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    Clinical Trial Results:
    Phase II randomised, double blind, multicentre study to assess the efficacy of AZD2281 in the treatment of patients with platinum sensitive serous ovarian cancer following treatment with two or more platinum containing regimens

    Summary
    EudraCT number
    		 2008-003439-18
    Trial protocol
    		 GB   BE   DE   PL   CZ   ES   EE   FR   AT   NL  
    Global end of trial date
    12 Oct 2023

    Results information
    Results version number
    		 v1(current)
    This version publication date
    22 Dec 2024
    First version publication date
    22 Dec 2024
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    D0810C00019
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 -
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    AstraZeneca
    Sponsor organisation address
    1 Francis Crick Avenue, Cambridge Biomedical Campus, United Kingdom, CB2 0AA
    Public contact
    Tsveta Milenkova, AstraZeneca, ClinicalTrialTransparency@astrazeneca.com
    Scientific contact
    Anitra Fielding, AstraZeneca, ClinicalTrialTransparency@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
    26 Nov 2012
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    26 Nov 2012
    Global end of trial reached?
    Yes
    Global end of trial date
    12 Oct 2023
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To determine the efficacy (assessed by PFS) of olaparib (capsule formulation) compared to placebo in the overall population.
    Protection of trial subjects
    Repeat dose interruptions are to be allowed as required, for a maximum of 4 weeks (28 days) on each occasion. Where toxicity reoccur following re-challenge with AZD2281 or matching placebo, and where further dose interruptions are considered inadequate for management of toxicity, then the patient is to be considered for dose reduction or must permanently discontinue treatment. Treatment must be interrupted if any NCI-CTCAE grade 3 or 4 adverse event occurs which the Investigator considers to be related to administration of AZD2281 or matching placebo. If this has not resolved to at least NCI-CTCAE grade 1 by the dose interruption period and/or the patient has undergone 2 dose reductions already, the patient must discontinue treatment. When toxicity resolves, the patient may restart with a 50% does reduction
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    28 Aug 2008
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Australia: 31
    Country: Number of subjects enrolled
    Belgium: 13
    Country: Number of subjects enrolled
    Canada: 6
    Country: Number of subjects enrolled
    Czechia: 1
    Country: Number of subjects enrolled
    Estonia: 1
    Country: Number of subjects enrolled
    France: 11
    Country: Number of subjects enrolled
    Germany: 32
    Country: Number of subjects enrolled
    Israel: 26
    Country: Number of subjects enrolled
    Netherlands: 5
    Country: Number of subjects enrolled
    Poland: 11
    Country: Number of subjects enrolled
    Romania: 7
    Country: Number of subjects enrolled
    Russian Federation: 13
    Country: Number of subjects enrolled
    Spain: 9
    Country: Number of subjects enrolled
    United Kingdom: 41
    Country: Number of subjects enrolled
    United States: 44
    Country: Number of subjects enrolled
    Ukraine: 14
    Worldwide total number of subjects
    265
    EEA total number of subjects
    90
    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)
    185
    From 65 to 84 years
    80
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 The first patient was enrolled on 28 August 2008 and the last patient was enrolled on 9 February 2010. Patients were enrolled at 82 centres in 16 countries. Of the 326 patients enrolled, 265 were randomized

    Pre-assignment
    Screening details
    		 It was planned that 250 women with advanced platinum sensitive serous ovarian cancer who had received 2 or more previous platinum-containing regimens and demonstrated an objective stable maintained response in the last platinum regimen prior to enrolment were to receive olaparib 400 mg bd or matching placebo in a 1:1 ratio. 265 randomised.

    Period 1
    Period 1 title
    Overall Study (overall period)
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Subject, Investigator, Monitor, Carer, Data analyst
    Blinding implementation details
    AZD2281 and placebo matched AZD2281 treatments were blinded. The active and placebo capsules were identical and presented in the same packaging to ensure blinding of the study medication.

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 olaparib 400 mg bd
    Arm description
    		 AZD2281 olaparib (AZD2281) 400 mg oral capsules twice daily
    Arm type
    		 Experimental

    Investigational medicinal product name
    olaparib
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    8 x 50 mg capsules consumed orally over 28 days at the same time each day with 240ml of water. they were swallowed whole at least 1 hour after food, and food could not be consumed 20 hours after taking a capsule

    Arm title
    		 Placebo bd
    Arm description
    		 olaparib matching placebo oral capsules twice daily
    Arm type
    		 Placebo

    Investigational medicinal product name
    placebo effect
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    the placebo was taken in the same way and form as the olaparib capsules

    Number of subjects in period 1
    		olaparib 400 mg bd Placebo bd
    Started
    136
    129
    Completed
    28
    11
    Not completed
    108
    118
         Adverse event, serious fatal
    98
    112
         Lost to follow-up
    2
    3
         Voluntary Discontinuation of Patient
    7
    3
         Protocol deviation
    1
    -

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    olaparib 400 mg bd
    Reporting group description
    		 AZD2281 olaparib (AZD2281) 400 mg oral capsules twice daily

    Reporting group title
    Placebo bd
    Reporting group description
    		 olaparib matching placebo oral capsules twice daily

