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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
    24 Apr 2024

    Results information
    Results version number
    		 v2(current)
    This version publication date
    25 Apr 2025
    First version publication date
    31 Mar 2023
    Other versions
    		 v1
    Version creation reason

    Trial information

    		 Close Top of page
    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, CH-4058
    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
    Final
    Date of interim/final analysis
    29 Jun 2024
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    24 Apr 2024
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The main purpose of this study was to evaluate the efficacy, safety, and pharmacokinetics (PK) of ipatasertib plus abiraterone and prednisone/prednisolone compared with placebo plus abiraterone and prednisone/prednisolone in participants with metastatic castrate-resistant prostate cancer (mCRPC).
    Protection of trial subjects
    All study participants were required to read and sign an Informed Consent Form (ICF).
    Background therapy
    		 All participants who did not undergo orchiectomy were on Gonadotropin-releasing hormone (GnRH) agonists or antagonists. All participants 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
    Yes
    Long term follow-up rationale
    		 Safety
    Long term follow-up duration
    		 76 Months
    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)
    286
    From 65 to 84 years
    787
    85 years and over
    28

    Subject disposition

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    Recruitment
    Recruitment details
    		 A total of 1101 male participants with mCRPC took part in the study at 181 investigative sites across 26 countries from June 30, 2017 to April 24, 2024.

    Pre-assignment
    Screening details
    		 Participants were randomized in 1:1 ratio to below treatment arms: abiraterone+prednisone/prednisolone+ipatasertib(Ipat+Abi) & abiraterone+prednisone/prednisolone+placebo(Pbo+Abi). 3 participants in Pbo & 1 in Ipat didn't receive any treatment. 5 participants randomized to Pbo took at least 1 dose of ipat & included in Ipat for safety analysis.

    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
    		 Pbo + Abi
    Arm description
    		 Participants received matching placebo along with abiraterone 1000 milligrams (mg), once a day (QD) and prednisone/prednisolone 5 mg, twice a day (BID) administered orally in each 28 day treatment cycle until disease progression, intolerable toxicity, elective withdrawal from the study, or study completion or termination.
    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, QD in each 28 day treatment cycle.

    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, BID at a dose of 5 mg in each 28 day treatment cycle.

    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, QD at a dose of 1000 mg in each 28 day treatment cycle.

    Arm title
    		 Ipat + Abi
    Arm description
    		 Participants received ipatasertib, 400 mg, QD along with abiraterone, 1000 mg, QD and prednisone/prednisolone, 5 mg, BID administered orally in each 28 day treatment cycle until disease progression, intolerable toxicity, elective withdrawal from the study, or study completion or termination.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Ipatasertib
    Investigational medicinal product code
    RO5532961
    Other name
    GDC-0068
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Ipatasertib was administered orally, QD at a dose of 400 mg in each 28 day treatment cycle.

    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, BID, at a dose of 5 mg in each 28 day treatment cycle.

    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, QD at a dose of 1000 mg in each 28 day treatment cycle.

    Number of subjects in period 1
    		Pbo + Abi Ipat + Abi
    Started
    554
    547
    Completed
    0
    0
    Not completed
    554
    547
         Consent withdrawn by subject
    44
    64
         Physician decision
    4
    6
         Reason Not Specified
    138
    150
         Death
    351
    318
         Progressive Disease
    3
    4
         Lost to follow-up
    14
    5

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Pbo + Abi
    Reporting group description
    		 Participants received matching placebo along with abiraterone 1000 milligrams (mg), once a day (QD) and prednisone/prednisolone 5 mg, twice a day (BID) administered orally in each 28 day treatment cycle until disease progression, intolerable toxicity, elective withdrawal from the study, or study completion or termination.

    Reporting group title
    Ipat + Abi
    Reporting group description
    		 Participants received ipatasertib, 400 mg, QD along with abiraterone, 1000 mg, QD and prednisone/prednisolone, 5 mg, BID administered orally in each 28 day treatment cycle until disease progression, intolerable toxicity, elective withdrawal from the study, or study completion or termination.

    Reporting group values
    		 Pbo + Abi Ipat + Abi Total
    Number of subjects
    		 554 547 1101
    Age categorical
    Units: subjects
    Age Continuous
    Units: years
        arithmetic mean (standard deviation)
    		 69.7 ( 8.2 ) 69.4 ( 8.0 ) -
    Sex: Female, Male
    Units: participants
        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
    Pbo + Abi
    Reporting group description
    		 Participants received matching placebo along with abiraterone 1000 milligrams (mg), once a day (QD) and prednisone/prednisolone 5 mg, twice a day (BID) administered orally in each 28 day treatment cycle until disease progression, intolerable toxicity, elective withdrawal from the study, or study completion or termination.

    Reporting group title
    Ipat + Abi
    Reporting group description
    		 Participants received ipatasertib, 400 mg, QD along with abiraterone, 1000 mg, QD and prednisone/prednisolone, 5 mg, BID administered orally in each 28 day treatment cycle until disease progression, intolerable toxicity, elective withdrawal from the study, or study completion or termination.

    Subject analysis set title
    Pbo + Abi
    Subject analysis set type
    		 Safety analysis
    Subject analysis set description
    Participants received matching placebo along with abiraterone 1000 mg, QD and prednisone/prednisolone, 5 mg, BID administered orally in each 28 day treatment cycle until disease progression, intolerable toxicity, elective withdrawal from the study, or study completion or termination.

    Subject analysis set title
    Ipat + Abi
    Subject analysis set type
    		 Safety analysis
    Subject analysis set description
    Participants received ipatasertib, 400 mg, QD along with abiraterone, 1000 mg, QD and prednisone/prednisolone, 5 mg, BID administered orally in each 28 day treatment cycle until disease progression, intolerable toxicity, elective withdrawal from the study, or study completion or termination.

    Primary: Investigator-assessed Radiographic Progression-free Survival (rPFS), per Prostate Cancer Working Group 3 (PCWG3) Criteria in Phosphatase and Tensin Homolog (PTEN) Loss Population

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    End point title
    		 Investigator-assessed Radiographic Progression-free Survival (rPFS), per Prostate Cancer Working Group 3 (PCWG3) Criteria in Phosphatase and Tensin Homolog (PTEN) Loss Population
    End point description
    rPFS=time from date of randomization to first occurrence of documented disease progression(PD), as assessed by investigator with use of PCWG3 criteria/death from any cause, whichever occurs first. PD for soft tissue=at least a 20% increase in sum of diameters(SOD) of target lesions, taking as reference smallest sum on study, including baseline& an absolute increase of at least 5 millimeters(mm) in SOD of target lesions; progression of non-target lesions; appearance of one/more new lesions according to Response Evaluation Criteria in Solid Tumors, Version 1.1(RECIST v1.1). PD for bone lesions= 2 or more new lesions compared to baseline followed by a confirmatory bone scan at least 6 weeks later according to PCWG3 criteria. PTEN loss population=all randomized participants with PTEN loss tumors by immunohistochemistry (IHC), regardless of whether /not the participant received the assigned treatment. Number analysed signifies the participants who were evaluable for the PTEN population.
    End point type
    Primary
    End point timeframe
    Up to approximately 32 months
    End point values
    		 Pbo + Abi Ipat + Abi
    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 + Abi vs Pbo + Abi
    Comparison groups
    Ipat + Abi v Pbo + Abi
    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 rPFS, per PCWG3 Criteria in ITT Population

