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    Clinical Trial Results:
    A Phase III, Open Label, Randomized Study to Assess the Efficacy and Safety of Olaparib (Lynparza™) Versus Enzalutamide or Abiraterone Acetate in Men with Metastatic Castration-Resistant Prostate Cancer Who Have Failed Prior Treatment with a New Hormonal Agent and Have Homologous Recombination Repair Gene Mutations (PROfound)

    Summary
    EudraCT number
    		 2016-000300-28
    Trial protocol
    		 SE   DK   NO   ES   AT   FR   IT  
    Global end of trial date
    20 Mar 2020

    Results information
    Results version number
    		 v1(current)
    This version publication date
    21 Oct 2023
    First version publication date
    21 Oct 2023
    Other versions

    Trial information

    		 Close Top of page
    Trial identification
    Sponsor protocol code
    D081DC00007
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 -
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    AstraZeneca Clinical Study Information Center
    Sponsor organisation address
    Melbourn Science Park, Royston, United Kingdom, SG8 6EE
    Public contact
    Global Clinical Lead, AstraZeneca Clinical Study Information Center, +1 8772409479, information.center@astrazeneca.com
    Scientific contact
    Global Clinical Lead, AstraZeneca Clinical Study Information Center, +1 8772409479, information.center@astrazeneca.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
    20 Mar 2020
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    20 Mar 2020
    Global end of trial reached?
    Yes
    Global end of trial date
    20 Mar 2020
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The primary endpoint of the study is radiographic progression free survival (rPFS) in subjects with BRCA1, BRCA2 or ATM mutations (Cohort A).
    Protection of trial subjects
    Patients given full and adequate oral and written information about the nature, purpose, possible risk and benefit of the study.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    06 Feb 2017
    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
    France: 62
    Country: Number of subjects enrolled
    Japan: 57
    Country: Number of subjects enrolled
    Canada: 32
    Country: Number of subjects enrolled
    Turkey: 30
    Country: Number of subjects enrolled
    Australia: 24
    Country: Number of subjects enrolled
    Korea, Democratic People's Republic of: 29
    Country: Number of subjects enrolled
    Netherlands: 21
    Country: Number of subjects enrolled
    United States: 33
    Country: Number of subjects enrolled
    Italy: 15
    Country: Number of subjects enrolled
    Taiwan: 15
    Country: Number of subjects enrolled
    Brazil: 14
    Country: Number of subjects enrolled
    Argentina: 9
    Country: Number of subjects enrolled
    Israel: 9
    Country: Number of subjects enrolled
    Germany: 12
    Country: Number of subjects enrolled
    Spain: 9
    Country: Number of subjects enrolled
    Sweden: 2
    Country: Number of subjects enrolled
    United Kingdom: 4
    Country: Number of subjects enrolled
    Austria: 6
    Country: Number of subjects enrolled
    Denmark: 1
    Country: Number of subjects enrolled
    Norway: 3
    Worldwide total number of subjects
    387
    EEA total number of subjects
    131
    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)
    116
    From 65 to 84 years
    260
    85 years and over
    11

    Subject disposition

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    Recruitment
    Recruitment details
    		 Subjects were divided into two cohorts based on HRR gene mutation status. Subjects with mutations in either BRCA1, BRCA2, or ATM are in Cohort A whereas subjects with mutations among 12 other genes involved in the HRR pathway (BARD1, BRIP1, CDK12, CHEK1,CHEK2, FANCL, PALB2, PPP2R2A, RAD51B, RAD51C, RAD51D, or RAD54L) are in Cohort B.

    Pre-assignment
    Screening details
    		 Consenting subjects were assessed to ensure they met eligibility criteria.

    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
    		 Subject, Investigator, Monitor, Carer, Assessor

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Cohort A Olaparib 300mg bd
    Arm description
    		 2x150mg film-coated tablets
    Arm type
    		 Experimental

    Investigational medicinal product name
    Olaparib
    Investigational medicinal product code
    Other name
    Lynparza
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    300mg twice daily (100mg and 150mg tablets)

    Arm title
    		 Cohort A Investigators choice of NHA
    Arm description
    		 either enzalutamide capsules (160 mg od) or abiraterone acetate tablets (1,000 mg od with 5 mg bid prednisone)
    Arm type
    		 Active comparator

    Investigational medicinal product name
    Enzalutamide
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    160mg once daily (40mg tablets)

    Investigational medicinal product name
    Abiraterone acetate
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    1000mg once daily (250mg or 500mg tablets) with prednisone 5mg bd

    Investigational medicinal product name
    Prednisone
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    5mg bd with abiraterone acetate 1000mg od. Prednisolone was permitted for use instead of prednisone

    Arm title
    		 Cohort B Olaparib 300mg bd
    Arm description
    		 2x150mg film-coated tablets
    Arm type
    		 Experimental

    Investigational medicinal product name
    Olaparib
    Investigational medicinal product code
    Other name
    Lynparza
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    300mg twice daily (100mg and 150mg tablets)

    Arm title
    		 Cohort B Investigators choice of NHA
    Arm description
    		 either enzalutamide capsules (160 mg od) or abiraterone acetate tablets (1,000 mg od with 5 mg bid prednisone)
    Arm type
    		 Active comparator

    Investigational medicinal product name
    Enzalutamide
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    160mg once daily (40mg tablets)

    Investigational medicinal product name
    Prednisone
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    5mg bd with abiraterone acetate 1000mg od. Prednisolone was permitted for use instead of prednisone

    Investigational medicinal product name
    Abiraterone acetate
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    1000mg once daily (250mg or 500mg tablets) with prednisone 5mg bd

