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    Clinical Trial Results:
    A Phase II Open-Label, Randomised, Comparative, International Multicentre Study to Compare the Safety and Efficacy of Two Different Doses of AZD2281 Given Orally Twice Daily Versus Intravenous Liposomal Doxorubicin Given Monthly in Patients With Advanced BRCA1- or BRCA2-Associated Ovarian Cancer Who Have Failed Previous Platinum-Based Chemotherapy

    Summary
    EudraCT number
    		 2007-007622-22
    Trial protocol
    		 GB   SE   BE   DE   ES  
    Global end of trial date
    30 Apr 2010

    Results information
    Results version number
    		 v1(current)
    This version publication date
    05 Oct 2019
    First version publication date
    05 Oct 2019
    Other versions

    Trial information

    		 Close Top of page
    Trial identification
    Sponsor protocol code
    D0810C00012
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 -
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    AstraZeneca
    Sponsor organisation address
    151 85, Sodertalje, Sweden,
    Public contact
    Paula del Rosario, AstraZeneca, +44 7884 735492, ClinicalTrialTransparency@astrazeneca.com
    Scientific contact
    Paula del Rosario, AstraZeneca, +44 7884 735492, 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
    13 Dec 2013
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    30 Apr 2010
    Global end of trial reached?
    Yes
    Global end of trial date
    30 Apr 2010
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To compare the efficacy of 2 different dose levels of olaparib with liposomal doxorubicin in patients with advanced BRCA1- or BRCA2- associated ovarian cancer. This was assessed by the following: Primary variable • Progression-free survival (PFS) Secondary variables • Objective response rate (complete response (CR) and partial response (PR)) at various timepoints and overall • Overall duration of response • Tumour size • CA-125 levels • Overall survival
    Protection of trial subjects
    The Patient Informed Consent Document will incorporate wording that complies with relevant data protection and privacy legislation. Pursuant to this wording, patients will authorise the collection, use and disclosure of their study data by the Investigator and by those persons who need that information for the purposes of the study. The Sponsor reserves the right to stop the study at any time on the basis of new information regarding safety or efficacy, or if study progress is unsatisfactory, or for other valid administrative reasons. After such a decision is made, the Investigator must inform all screened patients within 1 week. If any pregnancy occurs in the course of the study, then investigators or other site personnel must inform appropriate AstraZeneca representatives immediately but no later than the end of the next business day of when he or she becomes aware of it. The designated AstraZeneca representative works with the investigator to ensure that all relevant information is provided to the appropriate AstraZeneca Patient Safety data entry site within 30 calendar days. Any crossover patients must be followed for full safety assessments for 57 days.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    30 Jul 2008
    Long term follow-up planned
    Yes
    Long term follow-up rationale
    		 Regulatory reason, Safety
    Long term follow-up duration
    		 1 Months
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Australia: 6
    Country: Number of subjects enrolled
    Belgium: 4
    Country: Number of subjects enrolled
    Germany: 1
    Country: Number of subjects enrolled
    Israel: 24
    Country: Number of subjects enrolled
    Poland: 14
    Country: Number of subjects enrolled
    Spain: 2
    Country: Number of subjects enrolled
    Sweden: 2
    Country: Number of subjects enrolled
    United Kingdom: 18
    Country: Number of subjects enrolled
    United States: 26
    Worldwide total number of subjects
    97
    EEA total number of subjects
    41
    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)
    84
    From 65 to 84 years
    13
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 First patient enrolled on 30 July 2008 and last patient on 3 March 2009 at 25 centres in 9 countries

    Pre-assignment
    Screening details
    		 97 of 125 screened women with advanced BRCA 1/2 ovarian cancer who had chemotherapy were randomized

    Period 1
    Period 1 title
    Randomised part
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Not blinded

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Olaparib 200 mg bd
    Arm description
    		 Olaparib (AZD2281) 200 mg oral capsules twice daily
    Arm type
    		 Experimental

    Investigational medicinal product name
    AZD2281
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    200 mg bd orally

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

    Investigational medicinal product name
    AZD2281
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    400 mg bd orally

    Arm title
    		 Liposomal doxorubicin
    Arm description
    		 Liposomal doxorubicin 50 mg/m2 intravenously every 4 weeks
    Arm type
    		 Active comparator

    Investigational medicinal product name
    Doxil
    Investigational medicinal product code
    Other name
    Caelyx
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    50 mg/m2 i.v.

    Number of subjects in period 1
    		Olaparib 200 mg bd Olaparib 400 mg bd Liposomal doxorubicin
    Started
    32
    32
    33
    Completed
    32
    32
    32
    Not completed
    0
    0
    1
         Consent withdrawn by subject
    -
    -
    1
    Period 2
    Period 2 title
    Ongoing Initial Study Treatment at DCO
    Is this the baseline period?
    		 No
    Allocation method
    Randomised - controlled
    Blinding used
    		 Not blinded

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Olaparib 200 mg bd
    Arm description
    		 Olaparib (AZD2281) 200 mg oral capsules twice daily
    Arm type
    		 Experimental

    Investigational medicinal product name
    AZD2281
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    200 mg bd orally

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

    Investigational medicinal product name
    AZD2281
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    400 mg bd orally

    Arm title
    		 Liposomal doxorubicin
    Arm description
    		 Liposomal doxorubicin 50 mg/m2 iv every 4 weeks
    Arm type
    		 Experimental

    Investigational medicinal product name
    Doxil
    Investigational medicinal product code
    Other name
    Caelyx
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    50 mg/m2 i.v.

    Number of subjects in period 2
    		Olaparib 200 mg bd Olaparib 400 mg bd Liposomal doxorubicin
    Started
    32
    32
    32
    Discontinued initial study treatment
    22
    20
    25
    Completed
    10
    12
    7
    Not completed
    22
    20
    25
         Consent withdrawn by subject
    1
    2
    1
         Adverse event, non-fatal
    1
    2
    3
         Condition under investigation worsened
    19
    15
    13
         Unknown
    1
    -
    2
         Other reason
    -
    1
    6

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Olaparib 200 mg bd
    Reporting group description
    		 Olaparib (AZD2281) 200 mg oral capsules twice daily

    Reporting group title
    Olaparib 400 mg bd
    Reporting group description
    		 Olaparib (AZD2281) 400 mg oral capsules twice daily

    Reporting group title
    Liposomal doxorubicin
    Reporting group description
    		 Liposomal doxorubicin 50 mg/m2 intravenously every 4 weeks

    Reporting group values
    		 Olaparib 200 mg bd Olaparib 400 mg bd Liposomal doxorubicin Total
    Number of subjects
    		 32 32 33 97
    Age categorical
    Units: Subjects
        Adults (<50 years)
    		 7 10 12 29
        From >=50 to <65 years
    		 20 18 17 55
        65 years and over
    		 5 4 4 13
    Age Continuous
    Units: Years
        arithmetic mean (standard deviation)
    		 57.2 ± 8.53 53.8 ± 8.77 54.3 ± 9.32 -
    Sex: Female, Male
    Units: Subjects
        Female
    		 32 32 33 97
        Male
    		 0 0 0 0
    BRCA status
    Units: Subjects
        Deleterious BRCA1 mutation
    		 26 28 27 81
        Deleterious BRCA2 mutation
    		 6 4 6 16
    Race/Ethnicity, Customized
    Race/Ethnicity (Jewish ethnicity)
    Units: Subjects
        African-Caribbean
    		 0 0 1 1
        Ashkenazi Jewish
    		 8 10 11 29
        Sephardic Jewish
    		 0 0 2 2
        Not applicable
    		 20 21 19 60
        Other
    		 4 1 0 5
    Subject analysis sets

    Subject analysis set title
    Full analysis set
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    All randomised patients

    Subject analysis sets values
    		 Full analysis set
    Number of subjects
    97
    Age categorical
    Units: Subjects
        Adults (<50 years)
    29
        From >=50 to <65 years
    55
        65 years and over
    13
    Age Continuous
    Units: Years
        arithmetic mean (standard deviation)
    55.1 ± 8.92
    Sex: Female, Male
    Units: Subjects
        Female
    97
        Male
    0
    BRCA status
    Units: Subjects
        Deleterious BRCA1 mutation
    81
        Deleterious BRCA2 mutation
    16
    Race/Ethnicity, Customized
    Race/Ethnicity (Jewish ethnicity)
    Units: Subjects
        African-Caribbean
    1
        Ashkenazi Jewish
    29
        Sephardic Jewish
    2
        Not applicable
    60
        Other
    5

    End points

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    End points reporting groups
    Reporting group title
    Olaparib 200 mg bd
    Reporting group description
    		 Olaparib (AZD2281) 200 mg oral capsules twice daily

    Reporting group title
    Olaparib 400 mg bd
    Reporting group description
    		 Olaparib (AZD2281) 400 mg oral capsules twice daily

    Reporting group title
    Liposomal doxorubicin
    Reporting group description
    		 Liposomal doxorubicin 50 mg/m2 intravenously every 4 weeks
    Reporting group title
    Olaparib 200 mg bd
    Reporting group description
    		 Olaparib (AZD2281) 200 mg oral capsules twice daily

    Reporting group title
    Olaparib 400 mg bd
    Reporting group description
    		 Olaparib (AZD2281) 400 mg oral capsules twice daily

    Reporting group title
    Liposomal doxorubicin
    Reporting group description
    		 Liposomal doxorubicin 50 mg/m2 iv every 4 weeks

    Subject analysis set title
    Full analysis set
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    All randomised patients

    Primary: Progression free survival (PFS)