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    End point title
    		 Investigator-assessed rPFS, per PCWG3 Criteria in ITT Population
    End point description
    rPFS=time from date of randomization to first occurrence of documented PD, as assessed by investigator with use of PCWG3 criteria or death from any cause, whichever occurs first. PD for soft tissue was defined as at least a 20% increase in SOD of target lesions, taking as reference smallest sum on study, including baseline & an absolute increase of at least 5 mm in SOD of target lesions; progression of non-target lesions; appearance of one/more new lesions according to RECIST v1.1 criteria. PD for bone lesions was defined as 2 or more new lesions compared to baseline followed by a confirmatory bone scan at least 6 weeks later according to PCWG3 criteria. Kaplan-Meier (KM) estimate was used to determine median rPFS. ITT population included all randomized participants, whether or not the participants received the assigned treatment.
    End point type
    Primary
    End point timeframe
    Up to approximately 32 months
    End point values
    		 Pbo + Abi Ipat + Abi
    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 + Abi vs Pbo + Abi
    Comparison groups
    Pbo + Abi v Ipat + Abi
    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 (OS) in PTEN-loss Population

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    End point title
    		 Overall Survival (OS) in PTEN-loss Population
    End point description
    OS was defined as the time from randomization to death due to any cause. KM estimates were used to determine the median OS. PTEN loss population included all randomized participants with PTEN loss tumors by IHC, regardless of whether or not the participant received the assigned treatment. Number analysed signifies the participants who were evaluable for PTEN population.
    End point type
    Secondary
    End point timeframe
    Up to approximately 5.5 years
    End point values
    		 Pbo + Abi Ipat + Abi
    Number of subjects analysed
    261
    260
    Units: months
        median (confidence interval 95%)
    35.8 (30.8 to 39.6)
    36.8 (31.4 to 42.1)
    Statistical analysis title
    		 Ipat + Abi Vs Pbo + Abi
    Comparison groups
    Pbo + Abi v Ipat + Abi
    Number of subjects included in analysis
    521
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    		 = 0.5698
    Method
    		 Logrank
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.94
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.76
         upper limit
    		 1.17

    Secondary: OS in ITT Population

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    End point title
    		 OS in ITT Population
    End point description
    OS was defined as the time from randomization to death due to any cause. KM estimates were used to determine the median OS. ITT population included all randomized participants, whether or not the participants received the assigned treatment.
    End point type
    Secondary
    End point timeframe
    Up to approximately 5.5 years
    End point values
    		 Pbo + Abi Ipat + Abi
    Number of subjects analysed
    554
    547
    Units: months
        median (confidence interval 95%)
    36.5 (33.9 to 39.4)
    39.4 (36.5 to 42.9)
    Statistical analysis title
    		 Ipat + Abi Vs Pbo + Abi
    Comparison groups
    Pbo + Abi v Ipat + Abi
    Number of subjects included in analysis
    1101
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    		 = 0.2515
    Method
    		 Logrank
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.91
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.79
         upper limit
    		 1.07

    Secondary: Time to Pain Progression in PTEN-loss Population

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    End point title
    		 Time to Pain Progression in PTEN-loss Population
    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 participants who were asymptomatic at baseline or pain worsening for those who were mildly symptomatic at baseline. Pain severity was graded on a 10-point numeric rating scale [NRS], with 0=no pain and 10=severe pain. Pain severity progression was defined as a ≥ 2-point absolute increase from baseline. KM estimates were used to determine the median time to pain progression. PTEN loss population included all randomized participants with PTEN loss tumors by IHC, regardless of whether or not the participant received the assigned treatment. Number analysed signifies the participants who were evaluable for PTEN population.
    End point type
    Secondary
    End point timeframe
    Up to approximately 5.5 years
    End point values
    		 Pbo + Abi Ipat + Abi
    Number of subjects analysed
    261
    260
    Units: months
        median (confidence interval 95%)
    17.6 (14.6 to 27.7)
    25.8 (17.5 to 43.3)
    Statistical analysis title
    		 Ipat + Abi Vs Pbo + Abi
    Comparison groups
    Pbo + Abi v Ipat + Abi
    Number of subjects included in analysis
    521
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    		 = 0.601
    Method
    		 Logrank
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.76
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.58
         upper limit
    		 1.01

    Secondary: Time to Pain Progression in ITT Population

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    End point title
    		 Time to Pain Progression in ITT Population
    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 participants who were asymptomatic at baseline or pain worsening for those who were mildly symptomatic at baseline. Pain severity was graded on a 10-point NRS, with 0=no pain and 10=severe pain. Pain severity progression was defined as a ≥ 2-point absolute increase from baseline. KM estimates were used to determine the median time to pain progression. ITT population included all randomized participants, whether or not the participants received the assigned treatment.
    End point type
    Secondary
    End point timeframe
    Up to approximately 5.5 years
    End point values
    		 Pbo + Abi Ipat + Abi
    Number of subjects analysed
    554
    547
    Units: months
        median (confidence interval 95%)
    21.9 (17.5 to 27.7)
    25.9 (20.2 to 40.7)
    Statistical analysis title
    		 Ipat + Abi Vs Pbo + Abi
    Comparison groups
    Pbo + Abi v Ipat + Abi
    Number of subjects included in analysis
    1101
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    		 = 0.1723
    Method
    		 Logrank
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.87
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.72
         upper limit
    		 1.06

    Secondary: Time to Initiation of Cytotoxic Chemotherapy for PC in ITT Population

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    End point title
    		 Time to Initiation of Cytotoxic Chemotherapy for PC in ITT Population
    End point description
    Time to initiation of cytotoxic chemotherapy was 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 PC. KM estimates were used to determine the median time to initiation of cytotoxic chemotherapy. ITT population included all randomized participants, whether or not the participants received the assigned treatment. 9999=The upper limit of 95% confidence interval (CI) was not estimable due to insufficient number of participants with events.
    End point type
    Secondary
    End point timeframe
    Up to approximately 5.5 years
    End point values
    		 Pbo + Abi Ipat + Abi
    Number of subjects analysed
    554
    547
    Units: months
        median (confidence interval 95%)
    35.5 (30.9 to 40.3)
    40.4 (34.7 to 9999)
    Statistical analysis title
    		 Ipat + Abi Vs Pbo + Abi
    Comparison groups
    Pbo + Abi v Ipat + Abi
    Number of subjects included in analysis
    1101
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    		 = 0.0419
    Method
    		 Logrank
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.83
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.69
         upper limit
    		 0.99

    Secondary: Time to Initiation of Cytotoxic Chemotherapy for Prostate Cancer (PC) in PTEN-loss Population

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    End point title
    		 Time to Initiation of Cytotoxic Chemotherapy for Prostate Cancer (PC) in PTEN-loss Population
    End point description
    Time to initiation of cytotoxic chemotherapy was 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 PC. The KM estimates were used to determine the median time to initiation of cytotoxic chemotherapy. PTEN loss population included all randomized participants with PTEN loss tumors by IHC, regardless of whether or not the participant received the assigned treatment. Number analysed signifies the participants who were evaluable for PTEN population.
    End point type
    Secondary
    End point timeframe
    Up to approximately 5.5 years
    End point values
    		 Pbo + Abi Ipat + Abi
    Number of subjects analysed
    261
    260
    Units: months
        median (confidence interval 95%)
    33.6 (26.3 to 38.8)
    36.3 (30.5 to 58.6)
    Statistical analysis title
    		 Ipat + Abi Vs Pbo + Abi
    Comparison groups
    Pbo + Abi v Ipat + Abi
    Number of subjects included in analysis
    521
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    		 = 0.1566
    Method
    		 Logrank
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.83
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.65
         upper limit
    		 1.07

