected / exposed
    0 / 95 (0.00%)
    0 / 96 (0.00%)
    2 / 97 (2.06%)
    0 / 35 (0.00%)
    0 / 36 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Infections and infestations
    Abscess Limb
         subjects affected / exposed
    0 / 95 (0.00%)
    0 / 96 (0.00%)
    1 / 97 (1.03%)
    0 / 35 (0.00%)
    0 / 36 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Abscess Oral
         subjects affected / exposed
    0 / 95 (0.00%)
    1 / 96 (1.04%)
    0 / 97 (0.00%)
    0 / 35 (0.00%)
    0 / 36 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Anal Abscess
         subjects affected / exposed
    0 / 95 (0.00%)
    0 / 96 (0.00%)
    1 / 97 (1.03%)
    0 / 35 (0.00%)
    0 / 36 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Appendicitis
         subjects affected / exposed
    0 / 95 (0.00%)
    0 / 96 (0.00%)
    1 / 97 (1.03%)
    0 / 35 (0.00%)
    0 / 36 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Bacterial Pyelonephritis
         subjects affected / exposed
    0 / 95 (0.00%)
    0 / 96 (0.00%)
    1 / 97 (1.03%)
    0 / 35 (0.00%)
    0 / 36 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    Bronchitis
         subjects affected / exposed
    0 / 95 (0.00%)
    1 / 96 (1.04%)
    0 / 97 (0.00%)
    1 / 35 (2.86%)
    0 / 36 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Bronchopneumonia
         subjects affected / exposed
    0 / 95 (0.00%)
    0 / 96 (0.00%)
    1 / 97 (1.03%)
    0 / 35 (0.00%)
    0 / 36 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cystitis Escherichia
         subjects affected / exposed
    0 / 95 (0.00%)
    1 / 96 (1.04%)
    0 / 97 (0.00%)
    0 / 35 (0.00%)
    0 / 36 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Enterocolitis Infectious
         subjects affected / exposed
    0 / 95 (0.00%)
    1 / 96 (1.04%)
    0 / 97 (0.00%)
    0 / 35 (0.00%)
    0 / 36 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gastroenteritis
         subjects affected / exposed
    0 / 95 (0.00%)
    0 / 96 (0.00%)
    0 / 97 (0.00%)
    1 / 35 (2.86%)
    0 / 36 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Implant Site Infection
         subjects affected / exposed
    0 / 95 (0.00%)
    1 / 96 (1.04%)
    0 / 97 (0.00%)
    0 / 35 (0.00%)
    0 / 36 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Infective Exacerbation Of Chronic Obstructive Airways Disease
         subjects affected / exposed
    0 / 95 (0.00%)
    0 / 96 (0.00%)
    1 / 97 (1.03%)
    0 / 35 (0.00%)
    0 / 36 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Klebsiella Sepsis
         subjects affected / exposed
    0 / 95 (0.00%)
    0 / 96 (0.00%)
    1 / 97 (1.03%)
    0 / 35 (0.00%)
    0 / 36 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Lower Respiratory Tract Infection
         subjects affected / exposed
    1 / 95 (1.05%)
    0 / 96 (0.00%)
    0 / 97 (0.00%)
    0 / 35 (0.00%)
    0 / 36 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Lower Respiratory Tract Infection Viral
         subjects affected / exposed
    0 / 95 (0.00%)
    0 / 96 (0.00%)
    1 / 97 (1.03%)
    0 / 35 (0.00%)
    0 / 36 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Lung Abscess
         subjects affected / exposed
    0 / 95 (0.00%)
    1 / 96 (1.04%)
    0 / 97 (0.00%)
    0 / 35 (0.00%)
    0 / 36 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Lung Infection
         subjects affected / exposed
    0 / 95 (0.00%)
    0 / 96 (0.00%)
    2 / 97 (2.06%)
    0 / 35 (0.00%)
    0 / 36 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Neutropenic Sepsis
         subjects affected / exposed
    0 / 95 (0.00%)
    0 / 96 (0.00%)
    1 / 97 (1.03%)
    1 / 35 (2.86%)
