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    Clinical Trial Results:
    Orteronel maintenance therapy in patients with metastatic castration resistant prostate cancer and non-progressive disease after first-line docetaxel therapy: A multicenter randomized double-blind placebo-controlled phase III trial.

    Summary
    EudraCT number
    		 2011-002965-39
    Trial protocol
    		 GB  
    Global end of trial date
    20 Jul 2016

    Results information
    Results version number
    		 v1(current)
    This version publication date
    21 Dec 2018
    First version publication date
    21 Dec 2018
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    SAKK 08/11
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT01707966
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Swiss Group for Clinical Cancer Research (SAKK)
    Sponsor organisation address
    Effingerstrasse 33, Bern, Switzerland, 3008
    Public contact
    Kelly Cozens, University of Southampton Clinical Trials Unit, +44 02380795154, kc8@soton.ac.uk
    Scientific contact
    Kelly Cozens, University of Southampton Clinical Trials Unit, +44 2380795154, kc8@soton.ac.uk
    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
    15 Nov 2016
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    01 Sep 2014
    Global end of trial reached?
    Yes
    Global end of trial date
    20 Jul 2016
    Was the trial ended prematurely?
    Yes
    General information about the trial
    Main objective of the trial
    The aim of this study is to establish whether or not giving patients the trial drug orteronel (an androgen synthesis blocker) after their disease has been stabilised by chemotherapy (docetaxel), will lengthen the time that they are 'event free' (alive and without evidence of clinical progression of their cancer) in comparison to patients who receive a placebo.
    Protection of trial subjects
    Protection of trial subjects was ensured by Safety Monitoring, i.e. assessment of adverse events, serious adverse events, adverse drug reactions, and the continouus assessment of laboratory values (blood chemistry) and vital signs.
    Background therapy
    		 Background therapy was best supportive care (BSC). BSC was to be administered according to local standards and included but was not limited to appropriate pain management, management of disease related complications (e.g., urinary obstruction, hydronephrosis, skeletal related events), continued androgen deprivation in non-surgically castrated patients (mandatory).
    Evidence for comparator
    		 All patients received best supportive care and either orteronel or placebo. A placebo-controlled study design was chosen to test the effect of orteronel on patient status after disease stabilization succeeding docetaxel treatment.
    Actual start date of recruitment
    09 Nov 2012
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Switzerland: 41
    Country: Number of subjects enrolled
    United Kingdom: 6
    Worldwide total number of subjects
    47
    EEA total number of subjects
    6
    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)
    9
    From 65 to 84 years
    37
    85 years and over
    1

    Subject disposition

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    Recruitment
    Recruitment details
    		 192 patients were planned to be enrolled. 47 patients had been enrolled in Great Britain (2 centres; 6 patients) and Switzerland (15 centres; 41 patients) from 09-Nov-2012 to 17-Jul-2014. The trial was prematurely closed for accrual after the inclusion of 47 patients.

    Pre-assignment
    Screening details
    		 Eligibility criteria of a patient were checked by the investigator. Once a patient fullfils all inclusion criteria and not any of the exclusion criteria, he/she was randomized.

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

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 A - Orteronel
    Arm description
    		 Treatment arm A - Patients receiving BSC and orteronel
    Arm type
    		 Experimental

    Investigational medicinal product name
    Orteronel
    Investigational medicinal product code
    TAK-700
    Other name
    Pharmaceutical forms
    Coated tablet
    Routes of administration
    Oral use
    Dosage and administration details
    300 mg orteronel twice daily (b.i.d.)

    Arm title
    		 B - Placebo
    Arm description
    		 Treatment arm B - Patients receiving BSC and placebo
    Arm type
    		 Placebo

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Coated tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Placebo twice daily (b.i.d.)

    Number of subjects in period 1
    		A - Orteronel B - Placebo
    Started
    23
    24
    Completed
    23
    24
    Period 2
    Period 2 title
    Treatment period
    Is this the baseline period?
    		 No
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Subject, Investigator, Carer, Assessor
    Blinding implementation details
    Treatment allocation was unblinded for: 1) eight patients in Treatment arm A - Orteronel: Reasons for unblinding were a) for further treatment decision after progression (2 patients), b) patients wish after premature closure (3 patients), c) serious adverse event (2 patients), d) other (1 Patient) 2) seven patients in Treatment arm B - Placebo: Reasons for unblinding were a) for further treatment decision after progression (4 patients), b) patients wish after premature closure (3 patients)

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 A - Orteronel
    Arm description
    		 Treatment arm A - Patients receiving BSC and orteronel
    Arm type
    		 Experimental

    Investigational medicinal product name
    Orteronel
    Investigational medicinal product code
    TAK-700
    Other name
    Pharmaceutical forms
    Coated tablet
    Routes of administration
    Oral use
    Dosage and administration details
    300 mg orteronel twice daily (b.i.d.)

    Arm title
    		 B - Placebo
    Arm description
    		 Treatment arm B - Patients receiving BSC and placebo
    Arm type
    		 Placebo

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Coated tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Placebo twice daily (b.i.d.)

    Number of subjects in period 2
    		A - Orteronel B - Placebo
    Started
    23
    24
    Completed
    0
    0
    Not completed
    23
    24
         Physician decision
    1
    -
         Consent withdrawn by subject
    4
    4
         Progression
    15
    20
         Unacceptable toxicity
    3
    -

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    A - Orteronel
    Reporting group description
    		 Treatment arm A - Patients receiving BSC and orteronel

    Reporting group title
    B - Placebo
    Reporting group description
    		 Treatment arm B - Patients receiving BSC and placebo

    Reporting group values
    		 A - Orteronel B - Placebo Total
    Number of subjects
    		 23 24 47
    Age categorical
    Units: Subjects
        In utero
    		 0
        Preterm newborn infants (gestational age < 37 wks)
    		 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)
    		 0
        From 65-84 years
    		 0
        85 years and over
    		 0
    Age continuous
    Units: years
        median (full range (min-max))
    		 70.0 (51.0 to 80.0) 70.5 (63.0 to 85.0) -
    Gender categorical
    Units: Subjects
        Female
    		 0 0 0
        Male
    		 23 24 47

    End points

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    End points reporting groups
    Reporting group title
    A - Orteronel
    Reporting group description
    		 Treatment arm A - Patients receiving BSC and orteronel

    Reporting group title
    B - Placebo
    Reporting group description
    		 Treatment arm B - Patients receiving BSC and placebo
    Reporting group title
    A - Orteronel
    Reporting group description
    		 Treatment arm A - Patients receiving BSC and orteronel

    Reporting group title
    B - Placebo
    Reporting group description
    		 Treatment arm B - Patients receiving BSC and placebo

    Subject analysis set title
    ITT Population - Arm A
    Subject analysis set type
    		 Intention-to-treat
    Subject analysis set description
    All randomized patients were included in the ITT Population.

    Subject analysis set title
    ITT Population - Arm B
    Subject analysis set type
    		 Intention-to-treat
    Subject analysis set description
    All randomized patients were included in the ITT Population.

    Subject analysis set title
    Safety Population - Arm A
    Subject analysis set type
    		 Safety analysis
    Subject analysis set description
    As all patients received at least one dose of orteronel/placebo, all patients were included in the safety population.

    Subject analysis set title
    Safety Population - Arm B
    Subject analysis set type
    		 Safety analysis
    Subject analysis set description
    As all patients received at least one dose of orteronel/placebo, all patients were included in the safety population.

