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    Clinical Trial Results:
    A Phase III, Randomized, Double-Blind, Placebo-Controlled, Multicenter Trial Testing Ipatasertib Plus Abiraterone Plus Prednisone/Prednisolone, Relative to Placebo Plus Abiraterone Plus Prednisone/Prednisolone in Adult Male Patients with Asymptomatic or Mildly Symptomatic, Previously Untreated, Metastatic Castrate-Resistant Prostate Cancer

    Summary
    EudraCT number
    		 2016-004429-17
    Trial protocol
    		 NO   PT   DE   DK   HU   GB   AT   IE   BE   ES   GR   PL   FR   IT  
    Global end of trial date

    Results information
    Results version number
    		 v1
    This version publication date
    31 Mar 2023
    First version publication date
    31 Mar 2023
    Other versions
    		 v2

    Trial information

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    Trial identification
    Sponsor protocol code
    CO39303
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT03072238
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    F. Hoffmann-La Roche AG
    Sponsor organisation address
    Grenzacherstrasse 124, Basel, Switzerland, CH4070
    Public contact
    F. Hoffmann-La Roche AG, F. Hoffmann-La Roche AG, +41 616878333, global.trial_information@roche.com
    Scientific contact
    F. Hoffmann-La Roche AG, F. Hoffmann-La Roche AG, +41 616878333, global.trial_information@roche.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
    Interim
    Date of interim/final analysis
    16 Mar 2020
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    16 Mar 2020
    Global end of trial reached?
    No
    General information about the trial
    Main objective of the trial
    To evaluate the efficacy, safety, and pharmacokinetics of ipatasertib plus abiraterone and prednisone/prednisolone compared with placebo plus abiraterone and prednisone/prednisolone in subjects with metastatic castrate-resistant prostate cancer (mCRPC).
    Protection of trial subjects
    All study subjects were required to read and sign an Informed Consent Form.
    Background therapy
    		 All subjects who did not undergo orchiectomy were on Gonadotropin-releasing hormone (GnRH) agonists or antagonists. All subjects on the study were on prednisone/prednisolone 5mg BID concomitantly with the study medication.
    Evidence for comparator
    		 -
    Actual start date of recruitment
    30 Jun 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
    Australia: 67
    Country: Number of subjects enrolled
    Austria: 10
    Country: Number of subjects enrolled
    Belgium: 15
    Country: Number of subjects enrolled
    Brazil: 47
    Country: Number of subjects enrolled
    Canada: 37
    Country: Number of subjects enrolled
    China: 18
    Country: Number of subjects enrolled
    Costa Rica: 25
    Country: Number of subjects enrolled
    Denmark: 24
    Country: Number of subjects enrolled
    Spain: 106
    Country: Number of subjects enrolled
    France: 40
    Country: Number of subjects enrolled
    United Kingdom: 40
    Country: Number of subjects enrolled
    Greece: 31
    Country: Number of subjects enrolled
    Hungary: 44
    Country: Number of subjects enrolled
    Ireland: 12
    Country: Number of subjects enrolled
    Israel: 20
    Country: Number of subjects enrolled
    Italy: 60
    Country: Number of subjects enrolled
    Japan: 76
    Country: Number of subjects enrolled
    Korea, Republic of: 68
    Country: Number of subjects enrolled
    Mexico: 47
    Country: Number of subjects enrolled
    Norway: 11
    Country: Number of subjects enrolled
    Poland: 26
    Country: Number of subjects enrolled
    Portugal: 16
    Country: Number of subjects enrolled
    Russian Federation: 106
    Country: Number of subjects enrolled
    Thailand: 27
    Country: Number of subjects enrolled
    Taiwan: 21
    Country: Number of subjects enrolled
    United States: 107
    Worldwide total number of subjects
    1101
    EEA total number of subjects
    395
    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)
    287
    From 65 to 84 years
    786
    85 years and over
    28

    Subject disposition

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    Recruitment
    Recruitment details
    		 The study was conducted at 181 centers in 26 countries.

    Pre-assignment
    Screening details
    		 A total of 1611 subjects were screened, out of which 510 subjects failed screening. A total of 1101 subjects were enrolled at 181 sites.

    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

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Placebo + Abiraterone
    Arm description
    		 Subjects received Placebo plus Abiraterone (along with Prednisone/Prednisolone), administered orally in 28-day cycles.
    Arm type
    		 Active comparator

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Placebo was administered orally once daily (QD).

    Investigational medicinal product name
    Prednisone/Prednisolone
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Prednisone/Prednisolone was administered orally twice daily (BID) at a dose of 5mg.

    Investigational medicinal product name
    Abiraterone
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Abiraterone was administered orally once daily (QD) at a dose of 1000mg.

    Arm title
    		 Ipatasertib + Abiraterone
    Arm description
    		 Subjects received Ipatasertib plus Abiraterone (along with Prednisone/Prednisolone), administered orally in 28-day cycles.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Ipatasertib
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Ipatasertib was administered orally once daily (QD) at a dose of 400mg.

    Investigational medicinal product name
    Prednisone/Prednisolone
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Prednisone/Prednisolone was administered orally twice daily (BID) at a dose of 5mg.

    Investigational medicinal product name
    Abiraterone
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Abiraterone was administered orally once daily (QD) at a dose of 1000mg.

    Number of subjects in period 1
    		Placebo + Abiraterone Ipatasertib + Abiraterone
    Started
    554
    547
    Completed
    0
    0
    Not completed
    554
    547
         Ongoing on study
    377
    367
         Consent withdrawn by subject
    30
    51
         Physician decision
    1
    3
         Death
    139
    121
         Not specified
    -
    1
         Lost to follow-up
    7
    4

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Placebo + Abiraterone
    Reporting group description
    		 Subjects received Placebo plus Abiraterone (along with Prednisone/Prednisolone), administered orally in 28-day cycles.

    Reporting group title
    Ipatasertib + Abiraterone
    Reporting group description
    		 Subjects received Ipatasertib plus Abiraterone (along with Prednisone/Prednisolone), administered orally in 28-day cycles.

    Reporting group values
    		 Placebo + Abiraterone Ipatasertib + Abiraterone Total
    Number of subjects
    		 554 547 1101
    Age categorical
    Units: Subjects
        In utero
    		 0 0 0
        Preterm newborn infants (gestational age < 37 wks)
    		 0 0 0
        Newborns (0-27 days)
    		 0 0 0
        Infants and toddlers (28 days-23 months)
    		 0 0 0
        Children (2-11 years)
    		 0 0 0
        Adolescents (12-17 years)
    		 0 0 0
        Adults (18-64 years)
    		 141 146 287
        From 65-84 years
    		 400 386 786
        85 years and over
    		 13 15 28
    Age Continuous
    Units: years
        arithmetic mean (standard deviation)
    		 69.7 ( 8.2 ) 69.4 ( 8.0 ) -
    Sex: Female, Male
    Units:
        Female
    		 0 0 0
        Male
    		 554 547 1101
    Race/Ethnicity, Customized
    Ethnicity
    Units: Subjects
        Hispanic or Latino
    		 65 66 131
        Not Hispanic or Latino
    		 469 452 921
        Not Stated
    		 20 29 49
    Race/Ethnicity, Customized
    Race
    Units: Subjects
        American Indian or Alaska Native
    		 16 15 31
        Asian
    		 109 110 219
        Black or African American
    		 9 10 19
        Native Hawaiian or other Pacific Islander
    		 1 1 2
        White
    		 386 376 762
        Unknown
    		 33 35 68

    End points

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    End points reporting groups
    Reporting group title
    Placebo + Abiraterone
    Reporting group description
    		 Subjects received Placebo plus Abiraterone (along with Prednisone/Prednisolone), administered orally in 28-day cycles.

    Reporting group title
    Ipatasertib + Abiraterone
    Reporting group description
    		 Subjects received Ipatasertib plus Abiraterone (along with Prednisone/Prednisolone), administered orally in 28-day cycles.

