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    Clinical Trial Results:
    A Study in Japan and Ex-Japan to Characterize the Pharmacokinetic and Pharmacodynamic Response to Orteronel (TAK-700) in Chemotherapy-Naïve Patients With Castration-Resistant Prostate Cancer

    Summary
    EudraCT number
    2012-001539-30
    Trial protocol
    IE   GR   GB   NL  
    Global end of trial date
    01 Sep 2016

    Results information
    Results version number
    v1(current)
    This version publication date
    06 Feb 2018
    First version publication date
    06 Feb 2018
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    C21013
    Additional study identifiers
    ISRCTN number
    -
    US NCT number
    NCT01666314
    WHO universal trial number (UTN)
    U1111-1179-5750
    Sponsors
    Sponsor organisation name
    Takeda
    Sponsor organisation address
    One Takeda Parkway, Deerfield, IL, Japan, 60015
    Public contact
    Medical Director, Clinical Science, Takeda, +1 877-825-3327, clinicaltrialregistry@tpna.com
    Scientific contact
    Medical Director, Clinical Science, Takeda, +1 877-825-3327, clinicaltrialregistry@tpna.com
    Paediatric regulatory details
    Is trial part of an agreed paediatric investigation plan (PIP)
    No
    Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Results analysis stage
    Analysis stage
    Final
    Date of interim/final analysis
    01 Sep 2016
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    01 Sep 2016
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The purpose of this study was to determine whether orteronel plus prednisone more effectively reduces serum testosterone levels, compared to placebo plus prednisone when administered to subjects in Japan.
    Protection of trial subjects
    All study subjects were required to read and sign an Informed Consent Form.
    Background therapy
    -
    Evidence for comparator
    -
    Actual start date of recruitment
    20 Aug 2012
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    No
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Japan: 65
    Country: Number of subjects enrolled
    Australia: 8
    Country: Number of subjects enrolled
    Greece: 10
    Country: Number of subjects enrolled
    Ireland: 13
    Country: Number of subjects enrolled
    Netherlands: 13
    Country: Number of subjects enrolled
    United Kingdom: 3
    Country: Number of subjects enrolled
    United States: 25
    Worldwide total number of subjects
    137
    EEA total number of subjects
    39
    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)
    32
    From 65 to 84 years
    101
    85 years and over
    4

    Subject disposition

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    Recruitment
    Recruitment details
    Participants took part in the study at 43 investigative sites in Japan, United States, Greece, Australia, Netherlands, Ireland and United Kingdom from 20 August 2012 to 01 September 2016.

    Pre-assignment
    Screening details
    Male participants with a diagnosis of adenocarcinoma of the prostate were enrolled in the study. In Japan, participants were randomized to 200 mg orteronel, Placebo, 300 mg orteronel, or Placebo, BID, in a ratio of 2:1:2:1; ex-Japan participants were randomized to 200 mg orteronel, Placebo, 400 mg orteronel, or Placebo, BID, in a ratio of 2:1:2:1.

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

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    Placebo + Orteronel 200 mg (Japan)
    Arm description
    Orteronel placebo-matching tablets or Orteronel 200 mg, tablets, orally, twice daily (BID) in Cycle 1 (28 days) followed by orteronel 200 mg, tablets, orally, twice daily in 28 day cycles in Japan for up to 3 years. Study drug will be administered concomitantly with prednisone (or commercially available equivalent) 5 mg twice daily continuously throughout the study.
    Arm type
    Experimental

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Orteronel placebo-matching 200 mg tablets, orally, twice daily in Cycle 1 (28 days) in Japan for up to 2.5 years.

    Investigational medicinal product name
    Orteronel
    Investigational medicinal product code
    TAK-700
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Orteronel 200 mg, tablets, orally, twice daily in 28-day cycles in Japan for up to 2.5 years.

    Arm title
    Placebo + Orteronel 300 mg (Japan)
    Arm description
    Orteronel placebo-matching tablets or Orteronel 300 mg, tablets, orally, twice daily in Cycle 1 followed by orteronel 300 mg, tablets, orally, twice daily in 28 day cycles in Japan for up to 2.8 years. Study drug will be administered concomitantly with prednisone (or commercially available equivalent) 5 mg twice daily (BID) continuously throughout the study.
    Arm type
    Experimental

    Investigational medicinal product name
    Orteronel
    Investigational medicinal product code
    TAK-700
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Orteronel 300 mg tablets, orally, twice daily in Cycle 1 in 28-day cycles in Japan for up to 2.5 years.

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Orteronel placebo-matching 300 mg tablets, orally, twice daily in Cycle 1 in 28-day cycles in Japan for up to 2.5 years.

    Arm title
    Placebo + Orteronel 200 mg (Ex-Japan)
    Arm description
    Orteronel placebo-matching tablets, or Orteronel 200 mg, tablets, orally, twice daily in Cycle 1 followed by orteronel 200 mg, tablets, orally, twice daily in 28 day cycles outside of Japan (Ex-Japan) for up to 3.1 years. Study drug will be administered concomitantly with prednisone (or commercially available equivalent) 5 mg twice daily (BID) continuously throughout the study.
    Arm type
    Experimental

    Investigational medicinal product name
    Orteronel
    Investigational medicinal product code
    TAK-700
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Orteronel 200 mg tablets, orally, twice daily in 28-day cycles outside of Japan (Ex-Japan) for up to 2.5 years.

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Orteronel placebo-matching 200 mg tablets, orally, twice daily in Cycle 1 outside of Japan (Ex-Japan) for up to 2.5 years.

    Arm title
    Placebo + Orteronel 400 mg (Ex-Japan)
    Arm description
    Orteronel placebo-matching tablets, or Orteronel 400 mg, tablets, orally, twice daily in Cycle 1 followed by orteronel 400 mg, tablets, orally, twice daily in 28 day cycles Ex-Japan for up to 3.1 years. Study drug will be administered concomitantly with prednisone (or commercially available equivalent) 5 mg twice daily (BID) continuously throughout the study.
    Arm type
    Experimental

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Orteronel placebo-matching 400 mg tablets, orally, twice daily in Cycle 1 Ex-Japan for up to 2.5 years.

    Investigational medicinal product name
    Orteronel
    Investigational medicinal product code
    TAK-700
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Orteronel 400 mg, tablets, orally, twice daily in 28-day cycles Ex-Japan for up to 2.5.years.

    Number of subjects in period 1
    Placebo + Orteronel 200 mg (Japan) Placebo + Orteronel 300 mg (Japan) Placebo + Orteronel 200 mg (Ex-Japan) Placebo + Orteronel 400 mg (Ex-Japan)
    Started
    33
    32
    36
    36
    Completed
    0
    0
    0
    0
    Not completed
    33
    32
    36
    36
         Unsatisfactory Therapeutic Response
    7
    2
    1
    1
         Symptomatic Deterioration
    1
    -
    2
    -
         Adverse event, non-fatal
    3
    13
    7
    7
         Progressive Disease
    11
    9
    19
    20
         Reason not Specified
    10
    7
    5
    5
         Consent withdrawn by subject
    1
    1
    2
    3

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Overall Study
    Reporting group description
    -

    Reporting group values
    Overall Study Total
    Number of subjects
    137 137
    Age categorical
    Units: Subjects
        In utero
    0 0
        Preterm newborn infants (gestational age < 37 wks)
    0 0
        Newborns (0-27 days)
    0 0
        Infants and toddlers (28 days-23 months)
    0 0
        Children (2-11 years)
    0 0
        Adolescents (12-17 years)
    0 0
        Adults (18-64 years)
    32 32
        From 65-84 years
    101 101
        85 years and over
    4 4
    Age Continuous
    Units: years
        arithmetic mean (full range (min-max))
    70.6 (49 to 88) -
    Gender, Male/Female
    Units: Subjects
        Female
    0 0
        Male
    137 137
    Ethnicity (NIH/OMB)
    Units: Subjects
        Hispanic or Latino
    1 1
        Not Hispanic or Latino
    136 136
        Unknown or Not Reported
    0 0
    Race/Ethnicity, Customized
    Units: Subjects
        White
    70 70
        Black or African American
    2 2
        Asian - Japanese
    65 65
    Region of Enrollment
    Units: Subjects
        Japan
    65 65
        Australia
    8 8
        Greece
    10 10
        Ireland
    13 13
        Netherlands
    13 13
        United Kingdom
    3 3
        United States
    25 25
    Study Specific Characteristic | Height
    Units: cm
        arithmetic mean (full range (min-max))
    169.29 (151.0 to 189.0) -
    Study Specific Characteristic | Weight
    Units: kg
        arithmetic mean (full range (min-max))
    77.77 (44.7 to 134.6) -
    Study Specific Characteristic | Body Mass Index (BMI)
    Units: kg/m^2
        arithmetic mean (full range (min-max))
    26.96 (16.7 to 40.3) -

    End points

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    End points reporting groups
    Reporting group title
    Placebo + Orteronel 200 mg (Japan)
    Reporting group description
    Orteronel placebo-matching tablets or Orteronel 200 mg, tablets, orally, twice daily (BID) in Cycle 1 (28 days) followed by orteronel 200 mg, tablets, orally, twice daily in 28 day cycles in Japan for up to 3 years. Study drug will be administered concomitantly with prednisone (or commercially available equivalent) 5 mg twice daily continuously throughout the study.

    Reporting group title
    Placebo + Orteronel 300 mg (Japan)
    Reporting group description
    Orteronel placebo-matching tablets or Orteronel 300 mg, tablets, orally, twice daily in Cycle 1 followed by orteronel 300 mg, tablets, orally, twice daily in 28 day cycles in Japan for up to 2.8 years. Study drug will be administered concomitantly with prednisone (or commercially available equivalent) 5 mg twice daily (BID) continuously throughout the study.

    Reporting group title
    Placebo + Orteronel 200 mg (Ex-Japan)
    Reporting group description
    Orteronel placebo-matching tablets, or Orteronel 200 mg, tablets, orally, twice daily in Cycle 1 followed by orteronel 200 mg, tablets, orally, twice daily in 28 day cycles outside of Japan (Ex-Japan) for up to 3.1 years. Study drug will be administered concomitantly with prednisone (or commercially available equivalent) 5 mg twice daily (BID) continuously throughout the study.

    Reporting group title
    Placebo + Orteronel 400 mg (Ex-Japan)
    Reporting group description
    Orteronel placebo-matching tablets, or Orteronel 400 mg, tablets, orally, twice daily in Cycle 1 followed by orteronel 400 mg, tablets, orally, twice daily in 28 day cycles Ex-Japan for up to 3.1 years. Study drug will be administered concomitantly with prednisone (or commercially available equivalent) 5 mg twice daily (BID) continuously throughout the study.

    Subject analysis set title
    Orteronel 200 mg (Japan)
    Subject analysis set type
    Sub-group analysis
    Subject analysis set description
    Orteronel 200 mg, tablets, orally, twice daily in 28 day cycles in Japan for up to 3 years. Study drug will be administered concomitantly with prednisone (or commercially available equivalent) 5 mg twice daily (BID) continuously throughout the study.

    Subject analysis set title
    Orteronel 300 mg (Japan)
    Subject analysis set type
    Sub-group analysis
    Subject analysis set description
    Orteronel 300 mg, tablets, orally, twice daily in 28 day cycles in Japan for up to 2.8 years. Study drug will be administered concomitantly with prednisone (or commercially available equivalent) 5 mg twice daily (BID) continuously throughout the study.

    Subject analysis set title
    Orteronel 200 mg (Ex-Japan)
    Subject analysis set type
    Sub-group analysis
    Subject analysis set description
    Orteronel 200 mg, tablets, orally, twice daily in 28 day cycles Ex-Japan for up to 3.1 years. Study drug will be administered concomitantly with prednisone (or commercially available equivalent) 5 mg twice daily (BID) continuously throughout the study.

    Subject analysis set title
    Orteronel 400 mg (Ex-Japan)
    Subject analysis set type
    Sub-group analysis
    Subject analysis set description
    Orteronel 400 mg, tablets, orally, twice daily in 28 day cycles Ex-Japan for up to 3.1 years. Study drug will be administered concomitantly with prednisone (or commercially available equivalent) 5 mg twice daily (BID) continuously throughout the study.

    Subject analysis set title
    Placebo (Japan)
    Subject analysis set type
    Sub-group analysis
    Subject analysis set description
    Orteronel placebo-matching tablets, orally, twice daily in Cycle 1. Study drug will be administered concomitantly with prednisone (or commercially available equivalent) 5 mg twice daily (BID) continuously throughout the study.

    Subject analysis set title
    Placebo (Ex-Japan)
    Subject analysis set type
    Sub-group analysis
    Subject analysis set description
    Orteronel placebo-matching tablets, orally, twice daily in Cycle 1. Study drug will be administered concomitantly with prednisone (or commercially available equivalent) 5 mg twice daily (BID) continuously throughout the study.