    Secondary: Time to Function Deterioration per EORTC QLQ-C30 PF Scale and RF Scale in ITT Population

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    End point title
    		 Time to Function Deterioration per EORTC QLQ-C30 PF Scale and RF Scale in ITT Population
    End point description
    Time to function deterioration=time from date of randomization to date of 10-point or more score decrease on either EORTC QLQ-C30 5-item PF/2-item RF scale scores, held for two consecutive assessments or death within 28 days, whichever occurs first. EORTC QLQ-C30 consists of 30 questions that assess 5 aspects of participant functioning (physical,emotional,role,cognitive & social), 3 symptom scales (fatigue,nausea,vomiting&pain), GHS/QoL & 6 single items (dyspnea,insomnia,appetite loss,constipation,diarrhea & financial difficulties). PF scale has 5 questions about participants' physical functioning & daily activities. RF scale has 2 questions about work/daily activities & hobbies/leisurely activities. PF&RF are scored on a 4-point scale (1=Not at All to 4=Very Much). Obtained scores are linearly transformed to score range of 0-100, where higher scores=higher response level (better PF) & better functioning/support. ITT population.
    End point type
    Secondary
    End point timeframe
    Up to approximately 5.5 years
    End point values
    		 Pbo + Abi Ipat + Abi
    Number of subjects analysed
    554
    547
    Units: months
        median (confidence interval 95%)
    14.8 (12.0 to 18.2)
    9.2 (7.4 to 11.1)
    Statistical analysis title
    		 Ipat + Abi vs Pbo + Abi
    Comparison groups
    Pbo + Abi v Ipat + Abi
    Number of subjects included in analysis
    1101
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    		 = 0.0071
    Method
    		 Logrank
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    1.25
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 1.06
         upper limit
    		 1.47

    Secondary: Time to Function Deterioration per European Organisation for Research and Treatment of Cancer Core Quality of Life Questionnaire (EORTC QLQ-C30) Physical Function (PF) Scale and Role Function (RF) Scale in PTEN-loss Population

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    End point title
    		 Time to Function Deterioration per European Organisation for Research and Treatment of Cancer Core Quality of Life Questionnaire (EORTC QLQ-C30) Physical Function (PF) Scale and Role Function (RF) Scale in PTEN-loss Population
    End point description
    Time to function deterioration=time from date of randomization to date of 10-point/more score decrease on EORTC QLQ-C30 5-item PF/2-item RF scale scores, held for 2 consecutive assessments or death within 28 days,whichever occurs first. EORTC QLQ-C30 consists of 30 questions that assess 5 aspects of functioning (physical,emotional,role,cognitive,&social), 3 symptoms(fatigue,nausea,vomiting&pain), global health/quality of life(GHS/QoL)& 6 single items(dyspnea,insomnia,appetite loss,constipation,diarrhea&financial difficulties). PF has 5 questions about participants' physical functioning&daily activities. RF has 2 questions about work/daily activities&hobbies/leisurely activities. PF&RF are scored on a 4-point scale(1=Not at All to 4=Very Much). Obtained scores are linearly transformed to score range of 0-100, where higher scores=higher response level/better PF, functioning/support. PTEN loss population. Number analysed=participants who were evaluable for PTEN population.
    End point type
    Secondary
    End point timeframe
    Up to approximately 5.5 years
    End point values
    		 Pbo + Abi Ipat + Abi
    Number of subjects analysed
    261
    260
    Units: months
        median (confidence interval 95%)
    15.7 (12.1 to 21.2)
    12.5 (9.3 to 16.3)
    Statistical analysis title
    		 Ipat + Abi vs Pbo + Abi
    Comparison groups
    Pbo + Abi v Ipat + Abi
    Number of subjects included in analysis
    521
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    		 = 0.3198
    Method
    		 Logrank
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    1.13
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.89
         upper limit
    		 1.45

    Secondary: Time to Prostate-specific Antigen (PSA) Progression, per the PCWG3 Criteria in PTEN-loss Population

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    End point title
    		 Time to Prostate-specific Antigen (PSA) Progression, per the PCWG3 Criteria in PTEN-loss Population
    End point description
    Time to PSA progression was defined as the time from the date of randomization to the first occurrence of PSA progression, per the PCWG3 criteria. PSA progression was defined as a PSA increase that was ≥ 25% and ≥ 2 nanograms per milliliters (ng/mL) above the baseline or the nadir, which was confirmed by a second value ≥ 3 weeks later. KM estimate was used to determine the median time to PSA. PTEN loss population included all randomized participants with PTEN loss tumors by IHC, regardless of whether or not the participant received the assigned treatment. Number analysed signifies the participants who were evaluable for PTEN population.
    End point type
    Secondary
    End point timeframe
    Up to approximately 5.5 years
    End point values
    		 Pbo + Abi Ipat + Abi
    Number of subjects analysed
    261
    260
    Units: months
        median (confidence interval 95%)
    7.6 (6.5 to 9.3)
    12.6 (10.2 to 15.3)
    Statistical analysis title
    		 Ipat + Abi vs Pbo + Abi
    Comparison groups
    Pbo + Abi v Ipat + Abi
    Number of subjects included in analysis
    521
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    		 = 0.0045
    Method
    		 Logrank
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.73
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.59
         upper limit
    		 0.91

    Secondary: Time to PSA Progression, per the PCWG3 Criteria in ITT Population

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    End point title
    		 Time to PSA Progression, per the PCWG3 Criteria in ITT Population
    End point description
    Time to PSA progression was defined as the time from the date of randomization to the first occurrence of PSA progression, per the PCWG3 criteria. PSA progression was defined as a PSA increase that was ≥ 25% and ≥ 2 ng/mL above the baseline or the nadir, which was confirmed by a second value ≥ 3 weeks later. KM estimate was used to determine the median time to PSA. ITT population included all randomized participants, whether or not the participants received the assigned treatment.
    End point type
    Secondary
    End point timeframe
    Up to approximately 5.5 years
    End point values
    		 Pbo + Abi Ipat + Abi
    Number of subjects analysed
    554
    547
    Units: months
        median (confidence interval 95%)
    8.3 (7.4 to 9.3)
    12.6 (10.3 to 14.8)
    Statistical analysis title
    		 Ipat + Abi vs Pbo + Abi
    Comparison groups
    Pbo + Abi v Ipat + Abi
    Number of subjects included in analysis
    1101
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    		 < 0.0001
    Method
    		 Logrank
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.71
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.61
         upper limit
    		 0.83