    Subject analysis set title
    Eligible Population - Arm A
    Subject analysis set type
    		 Modified intention-to-treat
    Subject analysis set description
    Two patients failed to satisfy major entry criteria and were thus excluded from Arm A of the eligible population (EP). The decision to exclude patients from the EP was made by the coordinating investigators together with the trial team prior to the unblinding of the study and without looking at outcome data.

    Subject analysis set title
    Eligible Population - Arm B
    Subject analysis set type
    		 Modified intention-to-treat
    Subject analysis set description
    One patient failed to satisfy major entry criteria and was thus excluded from Arm B of the eligible population (EP). The decision to exclude patients from the EP was made by the coordinating investigators together with the trial team prior to the unblinding of the study and without looking at outcome data.

    Subject analysis set title
    RECIST-evaluable Population - Arm A
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    The RECIST-evaluable population was defined as the subset of patients who had measurable disease by modified RECIST 1.1 at the baseline assessment. 26 patients did not have measurable disease at baseline and where thus excluded from the RECIST-evaluable population.

    Subject analysis set title
    RECIST-evaluable Population - Arm B
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    The RECIST-evaluable population was defined as the subset of patients who had measurable disease by modified RECIST 1.1 at the baseline assessment. 26 patients did not have measurable disease at baseline and where thus excluded from the RECIST-evaluable population.

    Primary: Event-free survival (EFS)

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    End point title
    		 Event-free survival (EFS) [1]
    End point description
    The primary endpoint of this trial was event-free survival (EFS). EFS was calculated from registration until the event of interest. Patients not experiencing an event were censored at the date of the last available assessment or at initiation of a different treatment. Patients who were unblinded before they experienced an Event were censored at the date of the unblinding.
    End point type
    Primary
    End point timeframe
    From registration until event of interest.
    Notes
    [1] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: Statistical analyses of this endpoint are implemented in Primary Endpoint "Median EFS".
    End point values
    		 ITT Population - Arm A ITT Population - Arm B
    Number of subjects analysed
    23
    24
    Units: Number of EFS events
        EFS event - Yes
    14
    20
        EFS event - No
    9
    4
    No statistical analyses for this end point

    Primary: Median EFS

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    End point title
    		 Median EFS
    End point description
    End point type
    Primary
    End point timeframe
    From registration until event of interest.
    End point values
    		 ITT Population - Arm A ITT Population - Arm B
    Number of subjects analysed
    23
    20
    Units: Median EFS
        median (confidence interval 95%)
    8.5 (3.2 to 16.0)
    2.9 (2.7 to 3.9)
    Statistical analysis title
    		 Log-Rank Test
    Statistical analysis description
    Log-Rank Test
    Comparison groups
    ITT Population - Arm A v ITT Population - Arm B
    Number of subjects included in analysis
    43
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.001
    Method
    		 Logrank
    Confidence interval
    Statistical analysis title
    		 Cox Regression
    Statistical analysis description
    Cox Regression | Hazard Ratio
    Comparison groups
    ITT Population - Arm A v ITT Population - Arm B
    Number of subjects included in analysis
    43
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.002
    Method
    		 Regression, Cox
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.32
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.15
         upper limit
    		 0.65

    Primary: Event-free survival (EFS) - Supportive Analysis 1

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    End point title
    		 Event-free survival (EFS) - Supportive Analysis 1 [2]
    End point description
    A supportive analysis not censoring patients that were unblinded before they experienced an event was performed for the primary endpoint.
    End point type
    Primary
    End point timeframe
    From registration until event of interest.
    Notes
    [2] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: Statistical analyses of this endpoint are implemented in Primary Endpoint "Median EFS - Supportive Analysis 1".
    End point values
    		 ITT Population - Arm A ITT Population - Arm B
    Number of subjects analysed
    23
    24
    Units: Number of EFS events
        EFS event - Yes
    16
    21
        EFS event - No
    7
    3
    No statistical analyses for this end point

    Primary: Median EFS - Supportive Analysis 1

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    End point title
    		 Median EFS - Supportive Analysis 1
    End point description
    End point type
    Primary
    End point timeframe
    From registration until event of interest.
    End point values
    		 ITT Population - Arm A ITT Population - Arm B
    Number of subjects analysed
    23
    24
    Units: Median EFS
        median (confidence interval 95%)
    8.2 (3.2 to 14.2)
    2.9 (2.7 to 3.9)
    Statistical analysis title
    		 Log-Rank Test
    Statistical analysis description
    Log-Rank Test
    Comparison groups
    ITT Population - Arm B v ITT Population - Arm A
    Number of subjects included in analysis
    47
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.001
    Method
    		 Logrank
    Confidence interval
    Statistical analysis title
    		 Cox Regression
    Statistical analysis description
    Cox Regression | Hazard Ratio
    Comparison groups
    ITT Population - Arm A v ITT Population - Arm B
    Number of subjects included in analysis
    47
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.001
    Method
    		 Regression, Cox
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.33
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.16
         upper limit
    		 0.65

    Primary: Event-free survival (EFS) - Supportive Analysis 2

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    End point title
    		 Event-free survival (EFS) - Supportive Analysis 2 [3]
    End point description
    A supportive analysis counting unconfirmed PSA progressions and unconfirmed progressions on bone scans within the first 12 weeks as progressions was performed for the primary endpoint
    End point type
    Primary
    End point timeframe
    From registration until event of interest.
    Notes
    [3] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: Statistical analyses of this endpoint are implemented in Primary Endpoint "Median EFS - Supportive Analysis 2".
    End point values
    		 ITT Population - Arm A ITT Population - Arm B
    Number of subjects analysed
    23
    24
    Units: Number of EFS events
        EFS event - Yes
    17
    21
        EFS event - No
    6
    3
    No statistical analyses for this end point

    Primary: Median EFS - Supportive Analysis 2

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    End point title
    		 Median EFS - Supportive Analysis 2
    End point description
    End point type
    Primary
    End point timeframe
    From registration until event of interest.
    End point values
    		 ITT Population - Arm A ITT Population - Arm B
    Number of subjects analysed
    23
    24
    Units: Median EFS
        median (confidence interval 95%)
    7.0 (3.2 to 14.2)
    2.9 (2.7 to 3.9)
    Statistical analysis title
    		 Log-Rank Test - Supportive Analysis 2
    Statistical analysis description
    Log-Rank Test
    Comparison groups
    ITT Population - Arm A v ITT Population - Arm B
    Number of subjects included in analysis
    47
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.001
    Method
    		 Logrank
    Confidence interval
    Statistical analysis title
    		 Cox Regression - Supportive Analysis
    Statistical analysis description
    Cox Regression | Hazard Ratio
    Comparison groups
    ITT Population - Arm A v ITT Population - Arm B
    Number of subjects included in analysis
    47
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.002
    Method
    		 Regression, Cox
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.34
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.17
         upper limit
    		 0.67

    Primary: Event-free survival (EFS) - Efficacy Subset

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    End point title
    		 Event-free survival (EFS) - Efficacy Subset [4]
    End point description
    A supportive analysis based on the evaluable patients (EP) population was performed for the primary endpoint.
    End point type
    Primary
    End point timeframe
    From registration until event of interest.
    Notes
    [4] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: Statistical analyses of this endpoint are implemented in Primary Endpoint "Median EFS - Efficacy Subset".
    End point values
    		 Eligible Population - Arm A Eligible Population - Arm B
    Number of subjects analysed
    21
    23
    Units: Number of EFS events
        EFS event - Yes
    13
    19
        EFS event - No
    8
    4
    No statistical analyses for this end point