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    End point title
    		 Progression free survival (PFS)
    End point description
    PFS was defined as the time to progression from the date of randomisation until the date of radiological assessment of progression per RECIST criteria or death (by any cause in the absence of progression)
    End point type
    Primary
    End point timeframe
    Tumour assessment was to be assessed at screening, every 8 weeks during the study and at the withdrawal visit, up to 56 weeks. (Data cut-off for primary analysis of PFS: 15 September 2009)
    End point values
    		 Olaparib 200 mg bd Olaparib 400 mg bd Liposomal doxorubicin
    Number of subjects analysed
    32
    32
    33
    Units: Number of patients that progressed
    number (not applicable)
        Number of patients that progressed
    19
    20
    20
        Percentage of patients that progressed
    59.4
    62.5
    60.6
        Median PFS
    6.5
    8.8
    7.1
        Lower 95% Limit for Median PFS
    5.5
    5.4
    3.7
        Upper 95% Limit for Median PFS
    10.1
    9.2
    10.7
    Statistical analysis title
    		 Analysis of progression free survival
    Statistical analysis description
    Analysis of olaparib 200 or 400 mg bd (n=64) versus liposomal doxorubicin (n=33). A hazard ratio < 1 favours olaparib.
    Comparison groups
    Olaparib 200 mg bd v Olaparib 400 mg bd v Liposomal doxorubicin
    Number of subjects included in analysis
    97
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    		 = 0.6604 [1]
    Method
    		 Regression, Cox
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.88
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.51
         upper limit
    		 1.56
    Notes
    [1] - If the observed p-value for the combined olaparib groups is <0.025 (1-sided) then the result will be regarded as statistically significant.
    Statistical analysis title
    		 Analysis of progression free survival
    Statistical analysis description
    Analysis of olaparib 200 (n=32) versus liposomal doxorubicin (n=33). A hazard ratio < 1 favours olaparib.
    Comparison groups
    Olaparib 200 mg bd v Liposomal doxorubicin
    Number of subjects included in analysis
    65
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    		 = 0.7794 [2]
    Method
    		 Regression, Cox
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.91
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.48
         upper limit
    		 1.74
    Notes
    [2] - An observed p-value of <0.005 (1-sided) will be regarded as statistically significant for a given pairwise comparison.
    Statistical analysis title
    		 Analysis of progression-free survival
    Statistical analysis description
    Analysis of olaparib 400 (n=32) versus liposomal doxorubicin (n=33). A hazard ratio < 1 favours olaparib.
    Comparison groups
    Olaparib 400 mg bd v Liposomal doxorubicin
    Number of subjects included in analysis
    65
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    		 = 0.6604 [3]
    Method
    		 Regression, Cox
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.86
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.45
         upper limit
    		 1.62
    Notes
    [3] - An observed p-value of <0.005 (1-sided) will be regarded as statistically significant for a given pairwise comparison.

    Secondary: Objective response rate (ORR)

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    End point title
    		 Objective response rate (ORR)
    End point description
    ORR was defined according to RECIST. Complete response (CR) or partial response - (PR)- 30% decrease Patients with a best RECIST response of CR or PR had to have a confirmed response at least 28 days later.
    End point type
    Secondary
    End point timeframe
    At the time that 57 PFS events had occurred (Data cut-off for primary analysis of PFS: 15 September 2009)
    End point values
    		 Olaparib 200 mg bd Olaparib 400 mg bd Liposomal doxorubicin
    Number of subjects analysed
    32
    32
    33
    Units: Number of responders
    number (not applicable)
        Complete response
    0
    0
    0
        Number of Partial responders
    8
    10
    6
        % of Partial responders
    25.0
    31.3
    18.2
    Statistical analysis title
    		 Analysis of objective response rate
    Statistical analysis description
    Analysis of olaparib 200 or 400 (n=64) versus liposomal doxorubicin (n=33).
    Comparison groups
    Olaparib 200 mg bd v Olaparib 400 mg bd v Liposomal doxorubicin
    Number of subjects included in analysis
    97
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    		 = 0.1291 [4]
    Method
    		 Regression, Logistic
    Parameter type
    		 Odds ratio (OR)
    Point estimate
    2.27
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.79
         upper limit
    		 7.32
    Notes
    [4] - 2-sided p-value
    Statistical analysis title
    		 Analysis of objective response rate
    Statistical analysis description
    Analysis of olaparib 200 (n=32) versus liposomal doxorubicin (n=33).
    Comparison groups
    Olaparib 200 mg bd v Liposomal doxorubicin
    Number of subjects included in analysis
    65
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    		 = 0.3131 [5]
    Method
    		 Regression, Logistic
    Parameter type
    		 Odds ratio (OR)
    Point estimate
    1.9
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.55
         upper limit
    		 7.01
    Notes
    [5] - 2-sided p-value
    Statistical analysis title
    		 Analysis of objective response rate
    Statistical analysis description
    Analysis of olaparib 400 (n=32) versus liposomal doxorubicin (n=33).
    Comparison groups
    Olaparib 400 mg bd v Liposomal doxorubicin
    Number of subjects included in analysis
    65
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    		 = 0.1079
    Method
    		 Regression, Logistic
    Parameter type
    		 Odds ratio (OR)
    Point estimate
    2.69
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.81
         upper limit
    		 9.76

    Secondary: Disease control rate

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    End point title
    		 Disease control rate
    End point description
    The number of patients with confirmed CR (disappearance of all target lesions) or PR (30% decrease in the sum of the longest diameter of target lesions ) or SD ( small changes ) >4 months, divided by the number of randomised patients
    End point type
    Secondary
    End point timeframe
    At the time that 57 PFS events had occurred (Data cut-off for primary analysis of PFS: 15 September 2009)
    End point values
    		 Olaparib 200 mg bd Olaparib 400 mg bd Liposomal doxorubicin
    Number of subjects analysed
    32
    32
    33
    Units: Number (%) of responders
    number (not applicable)
        Number of Participants
    21
    21
    19
        % Participants
    65.6
    65.6
    57.6
    No statistical analyses for this end point

    Secondary: Overall duration of response

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    End point title
    		 Overall duration of response
    End point description
    The duration of response was defined as time (months) from initial assessment of PR/CR until earliest date of objective progression or death. (Values may be underestimated as some patients had not progressed at final analysis so true duration is likely to be greater than that in database.)
    End point type
    Secondary
    End point timeframe
    At the time that 57 PFS events had occurred (Data cut-off for primary analysis of PFS: 15 September 2009)
    End point values
    		 Olaparib 200 mg bd Olaparib 400 mg bd Liposomal doxorubicin Full analysis set
    Number of subjects analysed
    8 [6]
    10
    6
    18
    Units: Months
        median (confidence interval 95%)
    5.95 (3.71 to 999999999)
    6.80 (5.52 to 7.39)
    5.49 (4.67 to 9.13)
    6.24 (5.52 to 7.39)
    Notes
    [6] - The upper limit for the 95% CI for median was not reached.
    No statistical analyses for this end point

    Secondary: Best percentage change in tumour size

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    End point title
    		 Best percentage change in tumour size
    End point description
    The percentage change (reduction) from baseline in the sum of the lengths of the longest diameter (LD) of the RECIST target lesions were objectively documented, regardless of whether the patient was still taking study medication
    End point type
    Secondary
    End point timeframe
    At the time that 57 PFS events had occurred (Data cut-off for primary analysis of PFS: 15 September 2009)
    End point values
    		 Olaparib 200 mg bd Olaparib 400 mg bd Liposomal doxorubicin
    Number of subjects analysed
    32
    32
    33
    Units: Percent change
        median (full range (min-max))
    -15.90 (-75.30 to 31.48)
    -24.60 (-100.00 to 51.10)
    -14.3 (-87.5 to 32.4)
    No statistical analyses for this end point

    Secondary: Best percentage change from baseline in CA-125 levels

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    End point title
    		 Best percentage change from baseline in CA-125 levels
    End point description
    Best percentage change in cancer antigen 125 (CA-125) levels
    End point type
    Secondary
    End point timeframe
    At the time that 57 PFS events had occurred (Data cut-off for primary analysis of PFS: 15 September 2009)
    End point values
    		 Olaparib 200 mg bd Olaparib 400 mg bd Liposomal doxorubicin
    Number of subjects analysed
    30
    31
    33
    Units: Percent change
        median (full range (min-max))
    -37.42 (-98.77 to 327.76)
    -71.19 (-96.88 to 70.56)
    -55.8 (-99.5 to 192.1)
    No statistical analyses for this end point

    Secondary: Confirmed RECIST response and/or CA-125 response

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    End point title
    		 Confirmed RECIST response and/or CA-125 response
    End point description
    The percentage of patients reporting a RECIST confirmed response and/or a CA-125 response (in the absence of progression). A CA-125 response was defined as a confirmed greater or equal to 50% reduction in CA-125.
    End point type
    Secondary
    End point timeframe
    At the time that 57 PFS events had occurred (Data cut-off for primary analysis of PFS: 15 September 2009)
    End point values
    		 Olaparib 200 mg bd Olaparib 400 mg bd Liposomal doxorubicin
    Number of subjects analysed
    32
    32
    33
    Units: Percentage of participants
        number (not applicable)
    37.5
    59.4
    39.4
    No statistical analyses for this end point

    Secondary: Overall survival (OS)

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    End point title
    		 Overall survival (OS)
    End point description
    OS was defined as time from randomisation to date of death from any cause. Patients who had not died at time of analysis were censored at last date they were known to be alive. Median OS was not calculable for olaparib groups due to an insufficient number of deaths so the percentage of participants who died are shown along with 95% confidence intervals
    End point type
    Secondary
    End point timeframe
    At the time of the cut-off for the final analysis of overall survival (30 April 2010)
    End point values
    		 Olaparib 200 mg bd Olaparib 400 mg bd Liposomal doxorubicin
    Number of subjects analysed
    32
    32
    33
    Units: Number of deaths
    number (not applicable)
        Number of deaths
    9
    11
    13
        % of deaths
    28.1
    34.4
    39.4
    Statistical analysis title
    		 Analysis of overall survival
    Statistical analysis description
    Analysis of olaparib 200 or 400 (n=64) versus liposomal doxorubicin (n=33).
    Comparison groups
    Olaparib 200 mg bd v Olaparib 400 mg bd v Liposomal doxorubicin
    Number of subjects included in analysis
    97
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    		 = 0.5781 [7]
    Method
    		 Regression, Cox
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.82
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.41
         upper limit
    		 1.7
    Notes
    [7] - 2-sided p-value
    Statistical analysis title
    		 Analysis of overall survival
    Statistical analysis description
    Analysis of olaparib 200 (n=32) versus liposomal doxorubicin (n=33).
    Comparison groups
    Olaparib 200 mg bd v Liposomal doxorubicin
    Number of subjects included in analysis
    65
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    		 = 0.3417 [8]
    Method
    		 Regression, Cox
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.66
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.27
         upper limit
    		 1.55
    Notes
    [8] - 2-sided p-value
    Statistical analysis title
    		 Analysis of overall survival
    Statistical analysis description
    Analysis of olaparib 400 (n=32) versus liposomal doxorubicin (n=33).
    Comparison groups
    Olaparib 400 mg bd v Liposomal doxorubicin
    Number of subjects included in analysis
    65
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    		 = 0.9877 [9]
    Method
    		 Regression, Cox
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    1.01
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.44
         upper limit
    		 2.27
    Notes
    [9] - 2-sided p-value

    Secondary: Best quality of life (QoL) response for Trial Outcome Index (TOI)