    Subject analysis set title
    Placebo (Japan)
    Subject analysis set type
    Sub-group analysis
    Subject analysis set description
    Orteronel placebo-matching tablets, orally, twice daily in Cycle 1 (28 days). Study drug will be administered concomitantly with prednisone (or commercially available equivalent) 5 mg twice daily (BID) continuously throughout the study.

    Subject analysis set title
    Placebo (Ex-Japan)
    Subject analysis set type
    Sub-group analysis
    Subject analysis set description
    Orteronel placebo-matching tablets, orally, twice daily in Cycle 1. Study drug will be administered concomitantly with prednisone (or commercially available equivalent) 5 mg twice daily (BID) continuously throughout the study.

    Subject analysis set title
    Orteronel 200 mg (Ex-Japan)
    Subject analysis set type
    Sub-group analysis
    Subject analysis set description
    Orteronel 200 mg, tablets, orally, twice daily in 28 day cycles Ex-Japan for up to 3.1 years. Study drug will be administered concomitantly with prednisone (or commercially available equivalent) 5 mg twice daily (BID) continuously throughout the study.

    Subject analysis set title
    Orteronel 400 mg (Ex-Japan)
    Subject analysis set type
    Sub-group analysis
    Subject analysis set description
    Orteronel 400 mg, tablets, orally, twice daily in 28 day cycles Ex-Japan for up to 3.1 years. Study drug will be administered concomitantly with prednisone (or commercially available equivalent) 5 mg twice daily (BID) continuously throughout the study.

    Subject analysis set title
    Orteronel 200 mg (Japan)
    Subject analysis set type
    Sub-group analysis
    Subject analysis set description
    Orteronel 200 mg, tablets, orally, twice daily in 28 day cycles in Japan for up to 3 years. Study drug will be administered concomitantly with prednisone (or commercially available equivalent) 5 mg twice daily (BID) continuously throughout the study.

    Subject analysis set title
    Orteronel 300 mg (Japan)
    Subject analysis set type
    Sub-group analysis
    Subject analysis set description
    Orteronel 300 mg, tablets, orally, twice daily in 28 day cycles in Japan for up to 2.8 years. Study drug will be administered concomitantly with prednisone (or commercially available equivalent) 5 mg twice daily (BID) continuously throughout the study.

    Subject analysis set title
    Orteronel 200 mg (Ex-Japan)
    Subject analysis set type
    Sub-group analysis
    Subject analysis set description
    Orteronel 200 mg, tablets, orally, twice daily in 28 day cycles Ex-Japan for up to 3.1 years. Study drug will be administered concomitantly with prednisone (or commercially available equivalent) 5 mg twice daily (BID) continuously throughout the study.

    Subject analysis set title
    Orteronel 400 mg (Ex-Japan)
    Subject analysis set type
    Sub-group analysis
    Subject analysis set description
    Orteronel 400 mg, tablets, orally, twice daily in 28 day cycles Ex-Japan for up to 3.1 years. Study drug will be administered concomitantly with prednisone (or commercially available equivalent) 5 mg twice daily (BID) continuously throughout the study.

    Subject analysis set title
    Orteronel 200 mg (Japan)
    Subject analysis set type
    Sub-group analysis
    Subject analysis set description
    Orteronel 200 mg, tablets, orally, twice daily in 28 day cycles in Japan for up to 3 years. Study drug will be administered concomitantly with prednisone (or commercially available equivalent) 5 mg twice daily (BID) continuously throughout the study.

    Subject analysis set title
    Orteronel 300 mg (Japan)
    Subject analysis set type
    Sub-group analysis
    Subject analysis set description
    Orteronel 300 mg, tablets, orally, twice daily in 28 day cycles in Japan for up to 2.8 years. Study drug will be administered concomitantly with prednisone (or commercially available equivalent) 5 mg twice daily (BID) continuously throughout the study.

    Subject analysis set title
    Orteronel 200 mg (Ex-Japan)
    Subject analysis set type
    Sub-group analysis
    Subject analysis set description
    Orteronel 200 mg, tablets, orally, twice daily in 28 day cycles Ex-Japan for up to 3.1 years. Study drug will be administered concomitantly with prednisone (or commercially available equivalent) 5 mg twice daily (BID) continuously throughout the study.

    Subject analysis set title
    Orteronel 400 mg (Ex-Japan)
    Subject analysis set type
    Sub-group analysis
    Subject analysis set description
    Orteronel 400 mg, tablets, orally, twice daily in 28 day cycles Ex-Japan for up to 3.1 years. Study drug will be administered concomitantly with prednisone (or commercially available equivalent) 5 mg twice daily (BID) continuously throughout the study.

    Subject analysis set title
    Orteronel 200 mg (Ex-Japan)
    Subject analysis set type
    Sub-group analysis
    Subject analysis set description
    Orteronel 200 mg, tablets, orally, twice daily in 28 day cycles Ex-Japan for up to 3.1 years. Study drug will be administered concomitantly with prednisone (or commercially available equivalent) 5 mg twice daily (BID) continuously throughout the study.

    Subject analysis set title
    Orteronel 200 mg (Japan and ex-Japan)
    Subject analysis set type
    Sub-group analysis
    Subject analysis set description
    Orteronel 200 mg, tablets, orally, twice daily in 28 day cycles in Japan and ex-Japan for up to 3 years. Study drug will be administered concomitantly with prednisone (or commercially available equivalent) 5 mg twice daily (BID) continuously throughout the study.

    Primary: Percentage of Participants with Serum Testosterone Levels Reduced to ≤ 2 ng/dL After 4 Weeks of Treatment in Japan

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    End point title
    Percentage of Participants with Serum Testosterone Levels Reduced to ≤ 2 ng/dL After 4 Weeks of Treatment in Japan
    End point description
    Serum Ultra-sensitive testosterone was measured by liquid chromatography at a central laboratory.
    End point type
    Primary
    End point timeframe
    Baseline and Week 4
    End point values
    Orteronel 300 mg (Japan) Placebo (Japan)
    Number of subjects analysed
    22
    21
    Units: percentage of participants
        number (confidence interval 95%)
    100.0 (84.6 to 100.0)
    86.0 (63.7 to 97.0)
    Statistical analysis title
    Statistical analysis 1
    Comparison groups
    Placebo (Japan) v Orteronel 300 mg (Japan)
    Number of subjects included in analysis
    43
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    = 0.1078
    Method
    Fisher exact
    Confidence interval

    Secondary: Percentage of Participants with Serum Testosterone Levels Reduced to ≤ 2 ng/dL in Ex-Japan

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    End point title
    Percentage of Participants with Serum Testosterone Levels Reduced to ≤ 2 ng/dL in Ex-Japan
    End point description
    Serum Ultra-sensitive testosterone was measured by liquid chromatography at a central laboratory.
    End point type
    Secondary
    End point timeframe
    Baseline and Week 4
    End point values
    Orteronel 400 mg (Ex-Japan) Placebo (Ex-Japan)
    Number of subjects analysed
    24
    23
    Units: percentage of participants
        number (confidence interval 95%)
    79.0 (57.8 to 92.9)
    48.0 (26.8 to 69.4)
    Statistical analysis title
    Statistical Analysis 2
    Comparison groups
    Placebo (Ex-Japan) v Orteronel 400 mg (Ex-Japan)
    Number of subjects included in analysis
    47
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    = 0.0355
    Method
    Fisher exact
    Parameter type
    Odds ratio (OR)
    Point estimate
    4.145
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.9895
         upper limit
    18.7606

    Secondary: Percent Change from Baseline in Serum Testosterone Level after 4 Weeks of Treatment

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    End point title
    Percent Change from Baseline in Serum Testosterone Level after 4 Weeks of Treatment
    End point description
    Serum Ultra-sensitive testosterone was measured by liquid chromatography at a central laboratory.
    End point type
    Secondary
    End point timeframe
    Baseline and Week 4
    End point values
    Orteronel 200 mg (Japan) Orteronel 300 mg (Japan) Orteronel 200 mg (Ex-Japan) Orteronel 400 mg (Ex-Japan) Placebo (Japan) Placebo (Ex-Japan)
    Number of subjects analysed
    22
    22
    21
    22
    21
    20
    Units: percent change
        arithmetic mean (standard deviation)
    -97.245 ± 1.2548
    -96.812 ± 2.7055
    -86.268 ± 37.2015
    -53.954 ± 118.8050
    -87.666 ± 10.4250
    -63.702 ± 43.3941
    No statistical analyses for this end point

    Secondary: Percent Change from Baseline in Serum Testosterone Level after 12 Weeks of Treatment

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    End point title
    Percent Change from Baseline in Serum Testosterone Level after 12 Weeks of Treatment
    End point description
    Serum Ultra-sensitive testosterone was measured by liquid chromatography at a central laboratory.
    End point type
    Secondary
    End point timeframe
    Baseline and Week 12
    End point values
    Orteronel 200 mg (Japan) Orteronel 300 mg (Japan) Orteronel 200 mg (Ex-Japan) Orteronel 400 mg (Ex-Japan)
    Number of subjects analysed
    31
    26
    28
    31
    Units: percent change
        arithmetic mean (standard deviation)
    -95.804 ± 5.3367
    -95.703 ± 5.7468
    -91.311 ± 17.5217
    -14.442 ± 406.3116
    No statistical analyses for this end point

    Secondary: Percentage of Participants with Prostate-Specific Antigen Reduction ≥ 50% (PSA50) after 4 Weeks of Treatment

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    End point title
    Percentage of Participants with Prostate-Specific Antigen Reduction ≥ 50% (PSA50) after 4 Weeks of Treatment
    End point description
    A 50% PSA response rate (PSA50) was defined as PSA reduction ≥ 50% from Baseline.
    End point type
    Secondary
    End point timeframe
    Baseline and Week 4
    End point values
    Orteronel 200 mg (Japan) Orteronel 300 mg (Japan) Orteronel 200 mg (Ex-Japan) Orteronel 400 mg (Ex-Japan) Placebo (Japan) Placebo (Ex-Japan)
    Number of subjects analysed
    22
    22
    25
    24
    21
    23
    Units: percentage of participants
        number (confidence interval 95%)
    50.0 (28.2 to 71.8)
    41.0 (20.7 to 63.6)
    48.0 (27.8 to 68.7)
    46.0 (25.6 to 67.2)
    48.0 (25.7 to 70.2)
    17.0 (5.0 to 38.8)
    No statistical analyses for this end point

    Secondary: Percentage of Participants with PSA50 after 12 Weeks of Treatment

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    End point title
    Percentage of Participants with PSA50 after 12 Weeks of Treatment
    End point description
    A 50% PSA response rate (PSA50) was defined as PSA reduction ≥ 50% from Baseline.
    End point type
    Secondary
    End point timeframe
    Baseline and Week 12
    End point values
    Orteronel 200 mg (Japan) Orteronel 300 mg (Japan) Orteronel 200 mg (Ex-Japan) Orteronel 400 mg (Ex-Japan)
    Number of subjects analysed
    33
    32
    36
    36
    Units: percentage of participants
        number (confidence interval 95%)
    55.0 (36.4 to 71.9)
    47.0 (29.1 to 65.3)
    56.0 (38.1 to 72.1)
    44.0 (27.9 to 61.9)
    No statistical analyses for this end point

    Secondary: Absolute Values for Testosterone

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    End point title
    Absolute Values for Testosterone
    End point description
    Serum Ultra-sensitive testosterone was measured by liquid chromatography at a central laboratory.
    End point type
    Secondary
    End point timeframe
    Baseline, Cycle 1 Day 8 and Cycle 2 Day 1
    End point values
    Orteronel 200 mg (Japan) Orteronel 300 mg (Japan) Orteronel 200 mg (Ex-Japan) Orteronel 400 mg (Ex-Japan) Placebo (Japan) Placebo (Ex-Japan)
    Number of subjects analysed
    22
    22
    25
    24
    21
    23
    Units: ng/dL
    arithmetic mean (standard deviation)
        Baseline (n=22, 22, 25, 24, 21, 23)
    9.079 ± 4.4581
    10.148 ± 4.6504
    9.263 ± 5.6572
    14.588 ± 13.9833
    9.749 ± 3.8460
    9.173 ± 5.6123
        Cycle 1 Day 8 (n=22, 22, 20, 21, 20, 19)
    0.213 ± 0.0449
    0.251 ± 0.1727
    0.345 ± 0.2770
    6.658 ± 20.4347
    1.957 ± 2.2843
    3.509 ± 4.3471
        Cycle 2 Day 1 (n=22, 22, 21, 22, 21, 20)
    0.203 ± 0.0145
    0.270 ± 0.2311
    0.266 ± 0.1837
    11.720 ± 45.1753
    1.096 ± 0.7751
    3.095 ± 3.7254
    No statistical analyses for this end point

    Secondary: Absolute Values for Dehydroepiandrosterone Sulfate (DHEA-S)