    Primary: Median EFS - Efficacy Subset

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    End point title
    		 Median EFS - Efficacy Subset
    End point description
    End point type
    Primary
    End point timeframe
    From registration until event of interest.
    End point values
    		 Eligible Population - Arm A Eligible Population - Arm B
    Number of subjects analysed
    21
    23
    Units: Median EFS
        median (confidence interval 95%)
    8.2 (3.1 to 16.0)
    2.8 (2.6 to 3.9)
    Statistical analysis title
    		 Log-Rank Test
    Statistical analysis description
    Log-Rank Test
    Comparison groups
    Eligible Population - Arm A v Eligible Population - Arm B
    Number of subjects included in analysis
    44
    Analysis specification
    Pre-specified
    Analysis type
    		 other [5]
    P-value
    		 = 0.003
    Method
    		 Logrank
    Confidence interval
    Notes
    [5] - Log-Rank Test
    Statistical analysis title
    		 Cox Regression
    Statistical analysis description
    Cox Regression | Hazard Ratio
    Comparison groups
    Eligible Population - Arm A v Eligible Population - Arm B
    Number of subjects included in analysis
    44
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.005
    Method
    		 Regression, Cox
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.34
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.16
         upper limit
    		 0.72

    Secondary: PSA response (30%, 50%, 90%)

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    End point title
    		 PSA response (30%, 50%, 90%)
    End point description
    Only PSA values under treatment were be used for this endpoint. The number and proportion of 30%, 50% and 60% PSA responses are displayed together with 95% 2-sided exact Clopper-Pearson CIs.
    End point type
    Secondary
    End point timeframe
    From registration until any point under treatment.
    End point values
    		 ITT Population - Arm A ITT Population - Arm B
    Number of subjects analysed
    23
    24
    Units: PSA response
    number (confidence interval 95%)
        30% PSA response (% patients)
    73.9 (51.6 to 89.8)
    8.3 (1.0 to 27.0)
        50% PSA response (% patients)
    56.5 (34.5 to 76.8)
    4.2 (0.1 to 21.1)
        90% PSA response (% patients)
    8.7 (1.1 to 28.0)
    0.0 (0.0 to 0.0)
    Statistical analysis title
    		 PSA response (30%, 50% and 90%) - Fisher’s exact
    Statistical analysis description
    Fisher’s exact test
    Comparison groups
    ITT Population - Arm A v ITT Population - Arm B
    Number of subjects included in analysis
    47
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 < 0.001 [6]
    Method
    		 Fisher exact
    Confidence interval
    Notes
    [6] - 0.001 for 30% PSA Response 0.001 for 50% PSA Response

    Secondary: PSA response (best PSA response)

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    End point title
    		 PSA response (best PSA response)
    End point description
    Best response is summarized by treatment. The Wilcoxon-rank sum test was used to compare the treatment arms.
    End point type
    Secondary
    End point timeframe
    From registration until any point under treatment.
    End point values
    		 ITT Population - Arm A ITT Population - Arm B
    Number of subjects analysed
    23
    24
    Units: Best PSA response
        median (full range (min-max))
    -57.5 (-91.7 to 68.8)
    10.8 (-82.5 to 135.4)
    Statistical analysis title
    		 PSA response (best PSA response) - Wilcoxon
    Statistical analysis description
    Wilcoxon rank-sum test
    Comparison groups
    ITT Population - Arm A v ITT Population - Arm B
    Number of subjects included in analysis
    47
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 < 0.001
    Method
    		 Wilcoxon (Mann-Whitney)
    Confidence interval

    Secondary: Duration of PSA response (50%)

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    End point title
    		 Duration of PSA response (50%)
    End point description
    Of the 13 patients in the Orteronel arm who had a 50% PSA response, 8 patients had a confirmed PSA progression and 3 patients an unconfirmed PSA Progression. The patient in the Placebo arm who has a 50% PSA response did not have a PSA Progression.
    End point type
    Secondary
    End point timeframe
    Duration of PSA response is defined as the time from appearance of 50% PSA response to the time point of PSA Progression.
    End point values
    		 ITT Population - Arm A ITT Population - Arm B
    Number of subjects analysed
    8
    0 [7]
    Units: Duration of PSA response (50%) | months
        median (full range (min-max))
    6.5 (2.0 to 15.0)
    ( to )
    Notes
    [7] - The patient in the Placebo arm who had a 50% PSA response did not had a PSA Progression.
    No statistical analyses for this end point

    Secondary: Duration of PSA response (50%) incl. unconfirmed progression

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    End point title
    		 Duration of PSA response (50%) incl. unconfirmed progression
    End point description
    Of the 13 patients in the Orteronel arm who had a 50% PSA response, 8 patients had a confirmed PSA progression and 3 patients an unconfirmed PSA Progression. The patient in the Placebo arm who has a 50% PSA response did not have a PSA Progression.
    End point type
    Secondary
    End point timeframe
    Duration of PSA response is defined as the time from appearance of 50% PSA response to the time point of PSA Progression.
    End point values
    		 ITT Population - Arm A ITT Population - Arm B
    Number of subjects analysed
    11
    0 [8]
    Units: Duration of PSA response (50%)
        median (full range (min-max))
    6.0 (2.0 to 15.0)
    ( to )
    Notes
    [8] - The patient in the Placebo arm who had a 50% PSA response did not had a PSA Progression.
    No statistical analyses for this end point

    Secondary: Time to PSA progression

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    End point title
    		 Time to PSA progression
    End point description
    Patients not experiencing a PSA progression were censored at the date of the last available assessment or at initiation of a different treatment. Patients who were unblinded before they experienced an event will be censored at the date of the unblinding. Unconfirmed PSA progressions were not counted as progressions. PSA rise within the first 12 weeks was not considered as PSA Progression.
    End point type
    Secondary
    End point timeframe
    Time to PSA progression was defined as the time from registration to the time point of PSA progression.
    End point values
    		 ITT Population - Arm A ITT Population - Arm B
    Number of subjects analysed
    23
    24
    Units: Number of patients with PSA progression
    9
    6
    No statistical analyses for this end point

    Secondary: Time to PSA progression - Median time

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    End point title
    		 Time to PSA progression - Median time
    End point description
    Patients not experiencing a PSA progression were censored at the date of the last available assessment or at initiation of a different treatment. Patients who were unblinded before they experienced an event will be censored at the date of the unblinding. Unconfirmed PSA progressions were not counted as progressions. PSA rise within the first 12 weeks was not considered as PSA progression.
    End point type
    Secondary
    End point timeframe
    Time to PSA progression was defined as the time from registration to the time point of PSA progression.
    End point values
    		 ITT Population - Arm A ITT Population - Arm B
    Number of subjects analysed
    23
    24
    Units: Median time to PSA progression
        median (confidence interval 95%)
    8.5 (4.5 to 16.0)
    3.9 (2.8 to 12.6)
    Statistical analysis title
    		 Time to PSA progression - Log-Rank Test
    Statistical analysis description
    Log-Rank Test
    Comparison groups
    ITT Population - Arm A v ITT Population - Arm B
    Number of subjects included in analysis
    47
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.1
    Method
    		 Logrank
    Confidence interval
    Statistical analysis title
    		 Time to PSA progression - Cox Regression
    Statistical analysis description
    Cox Regression | Hazard Ratio
    Comparison groups
    ITT Population - Arm A v ITT Population - Arm B
    Number of subjects included in analysis
    47
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.2
    Method
    		 Regression, Cox
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.45
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.15
         upper limit
    		 1.33