    Number of subjects in period 1
    		Cohort A Olaparib 300mg bd Cohort A Investigators choice of NHA Cohort B Olaparib 300mg bd Cohort B Investigators choice of NHA
    Started
    162
    83
    94
    48
    Completed
    0
    0
    0
    0
    Not completed
    162
    83
    94
    48
         Adverse event, serious fatal
    88
    54
    67
    28
         Consent withdrawn by subject
    21
    7
    7
    6
         Disease progression
    -
    -
    -
    1
         Ongoing study at data cut off
    49
    21
    19
    12
         Study terminated by sponsor
    1
    -
    -
    -
         Investigator decision
    -
    1
    -
    -
         Screen failure
    -
    -
    -
    1
         Lost to follow-up
    3
    -
    1
    -

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Cohort A Olaparib 300mg bd
    Reporting group description
    		 2x150mg film-coated tablets

    Reporting group title
    Cohort A Investigators choice of NHA
    Reporting group description
    		 either enzalutamide capsules (160 mg od) or abiraterone acetate tablets (1,000 mg od with 5 mg bid prednisone)

    Reporting group title
    Cohort B Olaparib 300mg bd
    Reporting group description
    		 2x150mg film-coated tablets

    Reporting group title
    Cohort B Investigators choice of NHA
    Reporting group description
    		 either enzalutamide capsules (160 mg od) or abiraterone acetate tablets (1,000 mg od with 5 mg bid prednisone)

    Reporting group values
    		 Cohort A Olaparib 300mg bd Cohort A Investigators choice of NHA Cohort B Olaparib 300mg bd Cohort B Investigators choice of NHA Total
    Number of subjects
    		 162 83 94 48 387
    Age categorical
    Units: Subjects
        In utero
    		 0 0 0 0 0
        Preterm newborn infants (gestational age < 37 wks)
    		 0 0 0 0 0
        Newborns (0-27 days)
    		 0 0 0 0 0
        Infants and toddlers (28 days-23 months)
    		 0 0 0 0 0
        Children (2-11 years)
    		 0 0 0 0 0
        Adolescents (12-17 years)
    		 0 0 0 0 0
        Adults (18-64 years)
    		 54 23 28 11 116
        From 65-84 years
    		 105 59 64 35 263
        85 years and over
    		 3 1 2 2 8
    Age Continuous
    Units: Years
        arithmetic mean (standard deviation)
    		 68.0 ( 8.23 ) 68.1 ( 7.36 ) 69.2 ( 8.79 ) 70.3 ( 7.83 ) -
    Sex: Female, Male
    Units: Participants
        Female
    		 0 0 0 0 0
        Male
    		 162 83 94 48 387
    Race/Ethnicity, Customized
    Units: Subjects
        White
    		 109 55 54 30 248
        Black or African American
    		 2 1 5 0 8
        Asian
    		 43 19 26 17 105
        Other
    		 1 1 1 0 3
        Missing
    		 7 7 8 1 23

    End points

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    End points reporting groups
    Reporting group title
    Cohort A Olaparib 300mg bd
    Reporting group description
    		 2x150mg film-coated tablets

    Reporting group title
    Cohort A Investigators choice of NHA
    Reporting group description
    		 either enzalutamide capsules (160 mg od) or abiraterone acetate tablets (1,000 mg od with 5 mg bid prednisone)

    Reporting group title
    Cohort B Olaparib 300mg bd
    Reporting group description
    		 2x150mg film-coated tablets

    Reporting group title
    Cohort B Investigators choice of NHA
    Reporting group description
    		 either enzalutamide capsules (160 mg od) or abiraterone acetate tablets (1,000 mg od with 5 mg bid prednisone)

    Subject analysis set title
    Cohort A+B Olaparib 300mg bd
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    Subjects with HRR qualifying mutations (Cohort A+B)

    Subject analysis set title
    Cohort A+B Investigators Choice of NHA
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    Subjects with HRR qualifying mutations (Cohort A+B)

    Primary: Radiological Progression Free Survival (rPFS) by blinded independent central review (BICR) - Cohort A only

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    End point title
    		 Radiological Progression Free Survival (rPFS) by blinded independent central review (BICR) - Cohort A only [1]
    End point description
    The time from randomisation until the date of objective radiological disease progression (determined by RECIST 1.1 (soft tissue) and Prostate Cancer Working Group 3 (PCWG-3) (bone)) or death (by any cause in the absence of progression) regardless of whether the patient withdrew from randomised therapy or received another anti-cancer therapy prior to progression. Progression is defined using (i) Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.1) for soft tissue, as a >=20% increase in the sum of diameters of target lesions and an absolute increase of >=5mm taking as reference the smallest sum of diameters since treatment started including the baseline sum of diameters; (ii) Prostate Cancer Working Group 3 (PGWG-3) for bone as >= 2 new bone lesions on the 1st week 8 scan compared to baseline. The confirmatory scan, >=6 weeks later, must show >=2 more new bone lesions (for a total of >=4 new bone lesions since baseline).
    End point type
    Primary
    End point timeframe
    Tumor assessments every 8 weeks from randomisation until radiographic progression assessed by BICR (median duration of treatment of 7 and 4 months for Olaparib and Investigators Choice of NHA respectively).
    Notes
    [1] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: The study was designed to formally test these endpoints in only Cohort A patients, there is just 1 endpoint that is formally tested for both Cohort A and Cohort B which is rPFS. All other analyses are descriptive only
    End point values
    		 Cohort A Olaparib 300mg bd Cohort A Investigators choice of NHA
    Number of subjects analysed
    162
    83
    Units: Months
        median (confidence interval 95%)
    7.39 (6.24 to 9.33)
    3.55 (1.91 to 3.71)
    Statistical analysis title
    		 Primary analysis
    Statistical analysis description
    Radiological Progression Free Survival (rPFS) by blinded independent central review (BICR)
    Comparison groups
    Cohort A Olaparib 300mg bd v Cohort A Investigators choice of NHA
    Number of subjects included in analysis
    245
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [2]
    P-value
    		 < 0.0001 [3]
    Method
    		 Logrank
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.34
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.25
         upper limit
    		 0.47
    Notes
    [2] - Cohort A
    [3] - 2-sided

