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    Clinical Trial Results:
    A Phase III, Open Label, Randomised, Controlled, Multi-centre Study to assess the efficacy and safety of Olaparib Monotherapy versus Physician’s Choice Single Agent Chemotherapy in the Treatment of Platinum Sensitive Relapsed Ovarian Cancer in Patients carrying germline BRCA1/2 Mutations

    Summary
    EudraCT number
    		 2014-003438-20
    Trial protocol
    		 HU   BE   CZ   ES   IT  
    Global end of trial date
    19 Jul 2022

    Results information
    Results version number
    		 v1(current)
    This version publication date
    21 Sep 2022
    First version publication date
    21 Sep 2022
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    D0816C00010
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT02282020
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    AstraZeneca AB
    Sponsor organisation address
    151 85, Södertälje, Sweden,
    Public contact
    Global Clinical Leader, AstraZeneca AB, +1 877-240-9479, information.center@astrazeneca.com
    Scientific contact
    Global Clinical Leader, AstraZeneca AB, +1 877-240-9479, information.center@astrazeneca.com
    Paediatric regulatory details
    Is trial part of an agreed paediatric investigation plan (PIP)
    No
    Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Results analysis stage
    Analysis stage
    Final
    Date of interim/final analysis
    16 Apr 2021
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    19 Jul 2022
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To determine the efficacy of olaparib vs. physician’s choice single agent chemotherapy by assessment of Objective Response Rate (ORR) using blinded independent central review (BICR).
    Protection of trial subjects
    The study used an external IDMC to perform interim reviews of accumulating study safety data.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    24 Feb 2015
    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
    Italy: 49
    Country: Number of subjects enrolled
    United States: 41
    Country: Number of subjects enrolled
    Korea, Republic of: 33
    Country: Number of subjects enrolled
    Poland: 32
    Country: Number of subjects enrolled
    Czechia: 21
    Country: Number of subjects enrolled
    Mexico: 21
    Country: Number of subjects enrolled
    Brazil: 19
    Country: Number of subjects enrolled
    Spain: 14
    Country: Number of subjects enrolled
    Israel: 13
    Country: Number of subjects enrolled
    Canada: 8
    Country: Number of subjects enrolled
    Hungary: 8
    Country: Number of subjects enrolled
    Belgium: 4
    Country: Number of subjects enrolled
    Argentina: 3
    Worldwide total number of subjects
    266
    EEA total number of subjects
    128
    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)
    186
    From 65 to 84 years
    79
    85 years and over
    1

    Subject disposition

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    Recruitment
    Recruitment details
    		 A total of 678 patients were screened (gave informed consent) at 94 centres in 13 countries. Of the 678 patients screened, 266 patients were randomised from 78 sites in 13 countries worldwide. A wash-out period of up to 5 weeks was required for participants who have previously taken potent inhibitors or CYP3A4/5 inducers.

    Pre-assignment
    Screening details
    		 Participants were randomized in a 2:1 ratio between olaparib and single agent chemotherapy. Of the 266 patients randomised, 178 patients were in the olaparib arm and 88 in the chemotherapy arm.

    Period 1
    Period 1 title
    Overall Study (overall period)
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Not blinded

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Olaparib 300mg BID
    Arm description
    		 Participants received olaparib twice daily as a 300 mg tablet.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Olaparib
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    300 mg tablet taken twice daily.

    Arm title
    		 Single Agent Chemotherapy
    Arm description
    		 Participants received physician’s choice of chemotherapy, out of weekly paclitaxel, topotecan, pegylated liposomal doxorubicin, or gemcitabine.
    Arm type
    		 Active comparator

    Investigational medicinal product name
    Physicians choice of paclitaxel, topotecan, pegylated liposomal doxorubicin, or gemcitabine.
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Injection
    Routes of administration
    Intravenous use
    Dosage and administration details
    Administered dose and schedule as required for physicians choice of chemotherapy.

    Number of subjects in period 1
    		Olaparib 300mg BID Single Agent Chemotherapy
    Started
    178
    88
    Received Treatment
    178
    76
    Completed
    19
    0
    Not completed
    159
    88
         Severe Non-compliance to Protocol
    1
    -
         Consent withdrawn by subject
    7
    10
         Objective Disease Progression
    128
    30
         Adverse event, non-fatal
    18
    15
         Developed Discontinuation Criteria
    -
    2
         Miscellaneous
    5
    19
         Withdrew Consent Prior to Dosing
    -
    12

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Olaparib 300mg BID
    Reporting group description
    		 Participants received olaparib twice daily as a 300 mg tablet.

    Reporting group title
    Single Agent Chemotherapy
    Reporting group description
    		 Participants received physician’s choice of chemotherapy, out of weekly paclitaxel, topotecan, pegylated liposomal doxorubicin, or gemcitabine.

    Reporting group values
    		 Olaparib 300mg BID Single Agent Chemotherapy Total
    Number of subjects
    		 178 88 266
    Age categorical
    Units: Subjects
        Adults (18-50 years)
    		 31 15 46
        From 50-65 years
    		 101 39 140
        65 years and over
    		 46 34 80
    Age Continuous
    Units: Years
        arithmetic mean (standard deviation)
    		 58.5 ( 9.3 ) 60.4 ( 9.9 ) -
    Sex: Female, Male
    Units: Participants
        Female
    		 178 88 266
        Male
    		 0 0 0
    Race/Ethnicity, Customized
    Units: Subjects
        White
    		 148 75 223
        Black Or African American
    		 1 1 2
        Asian
    		 24 10 34
        American Indian Or Alaska Native
    		 4 2 6
        Other
    		 1 0 1
    Ethnicity (NIH/OMB)
    Units: Subjects
        Hispanic or Latino
    		 31 16 47
        Not Hispanic or Latino
    		 146 72 218
        Unknown or Not Reported
    		 1 0 1
    Subject analysis sets

    Subject analysis set title
    Olaparib 300 mg BID
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    Participants received olaparib twice daily as a 300 mg tablet.

    Subject analysis set title
    Selected Chemotherapy
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    Participants received physician’s choice of chemotherapy, out of weekly paclitaxel, topotecan, pegylated liposomal doxorubicin, or gemcitabine.

    Subject analysis sets values
    		 Olaparib 300 mg BID Selected Chemotherapy
    Number of subjects
    178
    88
    Age categorical
    Units: Subjects
        Adults (18-50 years)
    31
    15
        From 50-65 years
    101
    39
        65 years and over
    46
    34
    Age Continuous
    Units: Years
        arithmetic mean (standard deviation)
    58.5 ( 9.3 )
    60.4 ( 9.9 )
    Sex: Female, Male
    Units: Participants
        Female
    178
    88
        Male
    0
    0
    Race/Ethnicity, Customized
    Units: Subjects
        White
    148
    75
        Black Or African American
    1
    1
        Asian
    24
    10
        American Indian Or Alaska Native
    4
    2
        Other
    1
    0
    Ethnicity (NIH/OMB)
    Units: Subjects
        Hispanic or Latino
    31
    16
        Not Hispanic or Latino
    146
    72
        Unknown or Not Reported
    1
    0

    End points

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    End points reporting groups
    Reporting group title
    Olaparib 300mg BID
    Reporting group description
    		 Participants received olaparib twice daily as a 300 mg tablet.

    Reporting group title
    Single Agent Chemotherapy
    Reporting group description
    		 Participants received physician’s choice of chemotherapy, out of weekly paclitaxel, topotecan, pegylated liposomal doxorubicin, or gemcitabine.

    Subject analysis set title
    Olaparib 300 mg BID
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    Participants received olaparib twice daily as a 300 mg tablet.

    Subject analysis set title
    Selected Chemotherapy
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    Participants received physician’s choice of chemotherapy, out of weekly paclitaxel, topotecan, pegylated liposomal doxorubicin, or gemcitabine.

    Primary: Objective Response Rate (ORR)

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    End point title
    		 Objective Response Rate (ORR)
    End point description
    To determine the efficacy of olaparib vs. physician’s choice single agent chemotherapy by assessment of Objective Response Rate (ORR) using blinded independent central review (BICR) Response Evaluation Criteria In Solid Tumors (RECIST) 1.1 criteria was used by a Blinded Independent Central Review (BICR) to assess participant response to treatment ORR is the number of participants with Complete Response (CR) or Partial Response (PR) in the Measurable Disease Analysis Set (MDAS). MDAS includes all participants in the FAS with measurable disease at baseline (as per RECIST 1.1), determined using BICR. Complete response is declared when all lesions have disappeared or all lesions have disappeared and all nodal disease is < 10 mm each. Partial response is declared when there is a decrease in sum of diameters of target lesions ≥ 30%.
    End point type
    Primary
    End point timeframe
    RECIST follow-up assessments performed every 8 weeks (±1 week), up to 48 weeks, then every 12 weeks (±1 week) from randomisation, assessed from date of first patient randomised to data cut off: 10Oct2018 (approx. 3 years 8 months)
    End point values
    		 Olaparib 300mg BID Single Agent Chemotherapy
    Number of subjects analysed
    151
    72
    Units: Count of Participants
    109
    37
    Statistical analysis title
    		 ORR based by BICR, adjusted logistic regression
    Comparison groups
    Single Agent Chemotherapy v Olaparib 300mg BID
    Number of subjects included in analysis
    223
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.002
    Method
    		 Regression, Logistic
    Parameter type
    		 Odds ratio (OR)
    Point estimate
    2.53
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 1.4
         upper limit
    		 4.58

    Secondary: Progression Free Survival (PFS)

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    End point title
    		 Progression Free Survival (PFS)
    End point description
    To determine the efficacy of single agent olaparib vs. physician’s choice single agent chemotherapy by progression free survival (PFS) using BICR assessment according to RECIST 1.1 criteria PFS is defined as the time from randomization until the date of objective radiological disease progression according to RECIST 1.1 or death (by any cause in the absence of disease progression) regardless of whether the participant withdrew from randomized therapy or received another anti-cancer therapy prior to disease progression (i.e., date of RECIST progression/death or censoring – date of randomization +1).
    End point type
    Secondary
    End point timeframe
    RECIST follow-up assessments performed every 8 weeks (±1 week), up to 48 weeks, then every 12 weeks (±1 week) from randomisation, assessed from date of first patient randomised to data cut off: 10Oct2018 (approx. 3 years 8 months)
    End point values
    		 Olaparib 300mg BID Single Agent Chemotherapy
    Number of subjects analysed
    178
    88
    Units: Months
        median (confidence interval 95%)
    13.4 (10.9 to 14.1)
    9.2 (7.6 to 11.2)
    Statistical analysis title
    		 rPFS by BICR, stratified log rank test
    Comparison groups
    Single Agent Chemotherapy v Olaparib 300mg BID
    Number of subjects included in analysis
    266
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.013 [1]
    Method
    		 Logrank
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.62
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.43
         upper limit
    		 0.91
    Notes
    [1] - Determined using a log-rank test with a factor for time to disease progression after the end of last platinum based chemotherapy (6-12 months vs > 12 months).