    0 / 36 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Peritonitis
         subjects affected / exposed
    0 / 95 (0.00%)
    0 / 96 (0.00%)
    1 / 97 (1.03%)
    0 / 35 (0.00%)
    0 / 36 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pneumonia
         subjects affected / exposed
    2 / 95 (2.11%)
    4 / 96 (4.17%)
    3 / 97 (3.09%)
    1 / 35 (2.86%)
    1 / 36 (2.78%)
         occurrences causally related to treatment / all
    0 / 2
    1 / 4
    0 / 3
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Sepsis
         subjects affected / exposed
    1 / 95 (1.05%)
    2 / 96 (2.08%)
    1 / 97 (1.03%)
    0 / 35 (0.00%)
    0 / 36 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Septic Shock
         subjects affected / exposed
    0 / 95 (0.00%)
    0 / 96 (0.00%)
    1 / 97 (1.03%)
    0 / 35 (0.00%)
    0 / 36 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Staphylococcal Sepsis
         subjects affected / exposed
    0 / 95 (0.00%)
    0 / 96 (0.00%)
    0 / 97 (0.00%)
    1 / 35 (2.86%)
    0 / 36 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Tracheobronchitis
         subjects affected / exposed
    1 / 95 (1.05%)
    0 / 96 (0.00%)
    1 / 97 (1.03%)
    0 / 35 (0.00%)
    0 / 36 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    Placebo SAR302503 400 mg SAR302503 500 mg SAR302503 400 mg after cross-over SAR302503 500 mg after cross-over
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    76 / 95 (80.00%)
    96 / 96 (100.00%)
    94 / 97 (96.91%)
    33 / 35 (94.29%)
    36 / 36 (100.00%)
    Vascular disorders
    Hypertension
         subjects affected / exposed
    1 / 95 (1.05%)
    4 / 96 (4.17%)
    6 / 97 (6.19%)
    1 / 35 (2.86%)
    1 / 36 (2.78%)
         occurrences all number
    1
    5
    7
    1
    1
    Social circumstances
    Blood Product Transfusion Dependent
         subjects affected / exposed
    2 / 95 (2.11%)
    10 / 96 (10.42%)
    12 / 97 (12.37%)
    3 / 35 (8.57%)
    1 / 36 (2.78%)
         occurrences all number
    2
    10
    12
    3
    1
    General disorders and administration site conditions
    Asthenia
         subjects affected / exposed
    6 / 95 (6.32%)
    13 / 96 (13.54%)
    16 / 97 (16.49%)
    3 / 35 (8.57%)
    7 / 36 (19.44%)
         occurrences all number
    6
    19
    19
    4
    9
    Fatigue
         subjects affected / exposed
    9 / 95 (9.47%)
    24 / 96 (25.00%)
    14 / 97 (14.43%)
    7 / 35 (20.00%)
    5 / 36 (13.89%)
         occurrences all number
    9
    28
    22
    10
    7
    Local Swelling
         subjects affected / exposed
    1 / 95 (1.05%)
    5 / 96 (5.21%)
    0 / 97 (0.00%)
    0 / 35 (0.00%)
    0 / 36 (0.00%)
         occurrences all number
    1
    5
    0
    0
    0
    Oedema Peripheral
         subjects affected / exposed
    8 / 95 (8.42%)
    13 / 96 (13.54%)
    9 / 97 (9.28%)
    3 / 35 (8.57%)
    2 / 36 (5.56%)
         occurrences all number
    8
    14
    10
    3
    2
    Pain
         subjects affected / exposed
    0 / 95 (0.00%)
    3 / 96 (3.13%)
    2 / 97 (2.06%)
    1 / 35 (2.86%)
    2 / 36 (5.56%)
         occurrences all number
    0
    4
    2
    1
    2
    Pyrexia
         subjects affected / exposed
    2 / 95 (2.11%)
    7 / 96 (7.29%)
    6 / 97 (6.19%)
    2 / 35 (5.71%)
    3 / 36 (8.33%)
         occurrences all number
    3
    9
    10
    4
    3
    Psychiatric disorders
    Insomnia
         subjects affected / exposed
    0 / 95 (0.00%)
    5 / 96 (5.21%)
    1 / 97 (1.03%)
    0 / 35 (0.00%)
    0 / 36 (0.00%)
         occurrences all number
    0
    6
    1
    0
    0
    Injury, poisoning and procedural complications
    Contusion
         subjects affected / exposed
    1 / 95 (1.05%)