    Secondary: Time to PSA progression (incl. first 12 weeks)

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    End point title
    		 Time to PSA progression (incl. first 12 weeks)
    End point description
    Patients not experiencing a PSA progression were censored at the date of the last available assessment or at initiation of a different treatment. Patients who were unblinded before they experienced an event will be censored at the date of the unblinding. Unconfirmed PSA progressions were not counted as progressions. PSA rise within the first 12 weeks was not considered as PSA Progression. As quite many PSA progressions occurred within the first 12 weeks, especially in the placebo arm, another analysis was performed counting also (confirmed) PSA progressions within the first 12 weeks.
    End point type
    Secondary
    End point timeframe
    Time to PSA progression was defined as the time from registration to the time point of PSA progression.
    End point values
    		 ITT Population - Arm A ITT Population - Arm B
    Number of subjects analysed
    23
    24
    Units: Number of patients with PSA
    15
    20
    No statistical analyses for this end point

    Secondary: Time to PSA progression (incl. first 12 weeks) - Median time

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    End point title
    		 Time to PSA progression (incl. first 12 weeks) - Median time
    End point description
    Patients not experiencing a PSA progression were censored at the date of the last available assessment or at initiation of a different treatment. Patients who were unblinded before they experienced an event will be censored at the date of the unblinding. Unconfirmed PSA progressions were not counted as progressions. PSA rise within the first 12 weeks was not considered as PSA Progression. As quite many PSA progressions occurred within the first 12 weeks, especially in the placebo arm, another analysis was performed counting also (confirmed) PSA progressions within the first 12 weeks.
    End point type
    Secondary
    End point timeframe
    Time to PSA progression was defined as the time from registration to the time point of PSA progression.
    End point values
    		 ITT Population - Arm A ITT Population - Arm B
    Number of subjects analysed
    23
    24
    Units: Median time to PSA progression
        median (confidence interval 95%)
    6.5 (2.7 to 10.3)
    1.8 (1.1 to 2.9)
    Statistical analysis title
    		 Time to PSA progression (II) - Log-Rank Test
    Statistical analysis description
    Log-Rank Test
    Comparison groups
    ITT Population - Arm A v ITT Population - Arm B
    Number of subjects included in analysis
    47
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.004
    Method
    		 Logrank
    Confidence interval
    Statistical analysis title
    		 Time to PSA progression (II) - Cox Regression
    Statistical analysis description
    Cox Regression | Hazard Ratio
    Comparison groups
    ITT Population - Arm A v ITT Population - Arm B
    Number of subjects included in analysis
    47
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.006
    Method
    		 Regression, Cox
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.37
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.18
         upper limit
    		 0.75

    Secondary: Radiographic progression-free survival (rPFS)

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    End point title
    		 Radiographic progression-free survival (rPFS)
    End point description
    Patients not experiencing an event were censored at the date of the last available assessment or at initiation of a different treatment. Patients who were unblinded before they experienced an event were censored at the date of the unblinding. Unconfirmed progressions on bone scans within the first 12 weeks were counted as progressions.
    End point type
    Secondary
    End point timeframe
    Radiographic progression-free survival was defined as the time from baseline to radiographic disease progression or death due to disease or treatment, whichever occurs earlier.
    End point values
    		 ITT Population - Arm A ITT Population - Arm B
    Number of subjects analysed
    23
    24
    Units: Number of events
    13
    16
    No statistical analyses for this end point

    Secondary: Radiographic progression-free survival (rPFS) - Median rPFS

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    End point title
    		 Radiographic progression-free survival (rPFS) - Median rPFS
    End point description
    Patients not experiencing an event were censored at the date of the last available assessment or at initiation of a different treatment. Patients who were unblinded before they experienced an event will be censored at the date of the unblinding. Unconfirmed progressions on bone scans within the first 12 weeks were counted as progressions.
    End point type
    Secondary
    End point timeframe
    Radiographic progression-free survival was defined as the time from baseline to radiographic disease progression or death due to disease or treatment, whichever occurs earlier.
    End point values
    		 ITT Population - Arm A ITT Population - Arm B
    Number of subjects analysed
    23
    24
    Units: Median rPFS
        median (confidence interval 95%)
    8.5 (3.5 to 14.2)
    2.8 (2.7 to 5.6)
    Statistical analysis title
    		 Radiographic progression-free survival - Log-Rank
    Statistical analysis description
    Log-Rank Test
    Comparison groups
    ITT Population - Arm A v ITT Population - Arm B
    Number of subjects included in analysis
    47
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.02
    Method
    		 Logrank
    Confidence interval
    Statistical analysis title
    		 Radiographic progression-free survival - Cox Regr.
    Statistical analysis description
    Cox Regression | Hazard Ratio
    Comparison groups
    ITT Population - Arm A v ITT Population - Arm B
    Number of subjects included in analysis
    47
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.03
    Method
    		 Regression, Cox
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.42
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.2
         upper limit
    		 0.91

    Secondary: Overall survival

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    End point title
    		 Overall survival
    End point description
    Patients not experiencing an event were censored at the last known date they were known to be alive.
    End point type
    Secondary
    End point timeframe
    OS was calculated from randomization until death from any cause.
    End point values
    		 ITT Population - Arm A ITT Population - Arm B
    Number of subjects analysed
    23
    24
    Units: Number of deaths
    16
    14
    No statistical analyses for this end point

    Secondary: Overall survival - Median OS

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    End point title
    		 Overall survival - Median OS
    End point description
    Patients not experiencing an event were censored at the last known date they were known to be alive.
    End point type
    Secondary
    End point timeframe
    OS was calculated from randomization until death from any cause.
    End point values
    		 ITT Population - Arm A ITT Population - Arm B
    Number of subjects analysed
    23
    24 [9]
    Units: Median OS
        median (confidence interval 95%)
    17.2 (10.6 to 35.4)
    22.3 (7.6 to 9999.9)
    Notes
    [9] - upper confidence interval not available due to statistical reasons; dummy value (9999.9) entered
    No statistical analyses for this end point

    Other pre-specified: Event-free survival (EFS) - Subgroup analysis I

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    End point title
    		 Event-free survival (EFS) - Subgroup analysis I
    End point description
    A subgroup analysis based on the RECIST-evaluable patients population was performed for the primary endpoint.
    End point type
    Other pre-specified
    End point timeframe
    From registration until event of interest.
    End point values
    		 RECIST-evaluable Population - Arm A RECIST-evaluable Population - Arm B
    Number of subjects analysed
    10
    11
    Units: Number of events
    6
    10
    No statistical analyses for this end point

    Other pre-specified: Median EFS - Subgroup analysis I

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    End point title
    		 Median EFS - Subgroup analysis I
    End point description
    A subgroup analysis based on the RECIST-evaluable patients population was performed for the primary endpoint.
    End point type
    Other pre-specified
    End point timeframe
    From registration until event of interest.
    End point values
    		 RECIST-evaluable Population - Arm A RECIST-evaluable Population - Arm B
    Number of subjects analysed
    10 [10]
    11
    Units: Median EFS
        median (confidence interval 95%)
    6.3 (2.7 to 9999.9)
    2.9 (2.1 to 3.9)
    Notes
    [10] - upper confidence interval not available due to statistical reasons; dummy value (9999.9) entered
    Statistical analysis title
    		 Median EFS - Subgroup analysis I - Log-Rank Test
    Comparison groups
    RECIST-evaluable Population - Arm A v RECIST-evaluable Population - Arm B
    Number of subjects included in analysis
    21
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.09
    Method
    		 Logrank
    Confidence interval
    Statistical analysis title
    		 Median EFS - Subgroup analysis I - Cox Regression
    Statistical analysis description
    Cox-Regression | Hazard Ratio
    Comparison groups
    RECIST-evaluable Population - Arm A v RECIST-evaluable Population - Arm B
    Number of subjects included in analysis
    21
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.1
    Method
    		 Regression, Cox
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.43
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.15
         upper limit
    		 1.19