    Secondary: Time from Randomisation to Second Progression (PFS2)

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    End point title
    		 Time from Randomisation to Second Progression (PFS2)
    End point description
    To determine the efficacy of single agent olaparib vs. physician’s choice single agent chemotherapy by second progression (PFS2). Time from randomization to PFS2 is defined as the time from the date of randomization to the earliest of the progression events subsequent to first progression or death. The date of second progression was recorded by the investigator and defined according to local standard clinical practice, and could involve objective radiological, clinical, cancer antigen-125 (CA-125) progression or death. CA-125 progression was assessed per Gynecological Cancer Intergroup (GCIG) criteria.
    End point type
    Secondary
    End point timeframe
    Visits to occur every 12 weeks from the date of first progression, assessed from date of first patient randomised to data cut off: 16Apr2021 (approx. 6 years 2 months)
    End point values
    		 Olaparib 300mg BID Single Agent Chemotherapy
    Number of subjects analysed
    178
    88
    Units: Months
        median (confidence interval 95%)
    23.6 (19.2 to 26.0)
    19.6 (16.9 to 21.8)
    Statistical analysis title
    		 PFS2, stratified log rank rest
    Comparison groups
    Single Agent Chemotherapy v Olaparib 300mg BID
    Number of subjects included in analysis
    266
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.229 [2]
    Method
    		 Logrank
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.8
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.56
         upper limit
    		 1.15
    Notes
    [2] - Determined using a log-rank test with a factor for time to disease progression after the end of last platinum based chemotherapy (6-12 months vs > 12 months).

    Secondary: Overall Survival (OS)

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    End point title
    		 Overall Survival (OS)
    End point description
    To determine the efficacy of single agent olaparib vs. physician’s choice single agent chemotherapy by overall survival (OS). Overall survival is defined as the time from the date of randomisation until death due to any cause.
    End point type
    Secondary
    End point timeframe
    Visits to occur every 12 weeks from the date of first progression, assessed from date of first patient randomised to data cut off: 16Apr2021 (approx. 6 years 2 months)
    End point values
    		 Olaparib 300mg BID Single Agent Chemotherapy
    Number of subjects analysed
    178
    88
    Units: Months
        median (confidence interval 95%)
    34.9 (30.0 to 39.2)
    32.9 (23.5 to 43.2)
    Statistical analysis title
    		 OS, stratified log rank test
    Comparison groups
    Single Agent Chemotherapy v Olaparib 300mg BID
    Number of subjects included in analysis
    266
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.714 [3]
    Method
    		 Logrank
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    1.07
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.76
         upper limit
    		 1.49
    Notes
    [3] - Determined using a log-rank test with a factor for time to disease progression after the end of last platinum based chemotherapy (6-12 months vs > 12 months).

    Secondary: Time To Earliest Progression By RECIST 1.1 Or Cancer Antigen (CA) -125 Or Death

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    End point title
    		 Time To Earliest Progression By RECIST 1.1 Or Cancer Antigen (CA) -125 Or Death
    End point description
    To determine the efficacy of single agent olaparib vs. physician’s choice single agent chemotherapy by time to earliest progression by RECIST 1.1 or CA-125 or death. Response Evaluation Criteria In Solid Tumors (RECIST) 1.1 criteria was used to assess participant response to treatment. CA-125 progression was assessed per Gynecological Cancer Intergroup (GCIG).
    End point type
    Secondary
    End point timeframe
    RECIST and CA-125 follow-up assessments performed every 8 weeks (±1week), up to 48 weeks, then every 12 weeks (±1week) from randomisation, assessed from date of first patient randomised to data cut off: 10Oct2018 (approx. 3 years 8 months)
    End point values
    		 Olaparib 300mg BID Single Agent Chemotherapy
    Number of subjects analysed
    178
    88
    Units: Months
        median (confidence interval 95%)
    11.1 (9.7 to 13.8)
    7.9 (6.9 to 9.4)
    Statistical analysis title
    		 Earliest progression, stratified log rank test
    Comparison groups
    Single Agent Chemotherapy v Olaparib 300mg BID
    Number of subjects included in analysis
    266
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.005 [4]
    Method
    		 Logrank
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.59
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.41
         upper limit
    		 0.85
    Notes
    [4] - Determined using a log-rank test with a factor for time to disease progression after the end of last platinum based chemotherapy (6-12 months vs > 12 months).

    Secondary: Time From Randomization To First Subsequent Therapy Or Death (TFST)

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    End point title
    		 Time From Randomization To First Subsequent Therapy Or Death (TFST)
    End point description
    To determine the efficacy of single agent olaparib vs. physician’s choice single agent chemotherapy by time from randomisation to first subsequent therapy or death (TFST) TFST is defined as the time from the date of randomisation to the earlier of first subsequent chemotherapy start date or death. Anti-cancer treatments include chemotherapy and targeted agents.
    End point type
    Secondary
    End point timeframe
    Anti-cancer treatments initiated post discontinuation of study treatment and investigator’s opinion of response and date of progression recorded, assessed from date of first patient randomised to data cut off: 16Apr2021 (approx. 6 years 2 months)
    End point values
    		 Olaparib 300mg BID Single Agent Chemotherapy
    Number of subjects analysed
    178
    88
    Units: Months
        median (confidence interval 95%)
    15.4 (13.5 to 17.6)
    10.9 (9.2 to 14.2)
    Statistical analysis title
    		 TFST, stratified log rank test
    Comparison groups
    Single Agent Chemotherapy v Olaparib 300mg BID
    Number of subjects included in analysis
    266
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.001 [5]
    Method
    		 Logrank
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.49
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.35
         upper limit
    		 0.69
    Notes
    [5] - Model included factors for number of prior chemotherapy regimens received for ovarian cancer (2 or 3 prior lines vs 4 or more lines) and time to disease progression after the end of last platinum based chemotherapy (6-12 months vs > 12 months).

    Secondary: Time From Randomization To Second Subsequent Therapy Or Death (TSST)

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    End point title
    		 Time From Randomization To Second Subsequent Therapy Or Death (TSST)
    End point description
    To determine the efficacy of single agent olaparib vs. physician’s choice single agent chemotherapy by time from randomisation to second subsequent therapy or death (TSST) TSST was defined as the time from the date of randomisation to the earlier of second subsequent chemotherapy start date or death. Anti-cancer treatments include chemotherapy and targeted agents.
    End point type
    Secondary
    End point timeframe
    Anti-cancer treatments initiated post discontinuation of study treatment and investigator’s opinion of response and date of progression recorded, assessed from date of first patient randomised to data cut off: 16Apr2021 (approx. 6 years 2 months)
    End point values
    		 Olaparib 300mg BID Single Agent Chemotherapy
    Number of subjects analysed
    178
    88
    Units: Months
        median (confidence interval 95%)
    25.2 (21.3 to 27.8)
    19.9 (18.0 to 24.2)
    Statistical analysis title
    		 TSST, stratified log rank test
    Comparison groups
    Single Agent Chemotherapy v Olaparib 300mg BID
    Number of subjects included in analysis
    266
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.089 [6]
    Method
    		 Logrank
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.75
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.53
         upper limit
    		 1.05
    Notes
    [6] - Model included factors for number of prior chemotherapy regimens received for ovarian cancer (2 or 3 prior lines vs 4 or more lines) and time to disease progression after the end of last platinum based chemotherapy (6-12 months vs > 12 months).

    Secondary: Time From Randomization To Study Treatment Discontinuation Or Death (TDT)

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    End point title
    		 Time From Randomization To Study Treatment Discontinuation Or Death (TDT)
    End point description
    To determine the efficacy of single agent olaparib vs. physician’s choice single agent chemotherapy by time to study treatment discontinuation or death (TDT) TDT was defined as the time from randomization to the earlier of the date of study treatment discontinuation or death.
    End point type
    Secondary
    End point timeframe
    Patients randomised to Olaparib administer their tablets orally at a dose of 300 mg twice daily and continue Olaparib until objective disease progression. Assessed from date of first patient randomised to data cut off: 16Apr2021 (approx. 6 years 2 months)
    End point values
    		 Olaparib 300mg BID Single Agent Chemotherapy
    Number of subjects analysed
    178
    88
    Units: Months
        median (confidence interval 95%)
    13.1 (10.2 to 14.6)
    5.1 (4.7 to 6.5)
    Statistical analysis title
    		 TDT, stratified log rank test
    Comparison groups
    Single Agent Chemotherapy v Olaparib 300mg BID
    Number of subjects included in analysis
    266
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.001 [7]
    Method
    		 Logrank
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.2
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.14
         upper limit
    		 0.29
    Notes
    [7] - Model included factors for number of prior chemotherapy regimens received for ovarian cancer (2 or 3 prior lines vs 4 or more lines) and time to disease progression after the end of last platinum based chemotherapy (6-12 months vs > 12 months).