    Primary: Investigator-Assessed Radiographic Progression-Free Survival (rPFS) per PCWG3 criteria (PTEN Loss Population)

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    End point title
    		 Investigator-Assessed Radiographic Progression-Free Survival (rPFS) per PCWG3 criteria (PTEN Loss Population)
    End point description
    Radiographic progression-free survival is defined as time from date of randomization to the first occurrence of documented disease progression, as assessed by the investigator with use of the Prostate Cancer Working Group 3 (PCWG3) criteria or death from any cause, whichever occurs first. Disease progression for soft tissue is defined as at least a 20% increase in the sum of diameters of target lesions, taking as reference the smallest sum on study, including baseline, and an absolute increase of at least 5 mm in the sum of diameters of target lesions; progression of non target lesions; the appearance of one or more new lesions. Disease progression for bone lesions is defined as 2 or more new lesions compared to baseline followed by a confirmatory bone scan at least 6 weeks later. rPFS will be analyzed in subjects with phosphatase and tensin homolog (PTEN) - loss tumors (using the Ventana PTEN immunohistochemistry (IHC) assay).
    End point type
    Primary
    End point timeframe
    Up to approximately 31 months
    End point values
    		 Placebo + Abiraterone Ipatasertib + Abiraterone
    Number of subjects analysed
    261
    260
    Units: Months
        median (confidence interval 95%)
    16.5 (13.9 to 17.0)
    18.5 (16.3 to 22.1)
    Statistical analysis title
    		 (Ipat + Abir) vs (Plac + Abir)
    Comparison groups
    Placebo + Abiraterone v Ipatasertib + Abiraterone
    Number of subjects included in analysis
    521
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    		 = 0.0335
    Method
    		 Logrank
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.77
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.61
         upper limit
    		 0.98

    Primary: Investigator-Assessed Radiographic Progression-Free Survival (rPFS) per PCWG3 criteria (Intent-To-Treat (ITT) Population)

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    End point title
    		 Investigator-Assessed Radiographic Progression-Free Survival (rPFS) per PCWG3 criteria (Intent-To-Treat (ITT) Population)
    End point description
    Radiographic progression-free survival is defined as time from date of randomization to the first occurrence of documented disease progression, as assessed by the investigator with use of the Prostate Cancer Working Group 3 (PCWG3) criteria or death from any cause, whichever occurs first. Disease progression for soft tissue is defined as at least a 20% increase in the sum of diameters of target lesions, taking as reference the smallest sum on study, including baseline, and an absolute increase of at least 5 mm in the sum of diameters of target lesions; progression of non target lesions; the appearance of one or more new lesions. Disease progression for bone lesions is defined as 2 or more new lesions compared to baseline followed by a confirmatory bone scan at least 6 weeks later. rPFS will be analyzed in the Intent-to-Treat (ITT) population.
    End point type
    Primary
    End point timeframe
    Up to approximately 31 months
    End point values
    		 Placebo + Abiraterone Ipatasertib + Abiraterone
    Number of subjects analysed
    554
    547
    Units: Months
        median (confidence interval 95%)
    16.6 (15.6 to 19.1)
    19.2 (16.5 to 22.3)
    Statistical analysis title
    		 (Ipat + Abir) vs (Plac + Abir)
    Comparison groups
    Placebo + Abiraterone v Ipatasertib + Abiraterone
    Number of subjects included in analysis
    1101
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    		 = 0.0431
    Method
    		 Logrank
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.84
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.71
         upper limit
    		 0.99

    Secondary: Overall Survival

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    End point title
    		 Overall Survival
    End point description
    Overall Survival (OS) is defined as the time from randomization to death due to any cause. Data collection is still ongoing and the results will be disclosed within 1 year from the Study Completion Date.
    End point type
    Secondary
    End point timeframe
    Up to approximately 7 years
    End point values
    		 Placebo + Abiraterone Ipatasertib + Abiraterone
    Number of subjects analysed
    0 [1]
    0 [2]
    Units: Months
        median (confidence interval 95%)
    ( to )
    ( to )
    Notes
    [1] - Data collection is ongoing and results will be disclosed within 1 year from Study Completion Date.
    [2] - Data collection is ongoing and results will be disclosed within 1 year from Study Completion Date.
    No statistical analyses for this end point

    Secondary: Time to Function Deterioration

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    End point title
    		 Time to Function Deterioration
    End point description
    Time to function deterioration was defined as the time from the date of randomisation to the date of 10-point or more decrease on either the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire Core 30 (EORTC QLQ-C30) PF (Physical Functioning) or RF (Role Functioning) scale scores (range, 0-100) held for two consecutive assessments, or a 10 point or more score decrease followed by death (any cause) within 28 days, whichever occurs first. Data collection is still ongoing and the results will be disclosed within 1 year from the Study Completion Date.
    End point type
    Secondary
    End point timeframe
    Up to approximately 7 years
    End point values
    		 Placebo + Abiraterone Ipatasertib + Abiraterone
    Number of subjects analysed
    0 [3]
    0 [4]
    Units: Months
        median (confidence interval 95%)
    ( to )
    ( to )
    Notes
    [3] - Data collection is ongoing and results will be disclosed within 1 year from Study Completion Date.
    [4] - Data collection is ongoing and results will be disclosed within 1 year from Study Completion Date.
    No statistical analyses for this end point

    Secondary: Time to Prostate-Specific Antigen (PSA) Progression

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    End point title
    		 Time to Prostate-Specific Antigen (PSA) Progression
    End point description
    Time to PSA progression is defined as the time from the date of randomization to the first occurrence of PSA progression, per the PCWG3 criteria. PSA progression is defined as a PSA increase that is ≥ 25% and ≥ 2 ng/mL above the baseline or the nadir, which is confirmed by a second value ≥ 3 weeks later. Data collection is still ongoing and the results will be disclosed within 1 year from the Study Completion Date.
    End point type
    Secondary
    End point timeframe
    Up to approximately 7 years
    End point values
    		 Placebo + Abiraterone Ipatasertib + Abiraterone
    Number of subjects analysed
    0 [5]
    0 [6]
    Units: Months
        median (confidence interval 95%)
    ( to )
    ( to )
    Notes
    [5] - Data collection is ongoing and results will be disclosed within 1 year from Study Completion Date.
    [6] - Data collection is ongoing and results will be disclosed within 1 year from Study Completion Date.
    No statistical analyses for this end point

    Secondary: Time to Initiation of Cytotoxic Chemotherapy

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    End point title
    		 Time to Initiation of Cytotoxic Chemotherapy
    End point description
    Time to initiation of cytotoxic chemotherapy is defined as the time interval from the date of randomization to the date of initiation of cytotoxic chemotherapy (use of antineoplastic agents: docetaxel, cabazitaxel, mitoxantrone, estramustine, cisplatin, carboplatin, cyclophosphamide, doxorubicin, mitomycin, irinotecan, 5-fluorouracil, gemcitabine, or etoposide) for prostate cancer. Data collection is still ongoing and the results will be disclosed within 1 year from the Study Completion Date.
    End point type
    Secondary
    End point timeframe
    Up to approximately 7 years
    End point values
    		 Placebo + Abiraterone Ipatasertib + Abiraterone
    Number of subjects analysed
    0 [7]
    0 [8]
    Units: Months
        median (confidence interval 95%)
    ( to )
    ( to )
    Notes
    [7] - Data collection is ongoing and results will be disclosed within 1 year from Study Completion Date.
    [8] - Data collection is ongoing and results will be disclosed within 1 year from Study Completion Date.
    No statistical analyses for this end point