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    End point title
    		 Best quality of life (QoL) response for Trial Outcome Index (TOI)
    End point description
    Best HRQoL response using the TOI endpoint. Improvement was defined as a change from baseline of greater than or equal to +7. The TOI score ranges from 0-100.
    End point type
    Secondary
    End point timeframe
    At the time that 57 PFS events had occurred (Data cut-off for primary analysis of PFS: 15 September 2009)
    End point values
    		 Olaparib 200 mg bd Olaparib 400 mg bd Liposomal doxorubicin
    Number of subjects analysed
    25
    29
    27
    Units: Number of patients
    number (not applicable)
        Number Improved
    7
    5
    3
        % Improved
    21.9
    15.6
    9.1
        Number No change
    10
    10
    11
        % No change
    31.3
    31.3
    33.3
        Number Worsened
    3
    7
    6
        % Worsened
    9.4
    21.9
    18.2
        Number Non-evaluable
    5
    7
    7
        % Non-evaluable
    15.6
    21.9
    21.2
    No statistical analyses for this end point

    Secondary: Best QoL response for total Functional Analysis of Cancer Therapy - Ovarian (FACT-O)

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    End point title
    		 Best QoL response for total Functional Analysis of Cancer Therapy - Ovarian (FACT-O)
    End point description
    Best HRQoL response using the total FACT-O endpoint. Improvement was defined as a change from baseline of greater than or equal to +9.
    End point type
    Secondary
    End point timeframe
    At the time that 57 PFS events had occurred (Data cut-off for primary analysis of PFS: 15 September 2009)
    End point values
    		 Olaparib 200 mg bd Olaparib 400 mg bd Liposomal doxorubicin
    Number of subjects analysed
    25
    29
    27
    Units: Number of patients
    number (not applicable)
        Number Improved
    3
    6
    1
        % Improved
    9.4
    18.8
    3.0
        Number No Change
    14
    11
    11
        % No Change
    43.8
    34.4
    33.3
        Number Worsened
    3
    5
    7
        % Worsened
    9.4
    15.6
    21.2
        Number Non-evaluable
    5
    7
    8
        % Non-evaluable
    15.6
    21.9
    24.2
    No statistical analyses for this end point

    Secondary: Best QoL response for FACT-O symptom index (FOSI)

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    End point title
    		 Best QoL response for FACT-O symptom index (FOSI)
    End point description
    Best HRQoL response using the FOSI endpoint. Improvement was defined as a change from baseline of greater than or equal to +3.
    End point type
    Secondary
    End point timeframe
    At the time that 57 PFS events had occurred (Data cut-off for primary analysis of PFS: 15 September 2009)
    End point values
    		 Olaparib 200 mg bd Olaparib 400 mg bd Liposomal doxorubicin
    Number of subjects analysed
    25
    29
    27
    Units: Number of patients
    number (not applicable)
        Number Improved
    5
    4
    3
        % Improved
    15.6
    12.5
    9.1
        Number No change
    14
    9
    10
        % No change
    43.8
    28.1
    30.3
        Number Worsened
    1
    9
    7
        % Worsened
    3.1
    28.1
    21.2
        Number Non-evaluable
    5
    7
    7
        % Non-evaluable
    15.6
    21.9
    21.2
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    AEs with onset between first dose and last dose+30 days or AEs for ongoing patients at PFS DCO
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    13.0
    Reporting groups
    Reporting group title
    Olaparib 200 mg bd
    Reporting group description
    		 -

    Reporting group title
    Liposomal Doxorubicin
    Reporting group description
    		 -

    Reporting group title
    Olaparib 400 mg bd
    Reporting group description
    		 -