    Other pre-specified: Radiographic progression-free survival - Subgroup analysis II

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    End point title
    		 Radiographic progression-free survival - Subgroup analysis II
    End point description
    A subgroup analysis based on the RECIST-evaluable patients population was performed for the endpoint rPFS.
    End point type
    Other pre-specified
    End point timeframe
    From registration until event of interest.
    End point values
    		 RECIST-evaluable Population - Arm A RECIST-evaluable Population - Arm B
    Number of subjects analysed
    10
    11
    Units: Number of events
    5
    9
    No statistical analyses for this end point

    Other pre-specified: Median rPFS - Subgroup analysis II

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    End point title
    		 Median rPFS - Subgroup analysis II
    End point description
    A subgroup analysis based on the RECIST-evaluable patients population was performed for the endpoint rPFS.
    End point type
    Other pre-specified
    End point timeframe
    From registration until event of interest.
    End point values
    		 RECIST-evaluable Population - Arm A RECIST-evaluable Population - Arm B
    Number of subjects analysed
    10 [11]
    11
    Units: Median rPFS
        median (confidence interval 95%)
    8.2 (2.6 to 9999.9)
    2.8 (2.1 to 5.6)
    Notes
    [11] - upper confidence interval not available due to statistical reasons; dummy value (9999.9) entered
    Statistical analysis title
    		 rPFS - Subgroup analysis - Log-Rank Test
    Statistical analysis description
    Log-Rank Test
    Comparison groups
    RECIST-evaluable Population - Arm A v RECIST-evaluable Population - Arm B
    Number of subjects included in analysis
    21
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.08
    Method
    		 Logrank
    Confidence interval
    Statistical analysis title
    		 rPFS - Subgroup analysis - Cox Regression
    Statistical analysis description
    Cox Regression | Hazard Ratio
    Comparison groups
    RECIST-evaluable Population - Arm A v RECIST-evaluable Population - Arm B
    Number of subjects included in analysis
    21
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.1
    Method
    		 Regression, Cox
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.39
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.13
         upper limit
    		 1.2

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Adverse Events were reported from registration until 30 days after treatment stop.
    Adverse event reporting additional description
    All AEs from baseline until 30 days after treatment stop were reported
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 CTCAE
    Dictionary version
    4.0
    Reporting groups
    Reporting group title
    A - Orteronel
    Reporting group description
    		 Treatment arm A - Patients receiving BSC and orteronel

    Reporting group title
    B - Placebo
    Reporting group description
    		 Treatment arm B - Patients receiving BSC and placebo