    Secondary: Time to Pain Progression

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    End point title
    		 Time to Pain Progression
    End point description
    Time to pain progression was defined as the time from randomization to the first occurrence of confirmed clinically meaningful cancer-related pain progression event. Cancer-related pain progression refers to pain onset for subjects who are asymptomatic at baseline or pain worsening for those who are mildly symptomatic at baseline. Pain severity will be graded on a 10-point scale, with 0=no pain and 10=severe pain. Pain severity progression is defined as a ≥ 2-point absolute increase from baseline. Data collection is still ongoing and the results will be disclosed within 1 year from the Study Completion Date.
    End point type
    Secondary
    End point timeframe
    Up to approximately 7 years
    End point values
    		 Placebo + Abiraterone Ipatasertib + Abiraterone
    Number of subjects analysed
    0 [9]
    0 [10]
    Units: Months
        median (confidence interval 95%)
    ( to )
    ( to )
    Notes
    [9] - Data collection is ongoing and results will be disclosed within 1 year from Study Completion Date.
    [10] - Data collection is ongoing and results will be disclosed within 1 year from Study Completion Date.
    No statistical analyses for this end point

    Secondary: Investigator-Assessed rPFS per PCWG3 criteria in Subjects With PTEN-Loss Tumors by Next-Generation Sequencing (NGS)

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    End point title
    		 Investigator-Assessed rPFS per PCWG3 criteria in Subjects With PTEN-Loss Tumors by Next-Generation Sequencing (NGS)
    End point description
    Investigator-assessed rPFS is defined as time from date of randomization to the first occurrence of documented disease progression, as assessed by the investigator with use of the Prostate Cancer Working Group 3 (PCWG3) criteria or death from any cause, whichever occurs first and will be analyzed in subjects with PTEN-loss tumors by NGS. Data collection is still ongoing and the results will be disclosed within 1 year from the Study Completion Date.
    End point type
    Secondary
    End point timeframe
    Up to approximately 7 years
    End point values
    		 Placebo + Abiraterone Ipatasertib + Abiraterone
    Number of subjects analysed
    0 [11]
    0 [12]
    Units: Months
        median (confidence interval 95%)
    ( to )
    ( to )
    Notes
    [11] - Data collection is ongoing and results will be disclosed within 1 year from Study Completion Date.
    [12] - Data collection is ongoing and results will be disclosed within 1 year from Study Completion Date.
    No statistical analyses for this end point

    Secondary: Objective Response Rate (ORR)

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    End point title
    		 Objective Response Rate (ORR)
    End point description
    An objective response is defined as a complete response (CR) or partial response (PR) on two consecutive occasions >=4 weeks apart, as determined by the investigator using RECIST v1.1 and PCWG3 criteria, in subjects with measurable disease at baseline. Subjects without a post-baseline tumor assessment will be considered non-responders. Data collection is still ongoing and the results will be disclosed within 1 year from the Study Completion Date.
    End point type
    Secondary
    End point timeframe
    Up to approximately 7 years
    End point values
    		 Placebo + Abiraterone Ipatasertib + Abiraterone
    Number of subjects analysed
    0 [13]
    0 [14]
    Units: Percentage of Participants
        number (confidence interval 95%)
    ( to )
    ( to )
    Notes
    [13] - Data collection is ongoing and results will be disclosed within 1 year from Study Completion Date.
    [14] - Data collection is ongoing and results will be disclosed within 1 year from Study Completion Date.
    No statistical analyses for this end point

    Secondary: PSA Response Rate

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    End point title
    		 PSA Response Rate
    End point description
    PSA response rate is defined as the percentage of participants achieving a PSA decline ≥50% from baseline. Participants without a post-baseline PSA assessment will be considered non-responders. Data collection is still ongoing and the results will be disclosed within 1 year from the Study Completion Date.
    End point type
    Secondary
    End point timeframe
    Up to approximately 7 years
    End point values
    		 Placebo + Abiraterone Ipatasertib + Abiraterone
    Number of subjects analysed
    0 [15]
    0 [16]
    Units: Percentage of Participants
        number (confidence interval 95%)
    ( to )
    ( to )
    Notes
    [15] - Data collection is ongoing and results will be disclosed within 1 year from Study Completion Date.
    [16] - Data collection is ongoing and results will be disclosed within 1 year from Study Completion Date.
    No statistical analyses for this end point

    Secondary: Time to Symptomatic Skeletal Event (SSE)

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    End point title
    		 Time to Symptomatic Skeletal Event (SSE)
    End point description
    Time to SSE is defined as the time interval from the date of randomization to the date of an SSE. Data collection is still ongoing and the results will be disclosed within 1 year from the Study Completion Date.
    End point type
    Secondary
    End point timeframe
    Up to approximately 7 years
    End point values
    		 Placebo + Abiraterone Ipatasertib + Abiraterone
    Number of subjects analysed
    0 [17]
    0 [18]
    Units: Months
        median (confidence interval 95%)
    ( to )
    ( to )
    Notes
    [17] - Data collection is ongoing and results will be disclosed within 1 year from Study Completion Date.
    [18] - Data collection is ongoing and results will be disclosed within 1 year from Study Completion Date.
    No statistical analyses for this end point

    Secondary: Time to First Opioid Use

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    End point title
    		 Time to First Opioid Use
    End point description
    Time to first opioid use is defined as the documentation of the first opioid prescription for cancer-related pain followed by the subject’s record of opioid intake or availability of an Analgesic Quantification Algorithm (AQA) daily score. Subjects reporting use of opioid for cancer-related pain at baseline will be excluded from the analysis. Data collection is still ongoing and the results will be disclosed within 1 year from the Study Completion Date.
    End point type
    Secondary
    End point timeframe
    Up to approximately 7 years
    End point values
    		 Placebo + Abiraterone Ipatasertib + Abiraterone
    Number of subjects analysed
    0 [19]
    0 [20]
    Units: Months
        median (confidence interval 95%)
    ( to )
    ( to )
    Notes
    [19] - Data collection is ongoing and results will be disclosed within 1 year from Study Completion Date.
    [20] - Data collection is ongoing and results will be disclosed within 1 year from Study Completion Date.
    No statistical analyses for this end point

    Secondary: Plasma Concentrations of Ipatasertib at Specified Timepoints

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    End point title
    		 Plasma Concentrations of Ipatasertib at Specified Timepoints [21]
    End point description
    Plasma samples for pharmacokinetic characterization was collected at various timepoints in all subjects. The PK Evaluable population was defined as all participants who received Ipatasertib treatment with evaluable PK samples. Number Analyzed was the number of participants with data available for analyses at the specified timepoint.
    End point type
    Secondary
    End point timeframe
    1-3 hours post-dose (Cycle 1, Day 1; Cycle 1 Day 15 and Cycle 3 Day 1) and pre-dose at steady state (Cycle 1 Day 15, Cycle 3 Day 1, Cycle 6 Day 1) (each cycle length= 28 days)
    Notes
    [21] - 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: Plasma concentrations for ipatasertib are only reported for the arm treated with ipatasertib.
    End point values
    		 Ipatasertib + Abiraterone
    Number of subjects analysed
    544
    Units: ng/mL
    geometric mean (geometric coefficient of variation)
        Cycle 1 Day 1 Post-dose (n=499)
    212 ( 158 )
        Cycle 1 Day 15 Pre-dose (n=467)
    46.8 ( 160 )
        Cycle 1 Day 15 Post-dose (n=413)
    247 ( 138 )
        Cycle 3 Day 1 Pre-dose (n=407)
    35.4 ( 256 )
        Cycle 3 Day 1 Post-dose (n=403)
    207 ( 156 )
        Cycle 6 Day 1 Pre-dose (n=372)
    46.1 ( 134 )
    No statistical analyses for this end point

    Secondary: Duration of Response (DOR)