    Secondary: Confirmed Objective Response Rate (ORR) by blinded independent central review (BICR) - Cohort A only

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    End point title
    		 Confirmed Objective Response Rate (ORR) by blinded independent central review (BICR) - Cohort A only [4]
    End point description
    ORR is the percentage of patients with at least one visit response of Complete response (CR) or Partial response (PR), in their soft tissue disease assessed by Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.1), in the absence of progression on bone scan assessed by Prostate Cancer Working Group 3 (PCWG3)). Per RECIST v1.1, CR=Disappearance of all target lesions; PR = >=30% decrease in the sum of diameters of target lesions; For each treatment group, ORR is the number of patients with a CR and PR.
    End point type
    Secondary
    End point timeframe
    Tumor assessments every 8 weeks from randomisation until radiographic progression assessed by BICR (median duration of treatment of 7 and 4 months for Olaparib and Investigators Choice of NHA respectively).
    Notes
    [4] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: The study was designed to formally test these endpoints in only Cohort A patients, there is just 1 endpoint that is formally tested for both Cohort A and Cohort B which is rPFS. All other analyses are descriptive only
    End point values
    		 Cohort A Olaparib 300mg bd Cohort A Investigators choice of NHA
    Number of subjects analysed
    84
    43
    Units: Participants
        Response
    28
    1
        No response
    56
    42
    Statistical analysis title
    		 Secondary analysis
    Comparison groups
    Cohort A Olaparib 300mg bd v Cohort A Investigators choice of NHA
    Number of subjects included in analysis
    127
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [5]
    P-value
    		 < 0.0001
    Method
    		 Regression, Logistic
    Parameter type
    		 Odds ratio (OR)
    Point estimate
    20.86
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 4.18
         upper limit
    		 379.18
    Notes
    [5] - Cohort A

    Secondary: Radiological Progression Free Survival (rPFS) by blinded independent central review (BICR) - Cohort A+B

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    End point title
    		 Radiological Progression Free Survival (rPFS) by blinded independent central review (BICR) - Cohort A+B
    End point description
    The time from randomisation until the date of objective radiological disease progression (by RECIST 1.1 and Prostate Cancer Working Group 3 (PGWG-3)) or death (by any cause in the absence of progression) regardless of whether the patient withdrew from randomised therapy or received another anti-cancer therapy prior to progression.
    End point type
    Secondary
    End point timeframe
    Tumor assessments every 8 weeks from randomisation until radiographic progression assessed by BICR (median duration of treatment of 7 and 4 months for Olaparib and Investigators Choice of NHA respectively).
    End point values
    		 Cohort A+B Olaparib 300mg bd Cohort A+B Investigators Choice of NHA
    Number of subjects analysed
    256
    131
    Units: Months
        median (confidence interval 95%)
    5.82 (5.52 to 7.36)
    3.52 (2.2 to 3.65)
    Statistical analysis title
    		 Secondary analysis
    Comparison groups
    Cohort A+B Investigators Choice of NHA v Cohort A+B Olaparib 300mg bd
    Number of subjects included in analysis
    387
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [6]
    P-value
    		 < 0.0001
    Method
    		 Logrank
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.49
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.38
         upper limit
    		 0.63
    Notes
    [6] - Cohort A+B

    Secondary: Overall Survival (OS) - Cohort A only

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    End point title
    		 Overall Survival (OS) - Cohort A only [7]
    End point description
    Number of Participants with Overall Survival (OS) - Cohort A only.
    End point type
    Secondary
    End point timeframe
    Approximately 35 months after the first patient was randomised.
    Notes
    [7] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: The study was designed to formally test these endpoints in only Cohort A patients, there is just 1 endpoint that is formally tested for both Cohort A and Cohort B which is rPFS. All other analyses are descriptive only
    End point values
    		 Cohort A Olaparib 300mg bd Cohort A Investigators choice of NHA
    Number of subjects analysed
    162
    83
    Units: Participants
        Died
    91
    57
        Alive at data cut-off
    49
    21
        Terminated prior to death (withdrawn consent)
    22
    5
    Statistical analysis title
    		 Secondary analysis
    Comparison groups
    Cohort A Olaparib 300mg bd v Cohort A Investigators choice of NHA
    Number of subjects included in analysis
    245
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [8]
    P-value
    		 = 0.0175
    Method
    		 Logrank
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.69
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.5
         upper limit
    		 0.97
    Notes
    [8] - Cohort A

    Secondary: Time to pain progression - Cohort A only

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    End point title
    		 Time to pain progression - Cohort A only [9]
    End point description
    Time from randomisation to time point at which worsening in pain is observed (ie date of pain progression - date of randomisation + 1). Based on average Brief Pain Inventory - short form (BPI-SF) worst pain [Item 3] and Analgesic Quantification Algorithm [AQA] score.
    End point type
    Secondary
    End point timeframe
    Every 4 weeks from randomisation (for 7 consecutive days) throughout the study (median duration of treatment of 7 and 4 months for Olaparib and Investigators Choice of NHA respectively).
    Notes
    [9] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: The study was designed to formally test these endpoints in only Cohort A patients, there is just 1 endpoint that is formally tested for both Cohort A and Cohort B which is rPFS. All other analyses are descriptive only
    End point values
    		 Cohort A Olaparib 300mg bd Cohort A Investigators choice of NHA
    Number of subjects analysed
    162
    83
    Units: Months
        median (confidence interval 95%)
    99999999 (-99999999 to 99999999)
    9.92 (5.39 to 99999999)
    Statistical analysis title
    		 Secondary analysis
    Comparison groups
    Cohort A Olaparib 300mg bd v Cohort A Investigators choice of NHA
    Number of subjects included in analysis
    245
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [10]
    P-value
    		 = 0.0192
    Method
    		 Logrank
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.44
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.22
         upper limit
    		 0.91
    Notes
    [10] - Cohort A