    Serious adverse events
    		 Olaparib 200 mg bd Liposomal Doxorubicin Olaparib 400 mg bd
    Total subjects affected by serious adverse events
         subjects affected / exposed
    5 / 32 (15.63%)
    5 / 32 (15.63%)
    6 / 32 (18.75%)
         number of deaths (all causes)
    9
    13
    11
         number of deaths resulting from adverse events
    2
    0
    0
    Investigations
    HAEMOGLOBIN DECREASED
         subjects affected / exposed
    0 / 32 (0.00%)
    0 / 32 (0.00%)
    1 / 32 (3.13%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    MYELODYSPLASTIC SYNDROME
         subjects affected / exposed
    1 / 32 (3.13%)
    0 / 32 (0.00%)
    0 / 32 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    Vascular disorders
    DEEP VEIN THROMBOSIS
         subjects affected / exposed
    0 / 32 (0.00%)
    1 / 32 (3.13%)
    0 / 32 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Nervous system disorders
    CEREBROVASCULAR ACCIDENT
         subjects affected / exposed
    2 / 32 (6.25%)
    0 / 32 (0.00%)
    0 / 32 (0.00%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    SYNCOPE
         subjects affected / exposed
    1 / 32 (3.13%)
    1 / 32 (3.13%)
    0 / 32 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    General disorders and administration site conditions
    FATIGUE
         subjects affected / exposed
    1 / 32 (3.13%)
    1 / 32 (3.13%)
    0 / 32 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    PYREXIA
         subjects affected / exposed
    0 / 32 (0.00%)
    0 / 32 (0.00%)
    1 / 32 (3.13%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal disorders
    ABDOMINAL PAIN LOWER
         subjects affected / exposed
    0 / 32 (0.00%)
    1 / 32 (3.13%)
    0 / 32 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    CONSTIPATION
         subjects affected / exposed
    1 / 32 (3.13%)
    0 / 32 (0.00%)
    0 / 32 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    INTESTINAL OBSTRUCTION
         subjects affected / exposed
    1 / 32 (3.13%)
    0 / 32 (0.00%)
    1 / 32 (3.13%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    NAUSEA
         subjects affected / exposed
    0 / 32 (0.00%)
    1 / 32 (3.13%)
    0 / 32 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    SMALL INTESTINAL OBSTRUCTION
         subjects affected / exposed
    0 / 32 (0.00%)
    0 / 32 (0.00%)
    1 / 32 (3.13%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    SUBILEUS
         subjects affected / exposed
    0 / 32 (0.00%)
    0 / 32 (0.00%)
    1 / 32 (3.13%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    VOMITING
         subjects affected / exposed
    0 / 32 (0.00%)
    1 / 32 (3.13%)
    0 / 32 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    DYSPNOEA
         subjects affected / exposed
    0 / 32 (0.00%)
    1 / 32 (3.13%)
    0 / 32 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hepatobiliary disorders
    CHOLELITHIASIS
         subjects affected / exposed
    0 / 32 (0.00%)
    1 / 32 (3.13%)
    0 / 32 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    INTERVERTEBRAL DISC DEGENERATION
         subjects affected / exposed
    0 / 32 (0.00%)
    0 / 32 (0.00%)
    1 / 32 (3.13%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    MUSCULOSKELETAL CHEST PAIN
         subjects affected / exposed
    1 / 32 (3.13%)
    0 / 32 (0.00%)
    0 / 32 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Infections and infestations
    BACTERAEMIA
         subjects affected / exposed
    0 / 32 (0.00%)
    0 / 32 (0.00%)
    1 / 32 (3.13%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 0%
    Non-serious adverse events
    		 Olaparib 200 mg bd Liposomal Doxorubicin Olaparib 400 mg bd
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    32 / 32 (100.00%)
    31 / 32 (96.88%)
    32 / 32 (100.00%)
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    CANCER PAIN
         subjects affected / exposed
    0 / 32 (0.00%)
    0 / 32 (0.00%)
    1 / 32 (3.13%)
         occurrences all number
    0
    0
    1
    LIP NEOPLASM BENIGN
         subjects affected / exposed
    1 / 32 (3.13%)
    0 / 32 (0.00%)
    0 / 32 (0.00%)
         occurrences all number
    1
    0
    0
    PARANEOPLASTIC DERMATOMYOSITIS
         subjects affected / exposed
    1 / 32 (3.13%)
    0 / 32 (0.00%)
    0 / 32 (0.00%)
         occurrences all number
    1
    0
    0
    Vascular disorders
    FLUSHING
         subjects affected / exposed
    0 / 32 (0.00%)
    0 / 32 (0.00%)
    1 / 32 (3.13%)
         occurrences all number
    0
    0
    1
    HOT FLUSH
         subjects affected / exposed
    4 / 32 (12.50%)
    1 / 32 (3.13%)
    1 / 32 (3.13%)
         occurrences all number
    5
    1
    1
    HYPERTENSION
         subjects affected / exposed
    0 / 32 (0.00%)
    1 / 32 (3.13%)
    7 / 32 (21.88%)
         occurrences all number
    0
    2
    7
    HYPOTENSION
         subjects affected / exposed
    2 / 32 (6.25%)
    1 / 32 (3.13%)
    0 / 32 (0.00%)
         occurrences all number
    2
    1
    0
    LYMPHOEDEMA
         subjects affected / exposed
    0 / 32 (0.00%)
    0 / 32 (0.00%)
    1 / 32 (3.13%)
         occurrences all number
    0
    0
    1
    THROMBOPHLEBITIS
         subjects affected / exposed
    0 / 32 (0.00%)
    0 / 32 (0.00%)
    1 / 32 (3.13%)
         occurrences all number
    0
    0
    2
    THROMBOSIS
         subjects affected / exposed
    0 / 32 (0.00%)
    0 / 32 (0.00%)
    1 / 32 (3.13%)
         occurrences all number
    0
    0
    1
    VASCULITIS
         subjects affected / exposed
    0 / 32 (0.00%)
    0 / 32 (0.00%)
    1 / 32 (3.13%)
         occurrences all number
    0
    0
    1
    VENA CAVA THROMBOSIS
         subjects affected / exposed
    0 / 32 (0.00%)
    0 / 32 (0.00%)
    1 / 32 (3.13%)
         occurrences all number
    0
    0
    1
    VENOUS THROMBOSIS
         subjects affected / exposed
    0 / 32 (0.00%)
    1 / 32 (3.13%)
    1 / 32 (3.13%)
         occurrences all number
    0
    1
    1
    General disorders and administration site conditions
    ASTHENIA
         subjects affected / exposed
    6 / 32 (18.75%)
    4 / 32 (12.50%)
    11 / 32 (34.38%)
         occurrences all number
    8
    4
    20
    CATHETER SITE HAEMATOMA
         subjects affected / exposed
    0 / 32 (0.00%)
    0 / 32 (0.00%)
    1 / 32 (3.13%)
         occurrences all number
    0
    0
    1
    CATHETER SITE PAIN
         subjects affected / exposed
    0 / 32 (0.00%)
    0 / 32 (0.00%)
    1 / 32 (3.13%)
         occurrences all number
    0
    0
    1
    CHEST DISCOMFORT
         subjects affected / exposed
    0 / 32 (0.00%)
    1 / 32 (3.13%)
    0 / 32 (0.00%)
         occurrences all number
    0
    1
    0
    CHEST PAIN
         subjects affected / exposed
    1 / 32 (3.13%)
    0 / 32 (0.00%)
    0 / 32 (0.00%)
         occurrences all number
    1
    0
    0
    CHILLS
         subjects affected / exposed
    0 / 32 (0.00%)
    3 / 32 (9.38%)
    1 / 32 (3.13%)
         occurrences all number
    0
    3
    1
    DISCOMFORT
         subjects affected / exposed
    1 / 32 (3.13%)
    0 / 32 (0.00%)
    0 / 32 (0.00%)
         occurrences all number
    1
    0
    0
    FATIGUE
         subjects affected / exposed
    12 / 32 (37.50%)
    14 / 32 (43.75%)
    21 / 32 (65.63%)
         occurrences all number
    16
    20
    29
    LOCAL SWELLING
         subjects affected / exposed
    0 / 32 (0.00%)
    1 / 32 (3.13%)
    0 / 32 (0.00%)
         occurrences all number
    0
    1
    0
    MUCOSAL INFLAMMATION
         subjects affected / exposed
    0 / 32 (0.00%)
    7 / 32 (21.88%)
    0 / 32 (0.00%)
         occurrences all number
    0
    12
    0
    NON-CARDIAC CHEST PAIN
         subjects affected / exposed
    1 / 32 (3.13%)
    0 / 32 (0.00%)
    0 / 32 (0.00%)
         occurrences all number
    1
    0
    0
    OEDEMA PERIPHERAL
         subjects affected / exposed
    2 / 32 (6.25%)
    2 / 32 (6.25%)
    3 / 32 (9.38%)
         occurrences all number
    2
    2
    3
    PAIN
         subjects affected / exposed
    0 / 32 (0.00%)
    2 / 32 (6.25%)
    1 / 32 (3.13%)
         occurrences all number
    0
    2
    2
    PYREXIA
         subjects affected / exposed
    1 / 32 (3.13%)
    4 / 32 (12.50%)
    4 / 32 (12.50%)
         occurrences all number
    1
    4
    4
    SUPRAPUBIC PAIN
         subjects affected / exposed
    0 / 32 (0.00%)
    0 / 32 (0.00%)
    1 / 32 (3.13%)
         occurrences all number
    0
    0
    1
    Immune system disorders
    CONTRAST MEDIA ALLERGY
         subjects affected / exposed
    1 / 32 (3.13%)
    0 / 32 (0.00%)
    1 / 32 (3.13%)
         occurrences all number
    1
    0
    1
    DRUG HYPERSENSITIVITY
         subjects affected / exposed
    0 / 32 (0.00%)
    2 / 32 (6.25%)
    0 / 32 (0.00%)
         occurrences all number
    0
    2
    0
    HYPERSENSITIVITY
         subjects affected / exposed
    0 / 32 (0.00%)
    1 / 32 (3.13%)
    0 / 32 (0.00%)
         occurrences all number
    0
    1
    0
    Reproductive system and breast disorders
    ATROPHIC VULVOVAGINITIS
         subjects affected / exposed
    1 / 32 (3.13%)
    0 / 32 (0.00%)
    0 / 32 (0.00%)
         occurrences all number
    1
    0
    0
    BREAST PAIN
         subjects affected / exposed
    0 / 32 (0.00%)
    1 / 32 (3.13%)
    0 / 32 (0.00%)
         occurrences all number
    0
    1
    0
    PELVIC PAIN
         subjects affected / exposed
    0 / 32 (0.00%)
    0 / 32 (0.00%)
    1 / 32 (3.13%)
         occurrences all number
    0
    0
    1
    VAGINAL DISCHARGE
         subjects affected / exposed
    1 / 32 (3.13%)
    0 / 32 (0.00%)
    0 / 32 (0.00%)
         occurrences all number
    1
    0
    0
    VAGINAL HAEMORRHAGE
         subjects affected / exposed
    0 / 32 (0.00%)
    0 / 32 (0.00%)
    1 / 32 (3.13%)
         occurrences all number
    0
    0
    1
    VAGINAL LESION
         subjects affected / exposed
    0 / 32 (0.00%)
    1 / 32 (3.13%)
    0 / 32 (0.00%)
         occurrences all number
    0
    1
    0
    VULVAL ULCERATION
         subjects affected / exposed
    0 / 32 (0.00%)
    0 / 32 (0.00%)
    1 / 32 (3.13%)
         occurrences all number
    0
    0
    1
    VULVOVAGINAL DRYNESS
         subjects affected / exposed
    1 / 32 (3.13%)
    0 / 32 (0.00%)
    0 / 32 (0.00%)
         occurrences all number
    1
    0
    0
    VULVOVAGINAL PRURITUS
         subjects affected / exposed
    1 / 32 (3.13%)
    0 / 32 (0.00%)
    0 / 32 (0.00%)
         occurrences all number
    1
    0
    0
    Respiratory, thoracic and mediastinal disorders
    COUGH
         subjects affected / exposed
    6 / 32 (18.75%)
    5 / 32 (15.63%)
    6 / 32 (18.75%)
         occurrences all number
    8
    6
    6
    DYSPHONIA
         subjects affected / exposed
    0 / 32 (0.00%)
    0 / 32 (0.00%)
    1 / 32 (3.13%)
         occurrences all number
    0
    0
    1
    DYSPNOEA
         subjects affected / exposed
    2 / 32 (6.25%)
    4 / 32 (12.50%)
    2 / 32 (6.25%)
         occurrences all number
    2
    10
    2
    DYSPNOEA EXERTIONAL
         subjects affected / exposed
    0 / 32 (0.00%)
    0 / 32 (0.00%)
    2 / 32 (6.25%)
         occurrences all number
    0
    0
    2
    NASAL CONGESTION
         subjects affected / exposed
    1 / 32 (3.13%)
    1 / 32 (3.13%)
    0 / 32 (0.00%)
         occurrences all number
    1
    1
    0
    NASAL DRYNESS
         subjects affected / exposed
    0 / 32 (0.00%)
    1 / 32 (3.13%)
    0 / 32 (0.00%)
         occurrences all number
    0
    1
    0
    NASAL MUCOSAL DISORDER
         subjects affected / exposed
