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    Clinical Trial Results:
    A Phase IIIb, Randomised, Double-blind, Placebo-controlled, Multicentre Study of Olaparib Maintenance Retreatment in Patients with Epithelial Ovarian Cancer Previously Treated with a PARPi and Responding to Repeat Platinum Chemotherapy (OReO)

    Summary
    EudraCT number
    		 2016-003346-90
    Trial protocol
    		 FR   PL   BE   DE   GB   ES   IT  
    Global end of trial date
    17 Feb 2022

    Results information
    Results version number
    		 v1(current)
    This version publication date
    14 Oct 2022
    First version publication date
    14 Oct 2022
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    D0816C00014
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT03106987
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    AstraZeneca AB
    Sponsor organisation address
    Södertälje, Södertälje, Sweden, 151 85
    Public contact
    Global Clinical Head, AstraZeneca Clinical Study Information Center, +1 87724094 79, information.center@astrazeneca.com
    Scientific contact
    Global Clinical Head, AstraZeneca Clinical Study Information Center, +1 87724094 79, information.center@astrazeneca.com
    Paediatric regulatory details
    Is trial part of an agreed paediatric investigation plan (PIP)
    No
    Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Results analysis stage
    Analysis stage
    Final
    Date of interim/final analysis
    15 Feb 2021
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    15 Feb 2021
    Global end of trial reached?
    Yes
    Global end of trial date
    17 Feb 2022
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To assess the efficacy and tolerability of Olaparib retreatment, versus placebo, in non mucinous Epithelial ovarian cancer (EOC) patients
    Protection of trial subjects
    The study was performed in accordance with ethical principles that had their origin in the Declaration of Helsinki and were consistent with International Council for Harmonisation Good Clinical Practices (ICH-GCP) and the AstraZeneca policy on Bioethics and Human Biological Samples. The Principal Investigator ensured that each patient was given full and adequate oral and written information about the study. Patients provided signed and dated informed consent before any procedure specific to the study was conducted.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    08 Jun 2017
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Belgium: 6
    Country: Number of subjects enrolled
    Canada: 2
    Country: Number of subjects enrolled
    Denmark: 5
    Country: Number of subjects enrolled
    France: 58
    Country: Number of subjects enrolled
    Germany: 26
    Country: Number of subjects enrolled
    Israel: 4
    Country: Number of subjects enrolled
    Italy: 50
    Country: Number of subjects enrolled
    Norway: 5
    Country: Number of subjects enrolled
    Poland: 10
    Country: Number of subjects enrolled
    Spain: 46
    Country: Number of subjects enrolled
    United Kingdom: 8
    Worldwide total number of subjects
    220
    EEA total number of subjects
    206
    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)
    127
    From 65 to 84 years
    92
    85 years and over
    1

    Subject disposition

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    Recruitment
    Recruitment details
    		 This study was conducted at study centres in 11 countries (France, Italy, Spain, Germany, Poland, Belgium, Denmark, Israel, United Kingdom, Norway, and Canada) between 8-Jun-2017 and 15-Feb-2021.

    Pre-assignment
    Screening details
    		 Patients were randomised into 1 of 2 cohorts depending on their known BRCA1/2 status (BRCA1/2 +ve or BRCA1/2-ve). Within each cohort, patients were randomised in a 2 Olaparib:1 placebo ratio. Randomisation was stratified by prior use of bevacizumab and number of prior regimens of platinum-containing chemotherapy.

    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
    		 Olaparib (BRCA1/2 +ve)
    Arm description
    		 Patients received Olaparib 300mg tablets orally twice daily (bd) continuously
    Arm type
    		 Experimental

    Investigational medicinal product name
    Olaparib
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Patients received Olaparib 300mg tablets orally bd

    Arm title
    		 Placebo (BRCA1/2 +ve)
    Arm description
    		 Patients received Placebo 300mg tablets orally bd continuously
    Arm type
    		 Placebo

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Patients received Placebo 300mg tablets orally bd

    Arm title
    		 Olaparib (BRCA1/2 -ve)
    Arm description
    		 Patients received Olaparib 300mg tablets orally bd continuously
    Arm type
    		 Experimental

    Investigational medicinal product name
    Olaparib
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Patients received Olaparib 300mg tablets orally bd

    Arm title
    		 Placebo (BRCA1/2 -ve)
    Arm description
    		 Patients received Placebo 300mg tablets orally bd continuously
    Arm type
    		 Placebo

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Patients received Placebo 300mg tablets orally bd

    Number of subjects in period 1
    		Olaparib (BRCA1/2 +ve) Placebo (BRCA1/2 +ve) Olaparib (BRCA1/2 -ve) Placebo (BRCA1/2 -ve)
    Started
    74
    38
    72
    36
    Completed
    30
    15
    54
    25
    Not completed
    44
    23
    18
    11
         Adverse event, serious fatal
    37
    22
    12
    8
         Consent withdrawn by subject
    5
    1
    4
    1
         Lost to follow-up
    2
    -
    2
    2

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Olaparib (BRCA1/2 +ve)
    Reporting group description
    		 Patients received Olaparib 300mg tablets orally twice daily (bd) continuously

    Reporting group title
    Placebo (BRCA1/2 +ve)
    Reporting group description
    		 Patients received Placebo 300mg tablets orally bd continuously

    Reporting group title
    Olaparib (BRCA1/2 -ve)
    Reporting group description
    		 Patients received Olaparib 300mg tablets orally bd continuously

    Reporting group title
    Placebo (BRCA1/2 -ve)
    Reporting group description
    		 Patients received Placebo 300mg tablets orally bd continuously

    Reporting group values
    		 Olaparib (BRCA1/2 +ve) Placebo (BRCA1/2 +ve) Olaparib (BRCA1/2 -ve) Placebo (BRCA1/2 -ve) Total
    Number of subjects
    		 74 38 72 36 220
    Age Categorical
    Units: Patients
        < 50
    		 11 3 4 1 19
        ≥ 50 to < 65
    		 40 20 29 19 108
        ≥ 65 to < 75
    		 20 12 30 11 73
        ≥ 75
    		 3 3 9 5 20
    Age Continuous
    Units: Years
        arithmetic mean (standard deviation)
    		 59.2 ± 9.31 61.5 ± 9.22 64.2 ± 9.64 63.3 ± 9.05 -
    Sex: Female, Male
    Units:
        Female
    		 74 38 72 36 220
        Male
    		 0 0 0 0 0
    Race/Ethnicity, Customized
    Units: Subjects
        White
    		 71 35 66 33 205
        American Indian or Alaska Native
    		 0 0 0 0 0
        Asian
    		 0 0 0 0 0
        Black or African American
    		 0 0 1 0 1
        Hawaiian Native or Other Pacific Islander
    		 0 0 0 0 0
        Other
    		 3 3 5 2 13
        Missing Data
    		 0 0 0 1 1

    End points

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    End points reporting groups
    Reporting group title
    Olaparib (BRCA1/2 +ve)
    Reporting group description
    		 Patients received Olaparib 300mg tablets orally twice daily (bd) continuously

    Reporting group title
    Placebo (BRCA1/2 +ve)
    Reporting group description
    		 Patients received Placebo 300mg tablets orally bd continuously

    Reporting group title
    Olaparib (BRCA1/2 -ve)
    Reporting group description
    		 Patients received Olaparib 300mg tablets orally bd continuously

    Reporting group title
    Placebo (BRCA1/2 -ve)
    Reporting group description
    		 Patients received Placebo 300mg tablets orally bd continuously

    Primary: Efficacy: Progression-free survival (PFS)