    5 / 96 (5.21%)
    2 / 97 (2.06%)
    1 / 35 (2.86%)
    1 / 36 (2.78%)
         occurrences all number
    1
    6
    2
    1
    1
    Investigations
    Alanine Aminotransferase Increased
         subjects affected / exposed
    1 / 95 (1.05%)
    12 / 96 (12.50%)
    7 / 97 (7.22%)
    0 / 35 (0.00%)
    4 / 36 (11.11%)
         occurrences all number
    1
    16
    7
    0
    5
    Aspartate Aminotransferase Increased
         subjects affected / exposed
    0 / 95 (0.00%)
    6 / 96 (6.25%)
    8 / 97 (8.25%)
    1 / 35 (2.86%)
    1 / 36 (2.78%)
         occurrences all number
    0
    7
    9
    1
    1
    Blood Alkaline Phosphatase Increased
         subjects affected / exposed
    1 / 95 (1.05%)
    6 / 96 (6.25%)
    2 / 97 (2.06%)
    0 / 35 (0.00%)
    2 / 36 (5.56%)
         occurrences all number
    1
    6
    3
    0
    2
    Blood Creatinine Increased
         subjects affected / exposed
    1 / 95 (1.05%)
    11 / 96 (11.46%)
    17 / 97 (17.53%)
    2 / 35 (5.71%)
    4 / 36 (11.11%)
         occurrences all number
    1
    12
    26
    2
    4
    Lipase Increased
         subjects affected / exposed
    1 / 95 (1.05%)
    8 / 96 (8.33%)
    7 / 97 (7.22%)
    0 / 35 (0.00%)
    2 / 36 (5.56%)
         occurrences all number
    1
    8
    10
    0
    2
    Weight Decreased
         subjects affected / exposed
    5 / 95 (5.26%)
    5 / 96 (5.21%)
    12 / 97 (12.37%)
    6 / 35 (17.14%)
    3 / 36 (8.33%)
         occurrences all number
    5
    6
    12
    6
    3
    Weight Increased
         subjects affected / exposed
    4 / 95 (4.21%)
    12 / 96 (12.50%)
    8 / 97 (8.25%)
    1 / 35 (2.86%)
    3 / 36 (8.33%)
         occurrences all number
    4
    12
    8
    1
    3
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    13 / 95 (13.68%)
    50 / 96 (52.08%)
    43 / 97 (44.33%)
    21 / 35 (60.00%)
    19 / 36 (52.78%)
         occurrences all number
    15
    79
    77
    34
    32
    Leukopenia
         subjects affected / exposed
    0 / 95 (0.00%)
    1 / 96 (1.04%)
    3 / 97 (3.09%)
    2 / 35 (5.71%)
    0 / 36 (0.00%)
         occurrences all number
    0
    2
    3
    3
    0
    Neutropenia
         subjects affected / exposed
    0 / 95 (0.00%)
    6 / 96 (6.25%)
    12 / 97 (12.37%)
    3 / 35 (8.57%)
    3 / 36 (8.33%)
         occurrences all number
    0
    10
    17
    6
    3
    Thrombocytopenia
         subjects affected / exposed
    8 / 95 (8.42%)
    15 / 96 (15.63%)
    20 / 97 (20.62%)
    8 / 35 (22.86%)
    12 / 36 (33.33%)
         occurrences all number
    9
    22
    28
    9
    13
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    6 / 95 (6.32%)
    14 / 96 (14.58%)
    14 / 97 (14.43%)
    3 / 35 (8.57%)
    3 / 36 (8.33%)
         occurrences all number
    6
    17
    14
    4
    3
    Dyspnoea
         subjects affected / exposed
    6 / 95 (6.32%)
    11 / 96 (11.46%)
    13 / 97 (13.40%)
    4 / 35 (11.43%)
    4 / 36 (11.11%)
         occurrences all number
    6
    12
    16
    5
    4
    Dyspnoea Exertional
         subjects affected / exposed
    0 / 95 (0.00%)
    5 / 96 (5.21%)
    2 / 97 (2.06%)
    1 / 35 (2.86%)
    1 / 36 (2.78%)
         occurrences all number
    0
    5
    2
    1
    2
    Epistaxis
         subjects affected / exposed
    6 / 95 (6.32%)
    7 / 96 (7.29%)
    4 / 97 (4.12%)
    2 / 35 (5.71%)
    1 / 36 (2.78%)
         occurrences all number
    8
    9
    4
    3
    1
    Oropharyngeal Pain
         subjects affected / exposed
    0 / 95 (0.00%)
    5 / 96 (5.21%)
    4 / 97 (4.12%)
    0 / 35 (0.00%)
    0 / 36 (0.00%)
         occurrences all number
    0
    5
    4
    0
    0
    Pleural Effusion