    Secondary: Time to First Opioid Use in PTEN-loss Population

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    End point title
    		 Time to First Opioid Use in PTEN-loss Population
    End point description
    Time to first opioid use was defined as the time interval from the date of randomization to the date of an initiation of opioid analgesic use for cancer-related pain, and consumption reported on at least 7 consecutive days. KM estimate was used to determine the median time to first opioid use. PTEN loss population included all randomized participants with PTEN loss tumors by IHC, regardless of whether or not the participant received the assigned treatment. Number analysed signifies the participants who were evaluable for PTEN population. 99999 = Median and upper limit of 95% CI were not estimable due to insufficient number of participants with events.
    End point type
    Secondary
    End point timeframe
    Up to approximately 5.5 years
    End point values
    		 Pbo + Abi Ipat + Abi
    Number of subjects analysed
    261
    260
    Units: months
        median (confidence interval 95%)
    99999 (14.1 to 99999)
    99999 (21.5 to 99999)
    Statistical analysis title
    		 Ipat + Abi vs Pbo + Abi
    Comparison groups
    Pbo + Abi v Ipat + Abi
    Number of subjects included in analysis
    521
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    		 = 0.1359
    Method
    		 Logrank
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.79
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.57
         upper limit
    		 1.08

    Secondary: Time to First Opioid Use in ITT Population

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    End point title
    		 Time to First Opioid Use in ITT Population
    End point description
    Time to first opioid use was defined as the time interval from the date of randomization to the date of an initiation of opioid analgesic use for cancer-related pain, and consumption reported on at least 7 consecutive days. KM estimate was used to determine the median time to first opioid use. ITT population included all randomized participants, whether or not the participants received the assigned treatment. 99999 = The median & the 95% CI were not estimable due to insufficient number of participants with events.
    End point type
    Secondary
    End point timeframe
    Up to approximately 5.5 years
    End point values
    		 Pbo + Abi Ipat + Abi
    Number of subjects analysed
    554
    547
    Units: months
        median (confidence interval 95%)
    99999 (99999 to 99999)
    99999 (99999 to 99999)
    Statistical analysis title
    		 Ipat + Abi vs Pbo + Abi
    Comparison groups
    Pbo + Abi v Ipat + Abi
    Number of subjects included in analysis
    1101
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    		 = 0.1398
    Method
    		 Logrank
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.85
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.68
         upper limit
    		 1.06

    Secondary: Time to Symptomatic Skeletal Event (SSE) in PTEN-loss Population

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    End point title
    		 Time to Symptomatic Skeletal Event (SSE) in PTEN-loss Population
    End point description
    Time to SSE was defined as the time from randomization to the first occurrence of an SSE. An SSE was defined using one of the following: use of external-beam radiotherapy to relieve skeletal symptoms (including initiation of radium-223 to treat symptoms of bone metastases); occurrence of a new symptomatic pathological bone fracture (vertebral or non-vertebral); clinically apparent occurrence of spinal cord compression, or a tumor-related orthopedic surgical intervention. The KM estimates were used to determine the median time to SSE. PTEN loss population included all randomized participants with PTEN loss tumors by IHC, regardless of whether or not the participant received the assigned treatment. Number analysed signifies the participants who were evaluable for the PTEN population. 99999 = The median & 95% CI were not estimable due to insufficient number of participants with events.
    End point type
    Secondary
    End point timeframe
    Up to approximately 5.5 years
    End point values
    		 Pbo + Abi Ipat + Abi
    Number of subjects analysed
    261
    260
    Units: months
        median (confidence interval 95%)
    99999 (99999 to 99999)
    99999 (99999 to 99999)
    Statistical analysis title
    		 Ipat + Abi vs Pbo + Abi
    Comparison groups
    Pbo + Abi v Ipat + Abi
    Number of subjects included in analysis
    521
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    		 = 0.8239
    Method
    		 Logrank
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.95
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.61
         upper limit
    		 1.48

    Secondary: Time to SSE in ITT Population

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    End point title
    		 Time to SSE in ITT Population
    End point description
    Time to SSE was defined as the time from randomization to the first occurrence of an SSE. An SSE was defined using one of the following: use of external-beam radiotherapy to relieve skeletal symptoms (including initiation of radium-223 to treat symptoms of bone metastases); occurrence of a new symptomatic pathological bone fracture (vertebral or non-vertebral); clinically apparent occurrence of spinal cord compression, or a tumor-related orthopedic surgical intervention. KM estimates were used to determine the median time to SSE. ITT population included all randomized participants, whether or not the participants received the assigned treatment. 99999 = The median & 95% CI were not estimable due to insufficient number of participants with events.
    End point type
    Secondary
    End point timeframe
    Up to approximately 5.5 years
    End point values
    		 Pbo + Abi Ipat + Abi
    Number of subjects analysed
    554
    547
    Units: months
        median (confidence interval 95%)
    99999 (99999 to 99999)
    99999 (99999 to 99999)
    Statistical analysis title
    		 Ipat + Abi vs Pbo + Abi
    Comparison groups
    Pbo + Abi v Ipat + Abi
    Number of subjects included in analysis
    1101
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    		 = 0.6018
    Method
    		 Logrank
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.92
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.66
         upper limit
    		 1.27

    Secondary: Objective Response Rate (ORR) per RECIST V1.1 and PCWG3 Criteria in Participants With Measurable Disease in PTEN-loss Population

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    End point title
    		 Objective Response Rate (ORR) per RECIST V1.1 and PCWG3 Criteria in Participants With Measurable Disease in PTEN-loss Population
    End point description
    ORR=percentage of participants who had an objective response (OR) with measurable disease at baseline. OR=complete response (CR) or partial response (PR) on 2 consecutive occasions ≥4 weeks apart, as determined by investigator using RECIST v1.1 and PCWG3 criteria in participants with measurable disease at baseline. CR was defined as disappearance of all target lesions & any pathological lymph nodes (whether target or non-target) must have a reduction in short axis to < 10 mm. PR was defined as at least a 30% decrease in the SOD of target lesions, taking as reference the baseline SOD. An estimate of ORR was calculated for each treatment arm, and its 95% CI was calculated using the Clopper-pearson method. PTEN loss population included all randomized participants with PTEN loss tumors by IHC, regardless of whether or not the participant received the assigned treatment. Number analysed is the number of participants with measurable disease at baseline. Percentage have been rounded off.
    End point type
    Secondary
    End point timeframe
    Up to approximately 5.5 years
    End point values
    		 Pbo + Abi Ipat + Abi
    Number of subjects analysed
    96
    99
    Units: percentage of participants
        number (confidence interval 95%)
    42.7 (32.66 to 53.22)
    63.6 (53.36 to 73.07)
    Statistical analysis title
    		 Ipat + Abi vs Pbo + Abi
    Comparison groups
    Pbo + Abi v Ipat + Abi
    Number of subjects included in analysis
    195
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    		 = 0.003
    Method
    		 Cochran-Mantel-Haenszel
    Parameter type
    		 Difference in Overall Response Rate
    Point estimate
    20.93
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 6.2
         upper limit
    		 35.65

    Secondary: ORR per RECIST V1.1 and PCWG3 Criteria in Participants With Measurable Disease in ITT Population