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    End point title
    		 Efficacy: Progression-free survival (PFS)
    End point description
    PFS (per RECIST 1.1) was defined as the time from randomisation until the date of Investigator assessed objective radiological disease progression or death (by any cause in the absence of disease progression). Objective progression (per REC I ST 1.1) is defined as at least a 20% increase in the sum of the diameters of the target lesions and an absolute increase of >5 mm, or an overall non-target lesion assessment of progression or a new lesion. Patients who have not progressed or died at the time of analysis were censored at the time of the latest date of assessment from their last evaluable RECIST assessment.
    End point type
    Primary
    End point timeframe
    At randomization visit and at every 12 weeks (+/- 7 days) until objective radiological disease progression as determined by the investigator or other discontinuation criteria are met (assessed upto 3.8 years)
    End point values
    		 Olaparib (BRCA1/2 +ve) Placebo (BRCA1/2 +ve) Olaparib (BRCA1/2 -ve) Placebo (BRCA1/2 -ve)
    Number of subjects analysed
    74
    38
    72
    36
    Units: Months
        median (confidence interval 95%)
    4.3 (2.79 to 5.49)
    2.8 (2.73 to 4.96)
    5.3 (2.89 to 5.55)
    2.8 (2.79 to 2.89)
    Statistical analysis title
    		 Olaparib (BRCA1/2 +ve) vs Placebo (BRCA1/2 +ve)
    Comparison groups
    Placebo (BRCA1/2 +ve) v Olaparib (BRCA1/2 +ve)
    Number of subjects included in analysis
    112
    Analysis specification
    Pre-specified
    Analysis type
    		 [1]
    P-value
    		 = 0.022
    Method
    		 Stratified log-rank
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.566
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.372
         upper limit
    		 0.868
    Notes
    [1] - Hazard Ratio (Cox Proportional Hazards model)
    Statistical analysis title
    		 Olaparib (BRCA1/2 -ve) vs Placebo (BRCA1/2 -ve)
    Comparison groups
    Olaparib (BRCA1/2 -ve) v Placebo (BRCA1/2 -ve)
    Number of subjects included in analysis
    108
    Analysis specification
    Pre-specified
    Analysis type
    		 [2]
    P-value
    		 = 0.0023
    Method
    		 Stratified log-rank
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.43
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.264
         upper limit
    		 0.708
    Notes
    [2] - Hazard Ratio (Cox Proportional Hazards model)

    Secondary: Efficacy: Overall survival (OS)

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    End point title
    		 Efficacy: Overall survival (OS)
    End point description
    OS was defined as the time from the date of randomisation until death due to any cause. Patients not known to have died at the time of analysis were censored based on the last recorded date on which the patients were known to be alive. Here, arbitrary value 99.9999 represent that Upper limit was not calculated due to insufficient number of events.
    End point type
    Secondary
    End point timeframe
    From randomisation till Long-term follow-up (12-weekly beyond 30 days after last dose of study treatment) assessed upto 3.8 years
    End point values
    		 Olaparib (BRCA1/2 +ve) Placebo (BRCA1/2 +ve) Olaparib (BRCA1/2 -ve) Placebo (BRCA1/2 -ve)
    Number of subjects analysed
    74
    38
    72
    36
    Units: Months
        median (confidence interval 95%)
    20.1 (16.39 to 25.43)
    20.9 (15.21 to 23.92)
    23.2 (15.15 to 99.9999)
    30.2 (17.84 to 99.9999)
    No statistical analyses for this end point

    Secondary: Efficacy: Time to progression by Gynecologic Cancer Intergroup (GCIG) criteria

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    End point title
    		 Efficacy: Time to progression by Gynecologic Cancer Intergroup (GCIG) criteria
    End point description
    Time to progression by RECIST or CA-125 or death is defined as the time from randomisation to the earlier date of RECIST progression or CA-125 progression or death by any cause. Patients without a CA-125 progression or a RECIST progression who are still alive at the time of analysis were censored at the time of their last evaluable RECIST assessment and/or their last available CA-125 measurement, whichever is the earliest at the time of analysis. Patients that do not have any evaluable RECIST assessments or any CA-125 results post-randomisation were censored at the date of randomisation.
    End point type
    Secondary
    End point timeframe
    At screening (Visit 1) and at every 12 weeks (±7 days), until objective disease progression, based on progressive serial elevation of serum CA-125 according to the GCIG criteria, or until discontinuation for other reasons (assessed upto 3.8 years)
    End point values
    		 Olaparib (BRCA1/2 +ve) Placebo (BRCA1/2 +ve) Olaparib (BRCA1/2 -ve) Placebo (BRCA1/2 -ve)
    Number of subjects analysed
    74
    38
    72
    36
    Units: Months
        median (confidence interval 95%)
    2.8 (2.76 to 5.36)
    2.8 (2.73 to 3.98)
    2.9 (2.79 to 5.32)
    2.79 (2.63 to 2.79)
    No statistical analyses for this end point

    Secondary: Efficacy: Time to first subsequent treatment commencement (TFST)

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    End point title
    		 Efficacy: Time to first subsequent treatment commencement (TFST)
    End point description
    TFST was assessed as time from randomisation to first subsequent treatment commencement or death if this occurs before commencement of first subsequent treatment. Patients not known to have had a further subsequent therapy or death were censored at the last known time to have not received subsequent therapy.
    End point type
    Secondary
    End point timeframe
    From follow-up i.e. 30 days after last dose of study medication till end of study (assessed every 12 weeks upto 3.8 years)
    End point values
    		 Olaparib (BRCA1/2 +ve) Placebo (BRCA1/2 +ve) Olaparib (BRCA1/2 -ve) Placebo (BRCA1/2 -ve)
    Number of subjects analysed
    74
    38
    72
    36
    Units: Months
        median (confidence interval 95%)
    5.8 (4.67 to 9.17)
    5.1 (3.58 to 6.11)
    7.9 (5.88 to 11.07)
    4.3 (3.68 to 6.41)
    No statistical analyses for this end point

    Secondary: Efficacy: Time to second subsequent treatment commencement (TSST)

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    End point title
    		 Efficacy: Time to second subsequent treatment commencement (TSST)
    End point description
    TSST was assessed as time from randomisation to second subsequent treatment commencement or death if this occurs before commencement of second subsequent treatment. Patients not known to have had a further second subsequent therapy or death were censored at the last known time to have not received second subsequent therapy.
    End point type
    Secondary
    End point timeframe
    From follow-up i.e. 30 days after last dose of study medication till end of study (assessed every 12 weeks upto 3.8 years)
    End point values
    		 Olaparib (BRCA1/2 +ve) Placebo (BRCA1/2 +ve) Olaparib (BRCA1/2 -ve) Placebo (BRCA1/2 -ve)
    Number of subjects analysed
    74
    38
    72
    36
    Units: Months
        median (confidence interval 95%)
    13.1 (11.10 to 15.64)
    11.7 (8.61 to 13.60)
    15.4 (11.60 to 23.62)
    12.7 (10.35 to 16.62)
    No statistical analyses for this end point

    Secondary: Efficacy: Time to study treatment discontinuation (TDT)

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    End point title
    		 Efficacy: Time to study treatment discontinuation (TDT)
    End point description
    TDT was assessed as time from randomisation to study treatment discontinuation or death if this occurs before discontinuation of study treatment. Patients not known to have died at the time of analysis and not known to have discontinued study treatment were censored based on the last recorded date on which the patients were known to be alive.
    End point type
    Secondary
    End point timeframe
    From follow-up 30 days after last dose of study medication till long-term follow-up i.e. 12-weekly beyond 30 days after last dose of study treatment
    End point values
    		 Olaparib (BRCA1/2 +ve) Placebo (BRCA1/2 +ve) Olaparib (BRCA1/2 -ve) Placebo (BRCA1/2 -ve)
    Number of subjects analysed
    74
    38
    72
    36
    Units: Months
        median (confidence interval 95%)
    4.5 (3.35 to 5.59)
    3.4 (2.86 to 5.49)
    5.6 (3.42 to 5.78)
    3.1 (2.79 to 3.91)
    No statistical analyses for this end point

    Secondary: Efficacy: Change from baseline in Health-related quality of life (HRQoL)

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    End point title
    		 Efficacy: Change from baseline in Health-related quality of life (HRQoL)
    End point description
    Health related quality of life (HRQoL) of Olaparib maintenance retreatment compared to placebo as measured by the Functional Assessment of Cancer Therapy – Ovarian (FACT-O) Trial Outcome Index (TOI) was determined. HRQoL was analysed using the FACT-O tool by mixed model for repeated measures (MMRM) analysis of the change from baseline in TOI score. FACT-O TOI is scored from O to 100 with higher scores denoting better quality of life. The higher the score, the better the HRQoL.
    End point type
    Secondary
    End point timeframe
    At Baseline, and from Day 1 until objective disease progression (assessed upto 2 years)
    End point values
    		 Olaparib (BRCA1/2 +ve) Placebo (BRCA1/2 +ve) Olaparib (BRCA1/2 -ve) Placebo (BRCA1/2 -ve)
    Number of subjects analysed
    64
    35
    55
    35
    Units: Change in scores
        least squares mean (standard error)
    -1.27 ± 0.55
    1.67 ± 0.89
    -2.08 ± 0.60
    0.58 ± 0.90
    No statistical analyses for this end point