    Reporting group values
    		 olaparib 400 mg bd Placebo bd Total
    Number of subjects
    		 136 129 265
    Age categorical
    Units: Subjects
        In utero
    		 0 0 0
        Preterm newborn infants (gestational age < 37 wks)
    		 0 0 0
        Newborns (0-27 days)
    		 0 0 0
        Infants and toddlers (28 days-23 months)
    		 0 0 0
        Children (2-11 years)
    		 0 0 0
        Adolescents (12-17 years)
    		 0 0 0
        Adults (18-64 years)
    		 91 94 185
        From 65-84 years
    		 45 35 80
        85 years and over
    		 0 0 0
    Age Continuous
    Units: years
        arithmetic mean (standard deviation)
    		 58.9 ( 10.95 ) 58.5 ( 9.89 ) -
    Gender, Male/Female
    Units: Subjects
        Female
    		 136 129 265
        Male
    		 0 0 0
    Time to progression
    The time to disease progression from the completion of the penultimate platinum containing therapy (last dose) prior to enrolment on the study.
    Units: Subjects
        >6 to 12 months
    		 53 54 107
        >12 months
    		 83 75 158
    Objective response
    Objective response to the last platinum containing regimen prior to enrolment on the study: -CR-Complete Response (defined as normal radiological findings and CA-125 within the normal range) -PR-Partial Response (defined as a RECIST PR and/or GCIG CA-125 response)
    Units: Subjects
        Complete response
    		 57 63 120
        Partial response
    		 79 66 145
    Race
    Units: Subjects
        White
    		 130 126 256
        Black or African American
    		 2 1 3
        Asian
    		 2 2 4
        Other
    		 2 0 2
    Jewish descent
    Units: Subjects
        Not Jewish Descent
    		 115 112 227
        Ashkenazi Jewish
    		 17 12 29
        sephardic Jewish
    		 1 1 2
        Mizrahim Jewish
    		 2 1 3
        Other
    		 0 3 3
        Missing
    		 1 0 1
    ECOG performance status
    Units: Subjects
        (0) Normal activity
    		 110 95 205
        (1) restricted activity
    		 23 30 53
        (2) in bed <=50% of the time
    		 1 2 3
        Unknown
    		 2 2 4
    Primary Tumour Location
    Units: Subjects
        Ovary
    		 119 109 228
        Fallopian tube
    		 3 3 6
        Primary peritoneal
    		 14 16 30
        Other
    		 0 1 1
    Tumour Grade
    Units: Subjects
        Well differentiated (G1)
    		 0 0 0
        Mod. Differentiated (G2)
    		 36 34 70
        Poorly differentiated (G3)
    		 97 89 186
        undifferentiated (G4)
    		 2 4 6
        unassessable (GX)
    		 1 2 3
    FIGO stage
    Units: Subjects
        Stage IB
    		 0 1 1
        stage IC
    		 3 3 6
        Stage II
    		 1 0 1
        Stage IIA
    		 2 1 3
        Stage IIB
    		 3 1 4
        Stage IIC
    		 5 6 11
        Stage III
    		 10 7 17
        Stage IIIA
    		 4 3 7
        Stage IIIB
    		 8 12 20
        Stage IIIC
    		 81 76 157
        Stage IV
    		 17 17 34
        Unknown
    		 2 2 4
    Platinum sensitivity
    Units: Subjects
        >6 - ≤12 months
    		 53 54 107
        >12 months
    		 83 75 158
    Objective Response
    Units: Subjects
        Complete Response
    		 57 63 120
        Partial Response
    		 79 66 145
    Number of weeks from completion of last platinum therapy to randomisation
    Units: Subjects
        ≤8 weeks
    		 131 125 256
        >8 to ≤9 weeks
    		 1 3 4
        >9 to ≤10 weeks
    		 0 1 1
        >10 to ≤11 weeks
    		 0 0 0
        >11 to ≤12 weeks
    		 0 0 0
        >12 weeks
    		 3 0 3
        not progressing
    		 1 0 1
    Time from completion of final prior platinum chemotherapy to randomisation
    Units: days
        arithmetic mean (full range (min-max))
    		 43.2 (15 to 517) 40.0 (14 to 70) -
    Most recent progression to randomisation
    Units: days
        arithmetic mean (full range (min-max))
    		 213.9 (90 to 1123) 218.2 (56 to 1115) -

    End points

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    End points reporting groups
    Reporting group title
    olaparib 400 mg bd
    Reporting group description
    		 AZD2281 olaparib (AZD2281) 400 mg oral capsules twice daily

    Reporting group title
    Placebo bd
    Reporting group description
    		 olaparib matching placebo oral capsules twice daily

    Primary: Progression Free Survival (PFS) (According to Response Evaluation Criteria in Solid Tumours [RECIST])

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    End point title
    		 Progression Free Survival (PFS) (According to Response Evaluation Criteria in Solid Tumours [RECIST])
    End point description
    PFS was defined as the time from randomisation to the earlier date of radiological progression (per RECIST criteria) or death by any cause in the absence of objective progression. [Full analysis set (FAS)]
    End point type
    Primary
    End point timeframe
    Radiologic scans performed at baseline then every 12 weeks (+/- 1 week) for the first 60 weeks, then every 24 weeks (+/-1 week) thereafter
    End point values
    		 olaparib 400 mg bd Placebo bd
    Number of subjects analysed
    136
    129
    Units: Number of progressions
    60
    94
    Statistical analysis title
    		 Primary analysis of PFS
    Statistical analysis description
    HR < 1 favours olaparib
    Comparison groups
    olaparib 400 mg bd v Placebo bd
    Number of subjects included in analysis
    265
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    		 < 0.00001
    Method
    		 Regression, Cox
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.35
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.25
         upper limit
    		 0.49

    Primary: BRCA mutant subgroup: Progression Free Survival (PFS)

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    End point title
    		 BRCA mutant subgroup: Progression Free Survival (PFS)
    End point description
    PFS was defined as the time from randomisation to the earlier date of radiological progression (per RECIST criteria) or death by any cause in the absence of objective progression. [BRCA mutant analysis set]
    End point type
    Primary
    End point timeframe
    Radiologic scans performed at baseline then every 12 weeks (+/- 1 week) for the first 60 weeks, then every 24 weeks (+/-1 week) thereafter
    End point values
    		 olaparib 400 mg bd Placebo bd
    Number of subjects analysed
    74
    62
    Units: Number of progressions
    26
    46
    Statistical analysis title
    		 Analysis of PFS for BRCA mutant subgroup
    Statistical analysis description
    HR < 1 favours olaparib
    Comparison groups
    olaparib 400 mg bd v Placebo bd
    Number of subjects included in analysis
    136
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    		 < 0.00001
    Method
    		 Regression, Cox
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.18
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.11
         upper limit
    		 0.31