    Secondary: Duration of Response (DoR)

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    End point title
    		 Duration of Response (DoR)
    End point description
    To determine the efficacy of single agent olaparib vs. physician’s choice single agent chemotherapy by duration of response (DoR) by BICR using RECIST 1.1 criteria for evaluable patients, in MDAS. MDAS includes all participants in the FAS with measurable disease at baseline (as per RECIST 1.1), determined using BICR. Duration of response is the time from the first documentation of complete response (CR) or partial response (PR) until the date of progression or death, or the last evaluable RECIST assessment for participants that do not progress or progress after 2 missed assessments. Response Evaluation Criteria In Solid Tumors (RECIST) 1.1 criteria was used to assess participant response to treatment.
    End point type
    Secondary
    End point timeframe
    RECIST follow-up assessments performed every 8 weeks (±1 week), up to 48 weeks, then every 12 weeks (±1 week) from randomisation, assessed from date of first patient randomised to data cut off: 10Oct2018 (approx. 3 years 8 months)
    End point values
    		 Olaparib 300mg BID Single Agent Chemotherapy
    Number of subjects analysed
    109
    37
    Units: Months
        median (inter-quartile range (Q1-Q3))
    9.4 (5.6 to 25.7)
    10.2 (5.5 to 15.3)
    No statistical analyses for this end point

    Secondary: Time to Response (TTR)

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    End point title
    		 Time to Response (TTR)
    End point description
    To determine the efficacy of single agent olaparib vs. physician’s choice single agent chemotherapy by time to response (TTR) by BICR using RECIST 1.1 criteria for evaluable patients, in MDAS. MDAS includes all participants in the FAS with measurable disease at baseline (as per RECIST 1.1), determined using BICR. TTR was defined as the time from randomization until the date of first documented response by Blinded independent central review (BICR) assessment.
    End point type
    Secondary
    End point timeframe
    RECIST follow-up assessments performed every 8 weeks (±1 week), up to 48 weeks, then every 12 weeks (±1 week) from randomisation, assessed from date of first patient randomised to data cut off: 10Oct2018 (approx. 3 years 8 months)
    End point values
    		 Olaparib 300mg BID Single Agent Chemotherapy
    Number of subjects analysed
    109
    37
    Units: Months
        median (inter-quartile range (Q1-Q3))
    2.0 (1.8 to 3.9)
    3.5 (1.8 to 3.7)
    No statistical analyses for this end point

    Secondary: Mean Change From Baseline In Trial Outcome Index (TOI) Score

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    End point title
    		 Mean Change From Baseline In Trial Outcome Index (TOI) Score
    End point description
    To compare the efficacy of single agent olaparib versus physician’s choice single agent chemotherapy on the Health-related Quality of Life (HRQoL) as measured by the trial outcome index (TOI) of the Functional Assessment of Cancer Therapy – Ovarian (FACT-O) The TOI score was derived from the sum of the scores of the 25 items included in the physical well-being (7 items), functional well-being (7 items), and additional concerns ovarian cancer subscale (11 items) of the FACT-O questionnaire Version 4. TOI score ranges from 0 to 100, a higher score indicates a higher HRQoL. A negative change in score from baseline indicated a worsening in symptoms.
    End point type
    Secondary
    End point timeframe
    Baseline (Day 1) to Week 48 (±1 week). DCO: 10Oct2018
    End point values
    		 Olaparib 300mg BID Single Agent Chemotherapy
    Number of subjects analysed
    167
    62
    Units: Scores on a scale
        arithmetic mean (standard deviation)
    -2.4 ( 11.1 )
    -3.6 ( 9.8 )
    Statistical analysis title
    		 Change from baseline in TOI, MMRM
    Comparison groups
    Olaparib 300mg BID v Single Agent Chemotherapy
    Number of subjects included in analysis
    229
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.108
    Method
    		 Mixed models analysis
    Parameter type
    		 Mean difference (final values)
    Point estimate
    2.5
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.5
         upper limit
    		 5.5

    Secondary: Number of Participants Who Show an Improvement in TOI Score

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    End point title
    		 Number of Participants Who Show an Improvement in TOI Score
    End point description
    To compare the efficacy of single agent olaparib versus physician’s choice single agent chemotherapy on the Health-related Quality of Life (HRQoL) as measured by the trial outcome index (TOI) of the Functional Assessment of Cancer Therapy – Ovarian (FACT-O) The TOI score was derived from the sum of the scores of the 25 items included in the physical well-being (7 items), functional well-being (7 items), and additional concerns ovarian cancer subscale (11 items) of the FACT-O questionnaire Version 4. TOI score ranges from 0 to 100, a higher score indicates a higher health-related quality of life (HRQoL). A change in at least 10 points was considered clinically relevant.
    End point type
    Secondary
    End point timeframe
    Baseline (Day 1) to Week 48 (±1 week). DCO: 10Oct2018
    End point values
    		 Olaparib 300mg BID Single Agent Chemotherapy
    Number of subjects analysed
    168
    69
    Units: Count of Participants
    25
    5
    Statistical analysis title
    		 Improvement in TOI, adjusted logistic regression
    Comparison groups
    Single Agent Chemotherapy v Olaparib 300mg BID
    Number of subjects included in analysis
    237
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.092 [8]
    Method
    		 Regression, Logistic
    Parameter type
    		 Odds ratio (OR)
    Point estimate
    2.24
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.88
         upper limit
    		 6.86
    Notes
    [8] - Estimated from an unadjusted logistic regression model

    Secondary: Objective Response Rate (ORR) in Breast Cancer Susceptibility (BRCA) Gene Population by Blinded Independent Central Review (BICR)

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    End point title
    		 Objective Response Rate (ORR) in Breast Cancer Susceptibility (BRCA) Gene Population by Blinded Independent Central Review (BICR)
    End point description
    BRCA gene population includes participants identified as having a deleterious or suspected deleterious variant in either of the BRCA genes using variants identified with current and future BRCA mutation assays (eg, gene sequencing and large rearrangement analysis). The number of participants with complete or partial response per Response Evaluation Criteria In Solid Tumors (RECIST) 1.1 criteria. Partial response is declared when there is a decrease in sum of target disease ≥ 30%. Complete response is declared when all lesions have disappeared or all lesions have disappeared and all nodal disease is < 10 mm each.
    End point type
    Secondary
    End point timeframe
    RECIST follow-up assessments performed every 8 weeks (±1 week), up to 48 weeks, then every 12 weeks (±1 week) from randomisation, assessed from date of first patient randomised to data cut off: 10Oct2018 (approx. 3 years 8 months)
    End point values
    		 Olaparib 300mg BID Single Agent Chemotherapy
    Number of subjects analysed
    144
    70
    Units: Count of Participants
    103
    36
    Statistical analysis title
    		 ORR in BRCA by BICR, adjusted logistic regression
    Comparison groups
    Single Agent Chemotherapy v Olaparib 300mg BID
    Number of subjects included in analysis
    214
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.004 [9]
    Method
    		 Regression, Logistic
    Parameter type
    		 Odds ratio (OR)
    Point estimate
    2.4
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 1.32
         upper limit
    		 4.39
    Notes
    [9] - Determined using a log-rank test with a factor for time to disease progression after the end of last platinum based chemotherapy (6-12 months vs > 12 months).

    Secondary: Number of Participants who Experienced Disease Progression or Death in BRCA Gene Population by Blinded Independent Central Review (BICR)

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    End point title
    		 Number of Participants who Experienced Disease Progression or Death in BRCA Gene Population by Blinded Independent Central Review (BICR)
    End point description
    BRCA gene population includes participants identified as having a deleterious or suspected deleterious variant in either of the BRCA genes using variants identified with current and future BRCA mutation assays (eg, gene sequencing and large rearrangement analysis). Progressive disease was defined as at least 20% increase in the sum of diameters of target lesions, taking as reference the smallest sum of study. In addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of at least 5 mm.
    End point type
    Secondary
    End point timeframe
    RECIST follow-up assessments performed every 8 weeks (±1 week), up to 48 weeks, then every 12 weeks (±1 week) from randomisation, assessed from date of first patient randomised to data cut off: 10Oct2018 (approx. 3 years 8 months)
    End point values
    		 Olaparib 300mg BID Single Agent Chemotherapy
    Number of subjects analysed
    170
    84
    Units: Count of Participants
    105
    48
    Statistical analysis title
    		 PFS in BRCA by BICR, stratified log rank test
    Comparison groups
    Single Agent Chemotherapy v Olaparib 300mg BID
    Number of subjects included in analysis
    254
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.014 [10]
    Method
    		 Logrank
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.62
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.42
         upper limit
    		 0.91
    Notes
    [10] - Determined using a log-rank test with a factor for time to disease progression after the end of last platinum based chemotherapy (6-12 months vs > 12 months).