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    End point title
    		 Duration of Response (DOR)
    End point description
    Duration of Response (DOR) is defined as the time from first occurrence of a documented confirmed objective response until the time of documented disease progression as determined by the investigator using RECIST v1.1 and PCWG3 criteria, or death from any cause, whichever occurs first. Data collection is still ongoing and the results will be disclosed within 1 year from the Study Completion Date.
    End point type
    Secondary
    End point timeframe
    Up to approximately 7 years
    End point values
    		 Placebo + Abiraterone Ipatasertib + Abiraterone
    Number of subjects analysed
    0 [22]
    0 [23]
    Units: Months
        median (confidence interval 95%)
    ( to )
    ( to )
    Notes
    [22] - Data collection is ongoing and results will be disclosed within 1 year from Study Completion Date.
    [23] - Data collection is ongoing and results will be disclosed within 1 year from Study Completion Date.
    No statistical analyses for this end point

    Secondary: Percentage of Subjects with Adverse Events (AEs)

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    End point title
    		 Percentage of Subjects with Adverse Events (AEs)
    End point description
    An Adverse Event (AE) is any untoward medical occurrence in a subject administered a pharmaceutical product and which does not necessarily have to have a causal relationship with the treatment. An Adverse Event can therefore be any unfavorable and unintended sign (including abnormal laboratory values or abnormal clinical test results), symptom, or disease temporally associated with the use of a pharmaceutical product, whether or not considered related to the pharmaceutical product. Preexisting conditions which worsen during a study are also considered as Adverse Events. Data collection is still ongoing and the results will be disclosed within 1 year from the Study Completion Date.
    End point type
    Secondary
    End point timeframe
    Baseline up until 28 days after the last dose of study drug or initiation of subsequent lines of anti-cancer therapy, whichever occurs first (up to a maximum of 7 years).
    End point values
    		 Placebo + Abiraterone Ipatasertib + Abiraterone
    Number of subjects analysed
    0 [24]
    0 [25]
    Units: Percentage of Participants
    Notes
    [24] - Data collection is ongoing and results will be disclosed within 1 year from Study Completion Date.
    [25] - Data collection is ongoing and results will be disclosed within 1 year from Study Completion Date.
    No statistical analyses for this end point

    Secondary: Plasma Concentrations of Abiraterone at Specified Timepoints

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    End point title
    		 Plasma Concentrations of Abiraterone at Specified Timepoints
    End point description
    Plasma samples for pharmacokinetic characterization was collected at various timepoints in all subjects. The PK Evaluable population was defined as all participants who received Abiraterone treatment with evaluable PK samples. Number Analyzed is the number of participants with data available for analyses at the specified timepoint.
    End point type
    Secondary
    End point timeframe
    Pre-dose at steady state in Cycle 1, Day 15 and Cycle 3 Day 1 (each cycle length= 28 days)
    End point values
    		 Placebo + Abiraterone Ipatasertib + Abiraterone
    Number of subjects analysed
    537
    520
    Units: ng/mL
    geometric mean (geometric coefficient of variation)
        Cycle 1 Day 15 (n=508; n=470)
    11.2 ( 124 )
    9.40 ( 159 )
        Cycle 3 Day 1 (n=492; n=415)
    10.4 ( 120 )
    9.55 ( 159 )
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Baseline up until 28 days after the last dose of study drug or initiation of subsequent lines of anti-cancer therapy, whichever occurs first (up to a maximum of 7 years).
    Adverse event reporting additional description
    4 subjects from both treatment arms did not receive any study treatment. 5 subjects randomized to the placebo arm took at least one dose of ipatasertib prior to the Clinical Cut-off Date (CCOD) of 16th March 2020 and so as a result, the safety-evaluable population comprised 1097 subjects (551 in the Ipat + Abi arm and 546 in the Pbo + Abi arm).
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    23.0
    Reporting groups
    Reporting group title
    Ipatasertib + Abiraterone
    Reporting group description
    		 Subjects received Ipatasertib plus Abiraterone (along with Prednisone/Prednisolone), administered orally in 28-day cycles.

    Reporting group title
    Placebo + Abiraterone
    Reporting group description
    		 Subjects received Placebo plus Abiraterone (along with Prednisone/Prednisolone), administered orally in 28-day cycles.