    Secondary: Overall Survival (OS)

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    End point title
    		 Overall Survival (OS)
    End point description
    OS = time from randomisation to date of death from any cause. Patients who had not died at time of analysis were censored at last date patient was known to be alive.
    End point type
    Secondary
    End point timeframe
    Follow up every 12 weeks post progression
    End point values
    		 olaparib 400 mg bd Placebo bd
    Number of subjects analysed
    136
    129
    Units: Number of deaths
    98
    112
    Statistical analysis title
    		 Analysis of OS
    Statistical analysis description
    HR < 1 favours olaparib
    Comparison groups
    olaparib 400 mg bd v Placebo bd
    Number of subjects included in analysis
    265
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    		 = 0.02 [1]
    Method
    		 Regression, Cox
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.73
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.55
         upper limit
    		 0.95
    Notes
    [1] - p-value is nominal

    Secondary: BRCA mutant subgroup: Overall Survival (OS)

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    End point title
    		 BRCA mutant subgroup: Overall Survival (OS)
    End point description
    OS = time from randomisation to date of death from any cause. Patients who had not died at time of analysis were censored at last date patient was known to be alive. BRCA mutant subset.
    End point type
    Secondary
    End point timeframe
    Follow up every 12 weeks post progression
    End point values
    		 olaparib 400 mg bd Placebo bd
    Number of subjects analysed
    74
    62
    Units: Number of deaths
    49
    50
    Statistical analysis title
    		 OS analysis for BRCA mutant subgroup
    Statistical analysis description
    HR < 1 favours olaparib
    Comparison groups
    olaparib 400 mg bd v Placebo bd
    Number of subjects included in analysis
    136
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    		 = 0.02 [2]
    Method
    		 Regression, Cox
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.62
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.42
         upper limit
    		 0.93
    Notes
    [2] - p-value is nominal

    Secondary: Disease Control Rate

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    End point title
    		 Disease Control Rate
    End point description
    Disease control rate was defined as the percentage of patients who have at least 1 confirmed visit response of CR or PR or have demonstrated SD or NED for at least 23 weeks (ie, 24 weeks +/- 1 week) prior to any evidence of progression. [FAS]
    End point type
    Secondary
    End point timeframe
    Radiologic scans performed at baseline then every 12 weeks (+/- 1 week) for the first 60 weeks, then every 24 weeks (+/-1 week) thereafter
    End point values
    		 olaparib 400 mg bd Placebo bd
    Number of subjects analysed
    136
    129
    Units: percentage of participants
        number (not applicable)
    52.9
    24.8
    No statistical analyses for this end point

    Secondary: Objective Response Rate (ORR) (According to RECIST)

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    End point title
    		 Objective Response Rate (ORR) (According to RECIST)
    End point description
    For each treatment group, the ORR was the number of Complete Response (CR) and Partial Response (PR) divided by the number of patients in the group in the FAS with measurable disease at baseline (displayed as a percentage below). Evaluable for response set
    End point type
    Secondary
    End point timeframe
    Radiologic scans performed at baseline then every 12 weeks (+/- 1 week) for the first 60 weeks, then every 24 weeks (+/-1 week) thereafter
    End point values
    		 olaparib 400 mg bd Placebo bd
    Number of subjects analysed
    57
    48
    Units: percentage of participants
        number (not applicable)
    12.3
    4.2
    No statistical analyses for this end point

    Secondary: Percentage Change From Baseline in Tumour Size at Week 24

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    End point title
    		 Percentage Change From Baseline in Tumour Size at Week 24
    End point description
    Percentage change from baseline to Week 24 in target tumour size.
    End point type
    Secondary
    End point timeframe
    Radiologic scans performed at baseline then every 12 weeks (+/- 1week) for the first 60 weeks, then every 24 weeks (+/-1 week) thereafter
    End point values
    		 olaparib 400 mg bd Placebo bd
    Number of subjects analysed
    136
    129
    Units: Percent change in tumour size
        least squares mean (full range (min-max))
    0.0 (-100.0 to 45.0)
    33.5 (-36.4 to 39.4)
    Statistical analysis title
    		 Statistical analysis of the tumour size change
    Statistical analysis description
    LS mean < 0 favours olaparib
    Comparison groups
    olaparib 400 mg bd v Placebo bd
    Number of subjects included in analysis
    265
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    		 = 0.01221
    Method
    		 ANCOVA
    Parameter type
    		 Difference in LS means
    Point estimate
    -33.4
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -59.4
         upper limit
    		 -7.4

    Secondary: Duration of Response

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    End point title
    		 Duration of Response
    End point description
    Duration of response = time from assessment prior to timepoint where PR or CR confirmed (i.e. initial assessment of PR/CR), until earliest date of objective progression or death. [Responding patients only]. There were insufficient responses to enable conclusions to be drawn.
    End point type
    Secondary
    End point timeframe
    Radiologic scans performed at baseline then every 12 weeks (+/- 1 week) for the first 60 weeks, then every 24 weeks (+/-1 week) thereafter
    End point values
    		 olaparib 400 mg bd Placebo bd
    Number of subjects analysed
    136
    129
    Units: Number of responses
    7
    2
    No statistical analyses for this end point

    Secondary: Best Objective Response

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    End point title
    		 Best Objective Response
    End point description
    Best overall response from radiologic assessments. [FAS]
    End point type
    Secondary
    End point timeframe
    Radiologic scans performed at baseline then every 12 weeks (+/- 1week) for the first 60 weeks, then every 24 weeks (+/- 1 week) thereafter
    End point values
    		 olaparib 400 mg bd Placebo bd
    Number of subjects analysed
    136
    129
    Units: Participants
        Complete Response
    0
    0
        Partial Response
    7
    2
        No evidence of disease
    49
    42
        Stable Disease >= 11 weeks
    46
    25
        Disease Progression
    24
    55
        Not Evaluable
    10
    5
    No statistical analyses for this end point