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    End point title
    Absolute Values for Dehydroepiandrosterone Sulfate (DHEA-S)
    End point description
    Serum Ultra low level quantification of DHEA-S was measured by liquid chromatography and mass spectrometry (LC/MS) at a central laboratory.
    End point type
    Secondary
    End point timeframe
    Baseline, Cycle 1 Day 8 and Cycle 2 Day 1
    End point values
    Orteronel 200 mg (Japan) Orteronel 300 mg (Japan) Orteronel 200 mg (Ex-Japan) Orteronel 400 mg (Ex-Japan) Placebo (Japan) Placebo (Ex-Japan)
    Number of subjects analysed
    22
    22
    25
    24
    21
    23
    Units: nmol/L
    arithmetic mean (standard deviation)
        Baseline (n=22, 22, 25, 24, 21, 23)
    2529.0 ± 1309.39
    2340.9 ± 1606.36
    1783.0 ± 1554.76
    2155.7 ± 1591.51
    1928.0 ± 1306.59
    2601.7 ± 3009.41
        Cycle 1 Day 8 (n=22, 22, 23, 22, 21, 20)
    63.4 ± 55.11
    71.8 ± 80.23
    116.9 ± 161.01
    226.6 ± 328.70
    414.9 ± 392.63
    973.8 ± 1677.95
        Cycle 2 Day 1 (n=22, 22, 22, 22, 21, 20)
    14.5 ± 21.83
    36.3 ± 123.48
    21.5 ± 25.68
    180.6 ± 527.03
    268.9 ± 357.32
    815.7 ± 1918.88
    No statistical analyses for this end point

    Secondary: Absolute Values for Adrenocorticotropic Hormone (ACTH)

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    End point title
    Absolute Values for Adrenocorticotropic Hormone (ACTH)
    End point description
    Serum ACTH was measured by immunometric assay at the central laboratory.
    End point type
    Secondary
    End point timeframe
    Baseline, Cycle 1 Day 8 and Cycle 2 Day 1
    End point values
    Orteronel 200 mg (Japan) Orteronel 300 mg (Japan) Orteronel 200 mg (Ex-Japan) Orteronel 400 mg (Ex-Japan) Placebo (Japan) Placebo (Ex-Japan)
    Number of subjects analysed
    22
    22
    25
    24
    21
    23
    Units: pmol/L
    arithmetic mean (standard deviation)
        Baseline (n=22, 22, 25, 24, 21, 23)
    5.5 ± 2.54
    8.3 ± 4.98
    6.0 ± 4.05
    6.4 ± 4.04
    5.0 ± 1.66
    4.7 ± 2.06
        Cycle 1 Day 8 (n=22, 22, 21, 18, 21, 22)
    2.3 ± 1.55
    3.0 ± 2.70
    3.8 ± 3.04
    3.2 ± 2.56
    3.1 ± 2.68
    3.1 ± 2.62
        Cycle 2 Day 1 (n=22, 22, 24, 22, 21, 22)
    1.7 ± 1.08
    2.7 ± 2.17
    3.7 ± 4.38
    3.6 ± 2.26
    1.7 ± 1.19
    3.0 ± 1.73
    No statistical analyses for this end point

    Secondary: Absolute Values for Corticosterone

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    End point title
    Absolute Values for Corticosterone
    End point description
    Serum Corticosterone was measured by high pressure liquid chromatography with mass spectrometry at the central laboratory.
    End point type
    Secondary
    End point timeframe
    Baseline, Cycle 1 Day 8 and Cycle 2 Day 1
    End point values
    Orteronel 200 mg (Japan) Orteronel 300 mg (Japan) Orteronel 200 mg (Ex-Japan) Orteronel 400 mg (Ex-Japan) Placebo (Japan) Placebo (Ex-Japan)
    Number of subjects analysed
    22
    22
    25
    24
    21
    23
    Units: nmol/L
    arithmetic mean (standard deviation)
        Baseline (n=22, 22, 25, 24, 21, 23)
    6.515 ± 4.8246
    7.768 ± 6.8625
    10.030 ± 7.7341
    17.975 ± 35.0695
    5.946 ± 3.4433
    6.317 ± 4.1467
        Cycle 1 Day 8 (n=22, 22, 23, 21, 21, 20)
    11.067 ± 14.4220
    9.709 ± 13.4538
    48.668 ± 66.3904
    60.301 ± 77.5434
    1.530 ± 1.6404
    5.598 ± 7.1366
        Cycle 2 Day 1 (n=22, 22, 23, 22, 21, 20)
    11.108 ± 9.0708
    14.654 ± 9.2064
    29.929 ± 35.5565
    47.204 ± 53.4566
    0.758 ± 0.5108
    4.321 ± 6.4063
    No statistical analyses for this end point

    Secondary: Absolute Values for Cortisol

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    End point title
    Absolute Values for Cortisol
    End point description
    Serum Cortisol was measured by immunometric assay at the central laboratory.
    End point type
    Secondary
    End point timeframe
    Baseline, Cycle 1 Day 8 and Cycle 2 Day 1
    End point values
    Orteronel 200 mg (Japan) Orteronel 300 mg (Japan) Orteronel 200 mg (Ex-Japan) Orteronel 400 mg (Ex-Japan) Placebo (Japan) Placebo (Ex-Japan)
    Number of subjects analysed
    22
    22
    25
    24
    21
    23
    Units: nmol/L
    arithmetic mean (standard deviation)
        Baseline (n=22, 22, 25, 24, 21, 23)
    371.3 ± 119.38
    383.4 ± 125.98
    449.0 ± 131.54
    446.8 ± 193.09
    366.5 ± 116.69
    384.8 ± 117.14
        Cycle 1 Day 8 (n=22, 22, 24, 22, 21, 23)
    49.5 ± 25.53
    55.5 ± 55.97
    100.9 ± 87.38
    122.0 ± 88.70
    82.3 ± 46.16
    175.8 ± 107.82
        Cycle 2 Day 1 (n=22, 22, 24, 23, 20, 21)
    49.2 ± 21.71
    54.3 ± 39.93
    97.2 ± 85.66
    109.1 ± 83.19
    53.9 ± 24.92
    149.6 ± 122.91
    No statistical analyses for this end point

    Secondary: Absolute Values for Prostate-Specific Antigen (PSA)

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    End point title
    Absolute Values for Prostate-Specific Antigen (PSA)
    End point description
    Serum PSA was measured at the central laboratory.
    End point type
    Secondary
    End point timeframe
    Baseline and Cycle 2 Day 1
    End point values
    Orteronel 200 mg (Japan) Orteronel 300 mg (Japan) Orteronel 200 mg (Ex-Japan) Orteronel 400 mg (Ex-Japan) Placebo (Japan) Placebo (Ex-Japan)
    Number of subjects analysed
    22
    22
    25
    24
    21
    23
    Units: ng/mL
    arithmetic mean (standard deviation)
        Baseline (n=22, 22, 25, 24, 21, 23)
    27.227 ± 24.8821
    97.504 ± 293.9496
    165.992 ± 368.5016
    100.237 ± 210.5675
    37.588 ± 48.9413
    133.238 ± 189.9345
        Cycle 2 Day 1 (n=22, 22, 24, 23, 20, 21)
    18.005 ± 16.9858
    38.892 ± 95.0124
    117.257 ± 286.1870
    56.437 ± 97.1621
    24.325 ± 46.9725
    152.940 ± 261.9735
    No statistical analyses for this end point

    Secondary: Cmax: Maximum Observed Plasma Concentration for Orteronel and M-I Metabolite

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    End point title
    Cmax: Maximum Observed Plasma Concentration for Orteronel and M-I Metabolite
    End point description
    Maximum observed plasma concentration (Cmax) is the peak plasma concentration of a drug after administration, obtained directly from the plasma concentration-time curve.
    End point type
    Secondary
    End point timeframe
    Cycle 1 Day 1 Predose, 0.5, 1, 2, 3, 5, 8, 12 hours post-dose
    End point values
    Orteronel 200 mg (Japan) Orteronel 300 mg (Japan) Orteronel 200 mg (Ex-Japan) Orteronel 400 mg (Ex-Japan)
    Number of subjects analysed
    22
    22
    25
    24
    Units: ng/mL
    geometric mean (geometric coefficient of variation)
        Orteronel
    1520 ± 23.9
    2210 ± 33.9
    1300 ± 59.7
    1610 ± 50.3
        Orteronel Metabolite M-I
    272 ± 33.1
    422 ± 37.0
    199 ± 61.9
    261 ± 47.2
    No statistical analyses for this end point

    Secondary: AUC(0-12): Area Under the Plasma Concentration-Time Curve From Time 0 to 12 Hours Post-dose for Orteronel and M-I Metabolite

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    End point title
    AUC(0-12): Area Under the Plasma Concentration-Time Curve From Time 0 to 12 Hours Post-dose for Orteronel and M-I Metabolite
    End point description
    AUC(0-12) is measure of area under the curve over the dosing interval where the length of the dosing interval is time 0 to 12 hours in this study.
    End point type
    Secondary
    End point timeframe
    Cycle 1 Day 1 Predose, 0.5, 1, 2, 3, 5, 8, 12 hours post-dose
    End point values
    Orteronel 200 mg (Japan) Orteronel 300 mg (Japan) Orteronel 200 mg (Ex-Japan) Orteronel 400 mg (Ex-Japan)
    Number of subjects analysed
    22
    22
    25
    24
    Units: h*ng/mL
    geometric mean (geometric coefficient of variation)
        Orteronel
    8810 ± 16.4
    12800 ± 31.2
    7830 ± 51.1
    10200 ± 41.4
        Orteronel Metabolite M-I
    2130 ± 28.3
    3290 ± 33.8
    1570 ± 65.5
    2080 ± 44.8
    No statistical analyses for this end point

    Secondary: Tmax: Time to Reach the Maximum Plasma Concentration (Cmax) for Orteronel and M-I Metabolite

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    End point title
    Tmax: Time to Reach the Maximum Plasma Concentration (Cmax) for Orteronel and M-I Metabolite
    End point description
    Tmax: Time to reach the maximum plasma concentration (Cmax), equal to time (hours) to Cmax.
    End point type
    Secondary
    End point timeframe
    Cycle 1 Day 1 Predose, 0.5, 1, 2, 3, 5, 8, 12 hours post-dose
    End point values
    Orteronel 200 mg (Japan) Orteronel 300 mg (Japan) Orteronel 200 mg (Ex-Japan) Orteronel 400 mg (Ex-Japan)
    Number of subjects analysed
    22
    22
    25
    24
    Units: hours
    median (full range (min-max))
        Orteronel
    2.97 (1.00 to 5.10)
    2.43 (1.00 to 4.97)
    2.00 (0.500 to 7.93)
    1.92 (0.500 to 5.00)
        Orteronel Metabolite M-I
    5.00 (2.03 to 8.10)
    4.98 (2.00 to 8.23)
    5.05 (1.03 to 11.1)
    4.98 (1.22 to 11.2)
    No statistical analyses for this end point

    Secondary: AE (0-24) Cumulative Amount of Drug Excreted into the Urine for Orteronel and MI-Metabolite

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    End point title
    AE (0-24) Cumulative Amount of Drug Excreted into the Urine for Orteronel and MI-Metabolite
    End point description
    Cumulative amount of urine excreted time 0 to 24 hour.
    End point type
    Secondary
    End point timeframe
    Cycle 1 Day 1 Predose, 0.5, 1, 2, 3, 5, 8, 12 hours post-dose
    End point values
    Orteronel 200 mg (Japan) Orteronel 300 mg (Japan) Orteronel 200 mg (Ex-Japan) Orteronel 400 mg (Ex-Japan)
    Number of subjects analysed
    22
    22
    25
    24
    Units: mg
    geometric mean (geometric coefficient of variation)
        Orteronel
    115.0 ± 26.0
    164.0 ± 26.2
    95.3 ± 31.9
    161.0 ± 41.4
        Orteronel Metabolite M-I
    39.6 ± 31.5
    62.5 ± 26.6
    30.0 ± 40.1
    52.8 ± 46.4
    No statistical analyses for this end point

    Secondary: Cmax,ss: Maximum Observed Plasma Concentration at Steady State for Orteronel and MI-Metabolite

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    End point title
    Cmax,ss: Maximum Observed Plasma Concentration at Steady State for Orteronel and MI-Metabolite
    End point description
    Maximum observed steady-state plasma concentration during a dosing interval.
    End point type
    Secondary
    End point timeframe
    Cycle 1 Day 8 Predose, 0.5, 1, 2, 3, 5, 8, 12 hours post-dose
    End point values
    Orteronel 200 mg (Japan) Orteronel 300 mg (Japan) Orteronel 200 mg (Ex-Japan) Orteronel 400 mg (Ex-Japan)
    Number of subjects analysed
    22
    22
    25
    24
    Units: ng/mL
    geometric mean (geometric coefficient of variation)
        Orteronel
    2180 ± 22.4
    3210 ± 31.5
    1840 ± 37.1
    3100 ± 45.0
        Orteronel Metabolite M-I
    565 ± 32.4
    864 ± 39.5
    485 ± 75.4
    761 ± 81.3
    No statistical analyses for this end point