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    End point title
    		 ORR per RECIST V1.1 and PCWG3 Criteria in Participants With Measurable Disease in ITT Population
    End point description
    ORR was defined as the percentage of participants who had an OR with measurable disease at baseline. OR=CR or PR on 2 consecutive occasions ≥4 weeks apart, as determined by investigator using RECIST v1.1 and PCWG3 criteria in participants with measurable disease at baseline. CR was defined as disappearance of all target lesions & any pathological lymph nodes (whether target or non-target) must have a reduction in short axis to < 10 mm. PR was defined as at least a 30% decrease in SOD of target lesions, taking as reference the baseline SOD. An estimate of ORR was calculated for each treatment arm, and its 95% CI was calculated using the Clopper-Pearson method. ITT population included all randomized participants, whether or not the participants received the assigned treatment. Number analysed is the number of participants with measurable disease at baseline. Percentages have been rounded off.
    End point type
    Secondary
    End point timeframe
    Up to approximately 5.5 years
    End point values
    		 Pbo + Abi Ipat + Abi
    Number of subjects analysed
    225
    201
    Units: percentage of participants
        number (confidence interval 95%)
    46.2 (39.57 to 52.97)
    62.7 (55.60 to 69.39)
    Statistical analysis title
    		 Ipat + Abi vs Pbo + Abi
    Comparison groups
    Pbo + Abi v Ipat + Abi
    Number of subjects included in analysis
    426
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    		 = 0.0008
    Method
    		 Cochran-Mantel-Haenszel
    Parameter type
    		 Difference in Overall Response Rate
    Point estimate
    16.46
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 6.66
         upper limit
    		 26.27

    Secondary: Duration of Confirmed Response (DOCR) in PTEN-loss Population

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    End point title
    		 Duration of Confirmed Response (DOCR) in PTEN-loss Population
    End point description
    DOCR=time from the first documented OR (CR or PR) to documented PD as determined by investigator using RECIST v1.1 and PCWG3 criteria, or death from any cause, whichever occured first. CR=disappearance of all target lesions and any pathological lymph nodes (whether target or non-target) must have reduction in short axis to < 10 mm. PR=at least a 30% decrease in the SOD of target lesions, taking as reference the baseline SOD. PD=at least a 20% increase in the SOD of target lesions, taking as reference the smallest sum on study, including baseline, and an absolute increase of at least 5 mm in the SOD of target lesions; progression of non-target lesions; the appearance of one or more new lesions. DOR was estimated using the KM methodology. PTEN loss population included all randomized participants with PTEN loss tumors by IHC, regardless of whether or not the participant received the assigned treatment. Numberanalysed=participants with objective response i.e, responders,
    End point type
    Secondary
    End point timeframe
    Up to approximately 5.5 years
    End point values
    		 Pbo + Abi Ipat + Abi
    Number of subjects analysed
    41
    63
    Units: months
        median (confidence interval 95%)
    14.4 (12.1 to 18.5)
    19.6 (15.3 to 24.4)
    No statistical analyses for this end point

    Secondary: DOCR in ITT Population

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    End point title
    		 DOCR in ITT Population
    End point description
    DOCR=the time from the first documented OR (CR or PR) to documented PD as determined by investigator using RECIST v1.1 & PCWG3 criteria, or death from any cause, whichever occurred first. CR was defined as disappearance of all target lesions and any pathological lymph nodes (whether target or non-target) must have reduction in short axis to < 10 mm. PR was defined as at least a 30% decrease in the SOD of target lesions, taking as reference the baseline SOD. PD was defined as at least a 20% increase in the SOD of target lesions, taking as reference the smallest sum on study, including baseline, and an absolute increase of at least 5 mm in the SOD of target lesions; progression of non-target lesions; the appearance of one or more new lesions. DOR was estimated using the KM methodology. ITT population included all randomized participants, whether or not the participants received the assigned treatment. Number analysed=participants with objective response i.e, responders.
    End point type
    Secondary
    End point timeframe
    Up to approximately 5.5 years
    End point values
    		 Pbo + Abi Ipat + Abi
    Number of subjects analysed
    104
    126
    Units: months
        median (confidence interval 95%)
    16.3 (13.4 to 20.2)
    18.2 (14.4 to 22.1)
    No statistical analyses for this end point

    Secondary: PSA Response Rate in ITT Population

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    End point title
    		 PSA Response Rate in ITT Population
    End point description
    PSA response rate was defined as the percentage of participants achieving a PSA decline ≥ 50% from baseline. Participants without a post-baseline PSA assessment were considered to be non-responders. ITT population included all randomized participants, whether or not the participants received the assigned treatment. Number analysed= participants with data available for analysis. Percentages have been rounded off.
    End point type
    Secondary
    End point timeframe
    Up to approximately 5.5 years
    End point values
    		 Pbo + Abi Ipat + Abi
    Number of subjects analysed
    554
    546
    Units: percentage of participants
        number (confidence interval 95%)
    75.5 (71.65 to 78.98)
    81.3 (77.79 to 84.50)
    Statistical analysis title
    		 Ipat + Abi vs Pbo + Abi
    Comparison groups
    Pbo + Abi v Ipat + Abi
    Number of subjects included in analysis
    1100
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    		 = 0.0178
    Method
    		 Cochran-Mantel-Haenszel
    Parameter type
    		 Difference in Overall Response Rate
    Point estimate
    5.87
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.83
         upper limit
    		 10.9

    Secondary: PSA Response Rate in PTEN-loss Population

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    End point title
    		 PSA Response Rate in PTEN-loss Population
    End point description
    PSA response rate was defined as the percentage of participants achieving a PSA decline ≥ 50% from baseline. Participants without a post-baseline PSA assessment were considered to be non-responders. PTEN loss population included all randomized participants with PTEN loss tumors by IHC, regardless of whether or not the participant received the assigned treatment. Number analysed signifies the participants who were evaluable for PTEN population. Percentages have been rounded off.
    End point type
    Secondary
    End point timeframe
    Up to approximately 5.5 years
    End point values
    		 Pbo + Abi Ipat + Abi
    Number of subjects analysed
    261
    260
    Units: percentage of participants
        number (confidence interval 95%)
    71.6 (65.76 to 77.03)
    83.5 (78.38 to 87.77)
    Statistical analysis title
    		 Ipat + Abi vs Pbo + Abi
    Comparison groups
    Pbo + Abi v Ipat + Abi
    Number of subjects included in analysis
    521
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    		 = 0.0012
    Method
    		 Cochran-Mantel-Haenszel
    Parameter type
    		 Difference in Overall Response Rate
    Point estimate
    11.81
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 4.34
         upper limit
    		 19.29

    Secondary: Investigator-assessed rPFS per PCWG3 Criteria in PTEN-loss Population by Next-generation Sequencing (NGS)

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    End point title
    		 Investigator-assessed rPFS per PCWG3 Criteria in PTEN-loss Population by Next-generation Sequencing (NGS)
    End point description
    rPFS=time from date of randomization to the first occurrence of documented PD, as assessed by the investigator using the PCWG3 criteria or death from any cause, whichever occurs first. PD for soft tissue was defined as at least a 20% increase in the SOD of target lesions, taking as reference the smallest sum on study, including baseline, and an absolute increase of at least 5 mm in the SOD of target lesions; progression of non-target lesions; the appearance of one or more new lesions. PD for bone lesions was defined as 2 or more new lesions compared to baseline followed by a confirmatory bone scan at least 6 weeks later. PTEN loss population included all randomized participants with PTEN Loss tumors by NGS, regardless of whether or not the participant received the assigned treatment. Number analysed signifies the participants who were evaluable for PTEN population. 9999 = The upper limit of 95% CI was not estimable due to insufficient number of participants with events.
    End point type
    Secondary
    End point timeframe
    Up to approximately 32 months
    End point values
    		 Pbo + Abi Ipat + Abi
    Number of subjects analysed
    103
    105
    Units: months
        median (confidence interval 95%)
    14.2 (10.9 to 18.7)
    19.1 (13.9 to 9999)
    Statistical analysis title
    		 Ipat + Abi vs Pbo + Abi
    Comparison groups
    Pbo + Abi v Ipat + Abi
    Number of subjects included in analysis
    208
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    		 = 0.0246
    Method
    		 Logrank
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.65
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.45
         upper limit
    		 0.95