    Serious adverse events
    		 A - Orteronel B - Placebo
    Total subjects affected by serious adverse events
         subjects affected / exposed
    9 / 23 (39.13%)
    6 / 24 (25.00%)
         number of deaths (all causes)
    16
    14
         number of deaths resulting from adverse events
    1
    1
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Tumour progression
    Additional description: (suspected brain metastases)
         subjects affected / exposed
    0 / 23 (0.00%)
    1 / 24 (4.17%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    1 / 1
    Vascular disorders
    Peripheral ischaemia
         subjects affected / exposed
    0 / 23 (0.00%)
    1 / 24 (4.17%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac disorders
    Atrial fibrillation
         subjects affected / exposed
    1 / 23 (4.35%)
    0 / 24 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ventricular tachycardia
         subjects affected / exposed
    1 / 23 (4.35%)
    0 / 24 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nervous system disorders
    Somnolence
         subjects affected / exposed
    1 / 23 (4.35%)
    0 / 24 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Symptomatic spinal canal stenosis
         subjects affected / exposed
    1 / 23 (4.35%)
    0 / 24 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Paresthesia
         subjects affected / exposed
    0 / 23 (0.00%)
    1 / 24 (4.17%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Oedema
    Additional description: (upper belly, thigh, penis, scrotum)
         subjects affected / exposed
    0 / 23 (0.00%)
    1 / 24 (4.17%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Flu like Symptoms
         subjects affected / exposed
    0 / 23 (0.00%)
    1 / 24 (4.17%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal disorders
    EBV-associated mucocutaneous colonic ulcer
         subjects affected / exposed
    1 / 23 (4.35%)
    0 / 24 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Constipation
         subjects affected / exposed
    0 / 23 (0.00%)
    1 / 24 (4.17%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Pneumonitis
         subjects affected / exposed
    1 / 23 (4.35%)
    0 / 24 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Dyspnoea
         subjects affected / exposed
    1 / 23 (4.35%)
    0 / 24 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Skin and subcutaneous tissue disorders
    Erythroderma
         subjects affected / exposed
    1 / 23 (4.35%)
    0 / 24 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Endocrine disorders
    Adrenal insufficiency
         subjects affected / exposed
    1 / 23 (4.35%)
    0 / 24 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Pain in extremity
         subjects affected / exposed
    1 / 23 (4.35%)
    0 / 24 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Back pain
         subjects affected / exposed
    1 / 23 (4.35%)
    0 / 24 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bone pain
         subjects affected / exposed
    0 / 23 (0.00%)
    1 / 24 (4.17%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infections and infestations
    Lung infection
         subjects affected / exposed
    1 / 23 (4.35%)
    1 / 24 (4.17%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Sepsis
         subjects affected / exposed
    1 / 23 (4.35%)
    0 / 24 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    1 / 1
    0 / 0
    Gastroenteritis viral
         subjects affected / exposed
    1 / 23 (4.35%)
    0 / 24 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 0%
    Non-serious adverse events
    		 A - Orteronel B - Placebo
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    23 / 23 (100.00%)
    23 / 24 (95.83%)
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Disease progression
         subjects affected / exposed
    0 / 23 (0.00%)
    1 / 24 (4.17%)
         occurrences all number
    0
    1
    Tumor pain
         subjects affected / exposed
    0 / 23 (0.00%)
    1 / 24 (4.17%)
         occurrences all number
    0
    2
    Vascular disorders
    Hot flashes
         subjects affected / exposed
    5 / 23 (21.74%)
    2 / 24 (8.33%)
         occurrences all number
    6
    2
    Hypertension
         subjects affected / exposed
    7 / 23 (30.43%)
    7 / 24 (29.17%)
         occurrences all number
    21
    11
    Hypertension, due to pain both legs
         subjects affected / exposed
    1 / 23 (4.35%)
    0 / 24 (0.00%)
         occurrences all number
    2
    0
    Hypotension
         subjects affected / exposed
    1 / 23 (4.35%)
    0 / 24 (0.00%)
         occurrences all number
    1
    0
    Lympoedema
         subjects affected / exposed
    2 / 23 (8.70%)
    0 / 24 (0.00%)
         occurrences all number
    2
    0
    Peripheral ischemia, pain in lower leg
         subjects affected / exposed
    0 / 23 (0.00%)
    1 / 24 (4.17%)
         occurrences all number
    0
    1
    General disorders and administration site conditions
    Fatique
         subjects affected / exposed
    15 / 23 (65.22%)
    10 / 24 (41.67%)
         occurrences all number
    29
    15
    Pain
         subjects affected / exposed
    1 / 23 (4.35%)
    0 / 24 (0.00%)
         occurrences all number
    1
    0
    Left hip and groin pain
         subjects affected / exposed
    0 / 23 (0.00%)
    1 / 24 (4.17%)
         occurrences all number
    0
    1
    Oedema limbs
         subjects affected / exposed
    3 / 23 (13.04%)
    6 / 24 (25.00%)
         occurrences all number
    3
    6
    Oedema limbs, peripheral oedema
         subjects affected / exposed
    0 / 23 (0.00%)
    1 / 24 (4.17%)
         occurrences all number
    0
    1
    Fever
         subjects affected / exposed
    1 / 23 (4.35%)
    1 / 24 (4.17%)
         occurrences all number
    1
    1
    Flu like symptoms
         subjects affected / exposed
    1 / 23 (4.35%)
    3 / 24 (12.50%)
         occurrences all number
    1
    3
    Mild cold
         subjects affected / exposed
    1 / 23 (4.35%)
    0 / 24 (0.00%)
         occurrences all number
    3
    0
    Penis oedema
         subjects affected / exposed
    0 / 23 (0.00%)
    1 / 24 (4.17%)
         occurrences all number
    0
    3
    Scrotum oedema
         subjects affected / exposed
    0 / 23 (0.00%)
    1 / 24 (4.17%)
         occurrences all number
    0
    3
    Sweating
         subjects affected / exposed
    1 / 23 (4.35%)
    0 / 24 (0.00%)
         occurrences all number
    1
    0
    Thigh oedema
         subjects affected / exposed
    0 / 23 (0.00%)
    1 / 24 (4.17%)
         occurrences all number
    0
    3
    Underbelly oedema
         subjects affected / exposed
    0 / 23 (0.00%)
    1 / 24 (4.17%)
         occurrences all number
    0
    1
    Locilized oedema
         subjects affected / exposed
    1 / 23 (4.35%)
    0 / 24 (0.00%)
         occurrences all number
    1
    0
    Localized oedema, oedema in lower legs
         subjects affected / exposed
    1 / 23 (4.35%)
    0 / 24 (0.00%)
         occurrences all number
    1
    0
    Pain, bilateral shoulder pain
         subjects affected / exposed
    2 / 23 (8.70%)
    0 / 24 (0.00%)
         occurrences all number
    1
    0
    Pain, elbow pain
         subjects affected / exposed
    0 / 23 (0.00%)
    1 / 24 (4.17%)
         occurrences all number
    0
    1
    Pain, groin pain
         subjects affected / exposed
    0 / 23 (0.00%)
    1 / 24 (4.17%)
         occurrences all number
    0
    1
    Pain, left knee pain
         subjects affected / exposed
    0 / 23 (0.00%)
    1 / 24 (4.17%)
         occurrences all number
    0
    1
    Pain, sciatica
         subjects affected / exposed
    1 / 23 (4.35%)
    0 / 24 (0.00%)
         occurrences all number
    2
    0
    Pain, shoulder pain
         subjects affected / exposed
    0 / 23 (0.00%)
    1 / 24 (4.17%)
         occurrences all number
    0
    1
    Pain in extremity
         subjects affected / exposed
    3 / 23 (13.04%)
    4 / 24 (16.67%)
         occurrences all number
    5
    4
    Pain in extremity, pain hip left
         subjects affected / exposed
    0 / 23 (0.00%)
    1 / 24 (4.17%)
         occurrences all number
    0
    1
    Reproductive system and breast disorders
    Gynecomastia
         subjects affected / exposed
    1 / 23 (4.35%)
    0 / 24 (0.00%)
         occurrences all number
    1
    0
    Pelvic pain
         subjects affected / exposed
    1 / 23 (4.35%)
    1 / 24 (4.17%)
         occurrences all number
    1
    1
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    3 / 23 (13.04%)