    Secondary: Number of Participants who Experienced Second Progression or Death (PFS2) in BRCA Gene Population

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    End point title
    		 Number of Participants who Experienced Second Progression or Death (PFS2) in BRCA Gene Population
    End point description
    BRCA gene population includes participants identified as having a deleterious or suspected deleterious variant in either of the BRCA genes using variants identified with current and future BRCA mutation assays (eg, gene sequencing and large rearrangement analysis).
    End point type
    Secondary
    End point timeframe
    Visits to occur every 12 weeks from the date of first progression, assessed from date of first patient randomised to data cut off: 16Apr2021 (approx. 6 years 2 months)
    End point values
    		 Olaparib 300mg BID Single Agent Chemotherapy
    Number of subjects analysed
    170
    84
    Units: Count of Participants
    110
    48
    Statistical analysis title
    		 PFS2 in BRCA, stratified log rank test
    Comparison groups
    Single Agent Chemotherapy v Olaparib 300mg BID
    Number of subjects included in analysis
    254
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.213 [11]
    Method
    		 Logrank
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.8
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.56
         upper limit
    		 1.14
    Notes
    [11] - Determined using a log-rank test with a factor for time to disease progression after the end of last platinum based chemotherapy (6-12 months vs > 12 months).

    Secondary: Overall Survival (OS) in BRCA Gene Population

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    End point title
    		 Overall Survival (OS) in BRCA Gene Population
    End point description
    BRCA gene population includes participants identified as having a deleterious or suspected deleterious variant in either of the BRCA genes using variants identified with current and future BRCA mutation assays (eg, gene sequencing and large rearrangement analysis). OS in BRCA gene population was measured by the number of participants who died due to any cause.
    End point type
    Secondary
    End point timeframe
    Visits to occur every 12 weeks from the date of first progression, assessed from date of first patient randomised to data cut off: 16Apr2021 (approx. 6 years 2 months)
    End point values
    		 Olaparib 300mg BID Single Agent Chemotherapy
    Number of subjects analysed
    170
    84
    Units: Count of Participants
    111
    45
    Statistical analysis title
    		 OS in BRCA, stratified log rank test
    Comparison groups
    Single Agent Chemotherapy v Olaparib 300mg BID
    Number of subjects included in analysis
    254
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.699 [12]
    Method
    		 Logrank
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    1.07
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.76
         upper limit
    		 1.51
    Notes
    [12] - Determined using a log-rank test with a factor for time to disease progression after the end of last platinum based chemotherapy (6-12 months vs > 12 months).

    Secondary: Number of Participants who Discontinued Study Treatment or Died in BRCA Gene Population

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    End point title
    		 Number of Participants who Discontinued Study Treatment or Died in BRCA Gene Population
    End point description
    BRCA gene population includes participants identified as having a deleterious or suspected deleterious variant in either of the BRCA genes using variants identified with current and future BRCA mutation assays (eg, gene sequencing and large rearrangement analysis).
    End point type
    Secondary
    End point timeframe
    Patients randomised to Olaparib administer their tablets orally at a dose of 300 mg twice daily and continue Olaparib until objective disease progression. Assessed from date of first patient randomised to data cut off: 16Apr2021 (approx. 6 years 2 months)
    End point values
    		 Olaparib 300mg BID Single Agent Chemotherapy
    Number of subjects analysed
    170
    84
    Units: Count of Participants
    151
    76
    Statistical analysis title
    		 TDT in BRCA, stratified log rank test
    Comparison groups
    Single Agent Chemotherapy v Olaparib 300mg BID
    Number of subjects included in analysis
    254
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.001 [13]
    Method
    		 Logrank
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.18
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.12
         upper limit
    		 0.27
    Notes
    [13] - Model included factors for number of prior chemotherapy regimens received for ovarian cancer (2 or 3 prior lines vs 4 or more lines) and time to disease progression after the end of last platinum based chemotherapy (6-12 months vs > 12 months).

    Secondary: Number of Participants who Received Subsequent Chemotherapy or Died in BRCA Gene Population

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    End point title
    		 Number of Participants who Received Subsequent Chemotherapy or Died in BRCA Gene Population
    End point description
    BRCA gene population includes participants identified as having a deleterious or suspected deleterious variant in either of the BRCA genes using variants identified with current and future BRCA mutation assays (eg, gene sequencing and large rearrangement analysis). Anti-cancer treatments include chemotherapy and targeted agents.
    End point type
    Secondary
    End point timeframe
    Anti-cancer treatments initiated post discontinuation of study treatment and investigator’s opinion of response and date of progression recorded, assessed from date of first patient randomised to data cut off: 16Apr2021 (approx. 6 years 2 months)
    End point values
    		 Olaparib 300mg BID Single Agent Chemotherapy
    Number of subjects analysed
    170
    84
    Units: Count of Participants
    138
    66
    Statistical analysis title
    		 TFST in BRCA, stratified log rank test
    Comparison groups
    Olaparib 300mg BID v Single Agent Chemotherapy
    Number of subjects included in analysis
    254
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.001 [14]
    Method
    		 Logrank
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.46
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.33
         upper limit
    		 0.66
    Notes
    [14] - Model included factors for number of prior chemotherapy regimens received for ovarian cancer (2 or 3 prior lines vs 4 or more lines) and time to disease progression after the end of last platinum based chemotherapy (6-12 months vs > 12 months).

    Secondary: Number of Participants who Received Second Subsequent Chemotherapy or Died in BRCA Gene Population

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    End point title
    		 Number of Participants who Received Second Subsequent Chemotherapy or Died in BRCA Gene Population
    End point description
    BRCA gene population includes participants identified as having a deleterious or suspected deleterious variant in either of the BRCA genes using variants identified with current and future BRCA mutation assays (eg, gene sequencing and large rearrangement analysis). Anti-cancer treatments include chemotherapy and targeted agents.
    End point type
    Secondary
    End point timeframe
    Anti-cancer treatments initiated post discontinuation of study treatment and investigator’s opinion of response and date of progression recorded, assessed from date of first patient randomised to data cut off: 16Apr2021 (approx. 6 years 2 months)
    End point values
    		 Olaparib 300mg BID Single Agent Chemotherapy
    Number of subjects analysed
    170
    84
    Units: Count of Participants
    127
    56
    Statistical analysis title
    		 TSST, stratified log rank test
    Comparison groups
    Single Agent Chemotherapy v Olaparib 300mg BID
    Number of subjects included in analysis
    254
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.055 [15]
    Method
    		 Logrank
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.72
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.51
         upper limit
    		 1.01
    Notes
    [15] - Model included factors for number of prior chemotherapy regimens received for ovarian cancer (2 or 3 prior lines vs 4 or more lines) and time to disease progression after the end of last platinum based chemotherapy (6-12 months vs > 12 months).

    Secondary: Geometric Mean Plasma Concentration of Olaparib

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    End point title
    		 Geometric Mean Plasma Concentration of Olaparib [16]
    End point description
    Summary of plasma concentrations (ug/mL) of olaparib
    End point type
    Secondary
    End point timeframe
    Day 1, 1 hour post-dose and Day 29 pre-dose. DCO: 10Oct2018
    Notes
    [16] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Endpoint only applies to experimental arm
    End point values
    		 Olaparib 300mg BID
    Number of subjects analysed
    66
    Units: μg/mL
    geometric mean (geometric coefficient of variation)
        Day 1, 1 hour post-dose
    4.76 ( 112.93 )
        Day 29, pre-dose
    1.78 ( 100.54 )
    No statistical analyses for this end point

    Secondary: Number of Participants Who Experience at Least One Adverse Event (AE)

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    End point title
    		 Number of Participants Who Experience at Least One Adverse Event (AE)
    End point description
    An AE is the development of an undesirable medical condition or the deterioration of a pre-existing medical condition following or during exposure to a pharmaceutical product, whether or not considered causally related to the product.
    End point type
    Secondary
    End point timeframe
    Safety Follow-up 30 days after last dose of IP, assessed from the date of first patient randomised to data cut off: 16Apr2021 (approx. 6 years 2 months)
    End point values
    		 Olaparib 300mg BID Single Agent Chemotherapy
    Number of subjects analysed
    178
    76
    Units: Count of Participants
    175
    73
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    From first dose of study drug until 30 days following date of last dose
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    24.0
    Reporting groups
    Reporting group title
    Olaparib 300mg BID
    Reporting group description
    		 Participants received olaparib twice daily as a 300 mg tablet.

    Reporting group title
    Single Agent Chemotherapy
    Reporting group description
    		 Participants received physician’s choice of chemotherapy, out of weekly paclitaxel, topotecan, pegylated liposomal doxorubicin, or gemcitabine.