    Secondary: Tmax,ss: Time to reach the maximum plasma concentration (Cmax), equal to time (hours) to Cmax at Steady State for Orteronel and M-I Metabolite

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    End point title
    Tmax,ss: Time to reach the maximum plasma concentration (Cmax), equal to time (hours) to Cmax at Steady State for Orteronel and M-I Metabolite
    End point description
    Time to reach the maximum plasma concentration (Cmax), equal to time (hours) to Cmax at steady state.
    End point type
    Secondary
    End point timeframe
    Cycle 1 Day 8 Predose, 0.5, 1, 2, 3, 5, 8, 12 hours post-dose
    End point values
    Orteronel 200 mg (Japan) Orteronel 300 mg (Japan) Orteronel 200 mg (Ex-Japan) Orteronel 400 mg (Ex-Japan)
    Number of subjects analysed
    22
    22
    25
    24
    Units: hours
    median (confidence interval 95%)
        Orteronel
    2.05 (1.00 to 5.08)
    2.96 (1.00 to 5.17)
    2.00 (0.550 to 5.17)
    1.98 (0.500 to 3.08)
        Orteronel Metabolite M-I
    3.08 (2.00 to 5.17)
    4.78 (2.00 to 8.13)
    3.00 (1.00 to 5.07)
    3.00 (0 to 8.00)
    No statistical analyses for this end point

    Secondary: AUC(0-tau): Area Under the Plasma Concentration-time Curve from Time 0 to Time tau Over the Dosing Interval for Orteronel and M-I Metabolite

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    End point title
    AUC(0-tau): Area Under the Plasma Concentration-time Curve from Time 0 to Time tau Over the Dosing Interval for Orteronel and M-I Metabolite
    End point description
    Area under the plasma concentration-time curve during a dosing interval, where tau is the length of the dosing interval.
    End point type
    Secondary
    End point timeframe
    Cycle 1 Day 8 Predose, 0.5, 1, 2, 3, 5, 8, 12 hours post-dose
    End point values
    Orteronel 200 mg (Japan) Orteronel 300 mg (Japan) Orteronel 200 mg (Ex-Japan) Orteronel 400 mg (Ex-Japan)
    Number of subjects analysed
    22
    22
    25
    24
    Units: h*ng/mL
    geometric mean (geometric coefficient of variation)
        Orteronel
    13300 ± 20.4
    20400 ± 36.1
    12600 ± 36.2
    20000 ± 55.0
        Orteronel Metabolite M-I
    4840 ± 35.0
    7460 ± 46.3
    4340 ± 69.4
    6590 ± 78.0
    No statistical analyses for this end point

    Secondary: Rac: Accumulation index for Orteronel and M-I metabolite

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    End point title
    Rac: Accumulation index for Orteronel and M-I metabolite
    End point description
    Rac was calculated as the ratio of AUCtau to AUC12hr.
    End point type
    Secondary
    End point timeframe
    Cycle 1 Day 8 Predose, 0.5, 1, 2, 3, 5, 8, 12 hours post-dose
    End point values
    Orteronel 200 mg (Japan) Orteronel 300 mg (Japan) Orteronel 200 mg (Ex-Japan) Orteronel 400 mg (Ex-Japan)
    Number of subjects analysed
    22
    22
    25
    24
    Units: ratio
    geometric mean (geometric coefficient of variation)
        Orteronel
    1.51 ± 9.1
    1.59 ± 46.6
    1.62 ± 39.3
    1.97 ± 90.5
        Orteronel Metabolite M-I
    2.27 ± 17.5
    2.26 ± 43.0
    2.76 ± 45.0
    3.17 ± 77.7
    No statistical analyses for this end point

    Secondary: Ctrough,ss: Observed Predose Plasma Concentration at Steady State for Orteronel and M-I Metabolite

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    End point title
    Ctrough,ss: Observed Predose Plasma Concentration at Steady State for Orteronel and M-I Metabolite
    End point description
    Observed predose plasma concentration at steady state.
    End point type
    Secondary
    End point timeframe
    Cycle 1 Day 8 Predose
    End point values
    Orteronel 200 mg (Japan) Orteronel 300 mg (Japan) Orteronel 200 mg (Ex-Japan) Orteronel 400 mg (Ex-Japan)
    Number of subjects analysed
    22
    22
    24
    22
    Units: ng/mL
    geometric mean (geometric coefficient of variation)
        Orteronel
    710 ± 28.1
    1060 ± 63.7
    807 ± 45.4
    899 ± 59.8
        Orteronel Metbolite M-I
    291 ± 47.1
    444 ± 66.7
    314 ± 68.6
    417 ± 58.0
    No statistical analyses for this end point

    Secondary: Number of Participants with Treatment-Emergent Adverse events (AEs) and Serious Adverse Events (SAEs)

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    End point title
    Number of Participants with Treatment-Emergent Adverse events (AEs) and Serious Adverse Events (SAEs)
    End point description
    An Adverse Event (AE) is defined as any untoward medical occurrence in a clinical investigation participant administered a drug; it does not necessarily have to have a causal relationship with this treatment. An AE can therefore be any unfavorable and unintended sign (eg, a clinically significant abnormal laboratory finding),symptom, or disease temporally associated with the use of a drug, whether or not it is considered related to the drug. A treatment-emergent adverse event (TEAE) is defined as an adverse event with an onset that occurs after receiving study A serious adverse event is any experience that suggests a significant hazard, contraindication, side effect or precaution that: results in death, is life-threatening, required in-patient hospitalization or prolongation of existing hospitalization, results in persistent or significant disability/incapacity, is a congenital anomaly/birth defect or is medically significant.
    End point type
    Secondary
    End point timeframe
    From signing of the informed consent form through 30 days after the last dose of study drug, approximately 3.2 years
    End point values
    Orteronel 200 mg (Japan) Orteronel 300 mg (Japan) Orteronel 200 mg (Ex-Japan) Orteronel 400 mg (Ex-Japan) Placebo (Japan) Placebo (Ex-Japan)
    Number of subjects analysed
    33
    32
    36
    36
    21
    23
    Units: participants
        AE
    33
    32
    36
    36
    7
    18
        SAE
    8
    18
    16
    12
    0
    1
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    From signing of the informed consent form through 30 days after the last dose of study drug, approximately 3.2 years for serious adverse events and up to data-cut-off 12-Sep-2013 for non-serious adverse events.
    Adverse event reporting additional description
    At each visit the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment. Adverse events were summarized as per the treatment received.
    Assessment type
    Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    MedDRA
    Dictionary version
    16.0
    Reporting groups
    Reporting group title
    Placebo
    Reporting group description
    Orteronel placebo-matching tablets, orally, twice daily in Cycle 1 (28 days). Study drug will be administered concomitantly with prednisone (or commercially available equivalent) 5 mg twice daily (BID) continuously throughout the study.

    Reporting group title
    Orteronel 200 mg (Japan)
    Reporting group description
    Orteronel 200 mg, tablets, orally, twice daily in 28 day cycles in for up to 2.8 years. Study drug will be administered concomitantly with prednisone (or commercially available equivalent) 5 mg twice daily (BID) continuously throughout the study.

    Reporting group title
    Orteronel 300 mg (Japan)
    Reporting group description
    Orteronel 300 mg, tablets, orally, twice daily in 28 day cycles in Japan for up to 2.8 years. Study drug will be administered concomitantly with prednisone (or commercially available equivalent) 5 mg twice daily (BID) continuously throughout the study.

    Reporting group title
    Orteronel 200 mg (Ex-Japan)
    Reporting group description
    Orteronel 200 mg, tablets, orally, twice daily in 28 day cycles in for up to 3.1 years. Study drug will be administered concomitantly with prednisone (or commercially available equivalent) 5 mg twice daily (BID) continuously throughout the study.

    Reporting group title
    Orteronel 400mg (Ex-Japan)
    Reporting group description
    Orteronel 400 mg, tablets, orally, twice daily in 28 day cycles Ex-Japan for up to 3.1 years. Study drug will be administered concomitantly with prednisone (or commercially available equivalent) 5 mg twice daily (BID) continuously throughout the study.