    Secondary: Plasma Concentrations of Ipatasertib at Specified Timepoints

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    End point title
    		 Plasma Concentrations of Ipatasertib at Specified Timepoints [1]
    End point description
    Plasma samples for pharmacokinetic characterization was collected at various timepoints in all subjects. Pharmacokinetic (PK)-evaluable population included all participants who received ipatasertib treatment with evaluable PK samples. Number analyzed is the number of participants with data available for analysis. n=unique number of participants out all the assessed participants with data available for analysis at the specified timepoint. Different participants may have contributed data for each 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
    [1] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Plasma concentration for Ipatasertib is being reported for this outcome measure.
    End point values
    		 Ipat + Abi
    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: Percentage of Participants with Adverse Events (AEs)

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    End point title
    		 Percentage of Participants with Adverse Events (AEs)
    End point description
    An AE was any untoward medical occurrence in a participant administered a pharmaceutical product and which does not necessarily have to have a causal relationship with the treatment. An AE 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 were also considered as AEs. SE population included all participants who received any amount of the study treatment. 5 participants randomized to the placebo arm took at least one dose of ipatasertib and hence were included in the Ipat + Abi arm for safety analysis. Percentages have been rounded off.
    End point type
    Secondary
    End point timeframe
    Up to 28 days after last study drug administration (approximately 6.5 years)
    End point values
    		 Pbo + Abi Ipat + Abi
    Number of subjects analysed
    546
    551
    Units: percentage of participants
        number (not applicable)
    96.2
    99.6
    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. PK-evaluable population included all participants who received abiraterone treatment with evaluable PK samples. Number analyzed is the number of participants with data available for analysis. n=unique number of participants out of all the assessed participants with data available at the specified timepoint. Different participants may have contributed data for each 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
    		 Pbo + Abi Ipat + Abi
    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
    Serious and non serious AEs: From study start until 28 days after the last dose of study drug (up to a maximum of 6.5 years) All cause mortality: Up to 5.5 years
    Adverse event reporting additional description
    SE Population included all participants who received any amount of the study treatment. 5 participants randomized to the placebo arm took at least one dose of ipatasertib and hence were included in the Ipat + Abi arm for safety analysis.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    27.0
    Reporting groups
    Reporting group title
    Ipat + Abi
    Reporting group description
    		 Participants received ipatasertib, 400 mg, QD along with abiraterone, 1000 mg, QD and prednisone/prednisolone, 5 mg, BID administered orally in each 28 day treatment cycle until disease progression, intolerable toxicity, elective withdrawal from the study, or study completion or termination.

    Reporting group title
    Pbo + Abi
    Reporting group description
    		 Participants received matching placebo along with abiraterone 1000 mg, QD and prednisone/prednisolone 5 mg, BID administered orally in each 28 day treatment cycle until disease progression, intolerable toxicity, elective withdrawal from the study, or study completion or termination.