    0 / 32 (0.00%)
    1 / 32 (3.13%)
    0 / 32 (0.00%)
         occurrences all number
    0
    1
    0
    NASAL ULCER
         subjects affected / exposed
    1 / 32 (3.13%)
    0 / 32 (0.00%)
    0 / 32 (0.00%)
         occurrences all number
    1
    0
    0
    OROPHARYNGEAL PAIN
         subjects affected / exposed
    4 / 32 (12.50%)
    2 / 32 (6.25%)
    1 / 32 (3.13%)
         occurrences all number
    4
    2
    1
    PLEURITIC PAIN
         subjects affected / exposed
    0 / 32 (0.00%)
    1 / 32 (3.13%)
    0 / 32 (0.00%)
         occurrences all number
    0
    2
    0
    PRODUCTIVE COUGH
         subjects affected / exposed
    0 / 32 (0.00%)
    0 / 32 (0.00%)
    2 / 32 (6.25%)
         occurrences all number
    0
    0
    2
    RHINITIS ALLERGIC
         subjects affected / exposed
    0 / 32 (0.00%)
    1 / 32 (3.13%)
    0 / 32 (0.00%)
         occurrences all number
    0
    1
    0
    RHINORRHOEA
         subjects affected / exposed
    0 / 32 (0.00%)
    0 / 32 (0.00%)
    1 / 32 (3.13%)
         occurrences all number
    0
    0
    1
    SPUTUM DISCOLOURED
         subjects affected / exposed
    1 / 32 (3.13%)
    0 / 32 (0.00%)
    0 / 32 (0.00%)
         occurrences all number
    1
    0
    0
    THROAT IRRITATION
         subjects affected / exposed
    1 / 32 (3.13%)
    0 / 32 (0.00%)
    1 / 32 (3.13%)
         occurrences all number
    2
    0
    1
    WHEEZING
         subjects affected / exposed
    0 / 32 (0.00%)
    1 / 32 (3.13%)
    1 / 32 (3.13%)
         occurrences all number
    0
    1
    1
    Psychiatric disorders
    ANXIETY
         subjects affected / exposed
    2 / 32 (6.25%)
    2 / 32 (6.25%)
    1 / 32 (3.13%)
         occurrences all number
    2
    2
    2
    DEPRESSED MOOD
         subjects affected / exposed
    0 / 32 (0.00%)
    0 / 32 (0.00%)
    1 / 32 (3.13%)
         occurrences all number
    0
    0
    1
    DEPRESSION
         subjects affected / exposed
    1 / 32 (3.13%)
    0 / 32 (0.00%)
    1 / 32 (3.13%)
         occurrences all number
    1
    0
    1
    INSOMNIA
         subjects affected / exposed
    3 / 32 (9.38%)
    2 / 32 (6.25%)
    4 / 32 (12.50%)
         occurrences all number
    5
    3
    4
    STRESS
         subjects affected / exposed
    1 / 32 (3.13%)
    0 / 32 (0.00%)
    0 / 32 (0.00%)
         occurrences all number
    1
    0
    0
    Investigations
    ALANINE AMINOTRANSFERASE INCREASED
         subjects affected / exposed
    1 / 32 (3.13%)
    0 / 32 (0.00%)
    0 / 32 (0.00%)
         occurrences all number
    1
    0
    0
    BLOOD CREATININE INCREASED
         subjects affected / exposed
    0 / 32 (0.00%)
    0 / 32 (0.00%)
    1 / 32 (3.13%)
         occurrences all number
    0
    0
    2
    BLOOD MAGNESIUM DECREASED
         subjects affected / exposed
    1 / 32 (3.13%)
    1 / 32 (3.13%)
    0 / 32 (0.00%)
         occurrences all number
    1
    1
    0
    BODY TEMPERATURE INCREASED
         subjects affected / exposed
    1 / 32 (3.13%)
    0 / 32 (0.00%)
    3 / 32 (9.38%)
         occurrences all number
    2
    0
    4
    ELECTROCARDIOGRAM QT PROLONGED
         subjects affected / exposed
    1 / 32 (3.13%)
    0 / 32 (0.00%)
    0 / 32 (0.00%)
         occurrences all number
    1
    0
    0
    HAEMOGLOBIN DECREASED
         subjects affected / exposed
    0 / 32 (0.00%)
    0 / 32 (0.00%)
    1 / 32 (3.13%)
         occurrences all number
    0
    0
    2
    INTERNATIONAL NORMALISED RATIO INCREASED
         subjects affected / exposed
    0 / 32 (0.00%)
    1 / 32 (3.13%)
    0 / 32 (0.00%)
         occurrences all number
    0
    1
    0
    NEUTROPHIL COUNT DECREASED
         subjects affected / exposed
    0 / 32 (0.00%)
    1 / 32 (3.13%)
    0 / 32 (0.00%)
         occurrences all number
    0
    1
    0
    OCCULT BLOOD POSITIVE
         subjects affected / exposed
    0 / 32 (0.00%)
    0 / 32 (0.00%)
    1 / 32 (3.13%)
         occurrences all number
    0
    0
    1
    WEIGHT DECREASED
         subjects affected / exposed
    2 / 32 (6.25%)
    2 / 32 (6.25%)
    2 / 32 (6.25%)
         occurrences all number
    2
    2
    2
    Injury, poisoning and procedural complications
    CONTRAST MEDIA REACTION
         subjects affected / exposed
    0 / 32 (0.00%)
    0 / 32 (0.00%)
    1 / 32 (3.13%)
         occurrences all number
    0
    0
    1
    CONTUSION
         subjects affected / exposed
    0 / 32 (0.00%)
    1 / 32 (3.13%)
    0 / 32 (0.00%)
         occurrences all number
    0
    1
    0
    INCISIONAL HERNIA
         subjects affected / exposed
    0 / 32 (0.00%)
    1 / 32 (3.13%)
    0 / 32 (0.00%)
         occurrences all number
    0
    1
    0
    JOINT INJURY
         subjects affected / exposed
    0 / 32 (0.00%)
    0 / 32 (0.00%)
    1 / 32 (3.13%)
         occurrences all number
    0
    0
    1
    JOINT SPRAIN
         subjects affected / exposed
    1 / 32 (3.13%)
    0 / 32 (0.00%)
    0 / 32 (0.00%)
         occurrences all number
    1
    0
    0
    MUSCLE STRAIN
         subjects affected / exposed
    0 / 32 (0.00%)
    0 / 32 (0.00%)
    1 / 32 (3.13%)
         occurrences all number
    0
    0
    1
    PROCEDURAL PAIN
         subjects affected / exposed
    1 / 32 (3.13%)
    0 / 32 (0.00%)
    0 / 32 (0.00%)
         occurrences all number
    1
    0
    0
    WOUND
         subjects affected / exposed
    0 / 32 (0.00%)
    1 / 32 (3.13%)
    0 / 32 (0.00%)
         occurrences all number
    0
    1
    0
    Cardiac disorders
    CARDIAC DISORDER
         subjects affected / exposed
    1 / 32 (3.13%)
    0 / 32 (0.00%)
    0 / 32 (0.00%)
         occurrences all number
    1
    0
    0
    LEFT VENTRICULAR HYPERTROPHY
         subjects affected / exposed
    0 / 32 (0.00%)
    1 / 32 (3.13%)
    0 / 32 (0.00%)
         occurrences all number
    0
    1
    0
    PALPITATIONS
         subjects affected / exposed
    0 / 32 (0.00%)
    1 / 32 (3.13%)
    2 / 32 (6.25%)
         occurrences all number
    0
    1
    2
    TACHYCARDIA
         subjects affected / exposed
    1 / 32 (3.13%)
    0 / 32 (0.00%)
    0 / 32 (0.00%)
         occurrences all number
    1
    0
    0
    TRICUSPID VALVE INCOMPETENCE
         subjects affected / exposed
    0 / 32 (0.00%)
    1 / 32 (3.13%)
    0 / 32 (0.00%)
         occurrences all number
    0
    1
    0
    Nervous system disorders
    DIZZINESS
         subjects affected / exposed
    2 / 32 (6.25%)
    3 / 32 (9.38%)
    7 / 32 (21.88%)
         occurrences all number
    2
    3
    9
    DYSGEUSIA
         subjects affected / exposed
    5 / 32 (15.63%)
    0 / 32 (0.00%)
    5 / 32 (15.63%)
         occurrences all number
    5
    0
    5
    FORMICATION
         subjects affected / exposed
    0 / 32 (0.00%)
    0 / 32 (0.00%)
    1 / 32 (3.13%)
         occurrences all number
    0
    0
    1
    HEADACHE
         subjects affected / exposed
    8 / 32 (25.00%)
    8 / 32 (25.00%)
    9 / 32 (28.13%)
         occurrences all number
    10
    11
    11
    MEMORY IMPAIRMENT
         subjects affected / exposed
    2 / 32 (6.25%)
    1 / 32 (3.13%)
    1 / 32 (3.13%)
         occurrences all number
    2
    1
    1
    NEUROPATHY PERIPHERAL
         subjects affected / exposed
    2 / 32 (6.25%)
    2 / 32 (6.25%)
    3 / 32 (9.38%)
         occurrences all number
    4
    2
    3
    NEUROTOXICITY
         subjects affected / exposed
    1 / 32 (3.13%)
    0 / 32 (0.00%)
    1 / 32 (3.13%)
         occurrences all number
    1
    0
    1
    PARAESTHESIA
         subjects affected / exposed
    0 / 32 (0.00%)
    1 / 32 (3.13%)
    0 / 32 (0.00%)
         occurrences all number
    0
    1
    0
    PAROSMIA
         subjects affected / exposed
    1 / 32 (3.13%)
    0 / 32 (0.00%)
    1 / 32 (3.13%)
         occurrences all number
    1
    0
    1
    PERIPHERAL SENSORY NEUROPATHY
         subjects affected / exposed
    0 / 32 (0.00%)
    1 / 32 (3.13%)
    0 / 32 (0.00%)
         occurrences all number
    0
    1
    0
    POOR QUALITY SLEEP
         subjects affected / exposed
    1 / 32 (3.13%)
    0 / 32 (0.00%)
    0 / 32 (0.00%)
         occurrences all number
    1
    0
    0
    PRESYNCOPE
         subjects affected / exposed
    1 / 32 (3.13%)
    0 / 32 (0.00%)
    1 / 32 (3.13%)
         occurrences all number
    1
    0
    1
    RESTLESS LEGS SYNDROME
         subjects affected / exposed
    1 / 32 (3.13%)
    0 / 32 (0.00%)
    0 / 32 (0.00%)
         occurrences all number
    1
    0
    0
    SINUS HEADACHE
         subjects affected / exposed
    0 / 32 (0.00%)
    1 / 32 (3.13%)
    0 / 32 (0.00%)
         occurrences all number
    0
    1
    0
    Blood and lymphatic system disorders
    ANAEMIA
         subjects affected / exposed
    4 / 32 (12.50%)
    2 / 32 (6.25%)
    11 / 32 (34.38%)
         occurrences all number
    4
    2
    15
    ANAEMIA MACROCYTIC
         subjects affected / exposed
    0 / 32 (0.00%)
    0 / 32 (0.00%)
    1 / 32 (3.13%)
         occurrences all number
    0
    0
    1
    LEUKOPENIA
         subjects affected / exposed
    5 / 32 (15.63%)
    1 / 32 (3.13%)
    2 / 32 (6.25%)
         occurrences all number
    6
    1
    2
    LYMPHOPENIA
         subjects affected / exposed
    1 / 32 (3.13%)
    0 / 32 (0.00%)
    0 / 32 (0.00%)
         occurrences all number
    1
    0
    0
    NEUTROPENIA
         subjects affected / exposed
    2 / 32 (6.25%)
    6 / 32 (18.75%)
    3 / 32 (9.38%)
         occurrences all number
    2
    9
    5
    THROMBOCYTOPENIA
         subjects affected / exposed
    2 / 32 (6.25%)
    1 / 32 (3.13%)
    0 / 32 (0.00%)
         occurrences all number
    2
    1
    0
    Ear and labyrinth disorders
    DEAFNESS
         subjects affected / exposed
    0 / 32 (0.00%)
    1 / 32 (3.13%)
    0 / 32 (0.00%)
         occurrences all number
    0
    1
    0
    VERTIGO
         subjects affected / exposed
    1 / 32 (3.13%)
    0 / 32 (0.00%)
    1 / 32 (3.13%)
         occurrences all number
    1
    0
    1
    Eye disorders
    BLEPHAROSPASM
         subjects affected / exposed
    0 / 32 (0.00%)
    0 / 32 (0.00%)
    1 / 32 (3.13%)
         occurrences all number
    0
    0
    1
    CONJUNCTIVITIS
         subjects affected / exposed
    1 / 32 (3.13%)
    1 / 32 (3.13%)
    1 / 32 (3.13%)
         occurrences all number
    1
    1
    1
    CORNEAL DEPOSITS
         subjects affected / exposed
    0 / 32 (0.00%)
    0 / 32 (0.00%)
    1 / 32 (3.13%)
         occurrences all number
    0
    0
    1
    DRY EYE
         subjects affected / exposed
    0 / 32 (0.00%)
    2 / 32 (6.25%)
    0 / 32 (0.00%)
         occurrences all number
    0
    2
    0
    EYE INFLAMMATION
         subjects affected / exposed
    1 / 32 (3.13%)
    0 / 32 (0.00%)
    0 / 32 (0.00%)
         occurrences all number
    1
    0
    0
    EYELID OEDEMA
         subjects affected / exposed
    0 / 32 (0.00%)
    1 / 32 (3.13%)
    0 / 32 (0.00%)
         occurrences all number
    0
    1
    0
    EYELIDS PRURITUS
         subjects affected / exposed
    0 / 32 (0.00%)
    1 / 32 (3.13%)
    0 / 32 (0.00%)
         occurrences all number
    0
    1
    0
    KERATOCONJUNCTIVITIS SICCA
         subjects affected / exposed
    0 / 32 (0.00%)
    1 / 32 (3.13%)
    0 / 32 (0.00%)
         occurrences all number
    0
    1
    0
    LACRIMATION INCREASED
         subjects affected / exposed
    1 / 32 (3.13%)
    0 / 32 (0.00%)
    0 / 32 (0.00%)
         occurrences all number
    1
    0
    0
    PHOTOPHOBIA
         subjects affected / exposed
    0 / 32 (0.00%)
    1 / 32 (3.13%)
    0 / 32 (0.00%)
         occurrences all number
    0
    1
    0