    2 / 24 (8.33%)
         occurrences all number
    6
    3
    Dyspnoea
         subjects affected / exposed
    4 / 23 (17.39%)
    5 / 24 (20.83%)
         occurrences all number
    10
    6
    Pleural effusion
         subjects affected / exposed
    1 / 23 (4.35%)
    0 / 24 (0.00%)
         occurrences all number
    1
    0
    Pneumonitis
         subjects affected / exposed
    2 / 23 (8.70%)
    0 / 24 (0.00%)
         occurrences all number
    2
    0
    Psychiatric disorders
    Depressive affection
         subjects affected / exposed
    1 / 23 (4.35%)
    0 / 24 (0.00%)
         occurrences all number
    1
    0
    Agitation
         subjects affected / exposed
    0 / 23 (0.00%)
    1 / 24 (4.17%)
         occurrences all number
    0
    2
    Confusion
         subjects affected / exposed
    1 / 23 (4.35%)
    0 / 24 (0.00%)
         occurrences all number
    1
    0
    Depression
         subjects affected / exposed
    1 / 23 (4.35%)
    0 / 24 (0.00%)
         occurrences all number
    1
    0
    Insomnia
         subjects affected / exposed
    1 / 23 (4.35%)
    3 / 24 (12.50%)
         occurrences all number
    1
    3
    Psychosis
         subjects affected / exposed
    1 / 23 (4.35%)
    0 / 24 (0.00%)
         occurrences all number
    1
    0
    Suicidal ideation
         subjects affected / exposed
    1 / 23 (4.35%)
    0 / 24 (0.00%)
         occurrences all number
    1
    0
    Investigations
    Aspartate aminotransferase increased
         subjects affected / exposed
    0 / 23 (0.00%)
    1 / 24 (4.17%)
         occurrences all number
    0
    1
    Blood bilirubin increased
         subjects affected / exposed
    1 / 23 (4.35%)
    0 / 24 (0.00%)
         occurrences all number
    2
    0
    Creatinine increased
         subjects affected / exposed
    1 / 23 (4.35%)
    0 / 24 (0.00%)
         occurrences all number
    1
    0
    Electrocardiogram QT corrected interval prolonged
         subjects affected / exposed
    1 / 23 (4.35%)
    0 / 24 (0.00%)
         occurrences all number
    2
    0
    GGT increased
         subjects affected / exposed
    1 / 23 (4.35%)
    0 / 24 (0.00%)
         occurrences all number
    2
    0
    Lipase increased
         subjects affected / exposed
    4 / 23 (17.39%)
    0 / 24 (0.00%)
         occurrences all number
    1
    0
    Serum amylase increased
         subjects affected / exposed
    1 / 23 (4.35%)
    0 / 24 (0.00%)
         occurrences all number
    2
    0
    Weight loss
         subjects affected / exposed
    2 / 23 (8.70%)
    1 / 24 (4.17%)
         occurrences all number
    6
    1
    Injury, poisoning and procedural complications
    Bruising
         subjects affected / exposed
    0 / 23 (0.00%)
    1 / 24 (4.17%)
         occurrences all number
    0
    1
    Cardiac disorders
    Atrial fibrillation
         subjects affected / exposed
    1 / 23 (4.35%)
    0 / 24 (0.00%)
         occurrences all number
    1
    0
    2/6 systolic bruit
         subjects affected / exposed
    1 / 23 (4.35%)
    0 / 24 (0.00%)
         occurrences all number
    1
    0
    Frequency correction due to Bigeminus
         subjects affected / exposed
    0 / 23 (0.00%)
    1 / 24 (4.17%)
         occurrences all number
    0
    1
    Ventricular tachycardia
         subjects affected / exposed
    1 / 23 (4.35%)
    0 / 24 (0.00%)
         occurrences all number
    1
    0
    Nervous system disorders
    Sensory neuropathy to feet
         subjects affected / exposed
    1 / 23 (4.35%)
    0 / 24 (0.00%)
         occurrences all number
    1
    0
    Dizziness
         subjects affected / exposed
    3 / 23 (13.04%)
    1 / 24 (4.17%)
         occurrences all number
    9
    1
    Dysesthesia
         subjects affected / exposed
    0 / 23 (0.00%)
    1 / 24 (4.17%)
         occurrences all number
    0
    1
    Dysgeusia
         subjects affected / exposed
    1 / 23 (4.35%)
    1 / 24 (4.17%)
         occurrences all number
    1
    1
    Headache
         subjects affected / exposed
    3 / 23 (13.04%)
    1 / 24 (4.17%)
         occurrences all number
    3
    2
    Memory impairment
         subjects affected / exposed
    0 / 23 (0.00%)
    1 / 24 (4.17%)
         occurrences all number
    0
    1
    Symptomatic spinal canal stenosis
         subjects affected / exposed
    1 / 23 (4.35%)
    0 / 24 (0.00%)
         occurrences all number
    1
    0
    Paresthesia
         subjects affected / exposed
    4 / 23 (17.39%)
    1 / 24 (4.17%)
         occurrences all number
    4
    1
    Paresthesia, feet
         subjects affected / exposed
    1 / 23 (4.35%)
    0 / 24 (0.00%)
         occurrences all number
    2
    0
    Paresthesia, lower lip and chin
         subjects affected / exposed
    1 / 23 (4.35%)
    0 / 24 (0.00%)
         occurrences all number
    1
    0
    Peripheral sensory neuropathy
         subjects affected / exposed
    3 / 23 (13.04%)
    2 / 24 (8.33%)
         occurrences all number
    3
    2
    Somnolence
         subjects affected / exposed
    1 / 23 (4.35%)
    0 / 24 (0.00%)
         occurrences all number
    1
    0
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    1 / 23 (4.35%)
    0 / 24 (0.00%)
         occurrences all number
    1
    0
    Ear and labyrinth disorders
    Tinnitus
         subjects affected / exposed
    1 / 23 (4.35%)
    0 / 24 (0.00%)
         occurrences all number
    1
    0
    Eye disorders
    Eye pressure
         subjects affected / exposed
    0 / 23 (0.00%)
    1 / 24 (4.17%)
         occurrences all number
    0
    1
    Gastrointestinal disorders
    Gastrointestinal disorders, loss of appetite
         subjects affected / exposed
    0 / 23 (0.00%)
    1 / 24 (4.17%)
         occurrences all number
    0
    1
    Abdominal pain
         subjects affected / exposed
    2 / 23 (8.70%)
    2 / 24 (8.33%)
         occurrences all number
    3
    2
    Bloating
         subjects affected / exposed
    0 / 23 (0.00%)
    1 / 24 (4.17%)
         occurrences all number
    0
    1
    colonic stenosis
         subjects affected / exposed
    1 / 23 (4.35%)
    0 / 24 (0.00%)
         occurrences all number
    2
    0
    Colonic ulcer
         subjects affected / exposed
    1 / 23 (4.35%)
    0 / 24 (0.00%)
         occurrences all number
    1
    0
    Constipation
         subjects affected / exposed
    3 / 23 (13.04%)
    4 / 24 (16.67%)
         occurrences all number
    5
    5
    Diarrhoea
         subjects affected / exposed
    8 / 23 (34.78%)
    2 / 24 (8.33%)
         occurrences all number
    13
    2
    Dyspepsia
         subjects affected / exposed
    2 / 23 (8.70%)
    0 / 24 (0.00%)
         occurrences all number
    11
    0
    Dysphagia
         subjects affected / exposed
    1 / 23 (4.35%)
    0 / 24 (0.00%)
         occurrences all number
    1
    0
    Gastritis
         subjects affected / exposed
    1 / 23 (4.35%)
    0 / 24 (0.00%)
         occurrences all number
    3
    0
    Gastroparesis
         subjects affected / exposed
    0 / 23 (0.00%)
    1 / 24 (4.17%)
         occurrences all number
    0
    1
    Hemorrhoidal hemorrhage
         subjects affected / exposed
    0 / 23 (0.00%)
    1 / 24 (4.17%)
         occurrences all number
    0
    1
    Haemorrhoids
         subjects affected / exposed
    0 / 23 (0.00%)
    1 / 24 (4.17%)
         occurrences all number
    0
    1
    Nausea
         subjects affected / exposed
    12 / 23 (52.17%)
    6 / 24 (25.00%)
         occurrences all number
    19
    7
    Rash acneiform
         subjects affected / exposed
    2 / 23 (8.70%)
    0 / 24 (0.00%)
         occurrences all number
    2
    0
    Rectal haemorrhage
         subjects affected / exposed
    1 / 23 (4.35%)
    0 / 24 (0.00%)
         occurrences all number
    1
    0
    Vomiting
         subjects affected / exposed
    5 / 23 (21.74%)
    3 / 24 (12.50%)
         occurrences all number
    7
    4
    Hepatobiliary disorders
    Splenomegaly
         subjects affected / exposed
    1 / 23 (4.35%)
    0 / 24 (0.00%)
         occurrences all number
    1
    0
    Skin and subcutaneous tissue disorders
    Alopecia
         subjects affected / exposed
    4 / 23 (17.39%)
    0 / 24 (0.00%)
         occurrences all number
    5
    0
    Erythroderma
         subjects affected / exposed
    1 / 23 (4.35%)
    0 / 24 (0.00%)
         occurrences all number
    1
    0
    Nail discolouration
         subjects affected / exposed
    0 / 23 (0.00%)
    1 / 24 (4.17%)
         occurrences all number
    0
    1
    Nail loss
         subjects affected / exposed
    1 / 23 (4.35%)
    1 / 24 (4.17%)