    Serious adverse events
    		 Olaparib 300mg BID Single Agent Chemotherapy
    Total subjects affected by serious adverse events
         subjects affected / exposed
    46 / 178 (25.84%)
    14 / 76 (18.42%)
         number of deaths (all causes)
    116
    46
         number of deaths resulting from adverse events
    6
    1
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Gastric cancer
         subjects affected / exposed
    1 / 178 (0.56%)
    0 / 76 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Acute myeloid leukaemia
         subjects affected / exposed
    1 / 178 (0.56%)
    0 / 76 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Breast cancer
         subjects affected / exposed
    2 / 178 (1.12%)
    0 / 76 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lung neoplasm malignant
         subjects affected / exposed
    1 / 178 (0.56%)
    0 / 76 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Myelodysplastic syndrome
         subjects affected / exposed
    2 / 178 (1.12%)
    0 / 76 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Myeloid leukaemia
         subjects affected / exposed
    1 / 178 (0.56%)
    0 / 76 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Vascular disorders
    Deep vein thrombosis
         subjects affected / exposed
    3 / 178 (1.69%)
    0 / 76 (0.00%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Embolism
         subjects affected / exposed
    1 / 178 (0.56%)
    0 / 76 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Asthenia
         subjects affected / exposed
    2 / 178 (1.12%)
    1 / 76 (1.32%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Chest pain
         subjects affected / exposed
    1 / 178 (0.56%)
    0 / 76 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Malaise
         subjects affected / exposed
    0 / 178 (0.00%)
    1 / 76 (1.32%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Oedema peripheral
         subjects affected / exposed
    0 / 178 (0.00%)
    1 / 76 (1.32%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pyrexia
         subjects affected / exposed
    2 / 178 (1.12%)
    2 / 76 (2.63%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Immune system disorders
    Anaphylactic reaction
         subjects affected / exposed
    1 / 178 (0.56%)
    0 / 76 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Pleural effusion
         subjects affected / exposed
    3 / 178 (1.69%)
    2 / 76 (2.63%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pulmonary embolism
         subjects affected / exposed
    2 / 178 (1.12%)
    0 / 76 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Investigations
    Blood creatinine increased
         subjects affected / exposed
    1 / 178 (0.56%)
    0 / 76 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Radius fracture
         subjects affected / exposed
    1 / 178 (0.56%)
    1 / 76 (1.32%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Spinal compression fracture
         subjects affected / exposed
    1 / 178 (0.56%)
    0 / 76 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac disorders
    Cardiopulmonary failure
         subjects affected / exposed
    1 / 178 (0.56%)
    0 / 76 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Nervous system disorders
    Ischaemic stroke
         subjects affected / exposed
    1 / 178 (0.56%)
    0 / 76 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Syncope
         subjects affected / exposed
    2 / 178 (1.12%)
    0 / 76 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Subarachnoid haemorrhage
         subjects affected / exposed
    1 / 178 (0.56%)
    0 / 76 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    6 / 178 (3.37%)
    0 / 76 (0.00%)
         occurrences causally related to treatment / all
    0 / 7
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pancytopenia
         subjects affected / exposed
    2 / 178 (1.12%)
    0 / 76 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ear and labyrinth disorders
    Vertigo
         subjects affected / exposed
    1 / 178 (0.56%)
    0 / 76 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Tinnitus
         subjects affected / exposed
    1 / 178 (0.56%)
    0 / 76 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Abdominal pain upper
         subjects affected / exposed
    0 / 178 (0.00%)
    1 / 76 (1.32%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Mesenteric vein thrombosis
         subjects affected / exposed
    0 / 178 (0.00%)
    1 / 76 (1.32%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Intestinal obstruction
         subjects affected / exposed
    2 / 178 (1.12%)
    1 / 76 (1.32%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ileus
         subjects affected / exposed
    2 / 178 (1.12%)
    0 / 76 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Anal inflammation
         subjects affected / exposed
    0 / 178 (0.00%)
    1 / 76 (1.32%)
         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 / 178 (0.56%)
    0 / 76 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ascites
         subjects affected / exposed
    1 / 178 (0.56%)
    0 / 76 (0.00%)
         occurrences causally related to treatment / all
    0 / 5
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nausea
         subjects affected / exposed
    2 / 178 (1.12%)
    2 / 76 (2.63%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Oesophagitis
         subjects affected / exposed
    1 / 178 (0.56%)
    0 / 76 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Small intestinal obstruction
         subjects affected / exposed
    2 / 178 (1.12%)
    0 / 76 (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
    3 / 178 (1.69%)
    3 / 76 (3.95%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatobiliary disorders
    Cholecystitis
         subjects affected / exposed
    1 / 178 (0.56%)
    0 / 76 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal and urinary disorders
    Renal failure
         subjects affected / exposed
    1 / 178 (0.56%)
    0 / 76 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Diabetic nephropathy
         subjects affected / exposed
    1 / 178 (0.56%)
    0 / 76 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Urinary tract obstruction
         subjects affected / exposed
    1 / 178 (0.56%)
    0 / 76 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Periarthritis
         subjects affected / exposed
    1 / 178 (0.56%)
    0 / 76 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Rotator cuff syndrome
         subjects affected / exposed
    1 / 178 (0.56%)
    0 / 76 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pain in extremity
         subjects affected / exposed
    0 / 178 (0.00%)
    1 / 76 (1.32%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cervical spinal stenosis
         subjects affected / exposed
    1 / 178 (0.56%)
    0 / 76 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infections and infestations
    Corneal abscess
         subjects affected / exposed
    1 / 178 (0.56%)
    0 / 76 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastroenteritis
         subjects affected / exposed
    2 / 178 (1.12%)
    0 / 76 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Sepsis
         subjects affected / exposed
    2 / 178 (1.12%)
    0 / 76 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Device related infection
         subjects affected / exposed
    0 / 178 (0.00%)
    1 / 76 (1.32%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Herpes zoster
         subjects affected / exposed
    1 / 178 (0.56%)
    0 / 76 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonia
         subjects affected / exposed
    2 / 178 (1.12%)
    1 / 76 (1.32%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pyelonephritis
         subjects affected / exposed
    1 / 178 (0.56%)
    0 / 76 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Urinary tract infection
         subjects affected / exposed
    2 / 178 (1.12%)
    0 / 76 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Electrolyte imbalance
         subjects affected / exposed
    1 / 178 (0.56%)
    0 / 76 (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: 0%
    Non-serious adverse events
    		 Olaparib 300mg BID Single Agent Chemotherapy
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    175 / 178 (98.31%)
    73 / 76 (96.05%)
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Tumour pain
         subjects affected / exposed
    1 / 178 (0.56%)
    0 / 76 (0.00%)
         occurrences all number
    1
    0
    Vascular disorders
    Flushing
         subjects affected / exposed
    3 / 178 (1.69%)
    2 / 76 (2.63%)
         occurrences all number
    3
    3
    Embolism
         subjects affected / exposed
    2 / 178 (1.12%)
    0 / 76 (0.00%)
         occurrences all number
    2
    0
    Deep vein thrombosis
         subjects affected / exposed
    2 / 178 (1.12%)
    1 / 76 (1.32%)
         occurrences all number
    2
    1
    Hot flush
         subjects affected / exposed
    4 / 178 (2.25%)
    1 / 76 (1.32%)
         occurrences all number
    4
    1
    Hyperaemia
         subjects affected / exposed
    1 / 178 (0.56%)
    0 / 76 (0.00%)
         occurrences all number
    1
    0
    Hypertension
         subjects affected / exposed
    5 / 178 (2.81%)
    3 / 76 (3.95%)
         occurrences all number
    5
    3
    Hypotension
         subjects affected / exposed
    1 / 178 (0.56%)
    0 / 76 (0.00%)
         occurrences all number
    1
    0
    Jugular vein thrombosis
         subjects affected / exposed
    0 / 178 (0.00%)
    1 / 76 (1.32%)
         occurrences all number
    0
    1
    Lymphoedema
         subjects affected / exposed
    2 / 178 (1.12%)
    1 / 76 (1.32%)
         occurrences all number
    2
    1
    Peripheral venous disease
         subjects affected / exposed
    1 / 178 (0.56%)
    0 / 76 (0.00%)