         subjects affected / exposed
    0 / 95 (0.00%)
    4 / 96 (4.17%)
    1 / 97 (1.03%)
    2 / 35 (5.71%)
    1 / 36 (2.78%)
         occurrences all number
    0
    4
    1
    2
    1
    Nervous system disorders
    Dizziness
         subjects affected / exposed
    3 / 95 (3.16%)
    12 / 96 (12.50%)
    10 / 97 (10.31%)
    2 / 35 (5.71%)
    1 / 36 (2.78%)
         occurrences all number
    3
    16
    11
    2
    1
    Headache
         subjects affected / exposed
    1 / 95 (1.05%)
    13 / 96 (13.54%)
    6 / 97 (6.19%)
    1 / 35 (2.86%)
    1 / 36 (2.78%)
         occurrences all number
    1
    13
    6
    1
    1
    Lethargy
         subjects affected / exposed
    0 / 95 (0.00%)
    0 / 96 (0.00%)
    1 / 97 (1.03%)
    0 / 35 (0.00%)
    2 / 36 (5.56%)
         occurrences all number
    0
    0
    1
    0
    2
    Paraesthesia
         subjects affected / exposed
    1 / 95 (1.05%)
    1 / 96 (1.04%)
    3 / 97 (3.09%)
    1 / 35 (2.86%)
    2 / 36 (5.56%)
         occurrences all number
    1
    1
    3
    2
    3
    Ear and labyrinth disorders
    Vertigo
         subjects affected / exposed
    1 / 95 (1.05%)
    2 / 96 (2.08%)
    0 / 97 (0.00%)
    2 / 35 (5.71%)
    0 / 36 (0.00%)
         occurrences all number
    1
    2
    0
    2
    0
    Gastrointestinal disorders
    Abdominal Discomfort
         subjects affected / exposed
    1 / 95 (1.05%)
    2 / 96 (2.08%)
    3 / 97 (3.09%)
    0 / 35 (0.00%)
    2 / 36 (5.56%)
         occurrences all number
    1
    2
    4
    0
    2
    Abdominal Distension
         subjects affected / exposed
    2 / 95 (2.11%)
    5 / 96 (5.21%)
    6 / 97 (6.19%)
    0 / 35 (0.00%)
    0 / 36 (0.00%)
         occurrences all number
    2
    6
    7
    0
    0
    Abdominal Pain
         subjects affected / exposed
    15 / 95 (15.79%)
    15 / 96 (15.63%)
    14 / 97 (14.43%)
    4 / 35 (11.43%)
    6 / 36 (16.67%)
         occurrences all number
    17
    23
    19
    5
    7
    Abdominal Pain Upper
         subjects affected / exposed
    5 / 95 (5.26%)
    10 / 96 (10.42%)
    5 / 97 (5.15%)
    2 / 35 (5.71%)
    4 / 36 (11.11%)
         occurrences all number
    6
    12
    6
    2
    4
    Constipation
         subjects affected / exposed
    7 / 95 (7.37%)
    12 / 96 (12.50%)
    19 / 97 (19.59%)
    7 / 35 (20.00%)
    3 / 36 (8.33%)
         occurrences all number
    7
    13
    23
    8
    3
    Diarrhoea
         subjects affected / exposed
    15 / 95 (15.79%)
    67 / 96 (69.79%)
    57 / 97 (58.76%)
    10 / 35 (28.57%)
    14 / 36 (38.89%)
         occurrences all number
    19
    106
    87
    15
    18
    Dyspepsia
         subjects affected / exposed
    2 / 95 (2.11%)
    7 / 96 (7.29%)
    6 / 97 (6.19%)
    2 / 35 (5.71%)
    0 / 36 (0.00%)
         occurrences all number
    2
    9
    7
    2
    0
    Flatulence
         subjects affected / exposed
    0 / 95 (0.00%)
    3 / 96 (3.13%)
    1 / 97 (1.03%)
    1 / 35 (2.86%)
    2 / 36 (5.56%)
         occurrences all number
    0
    3
    1
    1
    4
    Nausea
         subjects affected / exposed
    15 / 95 (15.79%)
    64 / 96 (66.67%)
    51 / 97 (52.58%)
    20 / 35 (57.14%)
    16 / 36 (44.44%)
         occurrences all number
    15
    89
    62
    26
    30
    Vomiting
         subjects affected / exposed
    5 / 95 (5.26%)
    44 / 96 (45.83%)
    53 / 97 (54.64%)
    13 / 35 (37.14%)
    14 / 36 (38.89%)
         occurrences all number
    5
    83
    107
    22
    26
    Renal and urinary disorders
    Dysuria
         subjects affected / exposed
    0 / 95 (0.00%)
    6 / 96 (6.25%)
    0 / 97 (0.00%)
    2 / 35 (5.71%)
    0 / 36 (0.00%)
         occurrences all number
    0
    7