    VISION BLURRED
         subjects affected / exposed
    1 / 32 (3.13%)
    0 / 32 (0.00%)
    0 / 32 (0.00%)
         occurrences all number
    1
    0
    0
    VISUAL IMPAIRMENT
         subjects affected / exposed
    1 / 32 (3.13%)
    1 / 32 (3.13%)
    0 / 32 (0.00%)
         occurrences all number
    1
    1
    0
    Gastrointestinal disorders
    ABDOMINAL DISCOMFORT
         subjects affected / exposed
    0 / 32 (0.00%)
    0 / 32 (0.00%)
    2 / 32 (6.25%)
         occurrences all number
    0
    0
    2
    ABDOMINAL DISTENSION
         subjects affected / exposed
    3 / 32 (9.38%)
    5 / 32 (15.63%)
    3 / 32 (9.38%)
         occurrences all number
    3
    5
    4
    ABDOMINAL PAIN
         subjects affected / exposed
    12 / 32 (37.50%)
    12 / 32 (37.50%)
    8 / 32 (25.00%)
         occurrences all number
    18
    23
    18
    ABDOMINAL PAIN LOWER
         subjects affected / exposed
    0 / 32 (0.00%)
    1 / 32 (3.13%)
    1 / 32 (3.13%)
         occurrences all number
    0
    1
    1
    ABDOMINAL PAIN UPPER
         subjects affected / exposed
    1 / 32 (3.13%)
    2 / 32 (6.25%)
    2 / 32 (6.25%)
         occurrences all number
    1
    2
    2
    ANAL FISSURE
         subjects affected / exposed
    0 / 32 (0.00%)
    1 / 32 (3.13%)
    0 / 32 (0.00%)
         occurrences all number
    0
    1
    0
    ANAL SPHINCTER ATONY
         subjects affected / exposed
    0 / 32 (0.00%)
    0 / 32 (0.00%)
    1 / 32 (3.13%)
         occurrences all number
    0
    0
    1
    ANORECTAL VARICES HAEMORRHAGE
         subjects affected / exposed
    0 / 32 (0.00%)
    1 / 32 (3.13%)
    0 / 32 (0.00%)
         occurrences all number
    0
    1
    0
    ASCITES
         subjects affected / exposed
    2 / 32 (6.25%)
    0 / 32 (0.00%)
    0 / 32 (0.00%)
         occurrences all number
    10
    0
    0
    CONSTIPATION
         subjects affected / exposed
    9 / 32 (28.13%)
    12 / 32 (37.50%)
    6 / 32 (18.75%)
         occurrences all number
    11
    14
    7
    DIARRHOEA
         subjects affected / exposed
    8 / 32 (25.00%)
    10 / 32 (31.25%)
    12 / 32 (37.50%)
         occurrences all number
    11
    14
    16
    DRY MOUTH
         subjects affected / exposed
    0 / 32 (0.00%)
    3 / 32 (9.38%)
    4 / 32 (12.50%)
         occurrences all number
    0
    3
    5
    DYSPEPSIA
         subjects affected / exposed
    5 / 32 (15.63%)
    7 / 32 (21.88%)
    7 / 32 (21.88%)
         occurrences all number
    7
    7
    10
    DYSPHAGIA
         subjects affected / exposed
    0 / 32 (0.00%)
    2 / 32 (6.25%)
    1 / 32 (3.13%)
         occurrences all number
    0
    2
    1
    EPIGASTRIC DISCOMFORT
         subjects affected / exposed
    0 / 32 (0.00%)
    0 / 32 (0.00%)
    1 / 32 (3.13%)
         occurrences all number
    0
    0
    1
    FAECAL INCONTINENCE
         subjects affected / exposed
    0 / 32 (0.00%)
    0 / 32 (0.00%)
    1 / 32 (3.13%)
         occurrences all number
    0
    0
    1
    FLATULENCE
         subjects affected / exposed
    2 / 32 (6.25%)
    2 / 32 (6.25%)
    4 / 32 (12.50%)
         occurrences all number
    2
    2
    4
    GASTRITIS
         subjects affected / exposed
    0 / 32 (0.00%)
    0 / 32 (0.00%)
    2 / 32 (6.25%)
         occurrences all number
    0
    0
    2
    GASTROINTESTINAL DISORDER
         subjects affected / exposed
    1 / 32 (3.13%)
    0 / 32 (0.00%)
    0 / 32 (0.00%)
         occurrences all number
    1
    0
    0
    GASTROINTESTINAL SOUNDS ABNORMAL
         subjects affected / exposed
    1 / 32 (3.13%)
    0 / 32 (0.00%)
    0 / 32 (0.00%)
         occurrences all number
    1
    0
    0
    GASTROOESOPHAGEAL REFLUX DISEASE
         subjects affected / exposed
    1 / 32 (3.13%)
    2 / 32 (6.25%)
    3 / 32 (9.38%)
         occurrences all number
    1
    2
    3
    GINGIVAL BLEEDING
         subjects affected / exposed
    1 / 32 (3.13%)
    0 / 32 (0.00%)
    0 / 32 (0.00%)
         occurrences all number
    1
    0
    0
    GLOSSODYNIA
         subjects affected / exposed
    0 / 32 (0.00%)
    1 / 32 (3.13%)
    0 / 32 (0.00%)
         occurrences all number
    0
    1
    0
    HAEMORRHOIDS
         subjects affected / exposed
    1 / 32 (3.13%)
    3 / 32 (9.38%)
    1 / 32 (3.13%)
         occurrences all number
    1
    3
    1
    INTESTINAL OBSTRUCTION
         subjects affected / exposed
    0 / 32 (0.00%)
    2 / 32 (6.25%)
    0 / 32 (0.00%)
         occurrences all number
    0
    2
    0
    MOUTH ULCERATION
         subjects affected / exposed
    0 / 32 (0.00%)
    2 / 32 (6.25%)
    0 / 32 (0.00%)
         occurrences all number
    0
    2
    0
    NAUSEA
         subjects affected / exposed
    19 / 32 (59.38%)
    18 / 32 (56.25%)
    25 / 32 (78.13%)
         occurrences all number
    24
    35
    44
    ODYNOPHAGIA
         subjects affected / exposed
    1 / 32 (3.13%)
    1 / 32 (3.13%)
    0 / 32 (0.00%)
         occurrences all number
    1
    1
    0
    ORAL PAIN
         subjects affected / exposed
    1 / 32 (3.13%)
    2 / 32 (6.25%)
    0 / 32 (0.00%)
         occurrences all number
    1
    2
    0
    PROCTALGIA
         subjects affected / exposed
    0 / 32 (0.00%)
    0 / 32 (0.00%)
    1 / 32 (3.13%)
         occurrences all number
    0
    0
    1
    RECTAL HAEMORRHAGE
         subjects affected / exposed
    0 / 32 (0.00%)
    1 / 32 (3.13%)
    1 / 32 (3.13%)
         occurrences all number
    0
    1
    1
    RETCHING
         subjects affected / exposed
    0 / 32 (0.00%)
    0 / 32 (0.00%)
    1 / 32 (3.13%)
         occurrences all number
    0
    0
    1
    SALIVARY HYPERSECRETION
         subjects affected / exposed
    0 / 32 (0.00%)
    0 / 32 (0.00%)
    2 / 32 (6.25%)
         occurrences all number
    0
    0
    2
    SENSITIVITY OF TEETH
         subjects affected / exposed
    0 / 32 (0.00%)
    0 / 32 (0.00%)
    1 / 32 (3.13%)
         occurrences all number
    0
    0
    1
    SMALL INTESTINAL OBSTRUCTION
         subjects affected / exposed
    0 / 32 (0.00%)
    1 / 32 (3.13%)
    0 / 32 (0.00%)
         occurrences all number
    0
    1
    0
    STOMATITIS
         subjects affected / exposed
    0 / 32 (0.00%)
    19 / 32 (59.38%)
    1 / 32 (3.13%)
         occurrences all number
    0
    32
    1
    TOOTH DISCOLOURATION
         subjects affected / exposed
    0 / 32 (0.00%)
    0 / 32 (0.00%)
    1 / 32 (3.13%)
         occurrences all number
    0
    0
    1
    TOOTHACHE
         subjects affected / exposed
    1 / 32 (3.13%)
    0 / 32 (0.00%)
    0 / 32 (0.00%)
         occurrences all number
    1
    0
    0
    VOMITING
         subjects affected / exposed
    11 / 32 (34.38%)
    10 / 32 (31.25%)
    16 / 32 (50.00%)
         occurrences all number
    17
    16
    31
    Hepatobiliary disorders
    LIVER INJURY
         subjects affected / exposed
    0 / 32 (0.00%)
    1 / 32 (3.13%)
    1 / 32 (3.13%)
         occurrences all number
    0
    1
    1
    Skin and subcutaneous tissue disorders
    ACNE
         subjects affected / exposed
    0 / 32 (0.00%)
    1 / 32 (3.13%)
    0 / 32 (0.00%)
         occurrences all number
    0
    2
    0
    ALOPECIA
         subjects affected / exposed
    3 / 32 (9.38%)
    7 / 32 (21.88%)
    4 / 32 (12.50%)
         occurrences all number
    3
    7
    4
    BLISTER
         subjects affected / exposed
    0 / 32 (0.00%)
    4 / 32 (12.50%)
    0 / 32 (0.00%)
         occurrences all number
    0
    5
    0
    DERMATITIS ACNEIFORM
         subjects affected / exposed
    0 / 32 (0.00%)
    1 / 32 (3.13%)
    0 / 32 (0.00%)
         occurrences all number
    0
    1
    0
    DRY SKIN
         subjects affected / exposed
    1 / 32 (3.13%)
    4 / 32 (12.50%)
    0 / 32 (0.00%)
         occurrences all number
    1
    4
    0
    ERYTHEMA
         subjects affected / exposed
    0 / 32 (0.00%)
    6 / 32 (18.75%)
    0 / 32 (0.00%)
         occurrences all number
    0
    8
    0
    EXFOLIATIVE RASH
         subjects affected / exposed
    0 / 32 (0.00%)
    2 / 32 (6.25%)
    0 / 32 (0.00%)
         occurrences all number
    0
    2
    0
    HYPERHIDROSIS
         subjects affected / exposed
    0 / 32 (0.00%)
    0 / 32 (0.00%)
    1 / 32 (3.13%)
         occurrences all number
    0
    0
    1
    NAIL DISORDER
         subjects affected / exposed
    0 / 32 (0.00%)
    1 / 32 (3.13%)
    1 / 32 (3.13%)
         occurrences all number
    0
    1
    1
    NIGHT SWEATS
         subjects affected / exposed
    0 / 32 (0.00%)
    1 / 32 (3.13%)
    1 / 32 (3.13%)
         occurrences all number
    0
    1
    2
    ONYCHOCLASIS
         subjects affected / exposed
    0 / 32 (0.00%)
    1 / 32 (3.13%)
    0 / 32 (0.00%)
         occurrences all number
    0
    1
    0
    ONYCHOMADESIS
         subjects affected / exposed
    0 / 32 (0.00%)
    1 / 32 (3.13%)
    0 / 32 (0.00%)
         occurrences all number
    0
    1
    0
    PALMAR ERYTHEMA
         subjects affected / exposed
    0 / 32 (0.00%)
    1 / 32 (3.13%)
    0 / 32 (0.00%)
         occurrences all number
    0
    1
    0
    PALMAR-PLANTAR ERYTHRODYSAESTHESIA SYNDROME
         subjects affected / exposed
    0 / 32 (0.00%)
    20 / 32 (62.50%)
    0 / 32 (0.00%)
         occurrences all number
    0
    33
    0
    PETECHIAE
         subjects affected / exposed
    0 / 32 (0.00%)
    1 / 32 (3.13%)
    0 / 32 (0.00%)
         occurrences all number
    0
    1
    0
    PHOTOSENSITIVITY REACTION
         subjects affected / exposed
    0 / 32 (0.00%)
    1 / 32 (3.13%)
    0 / 32 (0.00%)
         occurrences all number
    0
    2
    0
    PIGMENTATION DISORDER
         subjects affected / exposed
    0 / 32 (0.00%)
    1 / 32 (3.13%)
    0 / 32 (0.00%)
         occurrences all number
    0
    1
    0
    PRURITUS
         subjects affected / exposed
    0 / 32 (0.00%)
    5 / 32 (15.63%)
    0 / 32 (0.00%)
         occurrences all number
    0
    5
    0
    RASH
         subjects affected / exposed
    3 / 32 (9.38%)
    14 / 32 (43.75%)
    3 / 32 (9.38%)
         occurrences all number
    4
    24
    4
    RASH GENERALISED
         subjects affected / exposed
    0 / 32 (0.00%)
    1 / 32 (3.13%)
    0 / 32 (0.00%)
         occurrences all number
    0
    1
    0
    RASH MACULAR
         subjects affected / exposed
    0 / 32 (0.00%)
    1 / 32 (3.13%)
    0 / 32 (0.00%)
         occurrences all number
    0
    1
    0
    RASH MACULO-PAPULAR
         subjects affected / exposed
    0 / 32 (0.00%)
    0 / 32 (0.00%)
    1 / 32 (3.13%)
         occurrences all number
    0
    0
    1
    SKIN BURNING SENSATION
         subjects affected / exposed
    0 / 32 (0.00%)
    1 / 32 (3.13%)
    0 / 32 (0.00%)
         occurrences all number
    0
    1
    0
    SKIN EROSION
         subjects affected / exposed
    0 / 32 (0.00%)
    1 / 32 (3.13%)
    0 / 32 (0.00%)
         occurrences all number
    0
    1
    0
    SKIN EXFOLIATION
         subjects affected / exposed
    0 / 32 (0.00%)
    1 / 32 (3.13%)
    0 / 32 (0.00%)
         occurrences all number
    0
    1
    0
    SKIN HYPERPIGMENTATION
         subjects affected / exposed
    0 / 32 (0.00%)
    3 / 32 (9.38%)
    0 / 32 (0.00%)
         occurrences all number
    0
    3
    0
    SKIN LESION
         subjects affected / exposed
    0 / 32 (0.00%)
    1 / 32 (3.13%)
    0 / 32 (0.00%)
         occurrences all number
    0
    1
    0
    SKIN ULCER
         subjects affected / exposed
    0 / 32 (0.00%)
    1 / 32 (3.13%)
    0 / 32 (0.00%)
         occurrences all number
    0
    1
    0
    URTICARIA
         subjects affected / exposed
    1 / 32 (3.13%)
    1 / 32 (3.13%)