    Serious adverse events
    		 Ipat + Abi Pbo + Abi
    Total subjects affected by serious adverse events
         subjects affected / exposed
    252 / 551 (45.74%)
    158 / 546 (28.94%)
         number of deaths (all causes)
    331
    358
         number of deaths resulting from adverse events
    4
    2
    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
    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
    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%)
    1 / 546 (0.18%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    0 / 1
    Malignant melanoma
         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
    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
    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
    Colorectal cancer
         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
    Laryngeal cancer stage 0
         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 adenocarcinoma stage I
         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
    Colon cancer
         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 / 1
    Renal 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
    Non-small cell lung cancer
         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
    Benign neoplasm of ampulla of Vater
         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
    Vascular disorders
    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
    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
    Hypotension
         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
    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
    Aortic dissection
         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
    Peripheral vascular disorder
         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
    Peripheral ischaemia
         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
    General disorders and administration site conditions
    Chest pain
         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
    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
    Death
         subjects affected / exposed
    4 / 551 (0.73%)
    3 / 546 (0.55%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 3
         deaths causally related to treatment / all
    0 / 4
    0 / 3
    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
    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
    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
    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
    Oedema peripheral
         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
    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
    Pyrexia
         subjects affected / exposed
    4 / 551 (0.73%)
    3 / 546 (0.55%)
         occurrences causally related to treatment / all
    0 / 4
    1 / 4
         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
    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
    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
    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
    Respiratory, thoracic and mediastinal disorders
    Dyspnoea
         subjects affected / exposed
    2 / 551 (0.36%)
    2 / 546 (0.37%)
         occurrences causally related to treatment / all
    0 / 2
    1 / 2
         deaths causally related to treatment / all
    0 / 1
    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
    1 / 551 (0.18%)
    3 / 546 (0.55%)
         occurrences causally related to treatment / all
    1 / 1
    2 / 3
         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
    Acute respiratory distress syndrome
         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
    Interstitial lung disease
         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
    Pulmonary oedema
         subjects affected / exposed
    1 / 551 (0.18%)
    0 / 546 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Psychiatric disorders
    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
    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
    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
    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%)
    4 / 546 (0.73%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 6
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    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
    4 / 551 (0.73%)
    4 / 546 (0.73%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 4
         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
    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
    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
    1 / 1
    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
    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%)
    2 / 546 (0.37%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
         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
    Compression 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
    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
    Thoracic vertebral 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
    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%)
    7 / 546 (1.28%)
         occurrences causally related to treatment / all
    1 / 3
    1 / 7
         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
    7 / 551 (1.27%)
    3 / 546 (0.55%)
         occurrences causally related to treatment / all
    0 / 7
    0 / 4
         deaths causally related to treatment / all
    0 / 1
    0 / 2
    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%)
    1 / 546 (0.18%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    0 / 1
    Cardiac arrest
         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 / 4
    0 / 2
    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 flutter
         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
    Atrial fibrillation
         subjects affected / exposed
    2 / 551 (0.36%)
    2 / 546 (0.37%)
         occurrences causally related to treatment / all
    0 / 2
    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
    Cardiac failure 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 / 1
    0 / 0
    Myocarditis
         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
    1 / 1
    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
    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
    Cerebrovascular accident
         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
    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
    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
    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
    2 / 551 (0.36%)
    2 / 546 (0.37%)
         occurrences causally related to treatment / all
    0 / 2
    2 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cerebral infarction
         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
    Polyneuropathy
         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
    Dizziness
         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
    Monoparesis
         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
    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
    7 / 551 (1.27%)
    3 / 546 (0.55%)
         occurrences causally related to treatment / all
    1 / 7
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ear and labyrinth disorders
    Vertigo
         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
    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
    Diarrhoea
         subjects affected / exposed
    14 / 551 (2.54%)
    0 / 546 (0.00%)
         occurrences causally related to treatment / all
    11 / 14
    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
    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
    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
    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
    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
    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
    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
    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
    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
    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
    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
    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
    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
    Ileus paralytic
         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
    Incarcerated inguinal hernia
         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
    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
    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
    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
    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
    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
    Upper gastrointestinal haemorrhage
         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
    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
    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
    Rectal haemorrhage
         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
    Gastric 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
    Inguinal hernia
         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
    Superior mesenteric 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
    Hepatobiliary disorders
    Cholangitis
         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
    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
    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
    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
    Biliary 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
    Cholecystitis acute
         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 / 1
    0 / 0
    Skin and subcutaneous tissue disorders
    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
    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
    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
    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
    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
    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
    Renal and urinary disorders
    Hydronephrosis
         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
    Acute kidney injury
         subjects affected / exposed
    5 / 551 (0.91%)
    4 / 546 (0.73%)
         occurrences causally related to treatment / all
    1 / 5
    0 / 4
         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
    Haematuria
         subjects affected / exposed
    11 / 551 (2.00%)
    6 / 546 (1.10%)
         occurrences causally related to treatment / all
    2 / 13
    0 / 7
         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 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
    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
    Urinary retention
         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 / 0
    0 / 0
    Urinary tract obstruction
         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
    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
    Urinary 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 kidney disease
         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
    Urinary incontinence
         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
    Endocrine disorders
    Adrenal insufficiency
         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
    Musculoskeletal and connective tissue disorders
    Arthralgia
         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
    Arthritis reactive
         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
    Back pain
         subjects affected / exposed
    6 / 551 (1.09%)
    6 / 546 (1.10%)
         occurrences causally related to treatment / all
    0 / 6
    1 / 6
         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
    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
    Intervertebral disc protrusion
         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
    Muscular weakness
         subjects affected / exposed
    2 / 551 (0.36%)
    4 / 546 (0.73%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 5
         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%)
    3 / 546 (0.55%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Sacral pain
         subjects affected / exposed
    0 / 551 (0.00%)
    3 / 546 (0.55%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infections and infestations
    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
    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
    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
    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
    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
    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
    Cellulitis
         subjects affected / exposed
    3 / 551 (0.54%)
    3 / 546 (0.55%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    COVID-19
         subjects affected / exposed
    5 / 551 (0.91%)
    4 / 546 (0.73%)
         occurrences causally related to treatment / all
    0 / 5
    0 / 4
         deaths causally related to treatment / all
    0 / 2
    0 / 1
    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
    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 / 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
    Gastroenteritis
         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 / 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
    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
    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
    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
    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
    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
    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
    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
    1 / 1
    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
    Pyelonephritis acute
         subjects affected / exposed
    2 / 551 (0.36%)
    1 / 546 (0.18%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pyelonephritis
         subjects affected / exposed
    2 / 551 (0.36%)
    2 / 546 (0.37%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 3
         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
    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
    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 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 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
         subjects affected / exposed
    16 / 551 (2.90%)
    10 / 546 (1.83%)
         occurrences causally related to treatment / all
    1 / 17
    0 / 10
         deaths causally related to treatment / all
    1 / 3
    0 / 1
    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
    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
    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
    Tracheobronchitis
         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
    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
    12 / 551 (2.18%)
    6 / 546 (1.10%)
         occurrences causally related to treatment / all
    1 / 15
    0 / 6
         deaths causally related to treatment / all
    0 / 1
    0 / 1
    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
    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 / 1
    0 / 0
    Sepsis
         subjects affected / exposed
    6 / 551 (1.09%)
    6 / 546 (1.10%)
         occurrences causally related to treatment / all
    1 / 6
    1 / 6
         deaths causally related to treatment / all
    0 / 1
    0 / 2
    Septic shock
         subjects affected / exposed
    5 / 551 (0.91%)
    0 / 546 (0.00%)
         occurrences causally related to treatment / all
    2 / 5
    0 / 0
         deaths causally related to treatment / all
    0 / 3
    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
    Pneumonia aspiration
         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
    Staphylococcal bacteraemia
         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 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
    Pneumocystis jirovecii pneumonia
         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
    Gastroenteritis viral
         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
    COVID-19 pneumonia
         subjects affected / exposed
    6 / 551 (1.09%)
    4 / 546 (0.73%)
         occurrences causally related to treatment / all
    0 / 6
    0 / 4
         deaths causally related to treatment / all
    0 / 1
    0 / 1
    Herpes zoster
         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
    Enteritis 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
    Endocarditis
         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
    Bacterial abdominal 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
    Urosepsis
         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
    Device related 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
    Sinusitis
         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
    Klebsiella bacteraemia
         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
    Appendicitis perforated
         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
    Pulmonary sepsis
         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
    Prostate 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
    Pseudomonas 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
    Pneumonia viral
         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
    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
    12 / 551 (2.18%)
    0 / 546 (0.00%)
         occurrences causally related to treatment / all
    9 / 13
    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
    25 / 551 (4.54%)
    1 / 546 (0.18%)
         occurrences causally related to treatment / all
    25 / 26
    1 / 1
         deaths causally related to treatment / all
    1 / 1
    0 / 0
    Hypokalaemia
         subjects affected / exposed
    3 / 551 (0.54%)
    2 / 546 (0.37%)
         occurrences causally related to treatment / all
    2 / 3
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hyponatraemia
         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
    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
    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
    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
    1 / 1
    0 / 0
    Hypomagnesaemia
         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
    Hypoglycaemia
         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
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Ipat + Abi Pbo + Abi
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    541 / 551 (98.19%)
    496 / 546 (90.84%)
    Vascular disorders
    Hypertension
         subjects affected / exposed
    86 / 551 (15.61%)
    94 / 546 (17.22%)
         occurrences all number
    102
    125
    Hot flush
         subjects affected / exposed
    28 / 551 (5.08%)
    38 / 546 (6.96%)
         occurrences all number
    31
    42
    General disorders and administration site conditions
    Pyrexia
         subjects affected / exposed
    38 / 551 (6.90%)
    23 / 546 (4.21%)
         occurrences all number
    45
    26
    Oedema peripheral
         subjects affected / exposed
    89 / 551 (16.15%)
    56 / 546 (10.26%)
         occurrences all number
    105
    73
    Fatigue
         subjects affected / exposed
    129 / 551 (23.41%)
    111 / 546 (20.33%)
         occurrences all number
    148
    141
    Asthenia
         subjects affected / exposed
    103 / 551 (18.69%)
    78 / 546 (14.29%)
         occurrences all number
    148
    99
    Respiratory, thoracic and mediastinal disorders
    Dyspnoea
         subjects affected / exposed
    36 / 551 (6.53%)
    29 / 546 (5.31%)
         occurrences all number
    37
    31
    Cough
         subjects affected / exposed
    47 / 551 (8.53%)
    50 / 546 (9.16%)
         occurrences all number
    52
    55
    Psychiatric disorders
    Insomnia
         subjects affected / exposed
    29 / 551 (5.26%)
    44 / 546 (8.06%)
         occurrences all number
    31
    50
    Product issues
    Device dislocation
         subjects affected / exposed
    0 / 551 (0.00%)
    1 / 546 (0.18%)
         occurrences all number
    0
    1
    Investigations
    Alanine aminotransferase increased
         subjects affected / exposed
    110 / 551 (19.96%)
    56 / 546 (10.26%)
         occurrences all number
    129
    67
    Aspartate aminotransferase increased
         subjects affected / exposed
    94 / 551 (17.06%)
    58 / 546 (10.62%)
         occurrences all number
    101
    71
    Blood creatinine increased
         subjects affected / exposed
    41 / 551 (7.44%)
    27 / 546 (4.95%)
         occurrences all number
    56
    35
    Weight decreased
         subjects affected / exposed
    78 / 551 (14.16%)
    23 / 546 (4.21%)
         occurrences all number
    94
    27
    Blood alkaline phosphatase increased
         subjects affected / exposed
    27 / 551 (4.90%)
    28 / 546 (5.13%)
         occurrences all number
    29
    32
    Glycosylated haemoglobin increased
         subjects affected / exposed
    30 / 551 (5.44%)
    7 / 546 (1.28%)
         occurrences all number
    32
    7
    Blood cholesterol increased
         subjects affected / exposed
    28 / 551 (5.08%)
    12 / 546 (2.20%)
         occurrences all number
    37
    12
    Lipase increased
         subjects affected / exposed
    30 / 551 (5.44%)
    27 / 546 (4.95%)
         occurrences all number
    48
    44
    Injury, poisoning and procedural complications
    Fall
         subjects affected / exposed
    42 / 551 (7.62%)
    53 / 546 (9.71%)
         occurrences all number
    58
    72
    Nervous system disorders
    Headache
         subjects affected / exposed
    58 / 551 (10.53%)
    48 / 546 (8.79%)
         occurrences all number
    68
    62
    Dizziness
         subjects affected / exposed
    41 / 551 (7.44%)
    35 / 546 (6.41%)
         occurrences all number
    47
    46
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    127 / 551 (23.05%)
    75 / 546 (13.74%)
         occurrences all number
    192
    107
    Gastrointestinal disorders
    Abdominal pain
         subjects affected / exposed
    32 / 551 (5.81%)
    22 / 546 (4.03%)
         occurrences all number
    38
    24
    Dyspepsia
         subjects affected / exposed
    37 / 551 (6.72%)
    27 / 546 (4.95%)
         occurrences all number
    40
    33
    Diarrhoea
         subjects affected / exposed
    441 / 551 (80.04%)
    137 / 546 (25.09%)
         occurrences all number
    969
    193
    Constipation
         subjects affected / exposed
    55 / 551 (9.98%)
    95 / 546 (17.40%)
         occurrences all number
    60
    111
    Vomiting
         subjects affected / exposed
    98 / 551 (17.79%)
    57 / 546 (10.44%)
         occurrences all number
    152
    75
    Nausea
         subjects affected / exposed
    159 / 551 (28.86%)
    65 / 546 (11.90%)
         occurrences all number
    214
    76
    Skin and subcutaneous tissue disorders
    Pruritus
         subjects affected / exposed
    48 / 551 (8.71%)
    16 / 546 (2.93%)
         occurrences all number
    66
    18
    Rash maculo-papular
         subjects affected / exposed
    48 / 551 (8.71%)
    8 / 546 (1.47%)
         occurrences all number
    67
    9
    Rash
         subjects affected / exposed
    150 / 551 (27.22%)
    48 / 546 (8.79%)
         occurrences all number
    193
    53
    Renal and urinary disorders
    Haematuria
         subjects affected / exposed
    35 / 551 (6.35%)
    33 / 546 (6.04%)
         occurrences all number
    50
    41
    Dysuria
         subjects affected / exposed
    30 / 551 (5.44%)
    20 / 546 (3.66%)
         occurrences all number
    33
    23
    Musculoskeletal and connective tissue disorders
    Pain in extremity
         subjects affected / exposed
    45 / 551 (8.17%)
    56 / 546 (10.26%)
         occurrences all number
    54
    68
    Bone pain
         subjects affected / exposed
    47 / 551 (8.53%)
    37 / 546 (6.78%)
         occurrences all number
    52
    52
    Back pain
         subjects affected / exposed
    105 / 551 (19.06%)
    127 / 546 (23.26%)
         occurrences all number
    135
    164
    Arthralgia
         subjects affected / exposed
    102 / 551 (18.51%)
    119 / 546 (21.79%)
         occurrences all number
    139
    155
    Muscle spasms
         subjects affected / exposed
    21 / 551 (3.81%)
    32 / 546 (5.86%)
         occurrences all number
    28
    34
    Infections and infestations
    Nasopharyngitis
         subjects affected / exposed
    48 / 551 (8.71%)
    52 / 546 (9.52%)
         occurrences all number
    68
    72
    Upper respiratory tract infection
         subjects affected / exposed
    39 / 551 (7.08%)
    50 / 546 (9.16%)
         occurrences all number
    52
    60
    Urinary tract infection
         subjects affected / exposed
    54 / 551 (9.80%)
    46 / 546 (8.42%)
         occurrences all number
    87
    61
    Metabolism and nutrition disorders
    Decreased appetite
         subjects affected / exposed
    107 / 551 (19.42%)
    62 / 546 (11.36%)
         occurrences all number
    128
    78
    Hyperglycaemia
         subjects affected / exposed
    220 / 551 (39.93%)
    95 / 546 (17.40%)
         occurrences all number
    366
    155
    Hypertriglyceridaemia
         subjects affected / exposed
    36 / 551 (6.53%)
    28 / 546 (5.13%)
         occurrences all number
    43
    36
    Hypokalaemia
         subjects affected / exposed
    48 / 551 (8.71%)
    44 / 546 (8.06%)
         occurrences all number
    70
    69
    Hypercholesterolaemia
         subjects affected / exposed
    33 / 551 (5.99%)
    15 / 546 (2.75%)
         occurrences all number
    36
    20