    Secondary: Best Percentage Change in Cancer Antigen 125 (CA-125) Levels

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    End point title
    		 Best Percentage Change in Cancer Antigen 125 (CA-125) Levels
    End point description
    Best percentage change from baseline in CA-125 level
    End point type
    Secondary
    End point timeframe
    CA-125 was measured at baseline then every 28 days on treatment
    End point values
    		 olaparib 400 mg bd Placebo bd
    Number of subjects analysed
    135
    128
    Units: percentage of change
        arithmetic mean (full range (min-max))
    -16.67 (-100.00 to 346.15)
    0.00 (-99.50 to 1436.84)
    No statistical analyses for this end point

    Secondary: RECIST and CA-125 Response Separately and Combined

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    End point title
    		 RECIST and CA-125 Response Separately and Combined
    End point description
    RECIST and CA-125 response separately and combined [Patients evaluable for either CA-125 response or RECIST response]
    End point type
    Secondary
    End point timeframe
    Radiologic scans performed at baseline then every 12 weeks (+/- 1week) for the first 60 weeks, then every 24 weeks (+/- 1 week) thereafter and monthly for CA-125 measurements
    End point values
    		 olaparib 400 mg bd Placebo bd
    Number of subjects analysed
    61
    53
    Units: Participants
        RECIST Response
    16
    2
        Confirmed RECIST Response
    7
    2
        Unconfirmed RECIST response
    9
    0
        CA-125 Response
    1
    1
        Confirmed RECIST or CA-125 Response
    8
    3
    No statistical analyses for this end point

    Secondary: Improvement Rate for FACT-O Symptom Index (FOSI)

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    End point title
    		 Improvement Rate for FACT-O Symptom Index (FOSI)
    End point description
    The percentage of patients with an improvement in FOSI. Improvement was defined as a change from baseline of greater than or equal to +3. [Evaluable for FOSI set]
    End point type
    Secondary
    End point timeframe
    Patient reported outcome questionnaire completed at baseline then every 28 days up to disease progression
    End point values
    		 olaparib 400 mg bd Placebo bd
    Number of subjects analysed
    117
    115
    Units: percentage of evaluable participants
        number (not applicable)
    17.1
    14.8
    No statistical analyses for this end point

    Secondary: Time to Earlier of CA-125 or RECIST Progression

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    End point title
    		 Time to Earlier of CA-125 or RECIST Progression
    End point description
    Time from randomisation to the earlier date of radiological progression (per RECIST criteria) or CA-125 or death by any cause in the absence of objective progression. [FAS]
    End point type
    Secondary
    End point timeframe
    Radiologic scans performed at baseline then every 12 weeks (+/- 1 week) for the first 60 weeks, then every 24 weeks (+/- 1 week) thereafter and monthly for CA-125 measurements
    End point values
    		 olaparib 400 mg bd Placebo bd
    Number of subjects analysed
    136
    129
    Units: Number of progressions
    66
    106
    Statistical analysis title
    		 Analysis of time to CA-125/RECIST progression
    Statistical analysis description
    HR < 1 favours olaparib
    Comparison groups
    olaparib 400 mg bd v Placebo bd
    Number of subjects included in analysis
    265
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    		 < 0.00001
    Method
    		 Regression, Cox
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.35
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.25
         upper limit
    		 0.47

    Secondary: Improvement Rate for Trial Outcome Index (TOI)

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    End point title
    		 Improvement Rate for Trial Outcome Index (TOI)
    End point description
    The percentage of patients with an improvement in TOI. Improvement was defined as a change from baseline of greater than or equal to +7. [Evaluable for TOI set]
    End point type
    Secondary
    End point timeframe
    Patient reported outcome questionnaire completed at baseline then every 28 days up to disease progression
    End point values
    		 olaparib 400 mg bd Placebo bd
    Number of subjects analysed
    115
    111
    Units: percentage of evaluable participants
        number (not applicable)
    20.0
    18.0
    No statistical analyses for this end point

    Secondary: Trial Outcome Index(TOI)Time to Worsening

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    End point title
    		 Trial Outcome Index(TOI)Time to Worsening
    End point description
    The time to worsening was compared between treatments for each of the TOI, FOSI and total FACT-O. [Evaluable for TOI set]
    End point type
    Secondary
    End point timeframe
    Patient reported outcome questionnaire completed at baseline then every 28 days up to disease progression
    End point values
    		 olaparib 400 mg bd Placebo bd
    Number of subjects analysed
    115
    111
    Units: Number worsening
    64
    56
    Statistical analysis title
    		 Analysis of TOI time to worsening
    Statistical analysis description
    HR < 1 favours olaparib
    Comparison groups
    olaparib 400 mg bd v Placebo bd
    Number of subjects included in analysis
    226
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    		 = 0.68
    Method
    		 Regression, Cox
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    1.08
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.75
         upper limit
    		 1.55

    Secondary: Improvement Rate for Total Functional Analysis of Cancer Therapy - Ovarian (FACT-O)

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    End point title
    		 Improvement Rate for Total Functional Analysis of Cancer Therapy - Ovarian (FACT-O)
    End point description
    The percentage of patients with an improvement in total FACT-O. Improvement was defined as a change from baseline of greater than or equal to +9. [Evaluable for FACT-O set]
    End point type
    Secondary
    End point timeframe
    Patient reported outcome questionnaire completed at baseline then every 28 days up to disease progression
    End point values
    		 olaparib 400 mg bd Placebo bd
    Number of subjects analysed
    114
    111
    Units: percentage of evaluable participants
        number (not applicable)
    21.1
    18.9
    No statistical analyses for this end point