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    From the time of signature of informed consent throughout the treatment period (median duration of treatment of 7.5 and 3.9 months for Olaparib and Investigators Choice of NHA respectively) up to and including the 30-day follow-up period
    Adverse event reporting additional description
    131 subjects randomised to Investigators Choice of NHA (IC) group (Full Analysis Set), however 1 subject did not receive treatment (resulting in 130 in Safety Analysis Set). Hence for IC group, Total number at risk for all-cause mortality = 131, Total # at Risk by any Serious Adverse Event = 130 and Total # at Risk by any Other Adverse Event = 130
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    22.1
    Reporting groups
    Reporting group title
    Cohort A+B Investigators choice of NHA
    Reporting group description
    		 either enzalutamide capsules (160 mg od) or abiraterone acetate tablets (1,000 mg od with 5 mg bid prednisone)

    Reporting group title
    Cohort A+B Olaparib 300mg bd
    Reporting group description
    		 2x150mg film-coated tablets

    Serious adverse events
    		 Cohort A+B Investigators choice of NHA Cohort A+B Olaparib 300mg bd
    Total subjects affected by serious adverse events
         subjects affected / exposed
    39 / 130 (30.00%)
    94 / 256 (36.72%)
         number of deaths (all causes)
    88
    160
         number of deaths resulting from adverse events
    1
    1
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Transitional cell carcinoma
    alternative dictionary used: MedDRA 22.0
         subjects affected / exposed
    1 / 130 (0.77%)
    0 / 256 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Glioma
    alternative dictionary used: MedDRA 22.0
         subjects affected / exposed
    0 / 130 (0.00%)
    1 / 256 (0.39%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastric cancer
    alternative dictionary used: MedDRA 22.0
         subjects affected / exposed
    1 / 130 (0.77%)
    0 / 256 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vascular disorders
    Deep vein thrombosis
    alternative dictionary used: MedDRA 22.0
         subjects affected / exposed
    1 / 130 (0.77%)
    0 / 256 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Embolism
    alternative dictionary used: MedDRA 22.0
         subjects affected / exposed
    0 / 130 (0.00%)
    1 / 256 (0.39%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Orthostatic hypotension
    alternative dictionary used: MedDRA 22.0
         subjects affected / exposed
    0 / 130 (0.00%)
    1 / 256 (0.39%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Arterial thrombosis
    alternative dictionary used: MedDRA 22.0
         subjects affected / exposed
    1 / 130 (0.77%)
    0 / 256 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Phlebitis
    alternative dictionary used: MedDRA 22.0
         subjects affected / exposed
    0 / 130 (0.00%)
    1 / 256 (0.39%)
         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
    Asthenia
    alternative dictionary used: MedDRA 22.0
         subjects affected / exposed
    1 / 130 (0.77%)
    4 / 256 (1.56%)
         occurrences causally related to treatment / all
    1 / 1
    1 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Death
    alternative dictionary used: MedDRA 22.0
         subjects affected / exposed
    1 / 130 (0.77%)
    0 / 256 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Fatigue
    alternative dictionary used: MedDRA 22.0
         subjects affected / exposed
    0 / 130 (0.00%)
    2 / 256 (0.78%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Sudden death
    alternative dictionary used: MedDRA 22.0
         subjects affected / exposed
    0 / 130 (0.00%)
    1 / 256 (0.39%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Pyrexia
    alternative dictionary used: MedDRA 22.0
         subjects affected / exposed
    2 / 130 (1.54%)
    3 / 256 (1.17%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pain
    alternative dictionary used: MedDRA 22.0
         subjects affected / exposed
    0 / 130 (0.00%)
    1 / 256 (0.39%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    General physical health deterioration
    alternative dictionary used: MedDRA 22.0
         subjects affected / exposed
    1 / 130 (0.77%)
    0 / 256 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Pneumonia aspiration
    alternative dictionary used: MedDRA 22.0
         subjects affected / exposed
    0 / 130 (0.00%)
    3 / 256 (1.17%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pleural effusion
    alternative dictionary used: MedDRA 22.0
         subjects affected / exposed
    1 / 130 (0.77%)
    0 / 256 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    1 / 1
    0 / 0
    Interstitial lung disease
    alternative dictionary used: MedDRA 22.0
         subjects affected / exposed
    0 / 130 (0.00%)
    1 / 256 (0.39%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Dyspnoea
    alternative dictionary used: MedDRA 22.0
         subjects affected / exposed
    1 / 130 (0.77%)
    4 / 256 (1.56%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Chronic obstructive pulmonary disease
    alternative dictionary used: MedDRA 22.0
         subjects affected / exposed
    0 / 130 (0.00%)
    1 / 256 (0.39%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonitis
    alternative dictionary used: MedDRA 22.0
         subjects affected / exposed
    0 / 130 (0.00%)
    1 / 256 (0.39%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumothorax
    alternative dictionary used: MedDRA 22.0
         subjects affected / exposed
    0 / 130 (0.00%)
    2 / 256 (0.78%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory failure
    alternative dictionary used: MedDRA 22.0
         subjects affected / exposed
    0 / 130 (0.00%)
    1 / 256 (0.39%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pulmonary embolism
    alternative dictionary used: MedDRA 22.0
         subjects affected / exposed
    1 / 130 (0.77%)
    5 / 256 (1.95%)
         occurrences causally related to treatment / all
    0 / 1
    2 / 5
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Psychiatric disorders
    Delirium
    alternative dictionary used: MedDRA 22.0