    Secondary: Number of patients with Adverse Events (AEs), and Serious Adverse Events (SAEs)

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    End point title
    		 Number of patients with Adverse Events (AEs), and Serious Adverse Events (SAEs)
    End point description
    All AEs/serious adverse events (SAEs) reported during the study were recorded.
    End point type
    Secondary
    End point timeframe
    At Baseline and from Day 1 till follow-up i.e. 30 days after last dose of study medication (assessed upto 3.8 years)
    End point values
    		 Olaparib (BRCA1/2 +ve) Placebo (BRCA1/2 +ve) Olaparib (BRCA1/2 -ve) Placebo (BRCA1/2 -ve)
    Number of subjects analysed
    74
    38
    72
    36
    Units: Patients
        Treatment emergent adverse event (TEAE)
    64
    33
    66
    31
        TEAE causally related to treatment (CRT)
    50
    23
    53
    14
        TEAE of CTCAE grade 3 or higher
    11
    2
    15
    3
        TEAE of CTCAE ≥ grade 3 CRT
    5
    1
    5
    1
        TEAE with outcome = death
    0
    0
    0
    0
        TEAE with outcome = death, CRT
    0
    0
    0
    0
        TESAE (including events with outcome = death)
    5
    0
    11
    2
        TESAE (including events with outcome = death), CRT
    1
    0
    3
    0
        TEAE = discontinuation of study medication
    2
    0
    1
    0
        TEAE = discontinuation of study medication, CRT
    1
    0
    0
    0
        TEAE leading to dose modification
    18
    6
    28
    2
        TEAE leading to dose modification, CRT
    14
    5
    21
    1
    No statistical analyses for this end point

    Secondary: Number of patients with Adverse Event of Special Interest (AESI)

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    End point title
    		 Number of patients with Adverse Event of Special Interest (AESI)
    End point description
    All AESIs reported during the study were recorded.
    End point type
    Secondary
    End point timeframe
    At Baseline and from Day 1 till long-term follow-up i.e. 12-weekly beyond 30 days after last dose of study treatment (assessed upto 3.8 years)
    End point values
    		 Olaparib (BRCA1/2 +ve) Placebo (BRCA1/2 +ve) Olaparib (BRCA1/2 -ve) Placebo (BRCA1/2 -ve)
    Number of subjects analysed
    74
    38
    72
    36
    Units: Patients
    1
    1
    1
    0
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    From Screening (Day -27 to Day 0) up to 12-weekly beyond 30 days after the last dose of study treatment (assessed up to 3.8 years)
    Assessment type
    		 Non-systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    24.0
    Reporting groups
    Reporting group title
    Olaparib (BRCA1/2 +ve)
    Reporting group description
    		 Patients received olaparib 300mg tablets orally twice daily (bd) continuously

    Reporting group title
    Placebo (BRCA1/2 +ve)
    Reporting group description
    		 Patients received placebo 300mg tablets administered orally twice daily (bd) continuously

    Reporting group title
    Olaparib (BRCA1/2 -ve)
    Reporting group description
    		 Patients received olaparib 300mg tablets orally twice daily (bd) continuously

    Reporting group title
    Placebo (BRCA1/2 -ve)
    Reporting group description
    		 Patients received placebo 300mg tablets administered orally twice daily (bd) continuously