    Serious adverse events
    Placebo Orteronel 200 mg (Japan) Orteronel 300 mg (Japan) Orteronel 200 mg (Ex-Japan) Orteronel 400mg (Ex-Japan)
    Total subjects affected by serious adverse events
         subjects affected / exposed
    10 / 44 (22.73%)
    8 / 33 (24.24%)
    18 / 32 (56.25%)
    16 / 36 (44.44%)
    12 / 36 (33.33%)
         number of deaths (all causes)
    0
    0
    2
    0
    0
         number of deaths resulting from adverse events
    Vascular disorders
    Deep vein thrombosis
         subjects affected / exposed
    0 / 44 (0.00%)
    0 / 33 (0.00%)
    0 / 32 (0.00%)
    1 / 36 (2.78%)
    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
    Venous thrombosis limb
         subjects affected / exposed
    0 / 44 (0.00%)
    0 / 33 (0.00%)
    0 / 32 (0.00%)
    1 / 36 (2.78%)
    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
    Hypertension
         subjects affected / exposed
    0 / 44 (0.00%)
    0 / 33 (0.00%)
    0 / 32 (0.00%)
    1 / 36 (2.78%)
    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
    Orthostatic Hypotension
         subjects affected / exposed
    0 / 44 (0.00%)
    0 / 33 (0.00%)
    0 / 32 (0.00%)
    0 / 36 (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
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Lung adenocarcinoma
         subjects affected / exposed
    0 / 44 (0.00%)
    1 / 33 (3.03%)
    0 / 32 (0.00%)
    0 / 36 (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
    Cancer pain
         subjects affected / exposed
    0 / 44 (0.00%)
    1 / 33 (3.03%)
    0 / 32 (0.00%)
    0 / 36 (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
    Rectal cancer
         subjects affected / exposed
    0 / 44 (0.00%)
    1 / 33 (3.03%)
    0 / 32 (0.00%)
    0 / 36 (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
    Renal neoplasm
         subjects affected / exposed
    0 / 44 (0.00%)
    1 / 33 (3.03%)
    0 / 32 (0.00%)
    0 / 36 (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
    Gastric cancer
         subjects affected / exposed
    0 / 44 (0.00%)
    0 / 33 (0.00%)
    1 / 32 (3.13%)
    0 / 36 (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 / 44 (0.00%)
    0 / 33 (0.00%)
    1 / 32 (3.13%)
    0 / 36 (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
    Pancreatic Carcinoma
         subjects affected / exposed
    0 / 44 (0.00%)
    0 / 33 (0.00%)
    0 / 32 (0.00%)
    1 / 36 (2.78%)
    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
    Metastatic Pain
         subjects affected / exposed
    0 / 44 (0.00%)
    0 / 33 (0.00%)
    0 / 32 (0.00%)
    1 / 36 (2.78%)
    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
    General disorders and administration site conditions
    General physical health deterioration
         subjects affected / exposed
    0 / 44 (0.00%)
    0 / 33 (0.00%)
    1 / 32 (3.13%)
    0 / 36 (0.00%)
    1 / 36 (2.78%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 2
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    Asthenia
         subjects affected / exposed
    1 / 44 (2.27%)
    0 / 33 (0.00%)
    0 / 32 (0.00%)
    1 / 36 (2.78%)
    1 / 36 (2.78%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Fatigue
         subjects affected / exposed
    0 / 44 (0.00%)
    0 / 33 (0.00%)
    0 / 32 (0.00%)
    1 / 36 (2.78%)
    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
    Device occlusion
         subjects affected / exposed
    0 / 44 (0.00%)
    0 / 33 (0.00%)
    0 / 32 (0.00%)
    1 / 36 (2.78%)
    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
    Injury, poisoning and procedural complications
    Head injury
         subjects affected / exposed
    0 / 44 (0.00%)
    0 / 33 (0.00%)
    0 / 32 (0.00%)
    0 / 36 (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
    Lumbar Vertebral Fracture
         subjects affected / exposed
    0 / 44 (0.00%)
    1 / 33 (3.03%)
    1 / 32 (3.13%)
    0 / 36 (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
    Spinal Compression Fracture
         subjects affected / exposed
    0 / 44 (0.00%)
    1 / 33 (3.03%)
    0 / 32 (0.00%)
    0 / 36 (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
    Thoracic Vertebral Fracture
         subjects affected / exposed
    0 / 44 (0.00%)
    0 / 33 (0.00%)
    1 / 32 (3.13%)
    0 / 36 (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
    Facial Bones Fracture
         subjects affected / exposed
    0 / 44 (0.00%)
    0 / 33 (0.00%)
    1 / 32 (3.13%)
    0 / 36 (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
    Investigations
    Pancreatic enzymes increased
         subjects affected / exposed
    0 / 44 (0.00%)
    0 / 33 (0.00%)
    1 / 32 (3.13%)
    0 / 36 (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
    Liver function test abnormal
         subjects affected / exposed
    1 / 44 (2.27%)
    0 / 33 (0.00%)
    1 / 32 (3.13%)
    0 / 36 (0.00%)
    0 / 36 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    International normalised ratio increased
         subjects affected / exposed
    1 / 44 (2.27%)
    0 / 33 (0.00%)
    0 / 32 (0.00%)
    0 / 36 (0.00%)
    1 / 36 (2.78%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cardiac disorders
    Cardiac disorder
         subjects affected / exposed
    0 / 44 (0.00%)
    0 / 33 (0.00%)
    1 / 32 (3.13%)
    0 / 36 (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
    Atrial fibrillation
         subjects affected / exposed
    1 / 44 (2.27%)
    0 / 33 (0.00%)
    0 / 32 (0.00%)
    1 / 36 (2.78%)
    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
    Coronary Artery Stenosis
         subjects affected / exposed
    0 / 44 (0.00%)
    1 / 33 (3.03%)
    0 / 32 (0.00%)
    0 / 36 (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
    Myocardial Ischaemia
         subjects affected / exposed
    0 / 44 (0.00%)
    1 / 33 (3.03%)
    0 / 32 (0.00%)
    0 / 36 (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
    Cardiac arrest
         subjects affected / exposed
    0 / 44 (0.00%)
    0 / 33 (0.00%)
    0 / 32 (0.00%)
    1 / 36 (2.78%)
    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
    Respiratory, thoracic and mediastinal disorders
    Chronic obstructive pulmonary disease
         subjects affected / exposed
    0 / 44 (0.00%)
    0 / 33 (0.00%)
    2 / 32 (6.25%)
    0 / 36 (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
    Pulmonary embolism
         subjects affected / exposed
    0 / 44 (0.00%)
    0 / 33 (0.00%)
    0 / 32 (0.00%)
    2 / 36 (5.56%)
    1 / 36 (2.78%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    1 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pleural effusion
         subjects affected / exposed
    1 / 44 (2.27%)
    0 / 33 (0.00%)
    0 / 32 (0.00%)
    1 / 36 (2.78%)
    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
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    1 / 44 (2.27%)
    1 / 33 (3.03%)
    1 / 32 (3.13%)
    1 / 36 (2.78%)
    0 / 36 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
    0 / 1
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pancytopenia
         subjects affected / exposed
    1 / 44 (2.27%)
    0 / 33 (0.00%)
    0 / 32 (0.00%)
    1 / 36 (2.78%)
    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
    Nervous system disorders
    Dizziness
         subjects affected / exposed
    0 / 44 (0.00%)
    0 / 33 (0.00%)
    1 / 32 (3.13%)
    0 / 36 (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
    Balance disorder
         subjects affected / exposed
    0 / 44 (0.00%)
    0 / 33 (0.00%)
    0 / 32 (0.00%)
    0 / 36 (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
    Aphasia
         subjects affected / exposed
    0 / 44 (0.00%)
    0 / 33 (0.00%)
    0 / 32 (0.00%)
    0 / 36 (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
    Spinal cord compression
         subjects affected / exposed
    1 / 44 (2.27%)
    0 / 33 (0.00%)
    0 / 32 (0.00%)
    1 / 36 (2.78%)
    1 / 36 (2.78%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Altered State Of Consciousness
         subjects affected / exposed
    0 / 44 (0.00%)
    0 / 33 (0.00%)
    1 / 32 (3.13%)
    0 / 36 (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
    Parkinsonism
         subjects affected / exposed
    0 / 44 (0.00%)
    0 / 33 (0.00%)
    0 / 32 (0.00%)
    1 / 36 (2.78%)
    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
    Parkinson's disease
         subjects affected / exposed
    0 / 44 (0.00%)
    0 / 33 (0.00%)
    0 / 32 (0.00%)
    1 / 36 (2.78%)
    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
    Eye disorders
    Cataract
         subjects affected / exposed
    0 / 44 (0.00%)
    0 / 33 (0.00%)
    1 / 32 (3.13%)
    0 / 36 (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 disorders
    Pancreatitis
         subjects affected / exposed
    1 / 44 (2.27%)
    1 / 33 (3.03%)
    1 / 32 (3.13%)
    0 / 36 (0.00%)
    0 / 36 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    1 / 1
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pancreatitis acute
         subjects affected / exposed
    1 / 44 (2.27%)
    0 / 33 (0.00%)
    1 / 32 (3.13%)
    0 / 36 (0.00%)
    0 / 36 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Duodenal ulcer
         subjects affected / exposed
    0 / 44 (0.00%)
    1 / 33 (3.03%)
    0 / 32 (0.00%)
    0 / 36 (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
    Constipation
         subjects affected / exposed
    0 / 44 (0.00%)
    0 / 33 (0.00%)
    0 / 32 (0.00%)
    1 / 36 (2.78%)
    1 / 36 (2.78%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal haemorrhage
         subjects affected / exposed
    1 / 44 (2.27%)
    0 / 33 (0.00%)
    0 / 32 (0.00%)
    1 / 36 (2.78%)
    1 / 36 (2.78%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Large Intestine Polyp
         subjects affected / exposed
    0 / 44 (0.00%)
    1 / 33 (3.03%)
    0 / 32 (0.00%)
    0 / 36 (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
    Nausea
         subjects affected / exposed
    0 / 44 (0.00%)
    1 / 33 (3.03%)
    0 / 32 (0.00%)
    0 / 36 (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
    Vomitting
         subjects affected / exposed
    0 / 44 (0.00%)
    1 / 33 (3.03%)
    0 / 32 (0.00%)
    0 / 36 (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 Angiodysplasia
         subjects affected / exposed
    0 / 44 (0.00%)
    0 / 33 (0.00%)
    0 / 32 (0.00%)
    1 / 36 (2.78%)
    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
    Diarrhoea
         subjects affected / exposed
    0 / 44 (0.00%)
    0 / 33 (0.00%)
    0 / 32 (0.00%)
    1 / 36 (2.78%)
    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
    Hepatobiliary disorders
    Hepatic function abnormal
         subjects affected / exposed
    1 / 44 (2.27%)
    0 / 33 (0.00%)
    2 / 32 (6.25%)
    0 / 36 (0.00%)
    0 / 36 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    2 / 2
    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 / 44 (0.00%)
    1 / 33 (3.03%)
    0 / 32 (0.00%)
    0 / 36 (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
    Bile Duct Stone
         subjects affected / exposed
    0 / 44 (0.00%)
    1 / 33 (3.03%)
    0 / 32 (0.00%)
    0 / 36 (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
    Renal and urinary disorders
    Haematuria
         subjects affected / exposed
    1 / 44 (2.27%)
    0 / 33 (0.00%)
    0 / 32 (0.00%)
    2 / 36 (5.56%)
    0 / 36 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Urinary tract obstruction
         subjects affected / exposed
    1 / 44 (2.27%)
    0 / 33 (0.00%)
    0 / 32 (0.00%)
    1 / 36 (2.78%)
    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
    Acute Kidney Injury
         subjects affected / exposed
    0 / 44 (0.00%)
    0 / 33 (0.00%)
    0 / 32 (0.00%)
    1 / 36 (2.78%)
    1 / 36 (2.78%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Renal Colic