         occurrences all number
    1
    1
    Hyperkeratosis tibial right
         subjects affected / exposed
    1 / 23 (4.35%)
    0 / 24 (0.00%)
         occurrences all number
    1
    0
    Skin ulceration
         subjects affected / exposed
    0 / 23 (0.00%)
    1 / 24 (4.17%)
         occurrences all number
    0
    2
    Renal and urinary disorders
    Hesitancy, poor urine flow
         subjects affected / exposed
    1 / 23 (4.35%)
    0 / 24 (0.00%)
         occurrences all number
    1
    0
    Nycturia
         subjects affected / exposed
    1 / 23 (4.35%)
    1 / 24 (4.17%)
         occurrences all number
    1
    1
    Pain left side
         subjects affected / exposed
    0 / 23 (0.00%)
    1 / 24 (4.17%)
         occurrences all number
    0
    1
    Prostatitis
         subjects affected / exposed
    0 / 23 (0.00%)
    1 / 24 (4.17%)
         occurrences all number
    0
    1
    Urinary tract infection
         subjects affected / exposed
    0 / 23 (0.00%)
    3 / 24 (12.50%)
         occurrences all number
    0
    3
    Urinary frequency, Nycturia
         subjects affected / exposed
    1 / 23 (4.35%)
    0 / 24 (0.00%)
         occurrences all number
    1
    0
    Urinary tract obstruction
         subjects affected / exposed
    1 / 23 (4.35%)
    0 / 24 (0.00%)
         occurrences all number
    1
    0
    Urinary tract pain
         subjects affected / exposed
    1 / 23 (4.35%)
    0 / 24 (0.00%)
         occurrences all number
    1
    0
    Endocrine disorders
    Adrenal insufficiency
         subjects affected / exposed
    1 / 23 (4.35%)
    0 / 24 (0.00%)
         occurrences all number
    1
    0
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    2 / 23 (8.70%)
    3 / 24 (12.50%)
         occurrences all number
    2
    4
    Arthralgia, left hip
         subjects affected / exposed
    0 / 23 (0.00%)
    1 / 24 (4.17%)
         occurrences all number
    0
    1
    Back pain
         subjects affected / exposed
    3 / 23 (13.04%)
    6 / 24 (25.00%)
         occurrences all number
    5
    7
    Back pain, Lower back pain
         subjects affected / exposed
    0 / 23 (0.00%)
    1 / 24 (4.17%)
         occurrences all number
    0
    2
    Back pain, lumbal pain
         subjects affected / exposed
    1 / 23 (4.35%)
    0 / 24 (0.00%)
         occurrences all number
    5
    0
    Bone pain
         subjects affected / exposed
    3 / 23 (13.04%)
    3 / 24 (12.50%)
         occurrences all number
    7
    7
    Bone pain, left spina
         subjects affected / exposed
    1 / 23 (4.35%)
    0 / 24 (0.00%)
         occurrences all number
    1
    0
    Bone pain, orbita
         subjects affected / exposed
    0 / 23 (0.00%)
    1 / 24 (4.17%)
         occurrences all number
    0
    1
    Bone pain, thoracal rip pain due to fall
         subjects affected / exposed
    1 / 23 (4.35%)
    0 / 24 (0.00%)
         occurrences all number
    2
    0
    Buttock pain
         subjects affected / exposed
    1 / 23 (4.35%)
    1 / 24 (4.17%)
         occurrences all number
    1
    2
    Flank pain
         subjects affected / exposed
    1 / 23 (4.35%)
    0 / 24 (0.00%)
         occurrences all number
    1
    0
    Generalized muscle weakness
         subjects affected / exposed
    0 / 23 (0.00%)
    1 / 24 (4.17%)
         occurrences all number
    0
    1
    Muscle weakness upper limb, weakness leg
         subjects affected / exposed
    1 / 23 (4.35%)
    0 / 24 (0.00%)
         occurrences all number
    1
    0
    Back, shoulder, leg aches
         subjects affected / exposed
    1 / 23 (4.35%)
    0 / 24 (0.00%)
         occurrences all number
    1
    0
    Iliosacral
         subjects affected / exposed
    0 / 23 (0.00%)
    1 / 24 (4.17%)
         occurrences all number
    0
    1
    Leg aches
         subjects affected / exposed
    1 / 23 (4.35%)
    0 / 24 (0.00%)
         occurrences all number
    1
    0
    Pain shoulder both sides
         subjects affected / exposed
    1 / 23 (4.35%)
    0 / 24 (0.00%)
         occurrences all number
    2
    0
    Myalgia
         subjects affected / exposed
    3 / 23 (13.04%)
    0 / 24 (0.00%)
         occurrences all number
    3
    0
    Neck pain
         subjects affected / exposed
    1 / 23 (4.35%)
    1 / 24 (4.17%)
         occurrences all number
    1
    1
    Osteonecrosis of jaw
         subjects affected / exposed
    1 / 23 (4.35%)
    0 / 24 (0.00%)
         occurrences all number
    1
    0
    Infections and infestations
    Chills after change of the nephrostoma
         subjects affected / exposed
    0 / 23 (0.00%)
    1 / 24 (4.17%)
         occurrences all number
    0
    1
    Bladder infection
         subjects affected / exposed
    1 / 23 (4.35%)
    0 / 24 (0.00%)
         occurrences all number
    2
    0
    Conjunctivitis
         subjects affected / exposed
    1 / 23 (4.35%)
    0 / 24 (0.00%)
         occurrences all number
    1
    0
    Herpes labialis
         subjects affected / exposed
    0 / 23 (0.00%)
    1 / 24 (4.17%)
         occurrences all number
    0
    1
    Infection upper respiratory system
         subjects affected / exposed
    1 / 23 (4.35%)
    0 / 24 (0.00%)
         occurrences all number
    1
    0
    Viral gastroenteritis
         subjects affected / exposed
    1 / 23 (4.35%)
    0 / 24 (0.00%)
         occurrences all number
    1
    0
    Viral infection respiratory airways with cough
         subjects affected / exposed
    0 / 23 (0.00%)
    1 / 24 (4.17%)
         occurrences all number
    0
    1
    Lip infection
         subjects affected / exposed
    0 / 23 (0.00%)
    1 / 24 (4.17%)
         occurrences all number
    0
    1
    Lung infection
         subjects affected / exposed
    1 / 23 (4.35%)
    1 / 24 (4.17%)
         occurrences all number
    1
    1
    Paronychia
         subjects affected / exposed
    1 / 23 (4.35%)
    0 / 24 (0.00%)
         occurrences all number
    1
    0
    Prostate infection
         subjects affected / exposed
    1 / 23 (4.35%)
    0 / 24 (0.00%)
         occurrences all number
    1
    0
    Sepsis
         subjects affected / exposed
    1 / 23 (4.35%)
    0 / 24 (0.00%)
         occurrences all number
    1
    0
    Metabolism and nutrition disorders
    Hypokalaemia
         subjects affected / exposed
    2 / 23 (8.70%)
    0 / 24 (0.00%)
         occurrences all number
    5
    0
    Anorexia
         subjects affected / exposed
    3 / 23 (13.04%)
    4 / 24 (16.67%)
         occurrences all number
    4
    6
    Hyperglycaemia
         subjects affected / exposed
    1 / 23 (4.35%)
    0 / 24 (0.00%)
         occurrences all number
    1
    0
    Hypocalcemia
         subjects affected / exposed
    1 / 23 (4.35%)
    0 / 24 (0.00%)
         occurrences all number
    1
    0
    Hypokalemia
         subjects affected / exposed
    2 / 23 (8.70%)
    0 / 24 (0.00%)
         occurrences all number
    5
    0
    Hyponatraemia
         subjects affected / exposed
    0 / 23 (0.00%)
    1 / 24 (4.17%)
         occurrences all number
    0
    1

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    13 Aug 2013
    Amended protocol version 2.0 of 13.08.2013 contains updated information on handling of orteronel/placebo and minor administrative changes regarding the Patient insurance for patients enrolled in the UK and Germany. Amended UK-specific appendix An amended UK-specific appendix (Version 2.0 of 19.08.2013) has been issued in order to reflect the amended protocol version 2.0 of 13.08.2013. Section 1 concerning abbreviations has been deleted. Otherwise, no changes to the content have been made.

    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.
    As patients in the trial were selected in the sense that they all had derived clinical benefit from docetaxel (PR or SD) and due to the small number of patients included the trial results have to be interpreted with caution.

    Online references
    http://www.ncbi.nlm.nih.gov/pubmed/27457964
    For support, Contact us.
    The status and protocol content of GB trials is no longer updated since 1 January 2021. For the UK, as of 31 January 2021, EU Law applies only to the territory of Northern Ireland (NI) to the extent foreseen in the Protocol on Ireland/NI. Legal notice
    As of 31 January 2023, all EU/EEA initial clinical trial applications must be submitted through CTIS . Updated EudraCT trials information and information on PIP/Art 46 trials conducted exclusively in third countries continues to be submitted through EudraCT and published on this website.

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