    Serious adverse events
    		 Ipatasertib + Abiraterone Placebo + Abiraterone
    Total subjects affected by serious adverse events
         subjects affected / exposed
    218 / 551 (39.56%)
    124 / 546 (22.71%)
         number of deaths (all causes)
    126
    143
         number of deaths resulting from adverse events
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Pancreatic carcinoma
         subjects affected / exposed
    1 / 551 (0.18%)
    1 / 546 (0.18%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bladder transitional cell carcinoma
         subjects affected / exposed
    1 / 551 (0.18%)
    0 / 546 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastric cancer
         subjects affected / exposed
    0 / 551 (0.00%)
    1 / 546 (0.18%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal stromal tumour
         subjects affected / exposed
    1 / 551 (0.18%)
    0 / 546 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lung neoplasm malignant
         subjects affected / exposed
    1 / 551 (0.18%)
    0 / 546 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Malignant melanoma
         subjects affected / exposed
    0 / 551 (0.00%)
    1 / 546 (0.18%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Metastases to meninges
         subjects affected / exposed
    1 / 551 (0.18%)
    0 / 546 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Adenocarcinoma gastric
         subjects affected / exposed
    0 / 551 (0.00%)
    1 / 546 (0.18%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Schwannoma
         subjects affected / exposed
    0 / 551 (0.00%)
    1 / 546 (0.18%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Tonsil cancer
         subjects affected / exposed
    0 / 551 (0.00%)
    1 / 546 (0.18%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vascular disorders
    Hypertension
         subjects affected / exposed
    1 / 551 (0.18%)
    0 / 546 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Artery dissection
         subjects affected / exposed
    1 / 551 (0.18%)
    0 / 546 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Deep vein thrombosis
         subjects affected / exposed
    3 / 551 (0.54%)
    0 / 546 (0.00%)
         occurrences causally related to treatment / all
    1 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Venous thrombosis
         subjects affected / exposed
    1 / 551 (0.18%)
    0 / 546 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypotension
         subjects affected / exposed
    1 / 551 (0.18%)
    0 / 546 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Fatigue
         subjects affected / exposed
    1 / 551 (0.18%)
    0 / 546 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Sudden cardiac death
         subjects affected / exposed
    0 / 551 (0.00%)
    1 / 546 (0.18%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Chest pain
         subjects affected / exposed
    1 / 551 (0.18%)
    0 / 546 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Asthenia
         subjects affected / exposed
    2 / 551 (0.36%)
    1 / 546 (0.18%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Adverse drug reaction
         subjects affected / exposed
    1 / 551 (0.18%)
    0 / 546 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    General physical health deterioration
         subjects affected / exposed
    2 / 551 (0.36%)
    0 / 546 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Hernia
         subjects affected / exposed
    1 / 551 (0.18%)
    0 / 546 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pain
         subjects affected / exposed
    0 / 551 (0.00%)
    1 / 546 (0.18%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Impaired healing
         subjects affected / exposed
    1 / 551 (0.18%)
    0 / 546 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Non-cardiac chest pain
         subjects affected / exposed
    1 / 551 (0.18%)
    0 / 546 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Oedema peripheral
         subjects affected / exposed
    1 / 551 (0.18%)
    0 / 546 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pyrexia
         subjects affected / exposed
    3 / 551 (0.54%)
    3 / 546 (0.55%)
         occurrences causally related to treatment / all
    0 / 3
    1 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Death
         subjects affected / exposed
    3 / 551 (0.54%)
    2 / 546 (0.37%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 2
         deaths causally related to treatment / all
    0 / 3
    0 / 2
    Immune system disorders
    Anaphylactic reaction
         subjects affected / exposed
    0 / 551 (0.00%)
    1 / 546 (0.18%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Reproductive system and breast disorders
    Prostatitis
         subjects affected / exposed
    1 / 551 (0.18%)
    0 / 546 (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
         subjects affected / exposed
    0 / 551 (0.00%)
    1 / 546 (0.18%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Dyspnoea
         subjects affected / exposed
    0 / 551 (0.00%)
    2 / 546 (0.37%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Epistaxis
         subjects affected / exposed
    0 / 551 (0.00%)
    1 / 546 (0.18%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypoxia
         subjects affected / exposed
    0 / 551 (0.00%)
    1 / 546 (0.18%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonitis
         subjects affected / exposed
    0 / 551 (0.00%)
    2 / 546 (0.37%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Pulmonary embolism
         subjects affected / exposed
    4 / 551 (0.73%)
    1 / 546 (0.18%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Psychiatric disorders
    Disorientation
         subjects affected / exposed
    0 / 551 (0.00%)
    1 / 546 (0.18%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Psychotic disorder
         subjects affected / exposed
    0 / 551 (0.00%)
    2 / 546 (0.37%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Confusional state
         subjects affected / exposed
    1 / 551 (0.18%)
    0 / 546 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Product issues
    Device dislocation
         subjects affected / exposed
    0 / 551 (0.00%)
    1 / 546 (0.18%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Investigations
    Alanine aminotransferase increased
         subjects affected / exposed
    7 / 551 (1.27%)
    1 / 546 (0.18%)
         occurrences causally related to treatment / all
    6 / 7
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Aspartate aminotransferase increased
         subjects affected / exposed
    5 / 551 (0.91%)
    1 / 546 (0.18%)
         occurrences causally related to treatment / all
    4 / 5
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Blood bilirubin increased
         subjects affected / exposed
    1 / 551 (0.18%)
    0 / 546 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Glycosylated haemoglobin increased
         subjects affected / exposed
    1 / 551 (0.18%)
    0 / 546 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Transaminases increased
         subjects affected / exposed
    1 / 551 (0.18%)
    0 / 546 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Patella fracture
         subjects affected / exposed
    1 / 551 (0.18%)
    0 / 546 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cystitis radiation
         subjects affected / exposed
    1 / 551 (0.18%)
    0 / 546 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Fall
         subjects affected / exposed
    2 / 551 (0.36%)
    3 / 546 (0.55%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Forearm fracture
         subjects affected / exposed
    1 / 551 (0.18%)
    1 / 546 (0.18%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Fracture displacement
         subjects affected / exposed
    0 / 551 (0.00%)
    1 / 546 (0.18%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Head injury
         subjects affected / exposed
    0 / 551 (0.00%)
    1 / 546 (0.18%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Hip fracture
         subjects affected / exposed
    2 / 551 (0.36%)
    1 / 546 (0.18%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Humerus fracture
         subjects affected / exposed
    0 / 551 (0.00%)
    1 / 546 (0.18%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypobarism
         subjects affected / exposed
    0 / 551 (0.00%)
    1 / 546 (0.18%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lumbar vertebral fracture
         subjects affected / exposed
    1 / 551 (0.18%)
    1 / 546 (0.18%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonitis chemical
         subjects affected / exposed
    1 / 551 (0.18%)
    0 / 546 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Skull fracture
         subjects affected / exposed
    0 / 551 (0.00%)
    1 / 546 (0.18%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Spinal compression fracture
         subjects affected / exposed
    1 / 551 (0.18%)
    1 / 546 (0.18%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Spinal fracture
         subjects affected / exposed
    1 / 551 (0.18%)
    0 / 546 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Subdural haematoma
         subjects affected / exposed
    1 / 551 (0.18%)
    0 / 546 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Subdural haemorrhage
         subjects affected / exposed
    0 / 551 (0.00%)
    1 / 546 (0.18%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Tendon rupture
         subjects affected / exposed
    0 / 551 (0.00%)
    1 / 546 (0.18%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Traumatic intracranial haemorrhage
         subjects affected / exposed
    0 / 551 (0.00%)
    1 / 546 (0.18%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Upper limb fracture
         subjects affected / exposed
    1 / 551 (0.18%)
    0 / 546 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Radiation proctitis
         subjects affected / exposed
    0 / 551 (0.00%)
    1 / 546 (0.18%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac disorders
    Angina pectoris
         subjects affected / exposed
    1 / 551 (0.18%)
    1 / 546 (0.18%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Acute myocardial infarction
         subjects affected / exposed
    3 / 551 (0.54%)
    6 / 546 (1.10%)
         occurrences causally related to treatment / all
    1 / 3
    2 / 6
         deaths causally related to treatment / all
    0 / 1
    0 / 4
    Acute left ventricular failure
         subjects affected / exposed
    1 / 551 (0.18%)
    0 / 546 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Acute coronary syndrome
         subjects affected / exposed
    0 / 551 (0.00%)
    1 / 546 (0.18%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Myocardial infarction
         subjects affected / exposed
    5 / 551 (0.91%)
    1 / 546 (0.18%)
         occurrences causally related to treatment / all
    0 / 5
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    0 / 1
    Myocardial ischaemia
         subjects affected / exposed
    1 / 551 (0.18%)
    0 / 546 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Sinus tachycardia
         subjects affected / exposed
    0 / 551 (0.00%)
    1 / 546 (0.18%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Coronary artery stenosis
         subjects affected / exposed
    1 / 551 (0.18%)
    1 / 546 (0.18%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cor pulmonale
         subjects affected / exposed
    0 / 551 (0.00%)
    1 / 546 (0.18%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiomyopathy
         subjects affected / exposed
    1 / 551 (0.18%)
    0 / 546 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac failure congestive
         subjects affected / exposed
    0 / 551 (0.00%)
    1 / 546 (0.18%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Cardiac failure
         subjects affected / exposed
    3 / 551 (0.54%)
    0 / 546 (0.00%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Cardiac arrest
         subjects affected / exposed
    2 / 551 (0.36%)
    0 / 546 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 2
    0 / 0
    Bradycardia
         subjects affected / exposed
    1 / 551 (0.18%)
    0 / 546 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Atrial fibrillation
         subjects affected / exposed
    1 / 551 (0.18%)
    2 / 546 (0.37%)
         occurrences causally related to treatment / all
    0 / 1
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Angina unstable
         subjects affected / exposed
    1 / 551 (0.18%)
    0 / 546 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Atrial flutter
         subjects affected / exposed
    1 / 551 (0.18%)
    0 / 546 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nervous system disorders
    Cerebral haemorrhage
         subjects affected / exposed
    0 / 551 (0.00%)
    1 / 546 (0.18%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Cerebral ischaemia
         subjects affected / exposed
    0 / 551 (0.00%)
    1 / 546 (0.18%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Sciatica
         subjects affected / exposed
    1 / 551 (0.18%)
    2 / 546 (0.37%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cerebrovascular accident
         subjects affected / exposed
    0 / 551 (0.00%)
    1 / 546 (0.18%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Dysarthria
         subjects affected / exposed
    1 / 551 (0.18%)
    0 / 546 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Headache
         subjects affected / exposed
    0 / 551 (0.00%)