    Serious adverse events
    		 Olaparib (BRCA1/2 +ve) Placebo (BRCA1/2 +ve) Olaparib (BRCA1/2 -ve) Placebo (BRCA1/2 -ve)
    Total subjects affected by serious adverse events
         subjects affected / exposed
    5 / 74 (6.76%)
    0 / 38 (0.00%)
    11 / 72 (15.28%)
    2 / 36 (5.56%)
         number of deaths (all causes)
    39
    22
    15
    8
         number of deaths resulting from adverse events
    0
    0
    0
    0
    Injury, poisoning and procedural complications
    Radius fracture
         subjects affected / exposed
    1 / 74 (1.35%)
    0 / 38 (0.00%)
    0 / 72 (0.00%)
    0 / 36 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cardiac disorders
    Supraventricular tachycardia
         subjects affected / exposed
    0 / 74 (0.00%)
    0 / 38 (0.00%)
    1 / 72 (1.39%)
    0 / 36 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    1 / 74 (1.35%)
    0 / 38 (0.00%)
    1 / 72 (1.39%)
    0 / 36 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Neutropenia
         subjects affected / exposed
    1 / 74 (1.35%)
    0 / 38 (0.00%)
    1 / 72 (1.39%)
    0 / 36 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Febrile neutropenia
         subjects affected / exposed
    0 / 74 (0.00%)
    0 / 38 (0.00%)
    1 / 72 (1.39%)
    0 / 36 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Pyrexia
         subjects affected / exposed
    1 / 74 (1.35%)
    0 / 38 (0.00%)
    0 / 72 (0.00%)
    0 / 36 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    General physical health deterioration
         subjects affected / exposed
    0 / 74 (0.00%)
    0 / 38 (0.00%)
    1 / 72 (1.39%)
    0 / 36 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Incarcerated hernia
         subjects affected / exposed
    0 / 74 (0.00%)
    0 / 38 (0.00%)
    0 / 72 (0.00%)
    1 / 36 (2.78%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Diverticulum
         subjects affected / exposed
    0 / 74 (0.00%)
    0 / 38 (0.00%)
    1 / 72 (1.39%)
    0 / 36 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Ileal perforation
         subjects affected / exposed
    0 / 74 (0.00%)
    0 / 38 (0.00%)
    1 / 72 (1.39%)
    0 / 36 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Ileus
         subjects affected / exposed
    0 / 74 (0.00%)
    0 / 38 (0.00%)
    1 / 72 (1.39%)
    0 / 36 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Subileus
         subjects affected / exposed
    0 / 74 (0.00%)
    0 / 38 (0.00%)
    1 / 72 (1.39%)
    0 / 36 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hepatobiliary disorders
    Hepatic haematoma
         subjects affected / exposed
    0 / 74 (0.00%)
    0 / 38 (0.00%)
    0 / 72 (0.00%)
    1 / 36 (2.78%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Pulmonary embolism
         subjects affected / exposed
    0 / 74 (0.00%)
    0 / 38 (0.00%)
    1 / 72 (1.39%)
    0 / 36 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Infections and infestations
    COVID-19 pneumonia
         subjects affected / exposed
    2 / 74 (2.70%)
    0 / 38 (0.00%)
    0 / 72 (0.00%)
    0 / 36 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Lower respiratory tract infection
         subjects affected / exposed
    0 / 74 (0.00%)
    0 / 38 (0.00%)
    1 / 72 (1.39%)
    0 / 36 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Sepsis
         subjects affected / exposed
    0 / 74 (0.00%)
    0 / 38 (0.00%)
    1 / 72 (1.39%)
    0 / 36 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 0%
    Non-serious adverse events
    		 Olaparib (BRCA1/2 +ve) Placebo (BRCA1/2 +ve) Olaparib (BRCA1/2 -ve) Placebo (BRCA1/2 -ve)
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    64 / 74 (86.49%)
    33 / 38 (86.84%)
    65 / 72 (90.28%)
    30 / 36 (83.33%)
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Breast neoplasm
         subjects affected / exposed
    0 / 74 (0.00%)
    1 / 38 (2.63%)
    0 / 72 (0.00%)
    0 / 36 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Oesophageal squamous cell carcinoma
         subjects affected / exposed
    1 / 74 (1.35%)
    0 / 38 (0.00%)
    0 / 72 (0.00%)
    0 / 36 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Basal cell carcinoma
         subjects affected / exposed
    0 / 74 (0.00%)
    0 / 38 (0.00%)
    1 / 72 (1.39%)
    0 / 36 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Vascular disorders
    Hot flush
         subjects affected / exposed
    2 / 74 (2.70%)
    2 / 38 (5.26%)
    0 / 72 (0.00%)
    0 / 36 (0.00%)
         occurrences all number
    2
    2
    0
    0
    Hypertension
         subjects affected / exposed
    2 / 74 (2.70%)
    1 / 38 (2.63%)
    1 / 72 (1.39%)
    3 / 36 (8.33%)
         occurrences all number
    2
    2
    1
    3
    Hypotension
         subjects affected / exposed
    1 / 74 (1.35%)
    0 / 38 (0.00%)
    1 / 72 (1.39%)
    0 / 36 (0.00%)
         occurrences all number
    2
    0
    1
    0
    Cyanosis
         subjects affected / exposed
    0 / 74 (0.00%)
    0 / 38 (0.00%)
    1 / 72 (1.39%)
    0 / 36 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Flushing
         subjects affected / exposed
    0 / 74 (0.00%)
    0 / 38 (0.00%)
    0 / 72 (0.00%)
    3 / 36 (8.33%)
         occurrences all number
    0
    0
    0
    3
    Varicose vein
         subjects affected / exposed
    0 / 74 (0.00%)
    0 / 38 (0.00%)
    1 / 72 (1.39%)
    0 / 36 (0.00%)
         occurrences all number
    0
    0
    1
    0
    General disorders and administration site conditions
    Asthenia
         subjects affected / exposed
    18 / 74 (24.32%)
    3 / 38 (7.89%)
    15 / 72 (20.83%)
    2 / 36 (5.56%)
         occurrences all number
    21
    3
    20
    2
    Axillary pain
         subjects affected / exposed
    0 / 74 (0.00%)
    1 / 38 (2.63%)
    0 / 72 (0.00%)
    0 / 36 (0.00%)
         occurrences all number
    0
    0
    0
    0
    Chest pain
         subjects affected / exposed
    1 / 74 (1.35%)
    0 / 38 (0.00%)
    0 / 72 (0.00%)
    0 / 36 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Fatigue
         subjects affected / exposed
    13 / 74 (17.57%)
    5 / 38 (13.16%)
    13 / 72 (18.06%)
    2 / 36 (5.56%)
         occurrences all number
    15
    5
    18
    3
    Illness
         subjects affected / exposed
    1 / 74 (1.35%)
    0 / 38 (0.00%)
    0 / 72 (0.00%)
    0 / 36 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Mucosal inflammation
         subjects affected / exposed
    1 / 74 (1.35%)
    0 / 38 (0.00%)
    1 / 72 (1.39%)
    0 / 36 (0.00%)
         occurrences all number
    1
    0
    1
    0
    Oedema peripheral
         subjects affected / exposed
    1 / 74 (1.35%)
    1 / 38 (2.63%)
    1 / 72 (1.39%)
    2 / 36 (5.56%)
         occurrences all number
    1
    1
    1
    2
    Pyrexia
         subjects affected / exposed
    1 / 74 (1.35%)
    0 / 38 (0.00%)
    3 / 72 (4.17%)
    1 / 36 (2.78%)
         occurrences all number
    1
    0
    4
    2
    Sluggishness
         subjects affected / exposed
    1 / 74 (1.35%)
    0 / 38 (0.00%)
    0 / 72 (0.00%)
    0 / 36 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Complication associated with device
         subjects affected / exposed
    0 / 74 (0.00%)
    0 / 38 (0.00%)
    1 / 72 (1.39%)
    0 / 36 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Gait disturbance
         subjects affected / exposed
    0 / 74 (0.00%)
    0 / 38 (0.00%)
    0 / 72 (0.00%)
    1 / 36 (2.78%)
         occurrences all number
    0
    0
    0
    1
    Influenza like illness
         subjects affected / exposed
    0 / 74 (0.00%)
    0 / 38 (0.00%)
    0 / 72 (0.00%)
    1 / 36 (2.78%)
         occurrences all number
    0
    0
    0
    1
    Oedema
         subjects affected / exposed
    0 / 74 (0.00%)
    0 / 38 (0.00%)
    1 / 72 (1.39%)
    0 / 36 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Xerosis
         subjects affected / exposed
    0 / 74 (0.00%)
    0 / 38 (0.00%)
    0 / 72 (0.00%)
    1 / 36 (2.78%)
         occurrences all number
    0
    0
    0
    1
    Immune system disorders
    Transplant rejection
         subjects affected / exposed
    0 / 74 (0.00%)
    1 / 38 (2.63%)
    0 / 72 (0.00%)
    0 / 36 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Reproductive system and breast disorders
    Breast pain
         subjects affected / exposed
    0 / 74 (0.00%)
    1 / 38 (2.63%)
    0 / 72 (0.00%)
    0 / 36 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Ovarian vein thrombosis
         subjects affected / exposed
    0 / 74 (0.00%)
    0 / 38 (0.00%)
    1 / 72 (1.39%)
    0 / 36 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Vaginal haemorrhage
         subjects affected / exposed
    0 / 74 (0.00%)
    0 / 38 (0.00%)
    0 / 72 (0.00%)
    1 / 36 (2.78%)
         occurrences all number
    0
    0
    0
    1
    Vulvovaginal dryness
         subjects affected / exposed
    0 / 74 (0.00%)
    0 / 38 (0.00%)
    1 / 72 (1.39%)
    0 / 36 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    5 / 74 (6.76%)
    1 / 38 (2.63%)
    5 / 72 (6.94%)
    2 / 36 (5.56%)
         occurrences all number
    5
    1
    6
    2
    Dysphonia
         subjects affected / exposed
    1 / 74 (1.35%)
    0 / 38 (0.00%)
    0 / 72 (0.00%)
    0 / 36 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Dyspnoea
         subjects affected / exposed
    7 / 74 (9.46%)
    2 / 38 (5.26%)
    7 / 72 (9.72%)
    0 / 36 (0.00%)
         occurrences all number
    8
    2
    7
    0
    Oropharyngeal pain
         subjects affected / exposed
    1 / 74 (1.35%)
    0 / 38 (0.00%)