         subjects affected / exposed
    0 / 44 (0.00%)
    0 / 33 (0.00%)
    0 / 32 (0.00%)
    1 / 36 (2.78%)
    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
    Skin and subcutaneous tissue disorders
    Dermatitis exfoliative
         subjects affected / exposed
    1 / 44 (2.27%)
    0 / 33 (0.00%)
    0 / 32 (0.00%)
    0 / 36 (0.00%)
    1 / 36 (2.78%)
         occurrences causally related to treatment / all
    0 / 1
    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
    Rotator Cuff Syndrome
         subjects affected / exposed
    0 / 44 (0.00%)
    0 / 33 (0.00%)
    1 / 32 (3.13%)
    0 / 36 (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
    Spinal Ligament Ossification
         subjects affected / exposed
    0 / 44 (0.00%)
    0 / 33 (0.00%)
    1 / 32 (3.13%)
    0 / 36 (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
    Lumbar Spinal Stenosis
         subjects affected / exposed
    0 / 44 (0.00%)
    0 / 33 (0.00%)
    1 / 32 (3.13%)
    0 / 36 (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
    Pathological Fracture
         subjects affected / exposed
    0 / 44 (0.00%)
    0 / 33 (0.00%)
    0 / 32 (0.00%)
    1 / 36 (2.78%)
    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
    Arthralgia
         subjects affected / exposed
    0 / 44 (0.00%)
    0 / 33 (0.00%)
    0 / 32 (0.00%)
    1 / 36 (2.78%)
    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
    Metabolism and nutrition disorders
    Diabetes mellitus
         subjects affected / exposed
    1 / 44 (2.27%)
    0 / 33 (0.00%)
    2 / 32 (6.25%)
    0 / 36 (0.00%)
    0 / 36 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    2 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Diabetic ketoacidosis
         subjects affected / exposed
    0 / 44 (0.00%)
    0 / 33 (0.00%)
    1 / 32 (3.13%)
    0 / 36 (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
    Hyponatraemia
         subjects affected / exposed
    0 / 44 (0.00%)
    0 / 33 (0.00%)
    1 / 32 (3.13%)
    0 / 36 (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
    Dehydration
         subjects affected / exposed
    0 / 44 (0.00%)
    0 / 33 (0.00%)
    0 / 32 (0.00%)
    0 / 36 (0.00%)
    3 / 36 (8.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Infections and infestations
    Pneumonia
         subjects affected / exposed
    2 / 44 (4.55%)
    0 / 33 (0.00%)
    2 / 32 (6.25%)
    2 / 36 (5.56%)
    2 / 36 (5.56%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    2 / 3
    0 / 2
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Bronchopneumonia
         subjects affected / exposed
    0 / 44 (0.00%)
    0 / 33 (0.00%)
    1 / 32 (3.13%)
    0 / 36 (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
    Influenza
         subjects affected / exposed
    0 / 44 (0.00%)
    0 / 33 (0.00%)
    1 / 32 (3.13%)
    0 / 36 (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
    Gastroenteritis viral
         subjects affected / exposed
    0 / 44 (0.00%)
    0 / 33 (0.00%)
    0 / 32 (0.00%)
    0 / 36 (0.00%)
    2 / 36 (5.56%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Escherichia sepsis
         subjects affected / exposed
    1 / 44 (2.27%)
    0 / 33 (0.00%)
    0 / 32 (0.00%)
    0 / 36 (0.00%)
    1 / 36 (2.78%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Respiratory tract infection
         subjects affected / exposed
    1 / 44 (2.27%)
    0 / 33 (0.00%)
    0 / 32 (0.00%)
    1 / 36 (2.78%)
    0 / 36 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Septic shock
         subjects affected / exposed
    0 / 44 (0.00%)
    0 / 33 (0.00%)
    0 / 32 (0.00%)
    1 / 36 (2.78%)
    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
    Streptococcal bacteraemia
         subjects affected / exposed
    0 / 44 (0.00%)
    0 / 33 (0.00%)
    0 / 32 (0.00%)
    1 / 36 (2.78%)
    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
    Urinary tract infection
         subjects affected / exposed
    0 / 44 (0.00%)
    0 / 33 (0.00%)
    0 / 32 (0.00%)
    1 / 36 (2.78%)
    1 / 36 (2.78%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Sepsis
         subjects affected / exposed
    0 / 44 (0.00%)
    1 / 33 (3.03%)
    0 / 32 (0.00%)
    1 / 36 (2.78%)
    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
    Pyelonephritis
         subjects affected / exposed
    0 / 44 (0.00%)
    0 / 33 (0.00%)
    1 / 32 (3.13%)
    0 / 36 (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
    Device Related Infection
         subjects affected / exposed
    0 / 44 (0.00%)
    0 / 33 (0.00%)
    0 / 32 (0.00%)
    0 / 36 (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
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    Placebo Orteronel 200 mg (Japan) Orteronel 300 mg (Japan) Orteronel 200 mg (Ex-Japan) Orteronel 400mg (Ex-Japan)
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    44 / 44 (100.00%)
    33 / 33 (100.00%)
    32 / 32 (100.00%)
    35 / 36 (97.22%)
    36 / 36 (100.00%)
    Vascular disorders
    Hot flush
         subjects affected / exposed
    7 / 44 (15.91%)
    3 / 33 (9.09%)
    5 / 32 (15.63%)
    5 / 36 (13.89%)
    10 / 36 (27.78%)
         occurrences all number
    7
    3
    5
    5
    10
    Hypertension
         subjects affected / exposed
    4 / 44 (9.09%)
    3 / 33 (9.09%)
    3 / 32 (9.38%)
    2 / 36 (5.56%)
    8 / 36 (22.22%)
         occurrences all number
    4
    3
    3
    2
    8
    Deep vein thrombosis
         subjects affected / exposed
    0 / 44 (0.00%)
    0 / 33 (0.00%)
    0 / 32 (0.00%)
    3 / 36 (8.33%)
    1 / 36 (2.78%)
         occurrences all number
    0
    0
    0
    3
    1
    Flushing
         subjects affected / exposed
    0 / 44 (0.00%)
    0 / 33 (0.00%)
    0 / 32 (0.00%)
    3 / 36 (8.33%)
    1 / 36 (2.78%)
         occurrences all number
    0
    0
    0
    3
    1
    Hypotension
         subjects affected / exposed
    0 / 44 (0.00%)
    0 / 33 (0.00%)
    0 / 32 (0.00%)
    1 / 36 (2.78%)
    2 / 36 (5.56%)
         occurrences all number
    0
    0
    0
    1
    2
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Cancer pain
         subjects affected / exposed
    2 / 44 (4.55%)
    1 / 33 (3.03%)
    3 / 32 (9.38%)
    0 / 36 (0.00%)
    0 / 36 (0.00%)
         occurrences all number
    2
    1
    4
    0
    0
    Metastatic pain
         subjects affected / exposed
    0 / 44 (0.00%)
    0 / 33 (0.00%)
    0 / 32 (0.00%)
    0 / 36 (0.00%)
    2 / 36 (5.56%)
         occurrences all number
    0
    0
    0
    0
    2
    Immune system disorders
    Seasonal allergy
         subjects affected / exposed
    0 / 44 (0.00%)
    0 / 33 (0.00%)
    0 / 32 (0.00%)
    1 / 36 (2.78%)
    2 / 36 (5.56%)
         occurrences all number
    0
    0
    0
    1
    2
    General disorders and administration site conditions
    Fatigue
         subjects affected / exposed
    8 / 44 (18.18%)
    0 / 33 (0.00%)
    2 / 32 (6.25%)
    19 / 36 (52.78%)
    15 / 36 (41.67%)
         occurrences all number
    9
    0
    3
    22
    17
    Oedema peripheral
         subjects affected / exposed
    4 / 44 (9.09%)
    8 / 33 (24.24%)
    6 / 32 (18.75%)
    7 / 36 (19.44%)
    5 / 36 (13.89%)
         occurrences all number
    4
    10
    7
    7
    6
    Malaise
         subjects affected / exposed
    4 / 44 (9.09%)
    4 / 33 (12.12%)
    6 / 32 (18.75%)
    3 / 36 (8.33%)
    0 / 36 (0.00%)
         occurrences all number
    5
    5
    7
    3
    0
    Face Oedema
         subjects affected / exposed
    0 / 44 (0.00%)
    2 / 33 (6.06%)
    2 / 32 (6.25%)
    0 / 36 (0.00%)
    0 / 36 (0.00%)
         occurrences all number
    0
    2
    3
    0
    0
    Pyrexia
         subjects affected / exposed
    0 / 44 (0.00%)
    0 / 33 (0.00%)
    2 / 32 (6.25%)
    0 / 36 (0.00%)
    0 / 36 (0.00%)
         occurrences all number
    0
    0
    2
    0
    0
    Peripheral swelling
         subjects affected / exposed
    0 / 44 (0.00%)
    0 / 33 (0.00%)
    0 / 32 (0.00%)
    1 / 36 (2.78%)
    2 / 36 (5.56%)
         occurrences all number
    0
    0
    0
    1
    2
    Psychiatric disorders
    Insomnia
         subjects affected / exposed
    2 / 44 (4.55%)
    2 / 33 (6.06%)
    2 / 32 (6.25%)
    6 / 36 (16.67%)
    4 / 36 (11.11%)
         occurrences all number
    2
    2
    2
    6
    4
    Depression
         subjects affected / exposed
    1 / 44 (2.27%)
    0 / 33 (0.00%)
    0 / 32 (0.00%)
    3 / 36 (8.33%)
    2 / 36 (5.56%)
         occurrences all number
    1
    0
    0
    3
    2
    Anxiety
         subjects affected / exposed
    0 / 44 (0.00%)
    0 / 33 (0.00%)
    0 / 32 (0.00%)
    2 / 36 (5.56%)
    2 / 36 (5.56%)
         occurrences all number
    0
    0
    0
    2
    2
    Restlessness
         subjects affected / exposed
    0 / 44 (0.00%)
    0 / 33 (0.00%)
    0 / 32 (0.00%)
    0 / 36 (0.00%)
    2 / 36 (5.56%)
         occurrences all number
    0
    0
    0
    0
    2
    Injury, poisoning and procedural complications
    Fall
         subjects affected / exposed
    2 / 44 (4.55%)
    3 / 33 (9.09%)
    5 / 32 (15.63%)
    2 / 36 (5.56%)
    5 / 36 (13.89%)
         occurrences all number
    2
    4
    8
    4
    6
    Contusion
         subjects affected / exposed
    0 / 44 (0.00%)
    1 / 33 (3.03%)
    3 / 32 (9.38%)
    3 / 36 (8.33%)
    0 / 36 (0.00%)
         occurrences all number
    0
    1
    3
    8
    0
    Rib fracture
         subjects affected / exposed
    0 / 44 (0.00%)
    2 / 33 (6.06%)
    1 / 32 (3.13%)
    0 / 36 (0.00%)
    0 / 36 (0.00%)
         occurrences all number
    0
    2
    1
    0
    0
    Spinal compression fracture
         subjects affected / exposed
    0 / 44 (0.00%)
    2 / 33 (6.06%)
    0 / 32 (0.00%)
    0 / 36 (0.00%)
    0 / 36 (0.00%)
         occurrences all number
    0
    4
    0
    0
    0
    Skin abrasion
         subjects affected / exposed
    0 / 44 (0.00%)
    0 / 33 (0.00%)
    2 / 32 (6.25%)
    0 / 36 (0.00%)
    0 / 36 (0.00%)
         occurrences all number
    0
    0
    2
    0
    0
    Thoracic vertebral fracture
         subjects affected / exposed
    0 / 44 (0.00%)
    0 / 33 (0.00%)
    2 / 32 (6.25%)
    0 / 36 (0.00%)
    0 / 36 (0.00%)
         occurrences all number
    0
    0
    2
    0
    0
    Meniscus injury
         subjects affected / exposed
    0 / 44 (0.00%)
    0 / 33 (0.00%)
    0 / 32 (0.00%)
    0 / 36 (0.00%)
    2 / 36 (5.56%)
         occurrences all number
    0
    0
    0
    0
    2
    Investigations
    Lipase increased
         subjects affected / exposed
    19 / 44 (43.18%)
    25 / 33 (75.76%)
    19 / 32 (59.38%)
    9 / 36 (25.00%)
    7 / 36 (19.44%)
         occurrences all number
    36
    46
    32
    10
    9
    Amylase increased
         subjects affected / exposed
    16 / 44 (36.36%)
    21 / 33 (63.64%)
    19 / 32 (59.38%)
    4 / 36 (11.11%)
    6 / 36 (16.67%)
         occurrences all number
    21
    35
    27
    7
    10
    Alanine aminotransferase increased
         subjects affected / exposed
    6 / 44 (13.64%)
    7 / 33 (21.21%)
    7 / 32 (21.88%)
    2 / 36 (5.56%)
    1 / 36 (2.78%)
         occurrences all number
    7
    7
    11
    4
    1
    Aspartate aminotransferase increased
         subjects affected / exposed
    6 / 44 (13.64%)
    7 / 33 (21.21%)
    7 / 32 (21.88%)
    2 / 36 (5.56%)
    1 / 36 (2.78%)
         occurrences all number
    8
    7
    11
    4
    1
    Gamma-glutamyltransferase increased
         subjects affected / exposed
    6 / 44 (13.64%)
    5 / 33 (15.15%)
    8 / 32 (25.00%)
    0 / 36 (0.00%)
    2 / 36 (5.56%)
         occurrences all number
    6
    6
    14
    0
    2
    Weight decreased
         subjects affected / exposed
    5 / 44 (11.36%)
    2 / 33 (6.06%)
    6 / 32 (18.75%)
    2 / 36 (5.56%)
    3 / 36 (8.33%)
         occurrences all number
    5
    2
    9
    2
    4
    Blood lactate dehydrogenase increased