    Secondary: FACT-O Symptom Index (FOSI) Time to Worsening

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    End point title
    		 FACT-O Symptom Index (FOSI) Time to Worsening
    End point description
    The time to worsening was compared between treatments for each of the TOI, FOSI and total FACT-O. [Evaluable for FOSI set]
    End point type
    Secondary
    End point timeframe
    Patient reported outcome questionnaire completed at baseline then every 28 days up to disease progression
    End point values
    		 olaparib 400 mg bd Placebo bd
    Number of subjects analysed
    117
    115
    Units: Number worsening
    77
    67
    Statistical analysis title
    		 Analysis of FOSI time to worsening
    Statistical analysis description
    HR < 1 favours olaparib
    Comparison groups
    olaparib 400 mg bd v Placebo bd
    Number of subjects included in analysis
    232
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    		 = 0.23
    Method
    		 Regression, Cox
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    1.22
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.88
         upper limit
    		 1.71

    Secondary: Functional Analysis of Cancer Therapy - Ovarian (FACT-O) Time to Worsening

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    End point title
    		 Functional Analysis of Cancer Therapy - Ovarian (FACT-O) Time to Worsening
    End point description
    The time to worsening was compared between treatments for each of the TOI, FOSI and total FACT-O. [Evaluable for FACT-O set]
    End point type
    Secondary
    End point timeframe
    Patient reported outcome questionnaire completed at baseline then every 28 days up to disease progression
    End point values
    		 olaparib 400 mg bd Placebo bd
    Number of subjects analysed
    114
    111
    Units: Number worsening
    72
    63
    Statistical analysis title
    		 Analysis of FACT-O time to worsening
    Statistical analysis description
    HR < 1 favours olaparib
    Comparison groups
    olaparib 400 mg bd v Placebo bd
    Number of subjects included in analysis
    225
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    		 = 0.39
    Method
    		 Regression, Cox
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    1.16
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.83
         upper limit
    		 1.64

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Adverse Events will be collected from time of signed informed consent throughout the treatment period and up to and including the 30-day follow-up period
    Adverse event reporting additional description
    128 participants in Placebo as 1 participant withdrew consent prior to treatment
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    19.0
    Reporting groups
    Reporting group title
    Placebo
    Reporting group description
    		 -

    Reporting group title
    Olaparib 400 mg bd
    Reporting group description
    		 -