    0 / 72 (0.00%)
    1 / 36 (2.78%)
         occurrences all number
    1
    0
    0
    1
    Rhinorrhoea
         subjects affected / exposed
    1 / 74 (1.35%)
    0 / 38 (0.00%)
    0 / 72 (0.00%)
    0 / 36 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Epistaxis
         subjects affected / exposed
    0 / 74 (0.00%)
    0 / 38 (0.00%)
    1 / 72 (1.39%)
    0 / 36 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Nasal dryness
         subjects affected / exposed
    0 / 74 (0.00%)
    0 / 38 (0.00%)
    0 / 72 (0.00%)
    1 / 36 (2.78%)
         occurrences all number
    0
    0
    0
    1
    Respiratory tract congestion
         subjects affected / exposed
    0 / 74 (0.00%)
    0 / 38 (0.00%)
    0 / 72 (0.00%)
    1 / 36 (2.78%)
         occurrences all number
    0
    0
    0
    1
    Psychiatric disorders
    Insomnia
         subjects affected / exposed
    2 / 74 (2.70%)
    1 / 38 (2.63%)
    0 / 72 (0.00%)
    0 / 36 (0.00%)
         occurrences all number
    3
    1
    0
    0
    Dyssomnia
         subjects affected / exposed
    0 / 74 (0.00%)
    0 / 38 (0.00%)
    0 / 72 (0.00%)
    1 / 36 (2.78%)
         occurrences all number
    0
    0
    0
    1
    Emotional disorder
         subjects affected / exposed
    0 / 74 (0.00%)
    0 / 38 (0.00%)
    0 / 72 (0.00%)
    1 / 36 (2.78%)
         occurrences all number
    0
    0
    0
    1
    Mental disorder
         subjects affected / exposed
    0 / 74 (0.00%)
    0 / 38 (0.00%)
    1 / 72 (1.39%)
    0 / 36 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Mood swings
         subjects affected / exposed
    0 / 74 (0.00%)
    0 / 38 (0.00%)
    1 / 72 (1.39%)
    0 / 36 (0.00%)
         occurrences all number
    0
    0
    2
    0
    Investigations
    Alanine aminotransferase increased
         subjects affected / exposed
    3 / 74 (4.05%)
    0 / 38 (0.00%)
    0 / 72 (0.00%)
    0 / 36 (0.00%)
         occurrences all number
    4
    0
    0
    0
    Aspartate aminotransferase increased
         subjects affected / exposed
    2 / 74 (2.70%)
    0 / 38 (0.00%)
    1 / 72 (1.39%)
    1 / 36 (2.78%)
         occurrences all number
    2
    0
    1
    1
    Blood albumin decreased
         subjects affected / exposed
    1 / 74 (1.35%)
    0 / 38 (0.00%)
    1 / 72 (1.39%)
    0 / 36 (0.00%)
         occurrences all number
    1
    0
    1
    0
    Blood alkaline phosphatase increased
         subjects affected / exposed
    1 / 74 (1.35%)
    0 / 38 (0.00%)
    0 / 72 (0.00%)
    1 / 36 (2.78%)
         occurrences all number
    1
    0
    0
    1
    Blood bilirubin increased
         subjects affected / exposed
    1 / 74 (1.35%)
    1 / 38 (2.63%)
    0 / 72 (0.00%)
    0 / 36 (0.00%)
         occurrences all number
    1
    1
    0
    0
    Blood creatinine increased
         subjects affected / exposed
    4 / 74 (5.41%)
    1 / 38 (2.63%)
    4 / 72 (5.56%)
    0 / 36 (0.00%)
         occurrences all number
    8
    1
    5
    0
    Blood urea increased
         subjects affected / exposed
    2 / 74 (2.70%)
    0 / 38 (0.00%)
    0 / 72 (0.00%)
    0 / 36 (0.00%)
         occurrences all number
    2
    0
    0
    0
    Creatinine renal clearance decreased
         subjects affected / exposed
    1 / 74 (1.35%)
    0 / 38 (0.00%)
    1 / 72 (1.39%)
    0 / 36 (0.00%)
         occurrences all number
    1
    0
    1
    0
    Gamma-glutamyltransferase increased
         subjects affected / exposed
    1 / 74 (1.35%)
    0 / 38 (0.00%)
    1 / 72 (1.39%)
    0 / 36 (0.00%)
         occurrences all number
    1
    0
    1
    0
    Lymphocyte count decreased
         subjects affected / exposed
    1 / 74 (1.35%)
    0 / 38 (0.00%)
    0 / 72 (0.00%)
    1 / 36 (2.78%)
         occurrences all number
    1
    0
    0
    1
    Neutrophil count decreased
         subjects affected / exposed
    1 / 74 (1.35%)
    0 / 38 (0.00%)
    0 / 72 (0.00%)
    1 / 36 (2.78%)
         occurrences all number
    1
    0
    0
    1
    Platelet count decreased
         subjects affected / exposed
    2 / 74 (2.70%)
    0 / 38 (0.00%)
    3 / 72 (4.17%)
    0 / 36 (0.00%)
         occurrences all number
    5
    0
    6
    0
    Weight decreased
         subjects affected / exposed
    1 / 74 (1.35%)
    0 / 38 (0.00%)
    0 / 72 (0.00%)
    0 / 36 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Glomerular filtration rate decreased
         subjects affected / exposed
    0 / 74 (0.00%)
    0 / 38 (0.00%)
    1 / 72 (1.39%)
    0 / 36 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Hepatic enzyme increased
         subjects affected / exposed
    0 / 74 (0.00%)
    0 / 38 (0.00%)
    1 / 72 (1.39%)
    0 / 36 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Weight increased
         subjects affected / exposed
    0 / 74 (0.00%)
    0 / 38 (0.00%)
    0 / 72 (0.00%)
    1 / 36 (2.78%)
         occurrences all number
    0
    0
    0
    1
    White blood cell count decreased
         subjects affected / exposed
    0 / 74 (0.00%)
    0 / 38 (0.00%)
    0 / 72 (0.00%)
    1 / 36 (2.78%)
         occurrences all number
    0
    0
    0
    1
    Injury, poisoning and procedural complications
    Contusion
         subjects affected / exposed
    2 / 74 (2.70%)
    0 / 38 (0.00%)
    0 / 72 (0.00%)
    0 / 36 (0.00%)
         occurrences all number
    2
    0
    0
    0
    Fall
         subjects affected / exposed
    1 / 74 (1.35%)
    0 / 38 (0.00%)
    0 / 72 (0.00%)
    0 / 36 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Rib fracture
         subjects affected / exposed
    0 / 74 (0.00%)
    1 / 38 (2.63%)
    0 / 72 (0.00%)
    0 / 36 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Eye contusion
         subjects affected / exposed
    0 / 74 (0.00%)
    0 / 38 (0.00%)
    1 / 72 (1.39%)
    0 / 36 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Foot fracture
         subjects affected / exposed
    0 / 74 (0.00%)
    0 / 38 (0.00%)
    1 / 72 (1.39%)
    0 / 36 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Hand fracture
         subjects affected / exposed
    0 / 74 (0.00%)
    0 / 38 (0.00%)
    1 / 72 (1.39%)
    0 / 36 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Cardiac disorders
    Palpitations
         subjects affected / exposed
    1 / 74 (1.35%)
    0 / 38 (0.00%)
    0 / 72 (0.00%)
    0 / 36 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Tachycardia
         subjects affected / exposed
    1 / 74 (1.35%)
    0 / 38 (0.00%)
    0 / 72 (0.00%)
    0 / 36 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Angina pectoris
         subjects affected / exposed
    0 / 74 (0.00%)
    0 / 38 (0.00%)
    1 / 72 (1.39%)
    0 / 36 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Sinus tachycardia
         subjects affected / exposed
    0 / 74 (0.00%)
    0 / 38 (0.00%)
    1 / 72 (1.39%)
    0 / 36 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Nervous system disorders
    Bell's palsy
         subjects affected / exposed
    1 / 74 (1.35%)
    0 / 38 (0.00%)
    0 / 72 (0.00%)
    0 / 36 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Dizziness
         subjects affected / exposed
    4 / 74 (5.41%)
    1 / 38 (2.63%)
    3 / 72 (4.17%)
    1 / 36 (2.78%)
         occurrences all number
    7
    1
    3
    1
    Dysgeusia
         subjects affected / exposed
    3 / 74 (4.05%)
    1 / 38 (2.63%)
    1 / 72 (1.39%)
    0 / 36 (0.00%)
         occurrences all number
    3
    1
    1
    0
    Headache
         subjects affected / exposed
    6 / 74 (8.11%)
    1 / 38 (2.63%)
    3 / 72 (4.17%)
    2 / 36 (5.56%)
         occurrences all number
    8
    1
    3
    2
    Neuropathy peripheral
         subjects affected / exposed
    1 / 74 (1.35%)
    2 / 38 (5.26%)
    2 / 72 (2.78%)
    1 / 36 (2.78%)
         occurrences all number
    1
    3
    2
    1
    Neurotoxicity
         subjects affected / exposed
    1 / 74 (1.35%)
    0 / 38 (0.00%)
    0 / 72 (0.00%)
    0 / 36 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Paraesthesia
         subjects affected / exposed
    2 / 74 (2.70%)
    0 / 38 (0.00%)
    1 / 72 (1.39%)
    0 / 36 (0.00%)
         occurrences all number
    2
    0
    1
    0
    Peripheral sensory neuropathy
         subjects affected / exposed
    1 / 74 (1.35%)
    0 / 38 (0.00%)
    0 / 72 (0.00%)
    0 / 36 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Polyneuropathy
         subjects affected / exposed
    1 / 74 (1.35%)
    0 / 38 (0.00%)
    0 / 72 (0.00%)
    0 / 36 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Sciatica
         subjects affected / exposed
    1 / 74 (1.35%)
    0 / 38 (0.00%)
    2 / 72 (2.78%)
    0 / 36 (0.00%)
         occurrences all number
    1
    0
    2
    0
    Syncope
         subjects affected / exposed
    1 / 74 (1.35%)
    0 / 38 (0.00%)
    1 / 72 (1.39%)
    0 / 36 (0.00%)
         occurrences all number
    1
    0
    1
    0
    Tremor
         subjects affected / exposed
    1 / 74 (1.35%)
    0 / 38 (0.00%)
    0 / 72 (0.00%)
    0 / 36 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Anosmia
         subjects affected / exposed
    0 / 74 (0.00%)
    0 / 38 (0.00%)
    1 / 72 (1.39%)
    0 / 36 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Hypoaesthesia
         subjects affected / exposed
    0 / 74 (0.00%)
    0 / 38 (0.00%)
    0 / 72 (0.00%)
    1 / 36 (2.78%)
         occurrences all number
    0
    0
    0
    1
    Post herpetic neuralgia
         subjects affected / exposed
    0 / 74 (0.00%)
    0 / 38 (0.00%)
    0 / 72 (0.00%)
    1 / 36 (2.78%)
         occurrences all number
    0
    0
    0