         subjects affected / exposed
    1 / 130 (0.77%)
    1 / 256 (0.39%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Confusional state
    alternative dictionary used: MedDRA 22.0
         subjects affected / exposed
    0 / 130 (0.00%)
    1 / 256 (0.39%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Ankle fracture
    alternative dictionary used: MedDRA 22.0
         subjects affected / exposed
    0 / 130 (0.00%)
    1 / 256 (0.39%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Concussion
    alternative dictionary used: MedDRA 22.0
         subjects affected / exposed
    0 / 130 (0.00%)
    1 / 256 (0.39%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cystitis radiation
    alternative dictionary used: MedDRA 22.0
         subjects affected / exposed
    0 / 130 (0.00%)
    1 / 256 (0.39%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Fall
    alternative dictionary used: MedDRA 22.0
         subjects affected / exposed
    2 / 130 (1.54%)
    1 / 256 (0.39%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Femur fracture
    alternative dictionary used: MedDRA 22.0
         subjects affected / exposed
    0 / 130 (0.00%)
    3 / 256 (1.17%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Fracture
    alternative dictionary used: MedDRA 22.0
         subjects affected / exposed
    0 / 130 (0.00%)
    1 / 256 (0.39%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastroenteritis radiation
    alternative dictionary used: MedDRA 22.0
         subjects affected / exposed
    0 / 130 (0.00%)
    1 / 256 (0.39%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Post-traumatic pain
    alternative dictionary used: MedDRA 22.0
         subjects affected / exposed
    0 / 130 (0.00%)
    1 / 256 (0.39%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Spinal compression fracture
    alternative dictionary used: MedDRA 22.0
         subjects affected / exposed
    0 / 130 (0.00%)
    1 / 256 (0.39%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Spinal fracture
    alternative dictionary used: MedDRA 22.0
         subjects affected / exposed
    0 / 130 (0.00%)
    1 / 256 (0.39%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Subdural haematoma
    alternative dictionary used: MedDRA 22.0
         subjects affected / exposed
    1 / 130 (0.77%)
    0 / 256 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac disorders
    Acute coronary syndrome
    alternative dictionary used: MedDRA 22.0
         subjects affected / exposed
    0 / 130 (0.00%)
    1 / 256 (0.39%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Coronary ostial stenosis
    alternative dictionary used: MedDRA 22.0
         subjects affected / exposed
    0 / 130 (0.00%)
    1 / 256 (0.39%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Myocardial infarction
    alternative dictionary used: MedDRA 22.0
         subjects affected / exposed
    1 / 130 (0.77%)
    1 / 256 (0.39%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Right ventricular failure
    alternative dictionary used: MedDRA 22.0
         subjects affected / exposed
    0 / 130 (0.00%)
    1 / 256 (0.39%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiopulmonary failure
    alternative dictionary used: MedDRA 22.0
         subjects affected / exposed
    0 / 130 (0.00%)
    2 / 256 (0.78%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 2
    Cardiomyopathy
    alternative dictionary used: MedDRA 22.0
         subjects affected / exposed
    1 / 130 (0.77%)
    0 / 256 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac failure acute
    alternative dictionary used: MedDRA 22.0
         subjects affected / exposed
    0 / 130 (0.00%)
    1 / 256 (0.39%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Cardiac failure
    alternative dictionary used: MedDRA 22.0
         subjects affected / exposed
    1 / 130 (0.77%)
    0 / 256 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Atrial fibrillation
    alternative dictionary used: MedDRA 22.0
         subjects affected / exposed
    0 / 130 (0.00%)
    1 / 256 (0.39%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Angina pectoris
    alternative dictionary used: MedDRA 22.0
         subjects affected / exposed
    2 / 130 (1.54%)
    1 / 256 (0.39%)
         occurrences causally related to treatment / all
    0 / 2
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Coronary artery stenosis
         subjects affected / exposed
    1 / 130 (0.77%)
    0 / 256 (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
    Cerebrovascular accident
    alternative dictionary used: MedDRA 22.0
         subjects affected / exposed
    0 / 130 (0.00%)
    3 / 256 (1.17%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cerebral infarction
    alternative dictionary used: MedDRA 22.0
         subjects affected / exposed
    0 / 130 (0.00%)
    1 / 256 (0.39%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ballismus
    alternative dictionary used: MedDRA 22.0
         subjects affected / exposed
    1 / 130 (0.77%)
    0 / 256 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Neuralgia
    alternative dictionary used: MedDRA 22.0
         subjects affected / exposed
    0 / 130 (0.00%)
    1 / 256 (0.39%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ischaemic stroke
    alternative dictionary used: MedDRA 22.0
         subjects affected / exposed
    1 / 130 (0.77%)
    0 / 256 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Dizziness
    alternative dictionary used: MedDRA 22.0
         subjects affected / exposed
    0 / 130 (0.00%)
    1 / 256 (0.39%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Spinal cord compression
    alternative dictionary used: MedDRA 22.0
         subjects affected / exposed
    1 / 130 (0.77%)
    1 / 256 (0.39%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Syncope
         subjects affected / exposed
    0 / 130 (0.00%)
    1 / 256 (0.39%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    Pancytopenia
    alternative dictionary used: MedDRA 22.0
         subjects affected / exposed
    0 / 130 (0.00%)
    1 / 256 (0.39%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Thrombocytopenia
    alternative dictionary used: MedDRA 22.0
         subjects affected / exposed
    0 / 130 (0.00%)
    4 / 256 (1.56%)