    Serious adverse events
    		 Placebo Olaparib 400 mg bd
    Total subjects affected by serious adverse events
         subjects affected / exposed
    11 / 128 (8.59%)
    31 / 136 (22.79%)
         number of deaths (all causes)
    77
    77
         number of deaths resulting from adverse events
    0
    1
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    SQUAMOUS CELL CARCINOMA OF THE ORAL CAVITY
         subjects affected / exposed
    0 / 128 (0.00%)
    1 / 136 (0.74%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    ACUTE LEUKAEMIA
         subjects affected / exposed
    0 / 128 (0.00%)
    1 / 136 (0.74%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    BLADDER CANCER
         subjects affected / exposed
    1 / 128 (0.78%)
    0 / 136 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    INTRADUCTAL PROLIFERATIVE BREAST LESION
         subjects affected / exposed
    0 / 128 (0.00%)
    1 / 136 (0.74%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    PAPILLARY THYROID CANCER
         subjects affected / exposed
    0 / 128 (0.00%)
    1 / 136 (0.74%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vascular disorders
    ESSENTIAL HYPERTENSION
         subjects affected / exposed
    1 / 128 (0.78%)
    0 / 136 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    DEEP VEIN THROMBOSIS
         subjects affected / exposed
    0 / 128 (0.00%)
    1 / 136 (0.74%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    VENA CAVA THROMBOSIS
         subjects affected / exposed
    0 / 128 (0.00%)
    1 / 136 (0.74%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    General disorders and administration site conditions
    PYREXIA
         subjects affected / exposed
    0 / 128 (0.00%)
    1 / 136 (0.74%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    NON-CARDIAC CHEST PAIN
         subjects affected / exposed
    0 / 128 (0.00%)
    1 / 136 (0.74%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    HERNIA PAIN
         subjects affected / exposed
    0 / 128 (0.00%)
    1 / 136 (0.74%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Immune system disorders
    IODINE ALLERGY
         subjects affected / exposed
    0 / 128 (0.00%)
    1 / 136 (0.74%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    ASTHMA
         subjects affected / exposed
    1 / 128 (0.78%)
    0 / 136 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    DYSPNOEA
         subjects affected / exposed
    0 / 128 (0.00%)
    2 / 136 (1.47%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    COUGH
         subjects affected / exposed
    0 / 128 (0.00%)
    1 / 136 (0.74%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    BRONCHIECTASIS
         subjects affected / exposed
    0 / 128 (0.00%)
    1 / 136 (0.74%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    PULMONARY EMBOLISM
         subjects affected / exposed
    0 / 128 (0.00%)
    1 / 136 (0.74%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Psychiatric disorders
    CONFUSIONAL STATE
         subjects affected / exposed
    0 / 128 (0.00%)
    1 / 136 (0.74%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    FEMUR FRACTURE
         subjects affected / exposed
    0 / 128 (0.00%)
    2 / 136 (1.47%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    HIP FRACTURE
         subjects affected / exposed
    0 / 128 (0.00%)
    1 / 136 (0.74%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    POST PROCEDURAL HAEMATOMA
         subjects affected / exposed
    0 / 128 (0.00%)
    1 / 136 (0.74%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac disorders
    CARDIOVASCULAR INSUFFICIENCY
         subjects affected / exposed
    0 / 128 (0.00%)
    1 / 136 (0.74%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nervous system disorders
    SYNCOPE
         subjects affected / exposed
    0 / 128 (0.00%)
    1 / 136 (0.74%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    HAEMORRHAGIC STROKE
         subjects affected / exposed
    0 / 128 (0.00%)
    1 / 136 (0.74%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    1 / 1
    APHASIA
         subjects affected / exposed
    0 / 128 (0.00%)
    1 / 136 (0.74%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    THROMBOCYTOPENIA
         subjects affected / exposed
    0 / 128 (0.00%)
    1 / 136 (0.74%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    PANCYTOPENIA
         subjects affected / exposed
    0 / 128 (0.00%)
    2 / 136 (1.47%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    ANAEMIA
         subjects affected / exposed
    0 / 128 (0.00%)
    3 / 136 (2.21%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal disorders
    INTRA-ABDOMINAL HAEMORRHAGE
         subjects affected / exposed
    0 / 128 (0.00%)
    1 / 136 (0.74%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    INTESTINAL OBSTRUCTION
         subjects affected / exposed
    1 / 128 (0.78%)
    1 / 136 (0.74%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    IMPAIRED GASTRIC EMPTYING
         subjects affected / exposed
    1 / 128 (0.78%)
    0 / 136 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    GASTRITIS
         subjects affected / exposed
    2 / 128 (1.56%)
    0 / 136 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    DIARRHOEA
         subjects affected / exposed
    0 / 128 (0.00%)
    1 / 136 (0.74%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    CONSTIPATION
         subjects affected / exposed
    0 / 128 (0.00%)
    2 / 136 (1.47%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    MELAENA
         subjects affected / exposed
    0 / 128 (0.00%)
    1 / 136 (0.74%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    ABDOMINAL INCARCERATED HERNIA
         subjects affected / exposed
    0 / 128 (0.00%)
    1 / 136 (0.74%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    ABDOMINAL PAIN
         subjects affected / exposed
    1 / 128 (0.78%)
    0 / 136 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    VOMITING
         subjects affected / exposed
    0 / 128 (0.00%)
    1 / 136 (0.74%)
         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
    3 / 128 (2.34%)
    2 / 136 (1.47%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    NAUSEA
         subjects affected / exposed
    0 / 128 (0.00%)
    1 / 136 (0.74%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    ARTHRALGIA
         subjects affected / exposed
    0 / 128 (0.00%)
    1 / 136 (0.74%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    BACK PAIN
         subjects affected / exposed
    0 / 128 (0.00%)
    1 / 136 (0.74%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    OSTEOPOROSIS
         subjects affected / exposed
    0 / 128 (0.00%)
    1 / 136 (0.74%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infections and infestations
    LIVER ABSCESS
         subjects affected / exposed
    0 / 128 (0.00%)
    1 / 136 (0.74%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    INFLUENZA
         subjects affected / exposed
    1 / 128 (0.78%)
    0 / 136 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    INFECTIVE EXACERBATION OF CHRONIC OBSTRUCTIVE AIRWAYS DISEASE
         subjects affected / exposed
    1 / 128 (0.78%)
    0 / 136 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    ENDOPHTHALMITIS
         subjects affected / exposed
    1 / 128 (0.78%)
    0 / 136 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    APPENDICITIS