    1
    Taste disorder
         subjects affected / exposed
    0 / 74 (0.00%)
    0 / 38 (0.00%)
    0 / 72 (0.00%)
    1 / 36 (2.78%)
         occurrences all number
    0
    0
    0
    1
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    13 / 74 (17.57%)
    2 / 38 (5.26%)
    15 / 72 (20.83%)
    1 / 36 (2.78%)
         occurrences all number
    18
    3
    21
    1
    Leukopenia
         subjects affected / exposed
    4 / 74 (5.41%)
    0 / 38 (0.00%)
    3 / 72 (4.17%)
    0 / 36 (0.00%)
         occurrences all number
    5
    0
    4
    0
    Neutropenia
         subjects affected / exposed
    4 / 74 (5.41%)
    4 / 38 (10.53%)
    8 / 72 (11.11%)
    3 / 36 (8.33%)
         occurrences all number
    5
    5
    13
    3
    Lymphopenia
         subjects affected / exposed
    2 / 74 (2.70%)
    0 / 38 (0.00%)
    6 / 72 (8.33%)
    0 / 36 (0.00%)
         occurrences all number
    2
    0
    6
    0
    Thrombocytopenia
         subjects affected / exposed
    2 / 74 (2.70%)
    0 / 38 (0.00%)
    4 / 72 (5.56%)
    0 / 36 (0.00%)
         occurrences all number
    2
    0
    5
    0
    Anaemia macrocytic
         subjects affected / exposed
    0 / 74 (0.00%)
    0 / 38 (0.00%)
    1 / 72 (1.39%)
    0 / 36 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Leukocytosis
         subjects affected / exposed
    0 / 74 (0.00%)
    0 / 38 (0.00%)
    1 / 72 (1.39%)
    0 / 36 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Microcytic anaemia
         subjects affected / exposed
    0 / 74 (0.00%)
    0 / 38 (0.00%)
    0 / 72 (0.00%)
    1 / 36 (2.78%)
         occurrences all number
    0
    0
    0
    1
    Neutrophilia
         subjects affected / exposed
    0 / 74 (0.00%)
    0 / 38 (0.00%)
    1 / 72 (1.39%)
    0 / 36 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Ear and labyrinth disorders
    Tinnitus
         subjects affected / exposed
    1 / 74 (1.35%)
    0 / 38 (0.00%)
    0 / 72 (0.00%)
    0 / 36 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Vertigo
         subjects affected / exposed
    1 / 74 (1.35%)
    0 / 38 (0.00%)
    4 / 72 (5.56%)
    1 / 36 (2.78%)
         occurrences all number
    1
    0
    4
    1
    Sudden hearing loss
         subjects affected / exposed
    0 / 74 (0.00%)
    0 / 38 (0.00%)
    1 / 72 (1.39%)
    0 / 36 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Eye disorders
    Dry eye
         subjects affected / exposed
    1 / 74 (1.35%)
    0 / 38 (0.00%)
    0 / 72 (0.00%)
    0 / 36 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Eye irritation
         subjects affected / exposed
    1 / 74 (1.35%)
    0 / 38 (0.00%)
    0 / 72 (0.00%)
    0 / 36 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Gastrointestinal disorders
    Abdominal distension
         subjects affected / exposed
    0 / 74 (0.00%)
    1 / 38 (2.63%)
    3 / 72 (4.17%)
    1 / 36 (2.78%)
         occurrences all number
    0
    1
    3
    1
    Abdominal pain
         subjects affected / exposed
    8 / 74 (10.81%)
    11 / 38 (28.95%)
    6 / 72 (8.33%)
    6 / 36 (16.67%)
         occurrences all number
    9
    14
    8
    6
    Abdominal pain upper
         subjects affected / exposed
    7 / 74 (9.46%)
    0 / 38 (0.00%)
    4 / 72 (5.56%)
    2 / 36 (5.56%)
         occurrences all number
    8
    0
    6
    2
    Aphthous ulcer
         subjects affected / exposed
    1 / 74 (1.35%)
    1 / 38 (2.63%)
    0 / 72 (0.00%)
    0 / 36 (0.00%)
         occurrences all number
    1
    1
    0
    0
    Constipation
         subjects affected / exposed
    9 / 74 (12.16%)
    6 / 38 (15.79%)
    9 / 72 (12.50%)
    2 / 36 (5.56%)
         occurrences all number
    9
    9
    9
    2
    Diarrhoea
         subjects affected / exposed
    10 / 74 (13.51%)
    5 / 38 (13.16%)
    12 / 72 (16.67%)
    2 / 36 (5.56%)
         occurrences all number
    14
    6
    13
    2
    Dry mouth
         subjects affected / exposed
    4 / 74 (5.41%)
    0 / 38 (0.00%)
    0 / 72 (0.00%)
    0 / 36 (0.00%)
         occurrences all number
    4
    0
    0
    0
    Dyspepsia
         subjects affected / exposed
    2 / 74 (2.70%)
    2 / 38 (5.26%)
    2 / 72 (2.78%)
    1 / 36 (2.78%)
         occurrences all number
    2
    3
    3
    1
    Dysphagia
         subjects affected / exposed
    0 / 74 (0.00%)
    1 / 38 (2.63%)
    0 / 72 (0.00%)
    0 / 36 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Flatulence
         subjects affected / exposed
    2 / 74 (2.70%)
    1 / 38 (2.63%)
    0 / 72 (0.00%)
    0 / 36 (0.00%)
         occurrences all number
    2
    2
    0
    0
    Gastrooesophageal reflux disease
         subjects affected / exposed
    1 / 74 (1.35%)
    0 / 38 (0.00%)
    1 / 72 (1.39%)
    0 / 36 (0.00%)
         occurrences all number
    1
    0
    1
    0
    Nausea
         subjects affected / exposed
    29 / 74 (39.19%)
    4 / 38 (10.53%)
    30 / 72 (41.67%)
    3 / 36 (8.33%)
         occurrences all number
    34
    5
    37
    3
    Odynophagia
         subjects affected / exposed
    1 / 74 (1.35%)
    0 / 38 (0.00%)
    0 / 72 (0.00%)
    0 / 36 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Stomatitis
         subjects affected / exposed
    1 / 74 (1.35%)
    0 / 38 (0.00%)
    1 / 72 (1.39%)
    0 / 36 (0.00%)
         occurrences all number
    1
    0
    1
    0
    Vomiting
         subjects affected / exposed
    8 / 74 (10.81%)
    4 / 38 (10.53%)
    6 / 72 (8.33%)
    1 / 36 (2.78%)
         occurrences all number
    11
    4
    10
    1
    Abdominal discomfort
         subjects affected / exposed
    0 / 74 (0.00%)
    0 / 38 (0.00%)
    2 / 72 (2.78%)
    0 / 36 (0.00%)
         occurrences all number
    0
    0
    2
    0
    Abnormal faeces
         subjects affected / exposed
    0 / 74 (0.00%)
    0 / 38 (0.00%)
    1 / 72 (1.39%)
    0 / 36 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Frequent bowel movements
         subjects affected / exposed
    0 / 74 (0.00%)
    0 / 38 (0.00%)
    1 / 72 (1.39%)
    0 / 36 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Gastritis
         subjects affected / exposed
    0 / 74 (0.00%)
    0 / 38 (0.00%)
    1 / 72 (1.39%)
    0 / 36 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Oesophagitis
         subjects affected / exposed
    0 / 74 (0.00%)
    0 / 38 (0.00%)
    0 / 72 (0.00%)
    1 / 36 (2.78%)
         occurrences all number
    0
    0
    0
    1
    Oesophageal pain
         subjects affected / exposed
    0 / 74 (0.00%)
    0 / 38 (0.00%)
    1 / 72 (1.39%)
    0 / 36 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Paraesthesia oral
         subjects affected / exposed
    0 / 74 (0.00%)
    0 / 38 (0.00%)
    1 / 72 (1.39%)
    0 / 36 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Skin and subcutaneous tissue disorders
    Alopecia
         subjects affected / exposed
    1 / 74 (1.35%)
    3 / 38 (7.89%)
    2 / 72 (2.78%)
    0 / 36 (0.00%)
         occurrences all number
    1
    3
    2
    0
    Dry skin
         subjects affected / exposed
    2 / 74 (2.70%)
    0 / 38 (0.00%)
    2 / 72 (2.78%)
    1 / 36 (2.78%)
         occurrences all number
    2
    0
    2
    2
    Hyperhidrosis
         subjects affected / exposed
    0 / 74 (0.00%)
    1 / 38 (2.63%)
    0 / 72 (0.00%)
    0 / 36 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Pruritus
         subjects affected / exposed
    1 / 74 (1.35%)
    2 / 38 (5.26%)
    0 / 72 (0.00%)
    1 / 36 (2.78%)
         occurrences all number
    1
    2
    0
    1
    Rash
         subjects affected / exposed
    1 / 74 (1.35%)
    1 / 38 (2.63%)
    2 / 72 (2.78%)
    1 / 36 (2.78%)
         occurrences all number
    1
    1
    5
    1
    Rash maculo-papular
         subjects affected / exposed
    1 / 74 (1.35%)
    0 / 38 (0.00%)
    0 / 72 (0.00%)
    0 / 36 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Rash pruritic
         subjects affected / exposed
    0 / 74 (0.00%)
    1 / 38 (2.63%)
    0 / 72 (0.00%)
    0 / 36 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Skin lesion
         subjects affected / exposed
    0 / 74 (0.00%)
    1 / 38 (2.63%)
    0 / 72 (0.00%)
    0 / 36 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Urticaria
         subjects affected / exposed
    0 / 74 (0.00%)
    1 / 38 (2.63%)
    0 / 72 (0.00%)
    0 / 36 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Blister
         subjects affected / exposed
    0 / 74 (0.00%)
    0 / 38 (0.00%)
    1 / 72 (1.39%)
    0 / 36 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Erythema
         subjects affected / exposed
    0 / 74 (0.00%)
    0 / 38 (0.00%)
    1 / 72 (1.39%)
    1 / 36 (2.78%)
         occurrences all number
    0
    0
    1
    1
    Nail disorder
         subjects affected / exposed
    0 / 74 (0.00%)
    0 / 38 (0.00%)
    1 / 72 (1.39%)
    0 / 36 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Palmar-plantar erythrodysaesthesia syndrome
         subjects affected / exposed
    0 / 74 (0.00%)
    0 / 38 (0.00%)
    0 / 72 (0.00%)
    1 / 36 (2.78%)
         occurrences all number
    0
    0
    0
    1
    Skin reaction
         subjects affected / exposed
    0 / 74 (0.00%)
    0 / 38 (0.00%)
    1 / 72 (1.39%)
    0 / 36 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Renal and urinary disorders
    Haematuria
         subjects affected / exposed
    0 / 74 (0.00%)
    1 / 38 (2.63%)
    0 / 72 (0.00%)
    0 / 36 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Dysuria
         subjects affected / exposed
    0 / 74 (0.00%)
    0 / 38 (0.00%)
    0 / 72 (0.00%)