    0
    2
    0
    Skin and subcutaneous tissue disorders
    Dry Skin
         subjects affected / exposed
    2 / 95 (2.11%)
    6 / 96 (6.25%)
    5 / 97 (5.15%)
    0 / 35 (0.00%)
    0 / 36 (0.00%)
         occurrences all number
    2
    7
    6
    0
    0
    Night Sweats
         subjects affected / exposed
    2 / 95 (2.11%)
    6 / 96 (6.25%)
    4 / 97 (4.12%)
    1 / 35 (2.86%)
    0 / 36 (0.00%)
         occurrences all number
    2
    7
    6
    1
    0
    Pruritus
         subjects affected / exposed
    2 / 95 (2.11%)
    6 / 96 (6.25%)
    7 / 97 (7.22%)
    1 / 35 (2.86%)
    0 / 36 (0.00%)
         occurrences all number
    2
    6
    8
    1
    0
    Pruritus Generalised
         subjects affected / exposed
    6 / 95 (6.32%)
    6 / 96 (6.25%)
    3 / 97 (3.09%)
    2 / 35 (5.71%)
    1 / 36 (2.78%)
         occurrences all number
    6
    6
    3
    2
    1
    Rash
         subjects affected / exposed
    0 / 95 (0.00%)
    4 / 96 (4.17%)
    5 / 97 (5.15%)
    1 / 35 (2.86%)
    1 / 36 (2.78%)
         occurrences all number
    0
    4
    5
    1
    1
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    6 / 95 (6.32%)
    7 / 96 (7.29%)
    2 / 97 (2.06%)
    3 / 35 (8.57%)
    1 / 36 (2.78%)
         occurrences all number
    7
    8
    2
    3
    1
    Back Pain
         subjects affected / exposed
    2 / 95 (2.11%)
    3 / 96 (3.13%)
    3 / 97 (3.09%)
    0 / 35 (0.00%)
    3 / 36 (8.33%)
         occurrences all number
    2
    3
    3
    0
    3
    Bone Pain
         subjects affected / exposed
    2 / 95 (2.11%)
    13 / 96 (13.54%)
    8 / 97 (8.25%)
    0 / 35 (0.00%)
    1 / 36 (2.78%)
         occurrences all number
    2
    17
    13
    0
    1
    Muscle Spasms
         subjects affected / exposed
    1 / 95 (1.05%)
    15 / 96 (15.63%)
    8 / 97 (8.25%)
    2 / 35 (5.71%)
    3 / 36 (8.33%)
         occurrences all number
    1
    21
    11
    3
    4
    Pain In Extremity
         subjects affected / exposed
    4 / 95 (4.21%)
    12 / 96 (12.50%)
    3 / 97 (3.09%)
    1 / 35 (2.86%)
    1 / 36 (2.78%)
         occurrences all number
    4
    13
    3
    1
    1
    Metabolism and nutrition disorders
    Decreased Appetite
         subjects affected / exposed
    3 / 95 (3.16%)
    6 / 96 (6.25%)
    9 / 97 (9.28%)
    2 / 35 (5.71%)
    4 / 36 (11.11%)
         occurrences all number
    3
    6
    10
    2
    4
    Hyperglycaemia
         subjects affected / exposed
    0 / 95 (0.00%)
    6 / 96 (6.25%)
    2 / 97 (2.06%)
    0 / 35 (0.00%)
    1 / 36 (2.78%)
         occurrences all number
    0
    6
    2
    0
    1
    Hyperkalaemia
         subjects affected / exposed
    1 / 95 (1.05%)
    5 / 96 (5.21%)
    9 / 97 (9.28%)
    1 / 35 (2.86%)
    0 / 36 (0.00%)
         occurrences all number
    1
    5
    14
    1
    0
    Hyperuricaemia
         subjects affected / exposed
    4 / 95 (4.21%)
    9 / 96 (9.38%)
    3 / 97 (3.09%)
    0 / 35 (0.00%)
    1 / 36 (2.78%)
         occurrences all number
    4
    11
    6
    0
    1
    Hypocalcaemia
         subjects affected / exposed
    1 / 95 (1.05%)
    4 / 96 (4.17%)
    3 / 97 (3.09%)
    0 / 35 (0.00%)
    2 / 36 (5.56%)
         occurrences all number
    1
    4
    4
    0
    2
    Infections and infestations
    Bronchitis
         subjects affected / exposed
    1 / 95 (1.05%)
    4 / 96 (4.17%)
    3 / 97 (3.09%)
    4 / 35 (11.43%)
    2 / 36 (5.56%)
         occurrences all number
    1
    6
    3
    4
    2
    Conjunctivitis
         subjects affected / exposed
    0 / 95 (0.00%)
    1 / 96 (1.04%)
    1 / 97 (1.03%)
    3 / 35 (8.57%)
    1 / 36 (2.78%)
         occurrences all number
    0
    1
    1