         subjects affected / exposed
    0 / 128 (0.00%)
    1 / 136 (0.74%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    PNEUMONIA
         subjects affected / exposed
    0 / 128 (0.00%)
    1 / 136 (0.74%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    URINARY TRACT INFECTION
         subjects affected / exposed
    1 / 128 (0.78%)
    1 / 136 (0.74%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    UPPER RESPIRATORY TRACT INFECTION
         subjects affected / exposed
    0 / 128 (0.00%)
    1 / 136 (0.74%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    DEHYDRATION
         subjects affected / exposed
    1 / 128 (0.78%)
    0 / 136 (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
    		 Placebo Olaparib 400 mg bd
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    111 / 128 (86.72%)
    129 / 136 (94.85%)
    Investigations
    BLOOD CREATININE INCREASED
         subjects affected / exposed
    2 / 128 (1.56%)
    9 / 136 (6.62%)
         occurrences all number
    2
    10
    Vascular disorders
    HOT FLUSH
         subjects affected / exposed
    16 / 128 (12.50%)
    5 / 136 (3.68%)
         occurrences all number
    18
    6
    HYPERTENSION
         subjects affected / exposed
    4 / 128 (3.13%)
    10 / 136 (7.35%)
         occurrences all number
    4
    10
    Nervous system disorders
    DIZZINESS
         subjects affected / exposed
    9 / 128 (7.03%)
    21 / 136 (15.44%)
         occurrences all number
    10
    28
    DYSGEUSIA
         subjects affected / exposed
    8 / 128 (6.25%)
    22 / 136 (16.18%)
         occurrences all number
    8
    26
    HEADACHE
         subjects affected / exposed
    17 / 128 (13.28%)
    29 / 136 (21.32%)
         occurrences all number
    20
    47
    NEUROPATHY PERIPHERAL
         subjects affected / exposed
    3 / 128 (2.34%)
    12 / 136 (8.82%)
         occurrences all number
    5
    13
    PARAESTHESIA
         subjects affected / exposed
    3 / 128 (2.34%)
    7 / 136 (5.15%)
         occurrences all number
    5
    9
    General disorders and administration site conditions
    FATIGUE
         subjects affected / exposed
    50 / 128 (39.06%)
    73 / 136 (53.68%)
         occurrences all number
    57
    92
    ASTHENIA
         subjects affected / exposed
    12 / 128 (9.38%)
    19 / 136 (13.97%)
         occurrences all number
    15
    26
    PYREXIA
         subjects affected / exposed
    4 / 128 (3.13%)
    13 / 136 (9.56%)
         occurrences all number
    4
    16
    OEDEMA PERIPHERAL
         subjects affected / exposed
    6 / 128 (4.69%)
    12 / 136 (8.82%)
         occurrences all number
    7
    14
    Blood and lymphatic system disorders
    NEUTROPENIA
         subjects affected / exposed
    5 / 128 (3.91%)
    7 / 136 (5.15%)
         occurrences all number
    7
    8
    ANAEMIA
         subjects affected / exposed
    7 / 128 (5.47%)
    26 / 136 (19.12%)
         occurrences all number
    8
    32
    Gastrointestinal disorders
    ABDOMINAL PAIN LOWER
         subjects affected / exposed
    10 / 128 (7.81%)
    7 / 136 (5.15%)
         occurrences all number
    10
    7
    ABDOMINAL DISTENSION
         subjects affected / exposed
    11 / 128 (8.59%)
    21 / 136 (15.44%)
         occurrences all number
    13
    24
    ABDOMINAL DISCOMFORT
         subjects affected / exposed
    7 / 128 (5.47%)
    6 / 136 (4.41%)
         occurrences all number
    7
    7
    ABDOMINAL PAIN UPPER
         subjects affected / exposed
    11 / 128 (8.59%)
    25 / 136 (18.38%)
         occurrences all number
    11
    28
    CONSTIPATION
         subjects affected / exposed
    14 / 128 (10.94%)
    30 / 136 (22.06%)
         occurrences all number
    15
    41
    DIARRHOEA
         subjects affected / exposed
    31 / 128 (24.22%)
    36 / 136 (26.47%)
         occurrences all number
    39
    62
    DYSPEPSIA
         subjects affected / exposed
    11 / 128 (8.59%)
    27 / 136 (19.85%)
         occurrences all number
    11
    34
    NAUSEA
         subjects affected / exposed
    46 / 128 (35.94%)
    96 / 136 (70.59%)
         occurrences all number
    58
    128
    STOMATITIS
         subjects affected / exposed
    4 / 128 (3.13%)
    12 / 136 (8.82%)
         occurrences all number
    4
    15
    VOMITING
         subjects affected / exposed
    18 / 128 (14.06%)
    47 / 136 (34.56%)
         occurrences all number
    20
    91
    ABDOMINAL PAIN
         subjects affected / exposed
    34 / 128 (26.56%)
    35 / 136 (25.74%)
         occurrences all number
    51
    44
    Respiratory, thoracic and mediastinal disorders
    DYSPNOEA
         subjects affected / exposed
    8 / 128 (6.25%)
    17 / 136 (12.50%)
         occurrences all number
    8
    20
    COUGH
         subjects affected / exposed
    13 / 128 (10.16%)
    23 / 136 (16.91%)
         occurrences all number
    14
    33
    Skin and subcutaneous tissue disorders
    RASH
         subjects affected / exposed
    12 / 128 (9.38%)
    8 / 136 (5.88%)
         occurrences all number
    13
    8
    PRURITUS
         subjects affected / exposed
    3 / 128 (2.34%)
    8 / 136 (5.88%)
         occurrences all number
    3
    10
    DRY SKIN
         subjects affected / exposed
    7 / 128 (5.47%)
    3 / 136 (2.21%)
         occurrences all number
    7
    3
    Psychiatric disorders
    INSOMNIA
         subjects affected / exposed
    9 / 128 (7.03%)
    9 / 136 (6.62%)
         occurrences all number
    10
    9
    DEPRESSION
         subjects affected / exposed
    9 / 128 (7.03%)
    11 / 136 (8.09%)
         occurrences all number
    10
    11
    ANXIETY
         subjects affected / exposed
    5 / 128 (3.91%)
    8 / 136 (5.88%)
         occurrences all number
    6
    8
    Musculoskeletal and connective tissue disorders
    ARTHRALGIA
         subjects affected / exposed
    18 / 128 (14.06%)
    24 / 136 (17.65%)
         occurrences all number
    19
    36
    BACK PAIN
         subjects affected / exposed
    14 / 128 (10.94%)
    25 / 136 (18.38%)
         occurrences all number
    16
    37
    MUSCLE SPASMS
         subjects affected / exposed
    5 / 128 (3.91%)
    13 / 136 (9.56%)
         occurrences all number
    5
    20
    MUSCULOSKELETAL PAIN
         subjects affected / exposed
    8 / 128 (6.25%)
    10 / 136 (7.35%)
         occurrences all number
    8
    10
    MYALGIA
         subjects affected / exposed
    8 / 128 (6.25%)
    7 / 136 (5.15%)
         occurrences all number
    9
    7
    PAIN IN EXTREMITY
         subjects affected / exposed
    7 / 128 (5.47%)
    12 / 136 (8.82%)
         occurrences all number
    8
    16
    Infections and infestations
    URINARY TRACT INFECTION
         subjects affected / exposed
    6 / 128 (4.69%)
    15 / 136 (11.03%)
         occurrences all number
    6
    21
    UPPER RESPIRATORY TRACT INFECTION
         subjects affected / exposed
    8 / 128 (6.25%)
    18 / 136 (13.24%)
         occurrences all number
    8
    24
    NASOPHARYNGITIS
         subjects affected / exposed
    14 / 128 (10.94%)
    21 / 136 (15.44%)
         occurrences all number
    17
    26
    Metabolism and nutrition disorders
    DECREASED APPETITE
         subjects affected / exposed
    17 / 128 (13.28%)
    29 / 136 (21.32%)
         occurrences all number
    22
    34
    HYPOMAGNESAEMIA
         subjects affected / exposed
    9 / 128 (7.03%)
    8 / 136 (5.88%)
         occurrences all number
    10
    10