         occurrences causally related to treatment / all
    0 / 0
    3 / 6
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Anaemia
    alternative dictionary used: MedDRA 22.0
         subjects affected / exposed
    0 / 130 (0.00%)
    23 / 256 (8.98%)
         occurrences causally related to treatment / all
    0 / 0
    18 / 24
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Febrile neutropenia
    alternative dictionary used: MedDRA 22.0
         subjects affected / exposed
    1 / 130 (0.77%)
    1 / 256 (0.39%)
         occurrences causally related to treatment / all
    0 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Neutropenia
    alternative dictionary used: MedDRA 22.0
         subjects affected / exposed
    0 / 130 (0.00%)
    3 / 256 (1.17%)
         occurrences causally related to treatment / all
    0 / 0
    3 / 3
         deaths causally related to treatment / all
    0 / 0
    1 / 1
    Eye disorders
    Diplopia
    alternative dictionary used: MedDRA 22.0
         subjects affected / exposed
    0 / 130 (0.00%)
    1 / 256 (0.39%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Abdominal pain
    alternative dictionary used: MedDRA 22.0
         subjects affected / exposed
    0 / 130 (0.00%)
    1 / 256 (0.39%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Obstructive pancreatitis
    alternative dictionary used: MedDRA 22.0
         subjects affected / exposed
    0 / 130 (0.00%)
    1 / 256 (0.39%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Obstruction gastric
    alternative dictionary used: MedDRA 22.0
         subjects affected / exposed
    0 / 130 (0.00%)
    1 / 256 (0.39%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nausea
    alternative dictionary used: MedDRA 22.0
         subjects affected / exposed
    2 / 130 (1.54%)
    2 / 256 (0.78%)
         occurrences causally related to treatment / all
    1 / 2
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Inguinal hernia
    alternative dictionary used: MedDRA 22.0
         subjects affected / exposed
    1 / 130 (0.77%)
    0 / 256 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastric ulcer haemorrhage
    alternative dictionary used: MedDRA 22.0
         subjects affected / exposed
    1 / 130 (0.77%)
    0 / 256 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastric ulcer
    alternative dictionary used: MedDRA 22.0
         subjects affected / exposed
    0 / 130 (0.00%)
    1 / 256 (0.39%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Diverticulum intestinal
    alternative dictionary used: MedDRA 22.0
         subjects affected / exposed
    0 / 130 (0.00%)
    1 / 256 (0.39%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Diarrhoea
    alternative dictionary used: MedDRA 22.0
         subjects affected / exposed
    0 / 130 (0.00%)
    1 / 256 (0.39%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Small intestinal obstruction
    alternative dictionary used: MedDRA 22.0
         subjects affected / exposed
    1 / 130 (0.77%)
    0 / 256 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vomiting
    alternative dictionary used: MedDRA 22.0
         subjects affected / exposed
    1 / 130 (0.77%)
    4 / 256 (1.56%)
         occurrences causally related to treatment / all
    0 / 1
    3 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Stress ulcer
    alternative dictionary used: MedDRA 22.0
         subjects affected / exposed
    0 / 130 (0.00%)
    1 / 256 (0.39%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Duodenal ulcer perforation
         subjects affected / exposed
    1 / 130 (0.77%)
    0 / 256 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Hepatobiliary disorders
    Cholecystitis acute
    alternative dictionary used: MedDRA 22.0
         subjects affected / exposed
    0 / 130 (0.00%)
    1 / 256 (0.39%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cholangitis
    alternative dictionary used: MedDRA 22.0
         subjects affected / exposed
    0 / 130 (0.00%)
    1 / 256 (0.39%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Budd-Chiari syndrome
    alternative dictionary used: MedDRA 22.0
         subjects affected / exposed
    0 / 130 (0.00%)
    1 / 256 (0.39%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Skin and subcutaneous tissue disorders
    Drug eruption
    alternative dictionary used: MedDRA 22.0
         subjects affected / exposed
    1 / 130 (0.77%)
    0 / 256 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Skin ulcer
         subjects affected / exposed
    0 / 130 (0.00%)
    1 / 256 (0.39%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal and urinary disorders
    Acute kidney injury
    alternative dictionary used: MedDRA 22.0
         subjects affected / exposed
    2 / 130 (1.54%)
    1 / 256 (0.39%)
         occurrences causally related to treatment / all
    0 / 2
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Chronic kidney disease
    alternative dictionary used: MedDRA 22.0
         subjects affected / exposed
    1 / 130 (0.77%)
    0 / 256 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Calculus bladder
    alternative dictionary used: MedDRA 22.0
         subjects affected / exposed
    0 / 130 (0.00%)
    1 / 256 (0.39%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hydronephrosis
    alternative dictionary used: MedDRA 22.0
         subjects affected / exposed
    1 / 130 (0.77%)
    1 / 256 (0.39%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Haematuria
    alternative dictionary used: MedDRA 22.0
         subjects affected / exposed
    1 / 130 (0.77%)
    3 / 256 (1.17%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nephrolithiasis
    alternative dictionary used: MedDRA 22.0
         subjects affected / exposed
    1 / 130 (0.77%)
    0 / 256 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Urinary tract obstruction
    alternative dictionary used: MedDRA 22.0
         subjects affected / exposed
    2 / 130 (1.54%)
    0 / 256 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Urinary retention
    alternative dictionary used: MedDRA 22.0
         subjects affected / exposed
    0 / 130 (0.00%)
    2 / 256 (0.78%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Renal impairment
    alternative dictionary used: MedDRA 22.0
         subjects affected / exposed