         subjects affected / exposed
    5 / 44 (11.36%)
    8 / 33 (24.24%)
    4 / 32 (12.50%)
    0 / 36 (0.00%)
    0 / 36 (0.00%)
         occurrences all number
    5
    8
    4
    0
    0
    Blood creatinine increased
         subjects affected / exposed
    2 / 44 (4.55%)
    0 / 33 (0.00%)
    5 / 32 (15.63%)
    2 / 36 (5.56%)
    1 / 36 (2.78%)
         occurrences all number
    2
    0
    5
    2
    1
    Blood alkaline phosphatase increased
         subjects affected / exposed
    1 / 44 (2.27%)
    1 / 33 (3.03%)
    6 / 32 (18.75%)
    0 / 36 (0.00%)
    0 / 36 (0.00%)
         occurrences all number
    1
    1
    7
    0
    0
    Blood urea increased
         subjects affected / exposed
    1 / 44 (2.27%)
    0 / 33 (0.00%)
    4 / 32 (12.50%)
    2 / 36 (5.56%)
    1 / 36 (2.78%)
         occurrences all number
    2
    0
    8
    2
    1
    White blood cell count decreased
         subjects affected / exposed
    3 / 44 (6.82%)
    3 / 33 (9.09%)
    3 / 32 (9.38%)
    0 / 36 (0.00%)
    0 / 36 (0.00%)
         occurrences all number
    5
    4
    5
    0
    0
    Weight increased
         subjects affected / exposed
    0 / 44 (0.00%)
    4 / 33 (12.12%)
    0 / 32 (0.00%)
    0 / 36 (0.00%)
    0 / 36 (0.00%)
         occurrences all number
    0
    4
    0
    0
    0
    Neutrophil count decreased
         subjects affected / exposed
    0 / 44 (0.00%)
    3 / 33 (9.09%)
    0 / 32 (0.00%)
    0 / 36 (0.00%)
    0 / 36 (0.00%)
         occurrences all number
    0
    4
    0
    0
    0
    Glycosylated haemoglobin increased
         subjects affected / exposed
    0 / 44 (0.00%)
    2 / 33 (6.06%)
    1 / 32 (3.13%)
    0 / 36 (0.00%)
    0 / 36 (0.00%)
         occurrences all number
    0
    2
    1
    0
    0
    White blood cell count increased
         subjects affected / exposed
    0 / 44 (0.00%)
    1 / 33 (3.03%)
    2 / 32 (6.25%)
    0 / 36 (0.00%)
    0 / 36 (0.00%)
         occurrences all number
    0
    1
    2
    0
    0
    Cardiac disorders
    Atrial fibrillation
         subjects affected / exposed
    1 / 44 (2.27%)
    0 / 33 (0.00%)
    0 / 32 (0.00%)
    0 / 36 (0.00%)
    3 / 36 (8.33%)
         occurrences all number
    1
    0
    0
    0
    3
    Sinus tachycardia
         subjects affected / exposed
    2 / 44 (4.55%)
    1 / 33 (3.03%)
    2 / 32 (6.25%)
    0 / 36 (0.00%)
    0 / 36 (0.00%)
         occurrences all number
    2
    1
    2
    0
    0
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    0 / 44 (0.00%)
    1 / 33 (3.03%)
    2 / 32 (6.25%)
    2 / 36 (5.56%)
    0 / 36 (0.00%)
         occurrences all number
    0
    1
    2
    2
    0
    Increased tendency to bruise
         subjects affected / exposed
    0 / 44 (0.00%)
    0 / 33 (0.00%)
    0 / 32 (0.00%)
    1 / 36 (2.78%)
    2 / 36 (5.56%)
         occurrences all number
    0
    0
    0
    1
    2
    Thrombocytopenia
         subjects affected / exposed
    0 / 44 (0.00%)
    0 / 33 (0.00%)
    0 / 32 (0.00%)
    2 / 36 (5.56%)
    0 / 36 (0.00%)
         occurrences all number
    0
    0
    0
    2
    0
    Respiratory, thoracic and mediastinal disorders
    Dyspnoea
         subjects affected / exposed
    0 / 44 (0.00%)
    0 / 33 (0.00%)
    3 / 32 (9.38%)
    5 / 36 (13.89%)
    4 / 36 (11.11%)
         occurrences all number
    0
    0
    3
    5
    5
    Cough
         subjects affected / exposed
    0 / 44 (0.00%)
    0 / 33 (0.00%)
    0 / 32 (0.00%)
    3 / 36 (8.33%)
    2 / 36 (5.56%)
         occurrences all number
    0
    0
    0
    3
    2
    Productive cough
         subjects affected / exposed
    0 / 44 (0.00%)
    0 / 33 (0.00%)
    0 / 32 (0.00%)
    2 / 36 (5.56%)
    0 / 36 (0.00%)
         occurrences all number
    0
    0
    0
    2
    0
    Pulmonary embolism
         subjects affected / exposed
    0 / 44 (0.00%)
    0 / 33 (0.00%)
    0 / 32 (0.00%)
    2 / 36 (5.56%)
    0 / 36 (0.00%)
         occurrences all number
    0
    0
    0
    2
    0
    Nervous system disorders
    Dysgeusia
         subjects affected / exposed
    3 / 44 (6.82%)
    2 / 33 (6.06%)
    4 / 32 (12.50%)
    4 / 36 (11.11%)
    4 / 36 (11.11%)
         occurrences all number
    3
    2
    4
    4
    4
    Dizziness
         subjects affected / exposed
    1 / 44 (2.27%)
    2 / 33 (6.06%)
    4 / 32 (12.50%)
    3 / 36 (8.33%)
    5 / 36 (13.89%)
         occurrences all number
    1
    2
    5
    3
    5
    Hypoaesthesia
         subjects affected / exposed
    1 / 44 (2.27%)
    0 / 33 (0.00%)
    3 / 32 (9.38%)
    2 / 36 (5.56%)
    1 / 36 (2.78%)
         occurrences all number
    1
    0
    4
    2
    1
    Somnolence
         subjects affected / exposed
    0 / 44 (0.00%)
    5 / 33 (15.15%)
    0 / 32 (0.00%)
    0 / 36 (0.00%)
    0 / 36 (0.00%)
         occurrences all number
    0
    6
    0
    0
    0
    Headache
         subjects affected / exposed
    0 / 44 (0.00%)
    2 / 33 (6.06%)
    1 / 32 (3.13%)
    3 / 36 (8.33%)
    1 / 36 (2.78%)
         occurrences all number
    0
    2
    1
    4
    2
    Paraesthesia
         subjects affected / exposed
    0 / 44 (0.00%)
    0 / 33 (0.00%)
    0 / 32 (0.00%)
    2 / 36 (5.56%)
    3 / 36 (8.33%)
         occurrences all number
    0
    0
    0
    3
    3
    Syncope
         subjects affected / exposed
    0 / 44 (0.00%)
    0 / 33 (0.00%)
    0 / 32 (0.00%)
    1 / 36 (2.78%)
    2 / 36 (5.56%)
         occurrences all number
    0
    0
    0
    1
    3
    Neuropathy peripheral
         subjects affected / exposed
    0 / 44 (0.00%)
    0 / 33 (0.00%)
    0 / 32 (0.00%)
    2 / 36 (5.56%)
    1 / 36 (2.78%)
         occurrences all number
    0
    0
    0
    2
    1
    Eye disorders
    Cataract
         subjects affected / exposed
    0 / 44 (0.00%)
    3 / 33 (9.09%)
    1 / 32 (3.13%)
    0 / 36 (0.00%)
    0 / 36 (0.00%)
         occurrences all number
    0
    3
    1
    0
    0
    Lacrimation increased
         subjects affected / exposed
    0 / 44 (0.00%)
    3 / 33 (9.09%)
    0 / 32 (0.00%)
    0 / 36 (0.00%)
    0 / 36 (0.00%)
         occurrences all number
    0
    3
    0
    0
    0
    Glaucoma
         subjects affected / exposed
    0 / 44 (0.00%)
    0 / 33 (0.00%)
    0 / 32 (0.00%)
    0 / 36 (0.00%)
    2 / 36 (5.56%)
         occurrences all number
    0
    0
    0
    0
    2
    Ear and labyrinth disorders
    Ear pain
         subjects affected / exposed
    0 / 44 (0.00%)
    0 / 33 (0.00%)
    0 / 32 (0.00%)
    1 / 36 (2.78%)
    2 / 36 (5.56%)
         occurrences all number
    0
    0
    0
    1
    2
    Gastrointestinal disorders
    Constipation
         subjects affected / exposed
    7 / 44 (15.91%)
    8 / 33 (24.24%)
    10 / 32 (31.25%)
    10 / 36 (27.78%)
    12 / 36 (33.33%)
         occurrences all number
    7
    9
    12
    13
    13
    Diarrhoea
         subjects affected / exposed
    11 / 44 (25.00%)
    4 / 33 (12.12%)
    5 / 32 (15.63%)
    15 / 36 (41.67%)
    13 / 36 (36.11%)
         occurrences all number
    12
    4
    6
    30
    16
    Nausea
         subjects affected / exposed
    7 / 44 (15.91%)
    5 / 33 (15.15%)
    7 / 32 (21.88%)
    13 / 36 (36.11%)
    12 / 36 (33.33%)
         occurrences all number
    12
    6
    10
    17
    16
    Vomiting
         subjects affected / exposed
    3 / 44 (6.82%)
    4 / 33 (12.12%)
    3 / 32 (9.38%)
    9 / 36 (25.00%)
    3 / 36 (8.33%)
         occurrences all number
    3
    4
    11
    12
    3
    Abdominal discomfort
         subjects affected / exposed
    4 / 44 (9.09%)
    4 / 33 (12.12%)
    2 / 32 (6.25%)
    1 / 36 (2.78%)
    2 / 36 (5.56%)
         occurrences all number
    4
    4
    3
    1
    2
    Abdominal pain upper
         subjects affected / exposed
    1 / 44 (2.27%)
    1 / 33 (3.03%)
    2 / 32 (6.25%)
    1 / 36 (2.78%)
    4 / 36 (11.11%)
         occurrences all number
    1
    1
    3
    1
    4
    Abdominal pain
         subjects affected / exposed
    2 / 44 (4.55%)
    2 / 33 (6.06%)
    0 / 32 (0.00%)
    4 / 36 (11.11%)
    3 / 36 (8.33%)
         occurrences all number
    2
    2
    0
    4
    3
    Stomatitis
         subjects affected / exposed
    4 / 44 (9.09%)
    2 / 33 (6.06%)
    2 / 32 (6.25%)
    3 / 36 (8.33%)
    2 / 36 (5.56%)
         occurrences all number
    4
    2
    2
    4
    7
    Chronic Gastritis
         subjects affected / exposed
    0 / 44 (0.00%)
    1 / 33 (3.03%)
    2 / 32 (6.25%)
    0 / 36 (0.00%)
    0 / 36 (0.00%)
         occurrences all number
    0
    1
    2
    0
    0
    Dyspepsia
         subjects affected / exposed
    0 / 44 (0.00%)
    1 / 33 (3.03%)
    2 / 32 (6.25%)
    1 / 36 (2.78%)
    3 / 36 (8.33%)
         occurrences all number
    0
    1
    2
    1
    3
    Abdominal distension
         subjects affected / exposed
    0 / 44 (0.00%)
    2 / 33 (6.06%)
    0 / 32 (0.00%)
    0 / 36 (0.00%)
    0 / 36 (0.00%)
         occurrences all number
    0
    3
    0
    0
    0
    Dental caries
         subjects affected / exposed
    0 / 44 (0.00%)
    0 / 33 (0.00%)
    2 / 32 (6.25%)
    0 / 36 (0.00%)
    0 / 36 (0.00%)
         occurrences all number
    0
    0
    3
    0
    0
    Pancreatitis
         subjects affected / exposed
    0 / 44 (0.00%)
    2 / 33 (6.06%)
    0 / 32 (0.00%)
    0 / 36 (0.00%)
    0 / 36 (0.00%)
         occurrences all number
    0
    2
    0
    0
    0
    Gastrooesophageal reflux disease
         subjects affected / exposed
    0 / 44 (0.00%)
    0 / 33 (0.00%)
    0 / 32 (0.00%)
    2 / 36 (5.56%)
    2 / 36 (5.56%)
         occurrences all number
    0
    0
    0
    2
    2
    Mouth ulceration
         subjects affected / exposed
    0 / 44 (0.00%)
    0 / 33 (0.00%)
    0 / 32 (0.00%)
    0 / 36 (0.00%)
    2 / 36 (5.56%)
         occurrences all number
    0
    0
    0
    0
    4
    Dysphagia
         subjects affected / exposed
    0 / 44 (0.00%)
    0 / 33 (0.00%)
    0 / 32 (0.00%)
    0 / 36 (0.00%)
    2 / 36 (5.56%)
         occurrences all number
    0
    0
    0
    0
    3
    Hepatobiliary disorders
    Hepatic function abnormal
         subjects affected / exposed
    0 / 44 (0.00%)
    0 / 33 (0.00%)
    3 / 32 (9.38%)
    0 / 36 (0.00%)
    0 / 36 (0.00%)
         occurrences all number
    0
    0
    4
    0
    0
    Renal and urinary disorders
    Haematuria
         subjects affected / exposed
    1 / 44 (2.27%)
    1 / 33 (3.03%)
    2 / 32 (6.25%)
    3 / 36 (8.33%)
    2 / 36 (5.56%)
         occurrences all number
    1
    1
    2
    4
    2
    Nocturia
         subjects affected / exposed
    3 / 44 (6.82%)
    0 / 33 (0.00%)
    0 / 32 (0.00%)
    2 / 36 (5.56%)
    1 / 36 (2.78%)
         occurrences all number
    4
    0
    0
    3
    1
    Dysuria
         subjects affected / exposed
    0 / 44 (0.00%)
    2 / 33 (6.06%)
    1 / 32 (3.13%)
    0 / 36 (0.00%)
    0 / 36 (0.00%)
         occurrences all number
    0
    2
    1
    0
    0
    Pollakiuria
         subjects affected / exposed
    0 / 44 (0.00%)
    3 / 33 (9.09%)
    0 / 32 (0.00%)
    1 / 36 (2.78%)
    3 / 36 (8.33%)
         occurrences all number
    0
    3
    0
    1
    3
    Renal failure
         subjects affected / exposed
    0 / 44 (0.00%)
    0 / 33 (0.00%)
    0 / 32 (0.00%)
    2 / 36 (5.56%)
    1 / 36 (2.78%)
         occurrences all number
    0
    0
    0
    2
    1
    Hydronephrosis
         subjects affected / exposed
    0 / 44 (0.00%)
    0 / 33 (0.00%)
    0 / 32 (0.00%)
    2 / 36 (5.56%)
    0 / 36 (0.00%)
         occurrences all number
    0
    0
    0
    2
    0
    Urinary retention
         subjects affected / exposed
    0 / 44 (0.00%)
    0 / 33 (0.00%)
    0 / 32 (0.00%)
    0 / 36 (0.00%)
    2 / 36 (5.56%)
         occurrences all number
    0
    0
    0
    0
    2
    Skin and subcutaneous tissue disorders
    Rash macular
         subjects affected / exposed
    3 / 44 (6.82%)
    0 / 33 (0.00%)
    0 / 32 (0.00%)
    3 / 36 (8.33%)
    4 / 36 (11.11%)