         occurrences all number
    1
    0
    Phlebitis
         subjects affected / exposed
    0 / 178 (0.00%)
    1 / 76 (1.32%)
         occurrences all number
    0
    1
    Thrombophlebitis superficial
         subjects affected / exposed
    2 / 178 (1.12%)
    0 / 76 (0.00%)
         occurrences all number
    2
    0
    Venous thrombosis
         subjects affected / exposed
    1 / 178 (0.56%)
    0 / 76 (0.00%)
         occurrences all number
    1
    0
    Thrombosis
         subjects affected / exposed
    0 / 178 (0.00%)
    1 / 76 (1.32%)
         occurrences all number
    0
    1
    General disorders and administration site conditions
    Asthenia
         subjects affected / exposed
    35 / 178 (19.66%)
    12 / 76 (15.79%)
         occurrences all number
    52
    16
    Fatigue
         subjects affected / exposed
    66 / 178 (37.08%)
    20 / 76 (26.32%)
         occurrences all number
    91
    26
    Influenza like illness
         subjects affected / exposed
    7 / 178 (3.93%)
    4 / 76 (5.26%)
         occurrences all number
    8
    5
    Mucosal inflammation
         subjects affected / exposed
    5 / 178 (2.81%)
    10 / 76 (13.16%)
         occurrences all number
    5
    11
    Oedema peripheral
         subjects affected / exposed
    16 / 178 (8.99%)
    10 / 76 (13.16%)
         occurrences all number
    24
    16
    Pyrexia
         subjects affected / exposed
    21 / 178 (11.80%)
    8 / 76 (10.53%)
         occurrences all number
    28
    10
    Application site pain
         subjects affected / exposed
    0 / 178 (0.00%)
    1 / 76 (1.32%)
         occurrences all number
    0
    1
    Catheter site erythema
         subjects affected / exposed
    1 / 178 (0.56%)
    0 / 76 (0.00%)
         occurrences all number
    1
    0
    Catheter site pain
         subjects affected / exposed
    0 / 178 (0.00%)
    2 / 76 (2.63%)
         occurrences all number
    0
    2
    Catheter site rash
         subjects affected / exposed
    0 / 178 (0.00%)
    1 / 76 (1.32%)
         occurrences all number
    0
    1
    Chest discomfort
         subjects affected / exposed
    0 / 178 (0.00%)
    2 / 76 (2.63%)
         occurrences all number
    0
    3
    Chest pain
         subjects affected / exposed
    2 / 178 (1.12%)
    2 / 76 (2.63%)
         occurrences all number
    3
    3
    Chills
         subjects affected / exposed
    7 / 178 (3.93%)
    1 / 76 (1.32%)
         occurrences all number
    9
    1
    Face oedema
         subjects affected / exposed
    0 / 178 (0.00%)
    2 / 76 (2.63%)
         occurrences all number
    0
    2
    Illness
         subjects affected / exposed
    1 / 178 (0.56%)
    0 / 76 (0.00%)
         occurrences all number
    7
    0
    General physical health deterioration
         subjects affected / exposed
    1 / 178 (0.56%)
    0 / 76 (0.00%)
         occurrences all number
    1
    0
    Feeling hot
         subjects affected / exposed
    1 / 178 (0.56%)
    0 / 76 (0.00%)
         occurrences all number
    1
    0
    Infusion site extravasation
         subjects affected / exposed
    0 / 178 (0.00%)
    1 / 76 (1.32%)
         occurrences all number
    0
    1
    Injection site bruising
         subjects affected / exposed
    1 / 178 (0.56%)
    0 / 76 (0.00%)
         occurrences all number
    1
    0
    Injection site reaction
         subjects affected / exposed
    1 / 178 (0.56%)
    0 / 76 (0.00%)
         occurrences all number
    1
    0
    Malaise
         subjects affected / exposed
    5 / 178 (2.81%)
    0 / 76 (0.00%)
         occurrences all number
    14
    0
    Localised oedema
         subjects affected / exposed
    1 / 178 (0.56%)
    0 / 76 (0.00%)
         occurrences all number
    1
    0
    Non-cardiac chest pain
         subjects affected / exposed
    1 / 178 (0.56%)
    1 / 76 (1.32%)
         occurrences all number
    1
    1
    Oedema
         subjects affected / exposed
    1 / 178 (0.56%)
    2 / 76 (2.63%)
         occurrences all number
    2
    2
    Medical device pain
         subjects affected / exposed
    1 / 178 (0.56%)
    0 / 76 (0.00%)
         occurrences all number
    1
    0
    Peripheral swelling
         subjects affected / exposed
    3 / 178 (1.69%)
    0 / 76 (0.00%)
         occurrences all number
    3
    0
    Pain
         subjects affected / exposed
    5 / 178 (2.81%)
    2 / 76 (2.63%)
         occurrences all number
    5
    2
    Swelling face
         subjects affected / exposed
    1 / 178 (0.56%)
    0 / 76 (0.00%)
         occurrences all number
    1
    0
    Immune system disorders
    Contrast media allergy
         subjects affected / exposed
    1 / 178 (0.56%)
    0 / 76 (0.00%)
         occurrences all number
    1
    0
    Drug hypersensitivity
         subjects affected / exposed
    0 / 178 (0.00%)
    2 / 76 (2.63%)
         occurrences all number
    0
    2
    Hypersensitivity
         subjects affected / exposed
    3 / 178 (1.69%)
    1 / 76 (1.32%)
         occurrences all number
    3
    1
    Seasonal allergy
         subjects affected / exposed
    4 / 178 (2.25%)
    3 / 76 (3.95%)
         occurrences all number
    4
    3
    Reproductive system and breast disorders
    Atrophic vulvovaginitis
         subjects affected / exposed
    1 / 178 (0.56%)
    0 / 76 (0.00%)
         occurrences all number
    1
    0
    Breast pain
         subjects affected / exposed
    1 / 178 (0.56%)
    0 / 76 (0.00%)
         occurrences all number
    1
    0
    Pelvic pain
         subjects affected / exposed
    2 / 178 (1.12%)
    0 / 76 (0.00%)
         occurrences all number
    2
    0
    Intermenstrual bleeding
         subjects affected / exposed
    0 / 178 (0.00%)
    1 / 76 (1.32%)
         occurrences all number
    0
    1
    Dyspareunia
         subjects affected / exposed
    0 / 178 (0.00%)
    1 / 76 (1.32%)
         occurrences all number
    0
    1
    Vulvovaginal burning sensation
         subjects affected / exposed
    0 / 178 (0.00%)
    1 / 76 (1.32%)
         occurrences all number
    0
    2
    Vaginal haemorrhage
         subjects affected / exposed
    1 / 178 (0.56%)
    1 / 76 (1.32%)
         occurrences all number
    1
    3
    Vaginal discharge
         subjects affected / exposed
    1 / 178 (0.56%)
    1 / 76 (1.32%)
         occurrences all number
    1
    1
    Vulvovaginal dryness
         subjects affected / exposed
    0 / 178 (0.00%)
    1 / 76 (1.32%)
         occurrences all number
    0
    1
    Vulvovaginal erythema
         subjects affected / exposed
    1 / 178 (0.56%)
    0 / 76 (0.00%)
         occurrences all number
    1
    0
    Vulvovaginal inflammation
         subjects affected / exposed
    1 / 178 (0.56%)
    0 / 76 (0.00%)
         occurrences all number
    1
    0
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    18 / 178 (10.11%)
    10 / 76 (13.16%)
         occurrences all number
    24
    10
    Dyspnoea
         subjects affected / exposed
    22 / 178 (12.36%)
    8 / 76 (10.53%)
         occurrences all number
    26
    8
    Epistaxis
         subjects affected / exposed
    0 / 178 (0.00%)
    5 / 76 (6.58%)
         occurrences all number
    0
    6
    Chronic obstructive pulmonary disease
         subjects affected / exposed
    1 / 178 (0.56%)
    0 / 76 (0.00%)
         occurrences all number
    1
    0
    Dysphonia
         subjects affected / exposed
    2 / 178 (1.12%)
    0 / 76 (0.00%)
         occurrences all number
    2
    0
    Dyspnoea exertional
         subjects affected / exposed
    2 / 178 (1.12%)
    2 / 76 (2.63%)
         occurrences all number
    3
    2
    Hiccups
         subjects affected / exposed
    3 / 178 (1.69%)
    0 / 76 (0.00%)
         occurrences all number
    4
    0
    Hypoxia
         subjects affected / exposed
    1 / 178 (0.56%)
    0 / 76 (0.00%)
         occurrences all number
    1
    0
    Nasal dryness
         subjects affected / exposed
    0 / 178 (0.00%)
    1 / 76 (1.32%)
         occurrences all number
    0
    1
    Nasal congestion
         subjects affected / exposed
    3 / 178 (1.69%)
    1 / 76 (1.32%)
         occurrences all number
    3
    1
    Laryngeal inflammation
         subjects affected / exposed
    4 / 178 (2.25%)
    0 / 76 (0.00%)
         occurrences all number
    4
    0
    Obstructive airways disorder
         subjects affected / exposed
    1 / 178 (0.56%)
    0 / 76 (0.00%)
         occurrences all number
    1
    0
    Pneumonitis
         subjects affected / exposed
    1 / 178 (0.56%)
    0 / 76 (0.00%)
         occurrences all number
    1
    0
    Oropharyngeal pain
         subjects affected / exposed
    5 / 178 (2.81%)
    1 / 76 (1.32%)
         occurrences all number
    5
    1
    Productive cough
         subjects affected / exposed
    1 / 178 (0.56%)
    1 / 76 (1.32%)
         occurrences all number
    1
    1
    Pulmonary embolism
         subjects affected / exposed
    2 / 178 (1.12%)
    1 / 76 (1.32%)
         occurrences all number
    2
    1
    Respiratory fatigue
         subjects affected / exposed
    0 / 178 (0.00%)
    1 / 76 (1.32%)
         occurrences all number
    0
    1
    Pulmonary mass
         subjects affected / exposed
    1 / 178 (0.56%)
    0 / 76 (0.00%)
         occurrences all number
    1
    0
    Rhinitis allergic
         subjects affected / exposed
    3 / 178 (1.69%)
    0 / 76 (0.00%)
         occurrences all number
    3
    0
    Rhinorrhoea
         subjects affected / exposed
    1 / 178 (0.56%)
    0 / 76 (0.00%)
         occurrences all number
    1
    0
    Sinus congestion
         subjects affected / exposed
    2 / 178 (1.12%)
    0 / 76 (0.00%)
         occurrences all number
    2
    0
    Throat irritation
         subjects affected / exposed
    0 / 178 (0.00%)
    1 / 76 (1.32%)
         occurrences all number
    0
    3
    Upper-airway cough syndrome
         subjects affected / exposed
    1 / 178 (0.56%)
    1 / 76 (1.32%)