    0 / 32 (0.00%)
         occurrences all number
    1
    1
    0
    XERODERMA
         subjects affected / exposed
    1 / 32 (3.13%)
    0 / 32 (0.00%)
    0 / 32 (0.00%)
         occurrences all number
    1
    0
    0
    Renal and urinary disorders
    BLADDER SPASM
         subjects affected / exposed
    1 / 32 (3.13%)
    1 / 32 (3.13%)
    0 / 32 (0.00%)
         occurrences all number
    1
    1
    0
    DYSURIA
         subjects affected / exposed
    1 / 32 (3.13%)
    1 / 32 (3.13%)
    1 / 32 (3.13%)
         occurrences all number
    1
    1
    1
    HAEMATURIA
         subjects affected / exposed
    0 / 32 (0.00%)
    0 / 32 (0.00%)
    1 / 32 (3.13%)
         occurrences all number
    0
    0
    1
    POLLAKIURIA
         subjects affected / exposed
    1 / 32 (3.13%)
    0 / 32 (0.00%)
    2 / 32 (6.25%)
         occurrences all number
    1
    0
    2
    RENAL IMPAIRMENT
         subjects affected / exposed
    0 / 32 (0.00%)
    1 / 32 (3.13%)
    0 / 32 (0.00%)
         occurrences all number
    0
    1
    0
    URETHRAL PAIN
         subjects affected / exposed
    1 / 32 (3.13%)
    0 / 32 (0.00%)
    0 / 32 (0.00%)
         occurrences all number
    1
    0
    0
    URINARY RETENTION
         subjects affected / exposed
    0 / 32 (0.00%)
    0 / 32 (0.00%)
    1 / 32 (3.13%)
         occurrences all number
    0
    0
    1
    Musculoskeletal and connective tissue disorders
    ARTHRALGIA
         subjects affected / exposed
    3 / 32 (9.38%)
    2 / 32 (6.25%)
    0 / 32 (0.00%)
         occurrences all number
    4
    4
    0
    BACK PAIN
         subjects affected / exposed
    3 / 32 (9.38%)
    5 / 32 (15.63%)
    6 / 32 (18.75%)
         occurrences all number
    3
    6
    6
    BONE PAIN
         subjects affected / exposed
    1 / 32 (3.13%)
    1 / 32 (3.13%)
    1 / 32 (3.13%)
         occurrences all number
    1
    1
    1
    CHONDROPATHY
         subjects affected / exposed
    1 / 32 (3.13%)
    0 / 32 (0.00%)
    0 / 32 (0.00%)
         occurrences all number
    1
    0
    0
    FLANK PAIN
         subjects affected / exposed
    2 / 32 (6.25%)
    0 / 32 (0.00%)
    0 / 32 (0.00%)
         occurrences all number
    2
    0
    0
    GROIN PAIN
         subjects affected / exposed
    1 / 32 (3.13%)
    2 / 32 (6.25%)
    0 / 32 (0.00%)
         occurrences all number
    1
    2
    0
    JOINT STIFFNESS
         subjects affected / exposed
    1 / 32 (3.13%)
    0 / 32 (0.00%)
    0 / 32 (0.00%)
         occurrences all number
    1
    0
    0
    MUSCLE SPASMS
         subjects affected / exposed
    2 / 32 (6.25%)
    0 / 32 (0.00%)
    2 / 32 (6.25%)
         occurrences all number
    2
    0
    4
    MUSCULOSKELETAL CHEST PAIN
         subjects affected / exposed
    0 / 32 (0.00%)
    1 / 32 (3.13%)
    1 / 32 (3.13%)
         occurrences all number
    0
    1
    1
    MUSCULOSKELETAL DISCOMFORT
         subjects affected / exposed
    0 / 32 (0.00%)
    0 / 32 (0.00%)
    1 / 32 (3.13%)
         occurrences all number
    0
    0
    1
    MUSCULOSKELETAL PAIN
         subjects affected / exposed
    2 / 32 (6.25%)
    2 / 32 (6.25%)
    1 / 32 (3.13%)
         occurrences all number
    3
    2
    1
    MUSCULOSKELETAL STIFFNESS
         subjects affected / exposed
    1 / 32 (3.13%)
    0 / 32 (0.00%)
    0 / 32 (0.00%)
         occurrences all number
    1
    0
    0
    MYALGIA
         subjects affected / exposed
    2 / 32 (6.25%)
    1 / 32 (3.13%)
    2 / 32 (6.25%)
         occurrences all number
    2
    1
    2
    NECK PAIN
         subjects affected / exposed
    0 / 32 (0.00%)
    0 / 32 (0.00%)
    1 / 32 (3.13%)
         occurrences all number
    0
    0
    1
    PAIN IN EXTREMITY
         subjects affected / exposed
    1 / 32 (3.13%)
    3 / 32 (9.38%)
    3 / 32 (9.38%)
         occurrences all number
    1
    3
    3
    PAIN IN JAW
         subjects affected / exposed
    0 / 32 (0.00%)
    0 / 32 (0.00%)
    1 / 32 (3.13%)
         occurrences all number
    0
    0
    1
    Infections and infestations
    BRONCHITIS
         subjects affected / exposed
    1 / 32 (3.13%)
    1 / 32 (3.13%)
    1 / 32 (3.13%)
         occurrences all number
    2
    1
    1
    CANDIDIASIS
         subjects affected / exposed
    0 / 32 (0.00%)
    1 / 32 (3.13%)
    0 / 32 (0.00%)
         occurrences all number
    0
    1
    0
    CELLULITIS
         subjects affected / exposed
    0 / 32 (0.00%)
    0 / 32 (0.00%)
    1 / 32 (3.13%)
         occurrences all number
    0
    0
    1
    EAR INFECTION
         subjects affected / exposed
    1 / 32 (3.13%)
    1 / 32 (3.13%)
    0 / 32 (0.00%)
         occurrences all number
    1
    1
    0
    ECZEMA INFECTED
         subjects affected / exposed
    0 / 32 (0.00%)
    1 / 32 (3.13%)
    0 / 32 (0.00%)
         occurrences all number
    0
    1
    0
    FOLLICULITIS
         subjects affected / exposed
    0 / 32 (0.00%)
    1 / 32 (3.13%)
    0 / 32 (0.00%)
         occurrences all number
    0
    1
    0
    FUNGAL INFECTION
         subjects affected / exposed
    1 / 32 (3.13%)
    0 / 32 (0.00%)
    0 / 32 (0.00%)
         occurrences all number
    1
    0
    0
    FURUNCLE
         subjects affected / exposed
    1 / 32 (3.13%)
    0 / 32 (0.00%)
    0 / 32 (0.00%)
         occurrences all number
    1
    0
    0
    GASTROENTERITIS
         subjects affected / exposed
    0 / 32 (0.00%)
    2 / 32 (6.25%)
    0 / 32 (0.00%)
         occurrences all number
    0
    2
    0
    GASTROINTESTINAL INFECTION
         subjects affected / exposed
    0 / 32 (0.00%)
    0 / 32 (0.00%)
    1 / 32 (3.13%)
         occurrences all number
    0
    0
    1
    GENITAL HERPES
         subjects affected / exposed
    0 / 32 (0.00%)
    1 / 32 (3.13%)
    0 / 32 (0.00%)
         occurrences all number
    0
    1
    0
    GINGIVAL INFECTION
         subjects affected / exposed
    0 / 32 (0.00%)
    1 / 32 (3.13%)
    0 / 32 (0.00%)
         occurrences all number
    0
    1
    0
    HERPES ZOSTER
         subjects affected / exposed
    0 / 32 (0.00%)
    0 / 32 (0.00%)
    1 / 32 (3.13%)
         occurrences all number
    0
    0
    1
    INCISION SITE ABSCESS
         subjects affected / exposed
    1 / 32 (3.13%)
    0 / 32 (0.00%)
    0 / 32 (0.00%)
         occurrences all number
    1
    0
    0
    INFECTED SEBACEOUS CYST
         subjects affected / exposed
    1 / 32 (3.13%)
    0 / 32 (0.00%)
    0 / 32 (0.00%)
         occurrences all number
    1
    0
    0
    INFLUENZA
         subjects affected / exposed
    3 / 32 (9.38%)
    1 / 32 (3.13%)
    2 / 32 (6.25%)
         occurrences all number
    4
    1
    3
    INTERTRIGO CANDIDA
         subjects affected / exposed
    0 / 32 (0.00%)
    2 / 32 (6.25%)
    0 / 32 (0.00%)
         occurrences all number
    0
    3
    0
    LOCALISED INFECTION
         subjects affected / exposed
    0 / 32 (0.00%)
    1 / 32 (3.13%)
    0 / 32 (0.00%)
         occurrences all number
    0
    1
    0
    LOWER RESPIRATORY TRACT INFECTION
         subjects affected / exposed
    1 / 32 (3.13%)
    0 / 32 (0.00%)
    1 / 32 (3.13%)
         occurrences all number
    1
    0
    1
    NAIL INFECTION
         subjects affected / exposed
    0 / 32 (0.00%)
    1 / 32 (3.13%)
    0 / 32 (0.00%)
         occurrences all number
    0
    1
    0
    NASOPHARYNGITIS
         subjects affected / exposed
    2 / 32 (6.25%)
    3 / 32 (9.38%)
    2 / 32 (6.25%)
         occurrences all number
    2
    3
    4
    ORAL CANDIDIASIS
         subjects affected / exposed
    0 / 32 (0.00%)
    1 / 32 (3.13%)
    0 / 32 (0.00%)
         occurrences all number
    0
    2
    0
    ORAL HERPES
         subjects affected / exposed
    0 / 32 (0.00%)
    0 / 32 (0.00%)
    1 / 32 (3.13%)
         occurrences all number
    0
    0
    1
    ORAL INFECTION
         subjects affected / exposed
    0 / 32 (0.00%)
    1 / 32 (3.13%)
    0 / 32 (0.00%)
         occurrences all number
    0
    1
    0
    PHARYNGITIS
         subjects affected / exposed
    1 / 32 (3.13%)
    1 / 32 (3.13%)
    0 / 32 (0.00%)
         occurrences all number
    1
    1
    0
    POSTOPERATIVE WOUND INFECTION
         subjects affected / exposed
    0 / 32 (0.00%)
    1 / 32 (3.13%)
    0 / 32 (0.00%)
         occurrences all number
    0
    1
    0
    PULPITIS DENTAL
         subjects affected / exposed
    0 / 32 (0.00%)
    0 / 32 (0.00%)
    1 / 32 (3.13%)
         occurrences all number
    0
    0
    1
    RHINITIS
         subjects affected / exposed
    0 / 32 (0.00%)
    0 / 32 (0.00%)
    2 / 32 (6.25%)
         occurrences all number
    0
    0
    2
    SINUSITIS
         subjects affected / exposed
    1 / 32 (3.13%)
    0 / 32 (0.00%)
    0 / 32 (0.00%)
         occurrences all number
    1
    0
    0
    TINEA PEDIS
         subjects affected / exposed
    0 / 32 (0.00%)
    2 / 32 (6.25%)
    0 / 32 (0.00%)
         occurrences all number
    0
    2
    0
    TONSILLITIS
         subjects affected / exposed
    0 / 32 (0.00%)
    0 / 32 (0.00%)
    2 / 32 (6.25%)
         occurrences all number
    0
    0
    2
    TOOTH ABSCESS
         subjects affected / exposed
    0 / 32 (0.00%)
    1 / 32 (3.13%)
    0 / 32 (0.00%)
         occurrences all number
    0
    1
    0
    UPPER RESPIRATORY TRACT INFECTION
         subjects affected / exposed
    5 / 32 (15.63%)
    2 / 32 (6.25%)
    2 / 32 (6.25%)
         occurrences all number
    6
    2
    2
    URINARY TRACT INFECTION
         subjects affected / exposed
    5 / 32 (15.63%)
    4 / 32 (12.50%)
    11 / 32 (34.38%)
         occurrences all number
    5
    7
    20
    VIRAL INFECTION
         subjects affected / exposed
    2 / 32 (6.25%)
    1 / 32 (3.13%)
    2 / 32 (6.25%)
         occurrences all number
    3
    1
    5
    VIRAL UPPER RESPIRATORY TRACT INFECTION
         subjects affected / exposed
    1 / 32 (3.13%)
    1 / 32 (3.13%)
    0 / 32 (0.00%)
         occurrences all number
    1
    1
    0
    VULVOVAGINAL CANDIDIASIS
         subjects affected / exposed
    1 / 32 (3.13%)
    0 / 32 (0.00%)
    1 / 32 (3.13%)
         occurrences all number
    1
    0
    1
    Metabolism and nutrition disorders
    CACHEXIA
         subjects affected / exposed
    1 / 32 (3.13%)
    0 / 32 (0.00%)
    0 / 32 (0.00%)
         occurrences all number
    1
    0
    0
    DECREASED APPETITE
         subjects affected / exposed
    5 / 32 (15.63%)
    8 / 32 (25.00%)
    5 / 32 (15.63%)
         occurrences all number
    5
    10
    8
    DEHYDRATION
         subjects affected / exposed
    0 / 32 (0.00%)
    1 / 32 (3.13%)
    0 / 32 (0.00%)
         occurrences all number
    0
    1
    0
    HYPERCALCAEMIA
         subjects affected / exposed
    1 / 32 (3.13%)
    0 / 32 (0.00%)
    0 / 32 (0.00%)
         occurrences all number
    1
    0
    0
    HYPERGLYCAEMIA
         subjects affected / exposed
    1 / 32 (3.13%)
    0 / 32 (0.00%)
    1 / 32 (3.13%)
         occurrences all number
    1
    0
    1
    HYPOKALAEMIA
         subjects affected / exposed
    1 / 32 (3.13%)
    1 / 32 (3.13%)
    1 / 32 (3.13%)
         occurrences all number
    1
    1
    1
    HYPOMAGNESAEMIA
         subjects affected / exposed
    2 / 32 (6.25%)
    1 / 32 (3.13%)
    1 / 32 (3.13%)
         occurrences all number
    2
    2
    1
    HYPOPROTEINAEMIA
         subjects affected / exposed
    0 / 32 (0.00%)
    0 / 32 (0.00%)
    1 / 32 (3.13%)
         occurrences all number
    0
    0
    1
    INCREASED APPETITE
         subjects affected / exposed
    1 / 32 (3.13%)
    0 / 32 (0.00%)
    0 / 32 (0.00%)
         occurrences all number
    1
    0
    0