    0 / 130 (0.00%)
    1 / 256 (0.39%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal failure
    alternative dictionary used: MedDRA 22.0
         subjects affected / exposed
    0 / 130 (0.00%)
    1 / 256 (0.39%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Endocrine disorders
    Adrenal insufficiency
    alternative dictionary used: MedDRA 22.0
         subjects affected / exposed
    0 / 130 (0.00%)
    1 / 256 (0.39%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Back pain
    alternative dictionary used: MedDRA 22.0
         subjects affected / exposed
    1 / 130 (0.77%)
    1 / 256 (0.39%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Arthralgia
    alternative dictionary used: MedDRA 22.0
         subjects affected / exposed
    0 / 130 (0.00%)
    1 / 256 (0.39%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Musculoskeletal pain
    alternative dictionary used: MedDRA 22.0
         subjects affected / exposed
    0 / 130 (0.00%)
    1 / 256 (0.39%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Musculoskeletal chest pain
    alternative dictionary used: MedDRA 22.0
         subjects affected / exposed
    0 / 130 (0.00%)
    2 / 256 (0.78%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Muscular weakness
    alternative dictionary used: MedDRA 22.0
         subjects affected / exposed
    0 / 130 (0.00%)
    2 / 256 (0.78%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bone pain
    alternative dictionary used: MedDRA 22.0
         subjects affected / exposed
    0 / 130 (0.00%)
    2 / 256 (0.78%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Spinal stenosis
    alternative dictionary used: MedDRA 22.0
         subjects affected / exposed
    0 / 130 (0.00%)
    1 / 256 (0.39%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Infections and infestations
    Cystitis
    alternative dictionary used: MedDRA 22.0
         subjects affected / exposed
    1 / 130 (0.77%)
    0 / 256 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cellulitis of male external genital organ
    alternative dictionary used: MedDRA 22.0
         subjects affected / exposed
    0 / 130 (0.00%)
    1 / 256 (0.39%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Anal abscess
    alternative dictionary used: MedDRA 22.0
         subjects affected / exposed
    1 / 130 (0.77%)
    0 / 256 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastroenteritis
    alternative dictionary used: MedDRA 22.0
         subjects affected / exposed
    1 / 130 (0.77%)
    0 / 256 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Urosepsis
    alternative dictionary used: MedDRA 22.0
         subjects affected / exposed
    1 / 130 (0.77%)
    0 / 256 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Urinary tract infection
    alternative dictionary used: MedDRA 22.0
         subjects affected / exposed
    4 / 130 (3.08%)
    5 / 256 (1.95%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 5
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Sepsis
    alternative dictionary used: MedDRA 22.0
         subjects affected / exposed
    3 / 130 (2.31%)
    3 / 256 (1.17%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pyelonephritis
    alternative dictionary used: MedDRA 22.0
         subjects affected / exposed
    0 / 130 (0.00%)
    1 / 256 (0.39%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonia
    alternative dictionary used: MedDRA 22.0
         subjects affected / exposed
    4 / 130 (3.08%)
    11 / 256 (4.30%)
         occurrences causally related to treatment / all
    0 / 4
    2 / 13
         deaths causally related to treatment / all
    0 / 3
    1 / 3
    Pharyngitis
    alternative dictionary used: MedDRA 22.0
         subjects affected / exposed
    0 / 130 (0.00%)
    1 / 256 (0.39%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infection
    alternative dictionary used: MedDRA 22.0
         subjects affected / exposed
    1 / 130 (0.77%)
    0 / 256 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Septic shock
    alternative dictionary used: MedDRA 22.0
         subjects affected / exposed
    0 / 130 (0.00%)
    1 / 256 (0.39%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Pneumocystis jirovecii pneumoni
         subjects affected / exposed
    0 / 130 (0.00%)
    1 / 256 (0.39%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nasopharyngitis
    alternative dictionary used: MedDRA 22.0
         subjects affected / exposed
    0 / 130 (0.00%)
    1 / 256 (0.39%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Decreased appetite
    alternative dictionary used: MedDRA 22.0
         subjects affected / exposed
    0 / 130 (0.00%)
    2 / 256 (0.78%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Dehydration
    alternative dictionary used: MedDRA 22.0
         subjects affected / exposed
    3 / 130 (2.31%)
    0 / 256 (0.00%)
         occurrences causally related to treatment / all
    1 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypocalcaemia
    alternative dictionary used: MedDRA 22.0
         subjects affected / exposed
    0 / 130 (0.00%)
    1 / 256 (0.39%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypoglycaemia
    alternative dictionary used: MedDRA 22.0
         subjects affected / exposed
    0 / 130 (0.00%)
    1 / 256 (0.39%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hyponatraemia
    alternative dictionary used: MedDRA 22.0
         subjects affected / exposed
    0 / 130 (0.00%)
    2 / 256 (0.78%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Cohort A+B Investigators choice of NHA Cohort A+B Olaparib 300mg bd
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    112 / 130 (86.15%)
    241 / 256 (94.14%)
    Investigations
    Weight decreased
    alternative dictionary used: MedDRA 22.0
         subjects affected / exposed
    7 / 130 (5.38%)
    21 / 256 (8.20%)
         occurrences all number
    7
    21
    Nervous system disorders
    Headache
    alternative dictionary used: MedDRA 22.0
         subjects affected / exposed
    3 / 130 (2.31%)
    16 / 256 (6.25%)
         occurrences all number
    3
    29
    Dysgeusia
    alternative dictionary used: MedDRA 22.0
         subjects affected / exposed
    2 / 130 (1.54%)
    18 / 256 (7.03%)
         occurrences all number
    2
    20