    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 participants 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 participant 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 reflect updates the Sponsor has made to language regarding data collection and management, ethical considerations and study documentation.
    30 Apr 2019
    Following updates were made: [1] Anti-diabetic medication must be recorded until the initiation of the next line of PC therapy, in order for the Sponsor to better characterize the hyperglycemia resulting from study treatment [2] In vivo drug-drug interaction data has been added to provide context to the existing restrictions on concomitant use of CYP3A4/5 inhibitors; [3] The FoundationOneTM next-generation sequencing (NGS) assay has been replaced by the newer FoundationOne CDx (FMI) NGS assay. [4] The key secondary endpoint of time to pain progression has been updated to specify that the initiation of opioid analgesic medication is assessed by the AQA score, which will be calculated based on the consumption of opioids documented in the eCRF; [5] An update has been made to the PCWG3 criteria to clarify that, in situations where the bone scan at Week 8 is missed, the first post-treatment bone scan should be treated as the “Week 8” bone scan.
    23 Dec 2020
    Following updates were made: [1] Language to clarify the use of investigational medicinal product accountability was added; [2] Language was added to clarify that AEs associated with special situation that also qualify as adverse events of special interest (AESIs) should be reported within 24 hours; [3] Language regarding investigator reporting of pregnancies was clarified; [4] Language in was amended for planned interim efficacy analysis to include the additional interim OS analysis.
    15 Nov 2022
    Following updates were made: The updates were made to indicate that after the final OS analysis, study visits were to be performed every 3 months instead of monthly for participants who are still on ipatasertib treatment. Only safety data were to be collected at study visits. Tumor assessments were to continue to be performed as per local practice and at the investigator’s discretion, but these data would not be collected. Participants who had already discontinued from study treatment and participants who were in the placebo arm and were receiving abiraterone only would no longer be followed after the final OS analysis, and no data were to be collected from them.

    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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