    1 / 36 (2.78%)
         occurrences all number
    0
    0
    0
    1
    Renal Failure
         subjects affected / exposed
    0 / 74 (0.00%)
    0 / 38 (0.00%)
    1 / 72 (1.39%)
    0 / 36 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Urinary incontinence
         subjects affected / exposed
    0 / 74 (0.00%)
    0 / 38 (0.00%)
    1 / 72 (1.39%)
    0 / 36 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Endocrine disorders
    Hypothyroidism
         subjects affected / exposed
    1 / 74 (1.35%)
    0 / 38 (0.00%)
    0 / 72 (0.00%)
    0 / 36 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    0 / 74 (0.00%)
    3 / 38 (7.89%)
    2 / 72 (2.78%)
    4 / 36 (11.11%)
         occurrences all number
    0
    3
    2
    4
    Arthritis
         subjects affected / exposed
    1 / 74 (1.35%)
    0 / 38 (0.00%)
    1 / 72 (1.39%)
    0 / 36 (0.00%)
         occurrences all number
    1
    0
    1
    0
    Back pain
         subjects affected / exposed
    2 / 74 (2.70%)
    1 / 38 (2.63%)
    2 / 72 (2.78%)
    1 / 36 (2.78%)
         occurrences all number
    2
    1
    2
    1
    Bone pain
         subjects affected / exposed
    1 / 74 (1.35%)
    0 / 38 (0.00%)
    0 / 72 (0.00%)
    0 / 36 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Flank pain
         subjects affected / exposed
    1 / 74 (1.35%)
    0 / 38 (0.00%)
    0 / 72 (0.00%)
    0 / 36 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Hypercreatinaemia
         subjects affected / exposed
    1 / 74 (1.35%)
    0 / 38 (0.00%)
    0 / 72 (0.00%)
    0 / 36 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Muscle spasms
         subjects affected / exposed
    4 / 74 (5.41%)
    1 / 38 (2.63%)
    2 / 72 (2.78%)
    0 / 36 (0.00%)
         occurrences all number
    4
    1
    2
    0
    Muscular weakness
         subjects affected / exposed
    1 / 74 (1.35%)
    0 / 38 (0.00%)
    1 / 72 (1.39%)
    0 / 36 (0.00%)
         occurrences all number
    1
    0
    1
    0
    Musculoskeletal discomfort
         subjects affected / exposed
    0 / 74 (0.00%)
    1 / 38 (2.63%)
    0 / 72 (0.00%)
    0 / 36 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Musculoskeletal pain
         subjects affected / exposed
    1 / 74 (1.35%)
    0 / 38 (0.00%)
    0 / 72 (0.00%)
    0 / 36 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Myalgia
         subjects affected / exposed
    1 / 74 (1.35%)
    0 / 38 (0.00%)
    1 / 72 (1.39%)
    0 / 36 (0.00%)
         occurrences all number
    1
    0
    1
    0
    Osteoporosis
         subjects affected / exposed
    1 / 74 (1.35%)
    0 / 38 (0.00%)
    0 / 72 (0.00%)
    0 / 36 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Pain in extremity
         subjects affected / exposed
    0 / 74 (0.00%)
    2 / 38 (5.26%)
    2 / 72 (2.78%)
    0 / 36 (0.00%)
         occurrences all number
    0
    2
    2
    0
    Intervertebral disc protrusion
         subjects affected / exposed
    0 / 74 (0.00%)
    0 / 38 (0.00%)
    1 / 72 (1.39%)
    0 / 36 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Musculoskeletal chest pain
         subjects affected / exposed
    0 / 74 (0.00%)
    0 / 38 (0.00%)
    0 / 72 (0.00%)
    1 / 36 (2.78%)
         occurrences all number
    0
    0
    0
    1
    Neck pain
         subjects affected / exposed
    0 / 74 (0.00%)
    0 / 38 (0.00%)
    1 / 72 (1.39%)
    0 / 36 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Spinal pain
         subjects affected / exposed
    0 / 74 (0.00%)
    0 / 38 (0.00%)
    0 / 72 (0.00%)
    1 / 36 (2.78%)
         occurrences all number
    0
    0
    0
    1
    Infections and infestations
    Bronchitis
         subjects affected / exposed
    1 / 74 (1.35%)
    0 / 38 (0.00%)
    0 / 72 (0.00%)
    0 / 36 (0.00%)
         occurrences all number
    1
    0
    0
    0
    COVID-19
         subjects affected / exposed
    1 / 74 (1.35%)
    0 / 38 (0.00%)
    0 / 72 (0.00%)
    1 / 36 (2.78%)
         occurrences all number
    1
    0
    0
    1
    Cystitis
         subjects affected / exposed
    1 / 74 (1.35%)
    0 / 38 (0.00%)
    0 / 72 (0.00%)
    0 / 36 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Gastroenteritis cryptosporidial
         subjects affected / exposed
    1 / 74 (1.35%)
    0 / 38 (0.00%)
    0 / 72 (0.00%)
    0 / 36 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Genital herpes
         subjects affected / exposed
    1 / 74 (1.35%)
    0 / 38 (0.00%)
    0 / 72 (0.00%)
    0 / 36 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Gingivitis
         subjects affected / exposed
    1 / 74 (1.35%)
    0 / 38 (0.00%)
    1 / 72 (1.39%)
    0 / 36 (0.00%)
         occurrences all number
    1
    0
    1
    0
    Herpes zoster
         subjects affected / exposed
    0 / 74 (0.00%)
    2 / 38 (5.26%)
    0 / 72 (0.00%)
    1 / 36 (2.78%)
         occurrences all number
    0
    2
    0
    1
    Hordeolum
         subjects affected / exposed
    0 / 74 (0.00%)
    1 / 38 (2.63%)
    0 / 72 (0.00%)
    0 / 36 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Influenza
         subjects affected / exposed
    2 / 74 (2.70%)
    0 / 38 (0.00%)
    0 / 72 (0.00%)
    0 / 36 (0.00%)
         occurrences all number
    4
    0
    0
    0
    Oral herpes
         subjects affected / exposed
    0 / 74 (0.00%)
    1 / 38 (2.63%)
    0 / 72 (0.00%)
    0 / 36 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Pleural infection
         subjects affected / exposed
    1 / 74 (1.35%)
    0 / 38 (0.00%)
    0 / 72 (0.00%)
    0 / 36 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Pharyngitis
         subjects affected / exposed
    0 / 74 (0.00%)
    1 / 38 (2.63%)
    0 / 72 (0.00%)
    0 / 36 (0.00%)
         occurrences all number
    0
    2
    0
    0
    Sinusitis
         subjects affected / exposed
    1 / 74 (1.35%)
    0 / 38 (0.00%)
    0 / 72 (0.00%)
    0 / 36 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Rhinitis
         subjects affected / exposed
    1 / 74 (1.35%)
    0 / 38 (0.00%)
    0 / 72 (0.00%)
    0 / 36 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Skin infection
         subjects affected / exposed
    2 / 74 (2.70%)
    0 / 38 (0.00%)
    0 / 72 (0.00%)
    0 / 36 (0.00%)
         occurrences all number
    2
    0
    0
    0
    Tooth abscess
         subjects affected / exposed
    0 / 74 (0.00%)
    1 / 38 (2.63%)
    0 / 72 (0.00%)
    0 / 36 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Urinary tract infection
         subjects affected / exposed
    2 / 74 (2.70%)
    4 / 38 (10.53%)
    3 / 72 (4.17%)
    0 / 36 (0.00%)
         occurrences all number
    2
    4
    3
    0
    Abscess jaw
         subjects affected / exposed
    0 / 74 (0.00%)
    0 / 38 (0.00%)
    1 / 72 (1.39%)
    0 / 36 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Nasopharyngitis
         subjects affected / exposed
    0 / 74 (0.00%)
    0 / 38 (0.00%)
    1 / 72 (1.39%)
    1 / 36 (2.78%)
         occurrences all number
    0
    0
    1
    1
    Otitis media
         subjects affected / exposed
    0 / 74 (0.00%)
    0 / 38 (0.00%)
    1 / 72 (1.39%)
    0 / 36 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Upper respiratory tract infection
         subjects affected / exposed
    0 / 74 (0.00%)
    0 / 38 (0.00%)
    2 / 72 (2.78%)
    1 / 36 (2.78%)
         occurrences all number
    0
    0
    2
    1
    Metabolism and nutrition disorders
    Decreased appetite
         subjects affected / exposed
    2 / 74 (2.70%)
    1 / 38 (2.63%)
    7 / 72 (9.72%)
    1 / 36 (2.78%)
         occurrences all number
    2
    1
    8
    1
    Hypercholesterolaemia
         subjects affected / exposed
    1 / 74 (1.35%)
    0 / 38 (0.00%)
    0 / 72 (0.00%)
    0 / 36 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Hyperglycaemia
         subjects affected / exposed
    0 / 74 (0.00%)
    1 / 38 (2.63%)
    0 / 72 (0.00%)
    0 / 36 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Hyperuricaemia
         subjects affected / exposed
    0 / 74 (0.00%)
    1 / 38 (2.63%)
    1 / 72 (1.39%)
    1 / 36 (2.78%)
         occurrences all number
    0
    1
    1
    0
    Hypermagnesaemia
         subjects affected / exposed
    1 / 74 (1.35%)
    0 / 38 (0.00%)
    0 / 72 (0.00%)
    0 / 36 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Hypocalcaemia
         subjects affected / exposed
    1 / 74 (1.35%)
    0 / 38 (0.00%)
    0 / 72 (0.00%)
    0 / 36 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Hypokalaemia
         subjects affected / exposed
    1 / 74 (1.35%)
    0 / 38 (0.00%)
    0 / 72 (0.00%)
    0 / 36 (0.00%)
         occurrences all number
    3
    0
    0
    0
    Hypomagnesaemia
         subjects affected / exposed
    1 / 74 (1.35%)
    1 / 38 (2.63%)
    0 / 72 (0.00%)
    1 / 36 (2.78%)
         occurrences all number
    1
    1
    0
    1
    Hyponatraemia
         subjects affected / exposed
    1 / 74 (1.35%)
    0 / 38 (0.00%)
    0 / 72 (0.00%)
    0 / 36 (0.00%)
         occurrences all number
    2
    0
    0
    0
    Folate deficiency
         subjects affected / exposed
    0 / 74 (0.00%)
    0 / 38 (0.00%)
    1 / 72 (1.39%)
    0 / 36 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Hyperchloraemia
         subjects affected / exposed
    0 / 74 (0.00%)
    0 / 38 (0.00%)
    1 / 72 (1.39%)
    0 / 36 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Hypernatraemia
         subjects affected / exposed
    0 / 74 (0.00%)
    0 / 38 (0.00%)
    1 / 72 (1.39%)
    0 / 36 (0.00%)
         occurrences all number
    0
    0
    1
    0