    1 / 546 (0.18%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Paraplegia
         subjects affected / exposed
    0 / 551 (0.00%)
    1 / 546 (0.18%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cerebrospinal fluid leakage
         subjects affected / exposed
    0 / 551 (0.00%)
    1 / 546 (0.18%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Seizure
         subjects affected / exposed
    2 / 551 (0.36%)
    2 / 546 (0.37%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Spinal cord compression
         subjects affected / exposed
    1 / 551 (0.18%)
    2 / 546 (0.37%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Syncope
         subjects affected / exposed
    1 / 551 (0.18%)
    1 / 546 (0.18%)
         occurrences causally related to treatment / all
    0 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    Immune thrombocytopenia
         subjects affected / exposed
    1 / 551 (0.18%)
    0 / 546 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Haemolysis
         subjects affected / exposed
    0 / 551 (0.00%)
    1 / 546 (0.18%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Febrile neutropenia
         subjects affected / exposed
    2 / 551 (0.36%)
    0 / 546 (0.00%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bicytopenia
         subjects affected / exposed
    0 / 551 (0.00%)
    1 / 546 (0.18%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Thrombocytopenia
         subjects affected / exposed
    1 / 551 (0.18%)
    1 / 546 (0.18%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Anaemia
         subjects affected / exposed
    4 / 551 (0.73%)
    2 / 546 (0.37%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Eye disorders
    Cataract
         subjects affected / exposed
    1 / 551 (0.18%)
    0 / 546 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Retinal detachment
         subjects affected / exposed
    1 / 551 (0.18%)
    0 / 546 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Abdominal distension
         subjects affected / exposed
    1 / 551 (0.18%)
    0 / 546 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Abdominal pain
         subjects affected / exposed
    0 / 551 (0.00%)
    2 / 546 (0.37%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Anal haemorrhage
         subjects affected / exposed
    1 / 551 (0.18%)
    0 / 546 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Haematemesis
         subjects affected / exposed
    0 / 551 (0.00%)
    1 / 546 (0.18%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrooesophageal reflux disease
         subjects affected / exposed
    0 / 551 (0.00%)
    1 / 546 (0.18%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal haemorrhage
         subjects affected / exposed
    0 / 551 (0.00%)
    1 / 546 (0.18%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastritis haemorrhagic
         subjects affected / exposed
    0 / 551 (0.00%)
    1 / 546 (0.18%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastritis
         subjects affected / exposed
    1 / 551 (0.18%)
    0 / 546 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Enterocolitis
         subjects affected / exposed
    1 / 551 (0.18%)
    1 / 546 (0.18%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Dysphagia
         subjects affected / exposed
    1 / 551 (0.18%)
    0 / 546 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Duodenal ulcer haemorrhage
         subjects affected / exposed
    1 / 551 (0.18%)
    0 / 546 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Duodenal ulcer
         subjects affected / exposed
    1 / 551 (0.18%)
    0 / 546 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Diarrhoea
         subjects affected / exposed
    12 / 551 (2.18%)
    0 / 546 (0.00%)
         occurrences causally related to treatment / all
    10 / 12
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Colonic fistula
         subjects affected / exposed
    1 / 551 (0.18%)
    0 / 546 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Chronic gastritis
         subjects affected / exposed
    1 / 551 (0.18%)
    0 / 546 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ileus
         subjects affected / exposed
    2 / 551 (0.36%)
    2 / 546 (0.37%)
         occurrences causally related to treatment / all
    0 / 2
    2 / 2
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Upper gastrointestinal haemorrhage
         subjects affected / exposed
    0 / 551 (0.00%)
    1 / 546 (0.18%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Small intestinal perforation
         subjects affected / exposed
    0 / 551 (0.00%)
    1 / 546 (0.18%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Small intestinal obstruction
         subjects affected / exposed
    1 / 551 (0.18%)
    0 / 546 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Rectal haemorrhage
         subjects affected / exposed
    0 / 551 (0.00%)
    2 / 546 (0.37%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pancreatitis acute
         subjects affected / exposed
    1 / 551 (0.18%)
    0 / 546 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pancreatitis
         subjects affected / exposed
    1 / 551 (0.18%)
    1 / 546 (0.18%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Oesophagitis
         subjects affected / exposed
    1 / 551 (0.18%)
    0 / 546 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nausea
         subjects affected / exposed
    1 / 551 (0.18%)
    1 / 546 (0.18%)
         occurrences causally related to treatment / all
    2 / 2
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Large intestine polyp
         subjects affected / exposed
    1 / 551 (0.18%)
    0 / 546 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ischaemic enteritis
         subjects affected / exposed
    1 / 551 (0.18%)
    0 / 546 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Intra-abdominal haematoma
         subjects affected / exposed
    1 / 551 (0.18%)
    0 / 546 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Intestinal obstruction
         subjects affected / exposed
    2 / 551 (0.36%)
    2 / 546 (0.37%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Incarcerated inguinal hernia
         subjects affected / exposed
    1 / 551 (0.18%)
    0 / 546 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ileus paralytic
         subjects affected / exposed
    1 / 551 (0.18%)
    0 / 546 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vomiting
         subjects affected / exposed
    4 / 551 (0.73%)
    1 / 546 (0.18%)
         occurrences causally related to treatment / all
    1 / 4
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Volvulus
         subjects affected / exposed
    0 / 551 (0.00%)
    1 / 546 (0.18%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatobiliary disorders
    Hepatitis acute
         subjects affected / exposed
    1 / 551 (0.18%)
    0 / 546 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatic function abnormal
         subjects affected / exposed
    2 / 551 (0.36%)
    0 / 546 (0.00%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Haemobilia
         subjects affected / exposed
    1 / 551 (0.18%)
    0 / 546 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Drug-induced liver injury
         subjects affected / exposed
    2 / 551 (0.36%)
    0 / 546 (0.00%)
         occurrences causally related to treatment / all
    2 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cholecystitis
         subjects affected / exposed
    1 / 551 (0.18%)
    2 / 546 (0.37%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cholangitis
         subjects affected / exposed
    0 / 551 (0.00%)
    1 / 546 (0.18%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bile duct obstruction
         subjects affected / exposed
    1 / 551 (0.18%)
    0 / 546 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatotoxicity
         subjects affected / exposed
    1 / 551 (0.18%)
    0 / 546 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypertransaminasaemia
         subjects affected / exposed
    0 / 551 (0.00%)
    1 / 546 (0.18%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Skin and subcutaneous tissue disorders
    Dermatitis allergic
         subjects affected / exposed
    1 / 551 (0.18%)
    0 / 546 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Dermatitis exfoliative
         subjects affected / exposed
    1 / 551 (0.18%)
    0 / 546 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Drug reaction with eosinophilia and systemic symptoms
         subjects affected / exposed
    1 / 551 (0.18%)
    0 / 546 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Erythema
         subjects affected / exposed
    1 / 551 (0.18%)
    0 / 546 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Rash
         subjects affected / exposed
    15 / 551 (2.72%)
    0 / 546 (0.00%)
         occurrences causally related to treatment / all
    16 / 17
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Rash maculo-papular
         subjects affected / exposed
    5 / 551 (0.91%)
    0 / 546 (0.00%)
         occurrences causally related to treatment / all
    5 / 5
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Stevens-Johnson syndrome
         subjects affected / exposed
    1 / 551 (0.18%)
    0 / 546 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Toxic skin eruption
         subjects affected / exposed
    1 / 551 (0.18%)
    0 / 546 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Erythema multiforme
         subjects affected / exposed
    3 / 551 (0.54%)
    0 / 546 (0.00%)
         occurrences causally related to treatment / all
    3 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal and urinary disorders
    Haematuria
         subjects affected / exposed
    10 / 551 (1.81%)
    4 / 546 (0.73%)
         occurrences causally related to treatment / all
    1 / 10
    0 / 5
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Acute kidney injury
         subjects affected / exposed
    3 / 551 (0.54%)
    3 / 546 (0.55%)
         occurrences causally related to treatment / all
    1 / 3
    0 / 3
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Dysuria
         subjects affected / exposed
    0 / 551 (0.00%)
    1 / 546 (0.18%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hydronephrosis
         subjects affected / exposed
    2 / 551 (0.36%)
    0 / 546 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nephrolithiasis
         subjects affected / exposed
    3 / 551 (0.54%)
    1 / 546 (0.18%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal failure
         subjects affected / exposed
    2 / 551 (0.36%)
    0 / 546 (0.00%)
         occurrences causally related to treatment / all
    3 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal tubular necrosis
         subjects affected / exposed
    0 / 551 (0.00%)
    1 / 546 (0.18%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ureterolithiasis
         subjects affected / exposed
    1 / 551 (0.18%)
    2 / 546 (0.37%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Urethral stenosis
         subjects affected / exposed
    0 / 551 (0.00%)
    1 / 546 (0.18%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Urinary tract obstruction
         subjects affected / exposed
    0 / 551 (0.00%)
    4 / 546 (0.73%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Urinary retention
         subjects affected / exposed
    1 / 551 (0.18%)
    2 / 546 (0.37%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Fasciitis
         subjects affected / exposed
    1 / 551 (0.18%)
    0 / 546 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Arthralgia
         subjects affected / exposed
    0 / 551 (0.00%)
    1 / 546 (0.18%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Arthritis reactive
         subjects affected / exposed
    0 / 551 (0.00%)
    1 / 546 (0.18%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Back pain
         subjects affected / exposed
    5 / 551 (0.91%)
    6 / 546 (1.10%)
         occurrences causally related to treatment / all
    0 / 5
    1 / 8
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bone pain
         subjects affected / exposed
    2 / 551 (0.36%)
    0 / 546 (0.00%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Intervertebral disc protrusion
         subjects affected / exposed
    0 / 551 (0.00%)
    1 / 546 (0.18%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Muscular weakness
         subjects affected / exposed
    2 / 551 (0.36%)
    3 / 546 (0.55%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Musculoskeletal pain
         subjects affected / exposed
    0 / 551 (0.00%)
    1 / 546 (0.18%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Osteoarthritis
         subjects affected / exposed
    0 / 551 (0.00%)
    1 / 546 (0.18%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Osteonecrosis
         subjects affected / exposed
    1 / 551 (0.18%)
    0 / 546 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Rhabdomyolysis
         subjects affected / exposed
    0 / 551 (0.00%)
    1 / 546 (0.18%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infections and infestations
    Bullous erysipelas
         subjects affected / exposed
    1 / 551 (0.18%)
    0 / 546 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Bronchitis
         subjects affected / exposed
    1 / 551 (0.18%)
    1 / 546 (0.18%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bronchiolitis
         subjects affected / exposed
    1 / 551 (0.18%)
    0 / 546 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Anal abscess
         subjects affected / exposed