         occurrences all number
    1
    1
    Psychiatric disorders
    Depression
         subjects affected / exposed
    9 / 178 (5.06%)
    2 / 76 (2.63%)
         occurrences all number
    9
    2
    Insomnia
         subjects affected / exposed
    17 / 178 (9.55%)
    5 / 76 (6.58%)
         occurrences all number
    18
    5
    Anxiety
         subjects affected / exposed
    4 / 178 (2.25%)
    6 / 76 (7.89%)
         occurrences all number
    6
    6
    Confusional state
         subjects affected / exposed
    1 / 178 (0.56%)
    1 / 76 (1.32%)
         occurrences all number
    1
    1
    Delusion
         subjects affected / exposed
    1 / 178 (0.56%)
    0 / 76 (0.00%)
         occurrences all number
    1
    0
    Irritability
         subjects affected / exposed
    1 / 178 (0.56%)
    0 / 76 (0.00%)
         occurrences all number
    1
    0
    Depressed mood
         subjects affected / exposed
    1 / 178 (0.56%)
    1 / 76 (1.32%)
         occurrences all number
    1
    1
    Nervousness
         subjects affected / exposed
    0 / 178 (0.00%)
    1 / 76 (1.32%)
         occurrences all number
    0
    1
    Restlessness
         subjects affected / exposed
    0 / 178 (0.00%)
    1 / 76 (1.32%)
         occurrences all number
    0
    1
    Sleep disorder
         subjects affected / exposed
    2 / 178 (1.12%)
    0 / 76 (0.00%)
         occurrences all number
    3
    0
    Product issues
    Thrombosis in device
         subjects affected / exposed
    1 / 178 (0.56%)
    0 / 76 (0.00%)
         occurrences all number
    1
    0
    Investigations
    Alanine aminotransferase increased
         subjects affected / exposed
    5 / 178 (2.81%)
    4 / 76 (5.26%)
         occurrences all number
    7
    4
    Neutrophil count decreased
         subjects affected / exposed
    16 / 178 (8.99%)
    10 / 76 (13.16%)
         occurrences all number
    34
    36
    Blood creatinine increased
         subjects affected / exposed
    14 / 178 (7.87%)
    1 / 76 (1.32%)
         occurrences all number
    25
    1
    Gamma-glutamyltransferase increased
         subjects affected / exposed
    6 / 178 (3.37%)
    4 / 76 (5.26%)
         occurrences all number
    8
    4
    White blood cell count decreased
         subjects affected / exposed
    18 / 178 (10.11%)
    9 / 76 (11.84%)
         occurrences all number
    34
    22
    Activated partial thromboplastin time prolonged
         subjects affected / exposed
    1 / 178 (0.56%)
    0 / 76 (0.00%)
         occurrences all number
    1
    0
    Amylase increased
         subjects affected / exposed
    1 / 178 (0.56%)
    0 / 76 (0.00%)
         occurrences all number
    1
    0
    Aspartate aminotransferase increased
         subjects affected / exposed
    3 / 178 (1.69%)
    3 / 76 (3.95%)
         occurrences all number
    5
    3
    Blood alkaline phosphatase increased
         subjects affected / exposed
    3 / 178 (1.69%)
    1 / 76 (1.32%)
         occurrences all number
    3
    1
    Blood bilirubin increased
         subjects affected / exposed
    4 / 178 (2.25%)
    0 / 76 (0.00%)
         occurrences all number
    7
    0
    Blood calcium decreased
         subjects affected / exposed
    1 / 178 (0.56%)
    0 / 76 (0.00%)
         occurrences all number
    1
    0
    Blood creatine increased
         subjects affected / exposed
    1 / 178 (0.56%)
    0 / 76 (0.00%)
         occurrences all number
    1
    0
    Blood culture positive
         subjects affected / exposed
    1 / 178 (0.56%)
    0 / 76 (0.00%)
         occurrences all number
    1
    0
    Blood lactate dehydrogenase increased
         subjects affected / exposed
    1 / 178 (0.56%)
    0 / 76 (0.00%)
         occurrences all number
    1
    0
    Blood potassium increased
         subjects affected / exposed
    1 / 178 (0.56%)
    0 / 76 (0.00%)
         occurrences all number
    1
    0
    Blood pressure increased
         subjects affected / exposed
    1 / 178 (0.56%)
    1 / 76 (1.32%)
         occurrences all number
    1
    1
    Blood urine present
         subjects affected / exposed
    1 / 178 (0.56%)
    0 / 76 (0.00%)
         occurrences all number
    1
    0
    Blood triglycerides increased
         subjects affected / exposed
    1 / 178 (0.56%)
    0 / 76 (0.00%)
         occurrences all number
    1
    0
    Haematocrit decreased
         subjects affected / exposed
    2 / 178 (1.12%)
    0 / 76 (0.00%)
         occurrences all number
    2
    0
    Glomerular filtration rate decreased
         subjects affected / exposed
    1 / 178 (0.56%)
    0 / 76 (0.00%)
         occurrences all number
    1
    0
    Body temperature increased
         subjects affected / exposed
    1 / 178 (0.56%)
    0 / 76 (0.00%)
         occurrences all number
    1
    0
    Haemoglobin decreased
         subjects affected / exposed
    3 / 178 (1.69%)
    0 / 76 (0.00%)
         occurrences all number
    3
    0
    International normalised ratio increased
         subjects affected / exposed
    1 / 178 (0.56%)
    0 / 76 (0.00%)
         occurrences all number
    1
    0
    Lipase increased
         subjects affected / exposed
    1 / 178 (0.56%)
    0 / 76 (0.00%)
         occurrences all number
    1
    0
    Lymphocyte count decreased
         subjects affected / exposed
    6 / 178 (3.37%)
    1 / 76 (1.32%)
         occurrences all number
    10
    4
    Mean cell haemoglobin increased
         subjects affected / exposed
    1 / 178 (0.56%)
    0 / 76 (0.00%)
         occurrences all number
    1
    0
    Mean cell volume abnormal
         subjects affected / exposed
    1 / 178 (0.56%)
    0 / 76 (0.00%)
         occurrences all number
    1
    0
    Mean cell volume increased
         subjects affected / exposed
    1 / 178 (0.56%)
    0 / 76 (0.00%)
         occurrences all number
    1
    0
    Platelet count decreased
         subjects affected / exposed
    8 / 178 (4.49%)
    3 / 76 (3.95%)
         occurrences all number
    26
    6
    Weight decreased
         subjects affected / exposed
    5 / 178 (2.81%)
    2 / 76 (2.63%)
         occurrences all number
    7
    3
    Transaminases increased
         subjects affected / exposed
    0 / 178 (0.00%)
    2 / 76 (2.63%)
         occurrences all number
    0
    2
    Red blood cell count decreased
         subjects affected / exposed
    1 / 178 (0.56%)
    0 / 76 (0.00%)
         occurrences all number
    1
    0
    Weight increased
         subjects affected / exposed
    1 / 178 (0.56%)
    0 / 76 (0.00%)
         occurrences all number
    2
    0
    Injury, poisoning and procedural complications
    Ankle fracture
         subjects affected / exposed
    0 / 178 (0.00%)
    1 / 76 (1.32%)
         occurrences all number
    0
    1
    Animal bite
         subjects affected / exposed
    1 / 178 (0.56%)
    0 / 76 (0.00%)
         occurrences all number
    1
    0
    Concussion
         subjects affected / exposed
    1 / 178 (0.56%)
    0 / 76 (0.00%)
         occurrences all number
    1
    0
    Head injury
         subjects affected / exposed
    1 / 178 (0.56%)
    0 / 76 (0.00%)
         occurrences all number
    1
    0
    Fall
         subjects affected / exposed
    5 / 178 (2.81%)
    2 / 76 (2.63%)
         occurrences all number
    7
    2
    Contusion
         subjects affected / exposed
    1 / 178 (0.56%)
    1 / 76 (1.32%)
         occurrences all number
    1
    1
    Humerus fracture
         subjects affected / exposed
    1 / 178 (0.56%)
    0 / 76 (0.00%)
         occurrences all number
    1
    0
    Injury
         subjects affected / exposed
    1 / 178 (0.56%)
    0 / 76 (0.00%)
         occurrences all number
    1
    0
    Joint injury
         subjects affected / exposed
    0 / 178 (0.00%)
    1 / 76 (1.32%)
         occurrences all number
    0
    1
    Meniscus injury
         subjects affected / exposed
    1 / 178 (0.56%)
    0 / 76 (0.00%)
         occurrences all number
    1
    0
    Procedural pain
         subjects affected / exposed
    2 / 178 (1.12%)
    0 / 76 (0.00%)
         occurrences all number
    2
    0
    Radius fracture
         subjects affected / exposed
    1 / 178 (0.56%)
    0 / 76 (0.00%)
         occurrences all number
    1
    0
    Skin abrasion
         subjects affected / exposed
    1 / 178 (0.56%)
    1 / 76 (1.32%)
         occurrences all number
    1
    1
    Spinal compression fracture
         subjects affected / exposed
    1 / 178 (0.56%)
    0 / 76 (0.00%)
         occurrences all number
    1
    0
    Urostomy complication
         subjects affected / exposed
    0 / 178 (0.00%)
    1 / 76 (1.32%)
         occurrences all number
    0
    1
    Spinal fracture
         subjects affected / exposed
    1 / 178 (0.56%)
    0 / 76 (0.00%)
         occurrences all number
    1
    0
    Cardiac disorders
    Sinus bradycardia
         subjects affected / exposed
    0 / 178 (0.00%)
    1 / 76 (1.32%)
         occurrences all number
    0
    1
    Palpitations
         subjects affected / exposed
    5 / 178 (2.81%)
    0 / 76 (0.00%)
         occurrences all number
    6
    0
    Arrhythmia
         subjects affected / exposed
    0 / 178 (0.00%)
    1 / 76 (1.32%)
         occurrences all number
    0
    1
    Tachycardia
         subjects affected / exposed
    2 / 178 (1.12%)
    1 / 76 (1.32%)
         occurrences all number
    2
    1
    Sinus tachycardia
         subjects affected / exposed
    1 / 178 (0.56%)
    0 / 76 (0.00%)
         occurrences all number
    1
    0
    Nervous system disorders
    Neuropathy peripheral
         subjects affected / exposed
    5 / 178 (2.81%)
    8 / 76 (10.53%)
         occurrences all number
    6
    8
    Dizziness
         subjects affected / exposed
    25 / 178 (14.04%)
    6 / 76 (7.89%)
         occurrences all number
    65
    6
    Headache
         subjects affected / exposed
    29 / 178 (16.29%)
    9 / 76 (11.84%)
         occurrences all number