    Dizziness
    alternative dictionary used: MedDRA 22.0
         subjects affected / exposed
    5 / 130 (3.85%)
    17 / 256 (6.64%)
         occurrences all number
    5
    18
    Blood and lymphatic system disorders
    Anaemia
    alternative dictionary used: MedDRA 22.0
         subjects affected / exposed
    20 / 130 (15.38%)
    110 / 256 (42.97%)
         occurrences all number
    23
    154
    Neutropenia
    alternative dictionary used: MedDRA 22.0
         subjects affected / exposed
    0 / 130 (0.00%)
    13 / 256 (5.08%)
         occurrences all number
    0
    16
    Lymphopenia
    alternative dictionary used: MedDRA 22.0
         subjects affected / exposed
    1 / 130 (0.77%)
    13 / 256 (5.08%)
         occurrences all number
    1
    15
    Thrombocytopenia
    alternative dictionary used: MedDRA 22.0
         subjects affected / exposed
    2 / 130 (1.54%)
    18 / 256 (7.03%)
         occurrences all number
    2
    22
    General disorders and administration site conditions
    Oedema peripheral
    alternative dictionary used: MedDRA 22.0
         subjects affected / exposed
    10 / 130 (7.69%)
    34 / 256 (13.28%)
         occurrences all number
    10
    36
    Pyrexia
    alternative dictionary used: MedDRA 22.0
         subjects affected / exposed
    4 / 130 (3.08%)
    15 / 256 (5.86%)
         occurrences all number
    4
    16
    Fatigue
    alternative dictionary used: MedDRA 22.0
         subjects affected / exposed
    28 / 130 (21.54%)
    68 / 256 (26.56%)
         occurrences all number
    28
    71
    Asthenia
    alternative dictionary used: MedDRA 22.0
         subjects affected / exposed
    18 / 130 (13.85%)
    37 / 256 (14.45%)
         occurrences all number
    19
    54
    Gastrointestinal disorders
    Constipation
    alternative dictionary used: MedDRA 22.0
         subjects affected / exposed
    19 / 130 (14.62%)
    49 / 256 (19.14%)
         occurrences all number
    21
    52
    Dyspepsia
    alternative dictionary used: MedDRA 22.0
         subjects affected / exposed
    3 / 130 (2.31%)
    20 / 256 (7.81%)
         occurrences all number
    3
    23
    Diarrhoea
    alternative dictionary used: MedDRA 22.0
         subjects affected / exposed
    9 / 130 (6.92%)
    54 / 256 (21.09%)
         occurrences all number
    9
    71
    Vomiting
    alternative dictionary used: MedDRA 22.0
         subjects affected / exposed
    17 / 130 (13.08%)
    49 / 256 (19.14%)
         occurrences all number
    19
    82
    Nausea
    alternative dictionary used: MedDRA 22.0
         subjects affected / exposed
    26 / 130 (20.00%)
    109 / 256 (42.58%)
         occurrences all number
    28
    136
    Stomatitis
         subjects affected / exposed
    2 / 130 (1.54%)
    13 / 256 (5.08%)
         occurrences all number
    2
    14
    Respiratory, thoracic and mediastinal disorders
    Cough
    alternative dictionary used: MedDRA 22.0
         subjects affected / exposed
    3 / 130 (2.31%)
    29 / 256 (11.33%)
         occurrences all number
    3
    32
    Dyspnoea
    alternative dictionary used: MedDRA 22.0
         subjects affected / exposed
    4 / 130 (3.08%)
    24 / 256 (9.38%)
         occurrences all number
    4
    25
    Psychiatric disorders
    Insomnia
    alternative dictionary used: MedDRA 22.0
         subjects affected / exposed
    4 / 130 (3.08%)
    14 / 256 (5.47%)
         occurrences all number
    4
    14
    Renal and urinary disorders
    Haematuria
    alternative dictionary used: MedDRA 22.0
         subjects affected / exposed
    10 / 130 (7.69%)
    6 / 256 (2.34%)
         occurrences all number
    11
    7
    Musculoskeletal and connective tissue disorders
    Arthralgia
    alternative dictionary used: MedDRA 22.0
         subjects affected / exposed
    14 / 130 (10.77%)
    25 / 256 (9.77%)
         occurrences all number
    16
    26
    Back pain
    alternative dictionary used: MedDRA 22.0
         subjects affected / exposed
    17 / 130 (13.08%)
    36 / 256 (14.06%)
         occurrences all number
    18
    44
    Musculoskeletal pain
    alternative dictionary used: MedDRA 22.0
         subjects affected / exposed
    6 / 130 (4.62%)
    17 / 256 (6.64%)
         occurrences all number
    6
    18
    Musculoskeletal chest pain
    alternative dictionary used: MedDRA 22.0
         subjects affected / exposed
    6 / 130 (4.62%)
    14 / 256 (5.47%)
         occurrences all number
    7
    14
    Pain in extremity
         subjects affected / exposed
    6 / 130 (4.62%)
    14 / 256 (5.47%)
         occurrences all number
    6
    18
    Infections and infestations
    Urinary tract infection
    alternative dictionary used: MedDRA 22.0
         subjects affected / exposed
    12 / 130 (9.23%)
    18 / 256 (7.03%)
         occurrences all number
    15
    22
    Metabolism and nutrition disorders
    Decreased appetite
    alternative dictionary used: MedDRA 22.0
         subjects affected / exposed
    24 / 130 (18.46%)
    78 / 256 (30.47%)
         occurrences all number
    25
    88

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    09 Mar 2017
    Version 2.0: Administration of other anti-cancer agents: remove following text “corticosteroids for the symptomatic control of brain metastases” because subjects with known brain metastases are excluded from the study
    04 Jun 2018
    Version 3.0: Abiraterone acetate 500mg tablets added to treatment regimens

    Interruptions (globally)
    Were there any global interruptions to the trial? No

    Limitations and caveats
    Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.
    None reported
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    The status and protocol content of GB trials is no longer updated since 1 January 2021. For the UK, as of 31 January 2021, EU Law applies only to the territory of Northern Ireland (NI) to the extent foreseen in the Protocol on Ireland/NI. Legal notice
    As of 31 January 2023, all EU/EEA initial clinical trial applications must be submitted through CTIS . Updated EudraCT trials information and information on PIP/Art 46 trials conducted exclusively in third countries continues to be submitted through EudraCT and published on this website.

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