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    19 Mar 2008
    Clarification that withdrawal was from study treatment rather than from study (Section 3.2.1, Section 3.2.2, Section 3.3.2, Section 3.5.2.1, Section 4.5.1, Section 4.5.1.1, Section 5.3.2, and Section 5.3.3. For any patient with a treatment-free interval of more than 12 months, then re-treatment with platinum should be the first option. However a patient may be considered for this study if there is a medical contra-indication to further platinum chemotherapy. This must be discussed both with the patient and with AstraZeneca prior to consent and any screening procedures (Section 4.3). Collection of demography data and extra data for cardiac monitoring (ECG and MUGA scans) and safety haematology and biochemistry (e.g. mean cell volume, amylase and lipase assessments) (Section 5.2.2, Section 5.2.9, Section 5.2.10, Section 3.3.3.5, Section 5.2.12.1)
    20 May 2008
    Change to number of doses of olaparib to be studied (Study title, Section 1.6, Section 3.2.1) Collection of OS as secondary objective, changes to statistical methods as a result of change in number in olaparib dose groups, clarification of patient management (Section 2.1, Section 2.2, Section 4.3, Section 5.2.14, Section 7.2, Section 7.4.1, Section 7.4.1.5, Section 7.5.1) Changes to management of toxicity based on the new dose group of 200 mg bd (Section 3.3.2) Inclusion criteria (Section 4.1) Exclusion criteria (Section 4.2) Clarification of safety assessments (Section 5.3.2)
    13 Nov 2008
    Synopsis, Target patient population Text changes to Synopsis, Key Procedures, Overall Survival (Section 7.4.1.5), Determination of sample size (Section 7.5), Adverse event reporting period Section 6.6) to account for overall survival as secondary endpoint. Inclusion Criteria (Section 4.1, criterion 7) Exclusion Criteria (Section 4.2, criterion 2) Exclusion Criteria (Section 4.2 previously criterion 5, now criterion 6) Assignment of patient E-code number and stratification (Section 4.3) Discontinuation from study treatment and (Section 4.5.1.2) and CT or MRI scans (Section 5.2.14) Treatment period(s) and assessments text (Section 5.3.2) Withdrawal visit text (Section 5.3.3) Crossover from liposomal doxorubicin text (Section 5.3.4) Patient management Post-Primary Analysis (new section) (Section 5.3.6)
    05 Apr 2010
    Key procedures and statistical summary (Synopsis), Table 5, crossover from liposomal doxorubicin text (Section 5.3.4), Table 6, Final follow-up visit text (Section 5.3.5), Patient management post primary analysis (Section 5.3.6), Figure 2, patient management post data cut-off text (Section 5.3.7, new text), Adverse event reporting period text (Section 6.6), Overall survival text (Section 7.4.1.5), Determination of sample size text (Section 7.5), Study timetable text (Section 11) Clinical experience text (Section 1.5) Management of olaparib toxicity text (Section 3.3.2) Exclusion criteria (Section 4.2; criterion 15) Discontinuation from study treatment text (Section 4.5.1.2), Crossover from liposomal doxorubicin text (Section 5.3.4) Table 7 (New table of study schedule for patients crossing over from liposomal doxorubicin to olaparib following approval of protocol amendment 4) Patient management post primary analysis (Section 5.3.6) Figure 2 Reporting of AE and SAE text (Section 6.2)

    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.
    The AEs reported include all events up to the OS data cut-off. After the PFS data cut-off, AEs were only collected for the olaparib and cross-over groups. The safety profile of these 2 groups at OS was consistent with that at the time of PFS.
    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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