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    27 Nov 2008
    Primary objective expanded to include patients with HRD tumours
    27 Nov 2008
    The window between last dose of platinum-containing regimen and starting study treatment extended. Clarification of aspects of the study design
    27 Nov 2008
    The following text regarding achievement of primary endpoint added: Tumour evaluations using CT/MRI according to RECIST will continue in the study until sufficient efficacy events for the analysis of PFS in the overall population, and the HRD sub-group have been confirmed. At this point investigators will be notified that CT/MRI for study purposes are no longer required
    27 Nov 2008
    Assessment Visit windows amended. Clarification of HRQL, CA-125, and CT/MRI assessments
    27 Nov 2008
    Amendment of inclusion criterion
    27 Nov 2008
    Amendment of exclusion criterion
    27 Nov 2008
    Amendment of restrictions
    27 Nov 2008
    Addition of following text to discontinuation criteria: Patients may continue to receive study treatment following objective progression provided that, in the opinion of the investigator, the patient is benefiting from the treatment and does not meet any other discontinuation criteria
    27 Nov 2008
    Amendment of management of toxicity of olaparib text
    14 May 2009
    Number of recruiting sites increased
    14 May 2009
    Statistical methods text added
    14 May 2009
    Visit days amended
    14 May 2009
    Inclusion criteria amended
    14 May 2009
    Restriction text amended
    14 May 2009
    Procedures for randomisation amended with the addition of the following text: It is recommended that patients commence study treatment as soon as possible after randomisation, and ideally within 3 days
    14 May 2009
    Screening text amended
    17 May 2010
    Interim analysis of PFS
    17 May 2010
    Analysis of PFS in the HRD population was removed as a co-primary objective.
    17 May 2010
    Secondary objective text “To obtain archival tumour samples for analyses of candidate biomarkers to identify the HRD subset of tumours for which increased sensitivity to AZD2281 is expected.” Changed to “To enable retrospective identification of tumours with increased sensitivity to olaparib by obtaining archival tumour samples for potential biomarker analyses.” and moved to exploratory objective. Associated secondary outcome variable text on candidate biomarkers moved to exploratory variable section
    17 May 2010
    Clarification that subset of patients with HRD tumours removed as an analysis population
    17 May 2010
    Addition of text on pneumonitis events
    17 May 2010
    Wording on contraception updated
    17 May 2010
    The number and total volume of blood to be drawn from each patient for clinical chemistry and haematology assessments was decreased
    17 May 2010
    The end of trial definition has been changed
    02 Nov 2010
    Estimated date of last subject completed changed from Q3 2010 to Q4 2012
    02 Nov 2010
    Changed assessments for survival from every 12 weeks to every 8 weeks following treatment discontinuation
    02 Nov 2010
    Patients and investigators will not be routinely unblinded to study treatment prior to the final OS analysis. Following a request to the study sponsor, patients and investigators may be unblinded on an individual basis if the information is essential for safety or subsequent treatment decisions following confirmed disease progression
    02 Nov 2010
    Patients who remain on study treatment will attend clinic every 8 weeks and the following assessments will be performed: physical examination, ECOG status, vital signs, haematology, clinical chemistry, urinalysis, AEs and concomitant medications. Dispensing visits may be performed on a 4 weekly basis, at the investigator’s discretion, at which AEs must be assessed as a minimum. Following the approval of amendment 4, and in line with the frequency of safety assessments, olaparib will be dispensed to patients every 56 days if local practice permits. No further CA-125 plasma samples will be required, no amylase and lipase will be tested, no HRQL assessments will be required, and aPTT and INR will only require testing when clinically indicated
    01 Nov 2011
    Addition of an interim analysis of OS, to be performed when approximately 100 deaths have occurred, with the final analysis of survival at the same maturity as the PFS analysis.
    01 Nov 2011
    Update of list of events olaparib is associated with; bone marrow findings consistent with myelodysplastic syndrome/acute myeloid leukaemia added to study treatment discontinuation criteria; amendment of management of toxicity of olaparib text; section added on bone marrow or blood cytogenetic analysis
    17 Oct 2012
    Estimated date of last subject completed changed from Q4 2012 to Q1 2015
    17 Oct 2012
    After the interim analysis of OS is performed when approximately 100 deaths have occurred, a subsequent interim analysis of survival will be performed at approximately the same maturity as the PFS analysis (~60% maturity) (per amendment 05). Additional analyses of OS data may be performed to meet Regulatory Agency requests or to assist in the understanding of the data, which in turn supports decision making at AstraZeneca. The final survival analysis will be performed at approximately 85% maturity (~222 deaths). Collection of survival data will not continue beyond 85% maturity
    17 Oct 2012
    Amendment of text describing circumstances under which code may be broken for SAEs, to clarify that investigators and patients would not be unblinded
    17 Oct 2012
    Timescale within which patients must be contacted following the data cut-off for the primary and all subsequent survival analyses to provide complete survival data reduced from 1 week to 4 days
    17 Oct 2012
    Time for reporting SAEs and follow up information to Parexel reduced from ‘no later than the end of the next business day’ to ‘no later than 24 hours’ of becoming aware of it
    17 Oct 2012
    The data cut-off date for analysis of the primary endpoint will be established when a total of 137 PFS events have been observed in the overall population. Analysis of OS will be performed when approximately 100 deaths have occurred and again at approximately the same maturity as the PFS analysis (~60% maturity). The final survival analysis will be performed at approximately 85% maturity (~222 deaths). There will be a final data cut-off defined when OS meets approximately 85% maturity, when the clinical study database will closed to new data and all patients will be unblinded. Patients who are receiving active treatment can either choose to discontinue from the study or where the investigator believes patients are gaining clinical benefit, patients may continue to receive study treatment. All patients will receive follow up care in accordance with standard local clinical practice.
    30 May 2013
    Section 7.2.3.3 was further clarified and Section 7.2.3.4 was added to request follow-up of current survival status at the final OS analysis. This includes those patients that withdraw consent or are classified as “lost to follow up.”

    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.
    For OM DoR: The subset of patients evaluable for response who responded to study treatment.Values in results table may be under-estimates as some patients had not progressed at final analysis,so true duration is likely to be greater than in database.
    For support, Contact us.
    The status and protocol content of GB trials is no longer updated since 1 January 2021. For the UK, as of 31 January 2021, EU Law applies only to the territory of Northern Ireland (NI) to the extent foreseen in the Protocol on Ireland/NI. Legal notice
    As of 31 January 2023, all EU/EEA initial clinical trial applications must be submitted through CTIS . Updated EudraCT trials information and information on PIP/Art 46 trials conducted exclusively in third countries continues to be submitted through EudraCT and published on this website.

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