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    11 Dec 2017
    Study Design, Rationale for Study Design, Doses, and Control Groups sections updated to limit enrolment for patients with documented prior exposure to PARPi. Inclusion Criteria updated to: a) Specify eligible histopathology by excluding carcinosarcoma, clear cell carcinoma and discussion for patients with mixed tumours. b) Limit enrolment for patients with documented prior exposure to PARPi. c) Clarify partial or complete radiological response is due to most recent chemotherapy. d) Allow calculation of CrCl estimate by using the Cockcroft-Gault equation of ≥51 mL/min or 24-hour urine test. Exclusion Criteria updated to: a) Allow eligibility of Neuropathy Grade 2. b) Remove: “Previous allogeneic bone marrow transplant or double umbilical cord blood transplantation”. c) Restrict eligibility for patients who had received a whole blood transfusion within 30 days prior to screening tests instead of 90 days prior to randomisation. Screen failure section clarified re-screening was permitted and the process to perform re-screening. Scheduled Assessments updated to: a) Add pregnancy testing for females of childbearing potential during each on site treatment visit. b) Remove requirements to complete additional eCRF when an AE of nausea or vomiting occurred. c) Clarify that if a patient discontinued treatment (and/or received a subsequent cancer therapy) prior to progression, then the patient should be followed until objective disease progression as defined by RECIST 1.1. Interim Analysis updated to include a pre-specified interim analysis for futility, ensuring that exposure of patients to an ineffective treatment was excluded. IDMC unblinded interim (or ongoing) efficacy and safety review to pick out a major risk:benefit discrepancy.
    04 Jan 2019
    Sample size estimate updated to 228 (assumptions on sample size were to be reviewed at the time of the interim analysis). Amended assumptions for expected median PFS in placebo treated patients (4.5 months) based on prior data; calculations of sample size adjusted to support detection of a 0.5 HR in both cohorts. Oxaliplatin added as an acceptable platinum chemotherapy. Inclusion criterion related to continued platinum sensitivity modified to allow patients who had no measurable disease following debulking surgery and a CA 125 which was not rising.
    15 Oct 2020
    Acceptable birth control methods updated so that women of childbearing potential and their partners, who were sexually active, must have agreed to use 1 highly effective form of contraception and their partners had to use a male condom. New section to detail assessments required for patients still on study treatment after primary PFS analysis. Data cut-off and subsequent database lock and timing for the primary analysis was clarified: after the later of the 2 cohorts reached the defined number of progression or death events. Updated timing of OS analysis to the time of the primary analysis for PFS, and again after 50% death events in either cohort or 60 months after FPI, whichever was earlier.

    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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