         occurrences all number
    3
    0
    0
    4
    4
    Rash maculo-papular
         subjects affected / exposed
    0 / 44 (0.00%)
    3 / 33 (9.09%)
    0 / 32 (0.00%)
    2 / 36 (5.56%)
    1 / 36 (2.78%)
         occurrences all number
    0
    4
    0
    2
    1
    Rash erythematous
         subjects affected / exposed
    0 / 44 (0.00%)
    0 / 33 (0.00%)
    0 / 32 (0.00%)
    0 / 36 (0.00%)
    2 / 36 (5.56%)
         occurrences all number
    0
    0
    0
    0
    2
    Urticaria
         subjects affected / exposed
    0 / 44 (0.00%)
    1 / 33 (3.03%)
    3 / 32 (9.38%)
    0 / 36 (0.00%)
    0 / 36 (0.00%)
         occurrences all number
    0
    1
    4
    0
    0
    Purpura
         subjects affected / exposed
    0 / 44 (0.00%)
    2 / 33 (6.06%)
    2 / 32 (6.25%)
    0 / 36 (0.00%)
    0 / 36 (0.00%)
         occurrences all number
    0
    2
    2
    0
    0
    Dry skin
         subjects affected / exposed
    0 / 44 (0.00%)
    1 / 33 (3.03%)
    2 / 32 (6.25%)
    1 / 36 (2.78%)
    2 / 36 (5.56%)
         occurrences all number
    0
    1
    2
    1
    2
    Eczema
         subjects affected / exposed
    0 / 44 (0.00%)
    1 / 33 (3.03%)
    2 / 32 (6.25%)
    0 / 36 (0.00%)
    0 / 36 (0.00%)
         occurrences all number
    0
    1
    2
    0
    0
    Haemorrhage subcutaneous
         subjects affected / exposed
    0 / 44 (0.00%)
    0 / 33 (0.00%)
    2 / 32 (6.25%)
    0 / 36 (0.00%)
    0 / 36 (0.00%)
         occurrences all number
    0
    0
    2
    0
    0
    Skin atrophy
         subjects affected / exposed
    0 / 44 (0.00%)
    0 / 33 (0.00%)
    0 / 32 (0.00%)
    3 / 36 (8.33%)
    1 / 36 (2.78%)
         occurrences all number
    0
    0
    0
    3
    2
    Ecchymosis
         subjects affected / exposed
    0 / 44 (0.00%)
    0 / 33 (0.00%)
    0 / 32 (0.00%)
    1 / 36 (2.78%)
    2 / 36 (5.56%)
         occurrences all number
    0
    0
    0
    1
    2
    Hyperhidrosis
         subjects affected / exposed
    0 / 44 (0.00%)
    0 / 33 (0.00%)
    0 / 32 (0.00%)
    2 / 36 (5.56%)
    1 / 36 (2.78%)
         occurrences all number
    0
    0
    0
    2
    1
    Rash pruritic
         subjects affected / exposed
    0 / 44 (0.00%)
    0 / 33 (0.00%)
    0 / 32 (0.00%)
    1 / 36 (2.78%)
    2 / 36 (5.56%)
         occurrences all number
    0
    0
    0
    1
    2
    Decubitus ulcer
         subjects affected / exposed
    0 / 44 (0.00%)
    0 / 33 (0.00%)
    0 / 32 (0.00%)
    0 / 36 (0.00%)
    2 / 36 (5.56%)
         occurrences all number
    0
    0
    0
    0
    3
    Rash papular
         subjects affected / exposed
    0 / 44 (0.00%)
    0 / 33 (0.00%)
    0 / 32 (0.00%)
    0 / 36 (0.00%)
    2 / 36 (5.56%)
         occurrences all number
    0
    0
    0
    0
    3
    Dermatitis acneiform
         subjects affected / exposed
    0 / 44 (0.00%)
    0 / 33 (0.00%)
    0 / 32 (0.00%)
    0 / 36 (0.00%)
    2 / 36 (5.56%)
         occurrences all number
    0
    0
    0
    0
    2
    Musculoskeletal and connective tissue disorders
    Muscle spasms
         subjects affected / exposed
    11 / 44 (25.00%)
    3 / 33 (9.09%)
    8 / 32 (25.00%)
    8 / 36 (22.22%)
    12 / 36 (33.33%)
         occurrences all number
    16
    3
    9
    11
    22
    Back pain
         subjects affected / exposed
    3 / 44 (6.82%)
    2 / 33 (6.06%)
    3 / 32 (9.38%)
    5 / 36 (13.89%)
    3 / 36 (8.33%)
         occurrences all number
    3
    2
    3
    6
    3
    Arthralgia
         subjects affected / exposed
    2 / 44 (4.55%)
    0 / 33 (0.00%)
    0 / 32 (0.00%)
    5 / 36 (13.89%)
    4 / 36 (11.11%)
         occurrences all number
    3
    0
    0
    6
    5
    Muscular weakness
         subjects affected / exposed
    2 / 44 (4.55%)
    0 / 33 (0.00%)
    2 / 32 (6.25%)
    4 / 36 (11.11%)
    4 / 36 (11.11%)
         occurrences all number
    2
    0
    2
    4
    4
    Musculoskeletal pain
         subjects affected / exposed
    0 / 44 (0.00%)
    3 / 33 (9.09%)
    0 / 32 (0.00%)
    3 / 36 (8.33%)
    3 / 36 (8.33%)
         occurrences all number
    0
    3
    0
    4
    4
    Musculoskeletal chest pain
         subjects affected / exposed
    2 / 44 (4.55%)
    0 / 33 (0.00%)
    0 / 32 (0.00%)
    2 / 36 (5.56%)
    3 / 36 (8.33%)
         occurrences all number
    2
    0
    0
    4
    3
    Lumbar spinal stenosis
         subjects affected / exposed
    0 / 44 (0.00%)
    1 / 33 (3.03%)
    2 / 32 (6.25%)
    0 / 36 (0.00%)
    0 / 36 (0.00%)
         occurrences all number
    0
    1
    2
    0
    0
    Osteoporosis
         subjects affected / exposed
    0 / 44 (0.00%)
    2 / 33 (6.06%)
    1 / 32 (3.13%)
    2 / 36 (5.56%)
    2 / 36 (5.56%)
         occurrences all number
    0
    2
    1
    2
    2
    Musculoskeletal discomfort
         subjects affected / exposed
    0 / 44 (0.00%)
    0 / 33 (0.00%)
    0 / 32 (0.00%)
    3 / 36 (8.33%)
    1 / 36 (2.78%)
         occurrences all number
    0
    0
    0
    3
    1
    Pain in extremity
         subjects affected / exposed
    0 / 44 (0.00%)
    0 / 33 (0.00%)
    0 / 32 (0.00%)
    1 / 36 (2.78%)
    2 / 36 (5.56%)
         occurrences all number
    0
    0
    0
    2
    2
    Myalgia
         subjects affected / exposed
    0 / 44 (0.00%)
    0 / 33 (0.00%)
    0 / 32 (0.00%)
    2 / 36 (5.56%)
    1 / 36 (2.78%)
         occurrences all number
    0
    0
    0
    4
    1
    Bone pain
         subjects affected / exposed
    0 / 44 (0.00%)
    0 / 33 (0.00%)
    0 / 32 (0.00%)
    1 / 36 (2.78%)
    2 / 36 (5.56%)
         occurrences all number
    0
    0
    0
    1
    2
    Groin pain
         subjects affected / exposed
    0 / 44 (0.00%)
    0 / 33 (0.00%)
    0 / 32 (0.00%)
    0 / 36 (0.00%)
    2 / 36 (5.56%)
         occurrences all number
    0
    0
    0
    0
    2
    Endocrine disorders
    Cushingoid
         subjects affected / exposed
    0 / 44 (0.00%)
    3 / 33 (9.09%)
    1 / 32 (3.13%)
    0 / 36 (0.00%)
    0 / 36 (0.00%)
         occurrences all number
    0
    3
    1
    0
    0
    Metabolism and nutrition disorders
    Diabetes mellitus
         subjects affected / exposed
    5 / 44 (11.36%)
    9 / 33 (27.27%)
    6 / 32 (18.75%)
    1 / 36 (2.78%)
    4 / 36 (11.11%)
         occurrences all number
    5
    10
    8
    1
    4
    Decreased appetite
         subjects affected / exposed
    5 / 44 (11.36%)
    1 / 33 (3.03%)
    5 / 32 (15.63%)
    9 / 36 (25.00%)
    7 / 36 (19.44%)
         occurrences all number
    7
    1
    8
    10
    8
    Hyponatraemia
         subjects affected / exposed
    4 / 44 (9.09%)
    2 / 33 (6.06%)
    2 / 32 (6.25%)
    1 / 36 (2.78%)
    4 / 36 (11.11%)
         occurrences all number
    4
    3
    2
    1
    4
    Dehydration
         subjects affected / exposed
    1 / 44 (2.27%)
    0 / 33 (0.00%)
    0 / 32 (0.00%)
    3 / 36 (8.33%)
    4 / 36 (11.11%)
         occurrences all number
    1
    0
    0
    3
    5
    Hyperglycaemia
         subjects affected / exposed
    3 / 44 (6.82%)
    1 / 33 (3.03%)
    2 / 32 (6.25%)
    1 / 36 (2.78%)
    2 / 36 (5.56%)
         occurrences all number
    3
    1
    2
    3
    2
    Hypokalaemia
         subjects affected / exposed
    2 / 44 (4.55%)
    2 / 33 (6.06%)
    0 / 32 (0.00%)
    5 / 36 (13.89%)
    1 / 36 (2.78%)
         occurrences all number
    2
    2
    0
    6
    1
    Hyperkalaemia
         subjects affected / exposed
    1 / 44 (2.27%)
    0 / 33 (0.00%)
    3 / 32 (9.38%)
    2 / 36 (5.56%)
    2 / 36 (5.56%)
         occurrences all number
    1
    0
    4
    4
    2
    Type 2 diabetes mellitus
         subjects affected / exposed
    0 / 44 (0.00%)
    0 / 33 (0.00%)
    0 / 32 (0.00%)
    2 / 36 (5.56%)
    4 / 36 (11.11%)
         occurrences all number
    0
    0
    0
    2
    5
    Hypoglycaemia
         subjects affected / exposed
    0 / 44 (0.00%)
    0 / 33 (0.00%)
    2 / 32 (6.25%)
    0 / 36 (0.00%)
    0 / 36 (0.00%)
         occurrences all number
    0
    0
    2
    0
    0
    Hyperlipidaemia
         subjects affected / exposed
    0 / 44 (0.00%)
    2 / 33 (6.06%)
    0 / 32 (0.00%)
    0 / 36 (0.00%)
    0 / 36 (0.00%)
         occurrences all number
    0
    2
    0
    0
    0
    Hypercholesterolaemia
         subjects affected / exposed
    0 / 44 (0.00%)
    0 / 33 (0.00%)
    0 / 32 (0.00%)
    2 / 36 (5.56%)
    2 / 36 (5.56%)
         occurrences all number
    0
    0
    0
    2
    2
    Hypomagnesaemia
         subjects affected / exposed
    0 / 44 (0.00%)
    0 / 33 (0.00%)
    0 / 32 (0.00%)
    2 / 36 (5.56%)
    1 / 36 (2.78%)
         occurrences all number
    0
    0
    0
    2
    1
    Infections and infestations
    Nasopharyngitis
         subjects affected / exposed
    7 / 44 (15.91%)
    8 / 33 (24.24%)
    8 / 32 (25.00%)
    0 / 36 (0.00%)
    0 / 36 (0.00%)
         occurrences all number
    7
    10
    13
    0
    0
    Upper respiratory trat infection
         subjects affected / exposed
    4 / 44 (9.09%)
    3 / 33 (9.09%)
    4 / 32 (12.50%)
    6 / 36 (16.67%)
    2 / 36 (5.56%)
         occurrences all number
    4
    4
    5
    7
    2
    Bronchitis
         subjects affected / exposed
    0 / 44 (0.00%)
    1 / 33 (3.03%)
    2 / 32 (6.25%)
    1 / 36 (2.78%)
    2 / 36 (5.56%)
         occurrences all number
    0
    1
    3
    5
    3
    Cystitis
         subjects affected / exposed
    0 / 44 (0.00%)
    3 / 33 (9.09%)
    0 / 32 (0.00%)
    0 / 36 (0.00%)
    0 / 36 (0.00%)
         occurrences all number
    0
    3
    0
    0
    0
    Influenza
         subjects affected / exposed
    0 / 44 (0.00%)
    2 / 33 (6.06%)
    1 / 32 (3.13%)
    2 / 36 (5.56%)
    2 / 36 (5.56%)
         occurrences all number
    0
    2
    1
    2
    2
    Herpes zoster
         subjects affected / exposed
    0 / 44 (0.00%)
    2 / 33 (6.06%)
    0 / 32 (0.00%)
    0 / 36 (0.00%)
    0 / 36 (0.00%)
         occurrences all number
    0
    2
    0
    0
    0
    Oesophageal candidiasis
         subjects affected / exposed
    0 / 44 (0.00%)
    0 / 33 (0.00%)
    2 / 32 (6.25%)
    0 / 36 (0.00%)
    0 / 36 (0.00%)
         occurrences all number
    0
    0
    2
    0
    0
    Pharyngitis
         subjects affected / exposed
    0 / 44 (0.00%)
    2 / 33 (6.06%)
    0 / 32 (0.00%)
    0 / 36 (0.00%)
    0 / 36 (0.00%)
         occurrences all number
    0
    2
    0
    0
    0
    Oral candidiasis
         subjects affected / exposed
    0 / 44 (0.00%)
    0 / 33 (0.00%)
    0 / 32 (0.00%)
    3 / 36 (8.33%)
    2 / 36 (5.56%)
         occurrences all number
    0
    0
    0
    4
    2
    Lower respiratory tract infection
         subjects affected / exposed
    0 / 44 (0.00%)
    0 / 33 (0.00%)
    0 / 32 (0.00%)
    0 / 36 (0.00%)
    4 / 36 (11.11%)
         occurrences all number
    0
    0
    0
    0
    6
    Sinusitis
         subjects affected / exposed
    0 / 44 (0.00%)
    0 / 33 (0.00%)
    0 / 32 (0.00%)
    0 / 36 (0.00%)
    2 / 36 (5.56%)
         occurrences all number
    0
    0
    0
    0
    2
    Tooth abscess
         subjects affected / exposed
    0 / 44 (0.00%)
    0 / 33 (0.00%)
    0 / 32 (0.00%)
    2 / 36 (5.56%)
    0 / 36 (0.00%)
         occurrences all number
    0
    0
    0
    2
    0
    Viral upper respiratory tract infection
         subjects affected / exposed
    0 / 44 (0.00%)
    0 / 33 (0.00%)
    0 / 32 (0.00%)
    0 / 36 (0.00%)
    2 / 36 (5.56%)
         occurrences all number
    0
    0
    0
    0
    2

    More information

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    Substantial protocol amendments (globally)

    Were there any global substantial amendments to the protocol? No

    Interruptions (globally)

    Were there any global interruptions to the trial? No

    Limitations and caveats

    Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.
    None reported
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