    2 / 551 (0.36%)
    2 / 546 (0.37%)
         occurrences causally related to treatment / all
    1 / 2
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Acute sinusitis
         subjects affected / exposed
    1 / 551 (0.18%)
    0 / 546 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    COVID-19
         subjects affected / exposed
    1 / 551 (0.18%)
    1 / 546 (0.18%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Lower respiratory tract infection
         subjects affected / exposed
    1 / 551 (0.18%)
    1 / 546 (0.18%)
         occurrences causally related to treatment / all
    0 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Cystitis
         subjects affected / exposed
    1 / 551 (0.18%)
    0 / 546 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Diverticulitis
         subjects affected / exposed
    2 / 551 (0.36%)
    2 / 546 (0.37%)
         occurrences causally related to treatment / all
    1 / 2
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Enterocolitis infectious
         subjects affected / exposed
    1 / 551 (0.18%)
    0 / 546 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Febrile infection
         subjects affected / exposed
    0 / 551 (0.00%)
    1 / 546 (0.18%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastroenteritis
         subjects affected / exposed
    1 / 551 (0.18%)
    3 / 546 (0.55%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Localised infection
         subjects affected / exposed
    1 / 551 (0.18%)
    0 / 546 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Influenza
         subjects affected / exposed
    0 / 551 (0.00%)
    3 / 546 (0.55%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infectious pleural effusion
         subjects affected / exposed
    1 / 551 (0.18%)
    0 / 546 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infection
         subjects affected / exposed
    2 / 551 (0.36%)
    0 / 546 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gingivitis
         subjects affected / exposed
    1 / 551 (0.18%)
    0 / 546 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastroenteritis salmonella
         subjects affected / exposed
    0 / 551 (0.00%)
    1 / 546 (0.18%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastroenteritis bacterial
         subjects affected / exposed
    0 / 551 (0.00%)
    1 / 546 (0.18%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cellulitis
         subjects affected / exposed
    3 / 551 (0.54%)
    1 / 546 (0.18%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Opportunistic infection
         subjects affected / exposed
    0 / 551 (0.00%)
    1 / 546 (0.18%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Osteomyelitis
         subjects affected / exposed
    1 / 551 (0.18%)
    0 / 546 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonia
         subjects affected / exposed
    13 / 551 (2.36%)
    7 / 546 (1.28%)
         occurrences causally related to treatment / all
    0 / 14
    0 / 7
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Pneumonia bacterial
         subjects affected / exposed
    2 / 551 (0.36%)
    0 / 546 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonia influenzal
         subjects affected / exposed
    1 / 551 (0.18%)
    0 / 546 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonia legionella
         subjects affected / exposed
    1 / 551 (0.18%)
    0 / 546 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonia pneumococcal
         subjects affected / exposed
    0 / 551 (0.00%)
    1 / 546 (0.18%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pulpitis dental
         subjects affected / exposed
    1 / 551 (0.18%)
    0 / 546 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pyelonephritis
         subjects affected / exposed
    2 / 551 (0.36%)
    1 / 546 (0.18%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pyelonephritis acute
         subjects affected / exposed
    2 / 551 (0.36%)
    1 / 546 (0.18%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Rash pustular
         subjects affected / exposed
    1 / 551 (0.18%)
    0 / 546 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal abscess
         subjects affected / exposed
    1 / 551 (0.18%)
    0 / 546 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory tract infection
         subjects affected / exposed
    2 / 551 (0.36%)
    1 / 546 (0.18%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Sepsis
         subjects affected / exposed
    3 / 551 (0.54%)
    3 / 546 (0.55%)
         occurrences causally related to treatment / all
    1 / 3
    1 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Septic shock
         subjects affected / exposed
    4 / 551 (0.73%)
    0 / 546 (0.00%)
         occurrences causally related to treatment / all
    2 / 4
    0 / 0
         deaths causally related to treatment / all
    0 / 2
    0 / 0
    Skin infection
         subjects affected / exposed
    2 / 551 (0.36%)
    0 / 546 (0.00%)
         occurrences causally related to treatment / all
    1 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Tracheobronchitis
         subjects affected / exposed
    0 / 551 (0.00%)
    2 / 546 (0.37%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Upper respiratory tract infection
         subjects affected / exposed
    2 / 551 (0.36%)
    1 / 546 (0.18%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Urinary tract infection
         subjects affected / exposed
    8 / 551 (1.45%)
    4 / 546 (0.73%)
         occurrences causally related to treatment / all
    0 / 10
    0 / 4
         deaths causally related to treatment / all
    0 / 1
    0 / 1
    Tooth infection
         subjects affected / exposed
    0 / 551 (0.00%)
    1 / 546 (0.18%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Decreased appetite
         subjects affected / exposed
    1 / 551 (0.18%)
    0 / 546 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Dehydration
         subjects affected / exposed
    11 / 551 (2.00%)
    0 / 546 (0.00%)
         occurrences causally related to treatment / all
    8 / 12
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Diabetes mellitus
         subjects affected / exposed
    1 / 551 (0.18%)
    0 / 546 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Electrolyte imbalance
         subjects affected / exposed
    0 / 551 (0.00%)
    1 / 546 (0.18%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hyperglycaemia
         subjects affected / exposed
    23 / 551 (4.17%)
    1 / 546 (0.18%)
         occurrences causally related to treatment / all
    24 / 24
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Hypokalaemia
         subjects affected / exposed
    3 / 551 (0.54%)
    1 / 546 (0.18%)
         occurrences causally related to treatment / all
    2 / 3
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hyponatraemia
         subjects affected / exposed
    2 / 551 (0.36%)
    0 / 546 (0.00%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Metabolic acidosis
         subjects affected / exposed
    1 / 551 (0.18%)
    0 / 546 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Type 2 diabetes mellitus
         subjects affected / exposed
    1 / 551 (0.18%)
    0 / 546 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypophosphataemia
         subjects affected / exposed
    0 / 551 (0.00%)
    1 / 546 (0.18%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Ipatasertib + Abiraterone Placebo + Abiraterone
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    541 / 551 (98.19%)
    486 / 546 (89.01%)
    Vascular disorders
    Hot flush
         subjects affected / exposed
    27 / 551 (4.90%)
    36 / 546 (6.59%)
         occurrences all number
    29
    39
    Hypertension
         subjects affected / exposed
    76 / 551 (13.79%)
    82 / 546 (15.02%)
         occurrences all number
    91
    113
    General disorders and administration site conditions
    Asthenia
         subjects affected / exposed
    99 / 551 (17.97%)
    68 / 546 (12.45%)
         occurrences all number
    135
    82
    Pyrexia
         subjects affected / exposed
    31 / 551 (5.63%)
    20 / 546 (3.66%)
         occurrences all number
    37
    22
    Fatigue
         subjects affected / exposed
    120 / 551 (21.78%)
    94 / 546 (17.22%)
         occurrences all number
    137
    114
    Oedema peripheral
         subjects affected / exposed
    71 / 551 (12.89%)
    48 / 546 (8.79%)
         occurrences all number
    80
    56
    Respiratory, thoracic and mediastinal disorders
    Dyspnoea
         subjects affected / exposed
    32 / 551 (5.81%)
    27 / 546 (4.95%)
         occurrences all number
    33
    28
    Cough
         subjects affected / exposed
    45 / 551 (8.17%)
    45 / 546 (8.24%)
         occurrences all number
    49
    48
    Psychiatric disorders
    Insomnia
         subjects affected / exposed
    24 / 551 (4.36%)
    41 / 546 (7.51%)
         occurrences all number
    25
    44
    Investigations
    Weight decreased
         subjects affected / exposed
    67 / 551 (12.16%)
    16 / 546 (2.93%)
         occurrences all number
    81
    18
    Blood creatinine increased
         subjects affected / exposed
    34 / 551 (6.17%)
    18 / 546 (3.30%)
         occurrences all number
    39
    21
    Aspartate aminotransferase increased
         subjects affected / exposed
    94 / 551 (17.06%)
    59 / 546 (10.81%)
         occurrences all number
    101
    72
    Alanine aminotransferase increased
         subjects affected / exposed
    110 / 551 (19.96%)
    56 / 546 (10.26%)
         occurrences all number
    127
    65
    Injury, poisoning and procedural complications
    Fall
         subjects affected / exposed
    34 / 551 (6.17%)
    45 / 546 (8.24%)
         occurrences all number
    45
    59
    Nervous system disorders
    Headache
         subjects affected / exposed
    53 / 551 (9.62%)
    42 / 546 (7.69%)
         occurrences all number
    60
    50
    Dizziness
         subjects affected / exposed
    36 / 551 (6.53%)
    34 / 546 (6.23%)
         occurrences all number
    41
    42
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    107 / 551 (19.42%)
    65 / 546 (11.90%)
         occurrences all number
    147
    85
    Gastrointestinal disorders
    Vomiting
         subjects affected / exposed
    92 / 551 (16.70%)
    47 / 546 (8.61%)
         occurrences all number
    139
    57
    Nausea
         subjects affected / exposed
    154 / 551 (27.95%)
    54 / 546 (9.89%)
         occurrences all number
    193
    62
    Dyspepsia
         subjects affected / exposed
    35 / 551 (6.35%)
    23 / 546 (4.21%)
         occurrences all number
    37
    28
    Diarrhoea
         subjects affected / exposed
    437 / 551 (79.31%)
    123 / 546 (22.53%)
         occurrences all number
    914
    164
    Abdominal pain
         subjects affected / exposed
    31 / 551 (5.63%)
    18 / 546 (3.30%)
         occurrences all number
    37
    20
    Constipation
         subjects affected / exposed
    44 / 551 (7.99%)
    78 / 546 (14.29%)
         occurrences all number
    47
    90
    Skin and subcutaneous tissue disorders
    Rash maculo-papular
         subjects affected / exposed
    47 / 551 (8.53%)
    6 / 546 (1.10%)
         occurrences all number
    65
    7
    Rash
         subjects affected / exposed
    141 / 551 (25.59%)
    42 / 546 (7.69%)
         occurrences all number
    178
    46
    Pruritus
         subjects affected / exposed
    45 / 551 (8.17%)
    15 / 546 (2.75%)
         occurrences all number
    60
    17
    Renal and urinary disorders
    Haematuria
         subjects affected / exposed
    31 / 551 (5.63%)
    27 / 546 (4.95%)
         occurrences all number
    39
    32
    Musculoskeletal and connective tissue disorders
    Pain in extremity
         subjects affected / exposed
    38 / 551 (6.90%)
    41 / 546 (7.51%)
         occurrences all number
    44
    50
    Musculoskeletal pain
         subjects affected / exposed
    30 / 551 (5.44%)
    34 / 546 (6.23%)
         occurrences all number
    36
    38
    Arthralgia
         subjects affected / exposed
    65 / 551 (11.80%)
    75 / 546 (13.74%)
         occurrences all number
    84
    80
    Back pain
         subjects affected / exposed
    81 / 551 (14.70%)
    107 / 546 (19.60%)
         occurrences all number
    94
    128
    Bone pain
         subjects affected / exposed
    39 / 551 (7.08%)
    30 / 546 (5.49%)
         occurrences all number
    42
    42
    Infections and infestations
    Urinary tract infection
         subjects affected / exposed
    41 / 551 (7.44%)
    39 / 546 (7.14%)
         occurrences all number
    58
    48
    Upper respiratory tract infection
         subjects affected / exposed
    36 / 551 (6.53%)
    49 / 546 (8.97%)
         occurrences all number
    46
    58
    Nasopharyngitis
         subjects affected / exposed
    44 / 551 (7.99%)
    45 / 546 (8.24%)
         occurrences all number
    58
    62
    Metabolism and nutrition disorders
    Decreased appetite
         subjects affected / exposed
    98 / 551 (17.79%)
    51 / 546 (9.34%)
         occurrences all number
    113
    64
    Hyperglycaemia
         subjects affected / exposed
    211 / 551 (38.29%)
    85 / 546 (15.57%)
         occurrences all number
    330
    125
    Hypertriglyceridaemia
         subjects affected / exposed
    31 / 551 (5.63%)
    22 / 546 (4.03%)
         occurrences all number
    35
    28
    Hypokalaemia
         subjects affected / exposed
    43 / 551 (7.80%)
    35 / 546 (6.41%)
         occurrences all number
    62
    55