    3
    1
    Gastroenteritis
         subjects affected / exposed
    0 / 95 (0.00%)
    5 / 96 (5.21%)
    0 / 97 (0.00%)
    0 / 35 (0.00%)
    0 / 36 (0.00%)
         occurrences all number
    0
    6
    0
    0
    0
    Nasopharyngitis
         subjects affected / exposed
    3 / 95 (3.16%)
    5 / 96 (5.21%)
    6 / 97 (6.19%)
    1 / 35 (2.86%)
    1 / 36 (2.78%)
         occurrences all number
    3
    7
    7
    1
    1
    Tooth Abscess
         subjects affected / exposed
    1 / 95 (1.05%)
    0 / 96 (0.00%)
    0 / 97 (0.00%)
    0 / 35 (0.00%)
    2 / 36 (5.56%)
         occurrences all number
    1
    0
    0
    0
    2
    Upper Respiratory Tract Infection
         subjects affected / exposed
    4 / 95 (4.21%)
    8 / 96 (8.33%)
    6 / 97 (6.19%)
    5 / 35 (14.29%)
    1 / 36 (2.78%)
         occurrences all number
    4
    10
    7
    5
    1
    Urinary Tract Infection
         subjects affected / exposed
    1 / 95 (1.05%)
    9 / 96 (9.38%)
    10 / 97 (10.31%)
    1 / 35 (2.86%)
    2 / 36 (5.56%)
         occurrences all number
    1
    14
    13
    3
    2

    More information

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    Substantial protocol amendments (globally)

    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    26 Jul 2011
    - The secondary endpoint of symptom response rate was changed from 40% to 50% reduction from baseline to end of Cycle 6 in the total symptom score. - Additional ECG assessments added to schedule. - An alert to the use of strong inhibitors of CYP2C19 with SAR302503 was added. - Wording for the modified MFSAF diary was clarified. - The assessment schedule was corrected.
    17 Feb 2012
    - Updated the inclusion and exclusion criteria of subjects who may be at risk for aspartate aminotransferase (AST), alanine aminotransferase (ALT), and/or bilirubin abnormalities. - Added more frequent monitoring of ALT, AST and bilirubin (total and direct). Following the occurrence of an episode of reversible hepatic failure in a subject treated with SAR302503 in a clinical trial, the entire SAR302503 development program was amended to add more frequent monitoring of ALT, AST and bilirubin (total and direct) during the first 3 cycles of treatment and in case severe liver enzyme elevations occurred at any time during study treatment. - Explicit instructions given for dose modifications in the case that elevations of transaminases and/or bilirubin were detected. - Added clarification to the concomitant medications section regarding the recommendation to not use oral contraceptives and hormonal replacement therapies that include estrogen (ie, ethinyl estradiol) and progesterone (ie, levonorgestrel) during study treatment. - Added study name JAKARTA.
    20 Nov 2012
    - Included use of a central pathology review of bone marrow biopsy samples. - Based on the preliminary data from study INT12497, SAR302503 was likely a moderate-to-potent inhibitor of CYP3A4 and based on this information, the concomitant medications section was adapted accordingly. - Dose modification for toxicity was clarified. - Guidance on dose reduction in case of Grade 3, 4 AEs and transfusion dependency was added. - The list of adverse event(s) of special interest (AESI) was updated. - Exploratory endpoint analyses were updated in the statistical section. - Administrative changes.
    27 Nov 2013
    - All subjects were permanently discontinued from further SAR302503 treatment, and all subjects, including those previously discontinued from the study, were asked to participate in the Thiamine Supplementation Period.

    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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