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    09 Nov 2017
    Following updates were made: [1] Clarification regarding Event reporting for hospitalisation and [2] Update for reviewing and handling protocol deviations.
    07 Mar 2018
    Following updates were made: [1] Clarification of glucose level monitoring during all clinic visits; [2] Modification of laboratory assessments for glucose level measurements and [3] Requirement for additional blood glucose level monitoring.
    01 Jun 2018
    Following updates were made: [1] Total Study size amended from 850 to 1100 subjects to support key secondary endpoint of overall survival; [2] Modification to plans for China extension cohort; [3] Total length of the study updated; [4] Clarification to Biopsy specimen requirements; [5] Guidance on the recording of opioids consumption for cancer-related pain has been added; [6] Criteria for rescreen has been amended; [7] Guidelines for management of diarrhea and Grade 1 hyperglycaemia updated and [8] Updates to the Statistical Analysis section with a testing algorithm for primary and key secondary endpoints.
    19 Oct 2018
    Following updates were made: [1] Addition of language following a Health Authority request to specify criteria for the discontinuation of ipatasertib/placebo and [2] Update to the Secondary Medical Monitor and contact information.
    13 Feb 2019
    Following updates were made: [1] Clarification regarding study treatment and concomitant use of CYP3A4 inhibitors or inducers with abiraterone; [2] Clarification on subject withdrawal of consent from the testing of his or her Research Biosample Repository (RBR) samples; [3] Key secondary endpoint of time-to-pain progression has been updated to specify that the initiation of opioid analgesic medication is assessed by the Analgesic Quantification Algorithm (AQA) score and [4] Minor changes have been made to Sections 7, 8 and 9 to reflect updates the Sponsor has made to language regarding data collection and management, ethical considerations and study documentation.

    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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