    79
    11
    Dysgeusia
         subjects affected / exposed
    13 / 178 (7.30%)
    6 / 76 (7.89%)
         occurrences all number
    16
    6
    Paraesthesia
         subjects affected / exposed
    7 / 178 (3.93%)
    5 / 76 (6.58%)
         occurrences all number
    8
    6
    Ageusia
         subjects affected / exposed
    0 / 178 (0.00%)
    1 / 76 (1.32%)
         occurrences all number
    0
    1
    Balance disorder
         subjects affected / exposed
    1 / 178 (0.56%)
    0 / 76 (0.00%)
         occurrences all number
    1
    0
    Burning sensation
         subjects affected / exposed
    0 / 178 (0.00%)
    1 / 76 (1.32%)
         occurrences all number
    0
    1
    Head titubation
         subjects affected / exposed
    1 / 178 (0.56%)
    0 / 76 (0.00%)
         occurrences all number
    3
    0
    Epilepsy
         subjects affected / exposed
    0 / 178 (0.00%)
    1 / 76 (1.32%)
         occurrences all number
    0
    1
    Hypoaesthesia
         subjects affected / exposed
    4 / 178 (2.25%)
    0 / 76 (0.00%)
         occurrences all number
    4
    0
    Neuralgia
         subjects affected / exposed
    0 / 178 (0.00%)
    1 / 76 (1.32%)
         occurrences all number
    0
    1
    Memory impairment
         subjects affected / exposed
    1 / 178 (0.56%)
    1 / 76 (1.32%)
         occurrences all number
    1
    1
    Lethargy
         subjects affected / exposed
    0 / 178 (0.00%)
    1 / 76 (1.32%)
         occurrences all number
    0
    1
    Neurotoxicity
         subjects affected / exposed
    0 / 178 (0.00%)
    3 / 76 (3.95%)
         occurrences all number
    0
    6
    Parosmia
         subjects affected / exposed
    1 / 178 (0.56%)
    0 / 76 (0.00%)
         occurrences all number
    1
    0
    Peripheral sensory neuropathy
         subjects affected / exposed
    1 / 178 (0.56%)
    1 / 76 (1.32%)
         occurrences all number
    1
    1
    Presyncope
         subjects affected / exposed
    4 / 178 (2.25%)
    0 / 76 (0.00%)
         occurrences all number
    4
    0
    Polyneuropathy
         subjects affected / exposed
    0 / 178 (0.00%)
    1 / 76 (1.32%)
         occurrences all number
    0
    1
    Retinal migraine
         subjects affected / exposed
    0 / 178 (0.00%)
    1 / 76 (1.32%)
         occurrences all number
    0
    1
    Restless legs syndrome
         subjects affected / exposed
    1 / 178 (0.56%)
    0 / 76 (0.00%)
         occurrences all number
    1
    0
    Sciatica
         subjects affected / exposed
    2 / 178 (1.12%)
    0 / 76 (0.00%)
         occurrences all number
    2
    0
    Sinus headache
         subjects affected / exposed
    1 / 178 (0.56%)
    0 / 76 (0.00%)
         occurrences all number
    1
    0
    Sensory loss
         subjects affected / exposed
    1 / 178 (0.56%)
    0 / 76 (0.00%)
         occurrences all number
    1
    0
    Seizure
         subjects affected / exposed
    1 / 178 (0.56%)
    0 / 76 (0.00%)
         occurrences all number
    2
    0
    Somnolence
         subjects affected / exposed
    4 / 178 (2.25%)
    0 / 76 (0.00%)
         occurrences all number
    4
    0
    Transient ischaemic attack
         subjects affected / exposed
    1 / 178 (0.56%)
    0 / 76 (0.00%)
         occurrences all number
    1
    0
    Taste disorder
         subjects affected / exposed
    8 / 178 (4.49%)
    0 / 76 (0.00%)
         occurrences all number
    8
    0
    Syncope
         subjects affected / exposed
    3 / 178 (1.69%)
    1 / 76 (1.32%)
         occurrences all number
    3
    1
    Tremor
         subjects affected / exposed
    1 / 178 (0.56%)
    0 / 76 (0.00%)
         occurrences all number
    1
    0
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    87 / 178 (48.88%)
    19 / 76 (25.00%)
         occurrences all number
    163
    22
    Neutropenia
         subjects affected / exposed
    29 / 178 (16.29%)
    22 / 76 (28.95%)
         occurrences all number
    41
    37
    Leukopenia
         subjects affected / exposed
    13 / 178 (7.30%)
    6 / 76 (7.89%)
         occurrences all number
    24
    6
    Thrombocytopenia
         subjects affected / exposed
    16 / 178 (8.99%)
    6 / 76 (7.89%)
         occurrences all number
    20
    11
    Lymphopenia
         subjects affected / exposed
    4 / 178 (2.25%)
    1 / 76 (1.32%)
         occurrences all number
    7
    1
    Macrocytosis
         subjects affected / exposed
    1 / 178 (0.56%)
    0 / 76 (0.00%)
         occurrences all number
    1
    0
    Neutrophilia
         subjects affected / exposed
    1 / 178 (0.56%)
    0 / 76 (0.00%)
         occurrences all number
    1
    0
    Ear and labyrinth disorders
    Hyperacusis
         subjects affected / exposed
    1 / 178 (0.56%)
    0 / 76 (0.00%)
         occurrences all number
    1
    0
    Ear congestion
         subjects affected / exposed
    0 / 178 (0.00%)
    1 / 76 (1.32%)
         occurrences all number
    0
    1
    Deafness
         subjects affected / exposed
    0 / 178 (0.00%)
    1 / 76 (1.32%)
         occurrences all number
    0
    1
    Ototoxicity
         subjects affected / exposed
    1 / 178 (0.56%)
    0 / 76 (0.00%)
         occurrences all number
    1
    0
    Tinnitus
         subjects affected / exposed
    2 / 178 (1.12%)
    1 / 76 (1.32%)
         occurrences all number
    3
    1
    Vertigo
         subjects affected / exposed
    6 / 178 (3.37%)
    1 / 76 (1.32%)
         occurrences all number
    17
    1
    Eye disorders
    Conjunctival discolouration
         subjects affected / exposed
    1 / 178 (0.56%)
    0 / 76 (0.00%)
         occurrences all number
    1
    0
    Cataract
         subjects affected / exposed
    1 / 178 (0.56%)
    0 / 76 (0.00%)
         occurrences all number
    1
    0
    Corneal disorder
         subjects affected / exposed
    1 / 178 (0.56%)
    0 / 76 (0.00%)
         occurrences all number
    1
    0
    Dry eye
         subjects affected / exposed
    1 / 178 (0.56%)
    1 / 76 (1.32%)
         occurrences all number
    1
    1
    Eye disorder
         subjects affected / exposed
    1 / 178 (0.56%)
    0 / 76 (0.00%)
         occurrences all number
    1
    0
    Eye pain
         subjects affected / exposed
    0 / 178 (0.00%)
    1 / 76 (1.32%)
         occurrences all number
    0
    1
    Lacrimation increased
         subjects affected / exposed
    2 / 178 (1.12%)
    0 / 76 (0.00%)
         occurrences all number
    2
    0
    Macular oedema
         subjects affected / exposed
    0 / 178 (0.00%)
    1 / 76 (1.32%)
         occurrences all number
    0
    1
    Periorbital oedema
         subjects affected / exposed
    1 / 178 (0.56%)
    0 / 76 (0.00%)
         occurrences all number
    1
    0
    Photophobia
         subjects affected / exposed
    1 / 178 (0.56%)
    0 / 76 (0.00%)
         occurrences all number
    1
    0
    Scleral disorder
         subjects affected / exposed
    1 / 178 (0.56%)
    0 / 76 (0.00%)
         occurrences all number
    1
    0
    Vision blurred
         subjects affected / exposed
    2 / 178 (1.12%)
    0 / 76 (0.00%)
         occurrences all number
    2
    0
    Vitreous haemorrhage
         subjects affected / exposed
    1 / 178 (0.56%)
    0 / 76 (0.00%)
         occurrences all number
    1
    0
    Visual impairment
         subjects affected / exposed
    2 / 178 (1.12%)
    1 / 76 (1.32%)
         occurrences all number
    2
    1
    Gastrointestinal disorders
    Abdominal distension
         subjects affected / exposed
    11 / 178 (6.18%)
    1 / 76 (1.32%)
         occurrences all number
    12
    1
    Abdominal pain
         subjects affected / exposed
    41 / 178 (23.03%)
    11 / 76 (14.47%)
         occurrences all number
    80
    15
    Abdominal pain upper
         subjects affected / exposed
    21 / 178 (11.80%)
    4 / 76 (5.26%)
         occurrences all number
    36
    4
    Diarrhoea
         subjects affected / exposed
    52 / 178 (29.21%)
    13 / 76 (17.11%)
         occurrences all number
    149
    16
    Constipation
         subjects affected / exposed
    24 / 178 (13.48%)
    17 / 76 (22.37%)
         occurrences all number
    28
    23
    Dyspepsia
         subjects affected / exposed
    19 / 178 (10.67%)
    7 / 76 (9.21%)
         occurrences all number
    26
    8
    Flatulence
         subjects affected / exposed
    1 / 178 (0.56%)
    4 / 76 (5.26%)
         occurrences all number
    1
    5
    Nausea
         subjects affected / exposed
    115 / 178 (64.61%)
    24 / 76 (31.58%)
         occurrences all number
    240
    47
    Gastrooesophageal reflux disease
         subjects affected / exposed
    10 / 178 (5.62%)
    2 / 76 (2.63%)
         occurrences all number
    10
    2
    Stomatitis
         subjects affected / exposed
    8 / 178 (4.49%)
    14 / 76 (18.42%)
         occurrences all number
    11
    28
    Vomiting
         subjects affected / exposed
    66 / 178 (37.08%)
    14 / 76 (18.42%)
         occurrences all number
    165
    20
    Abdominal pain lower
         subjects affected / exposed
    2 / 178 (1.12%)
    0 / 76 (0.00%)
         occurrences all number
    2
    0
    Abdominal discomfort
         subjects affected / exposed
    3 / 178 (1.69%)
    1 / 76 (1.32%)
         occurrences all number
    5
    1
    Anal incontinence
         subjects affected / exposed
    1 / 178 (0.56%)
    0 / 76 (0.00%)
         occurrences all number
    1
    0
    Anorectal discomfort
         subjects affected / exposed
    1 / 178 (0.56%)
    0 / 76 (0.00%)
         occurrences all number
    2
    0
    Aphthous ulcer
         subjects affected / exposed
    4 / 178 (2.25%)
    0 / 76 (0.00%)
         occurrences all number
    5
    0
    Aptyalism
         subjects affected / exposed
    1 / 178 (0.56%)
    0 / 76 (0.00%)
         occurrences all number
    1
    0
    Ascites
         subjects affected / exposed
    2 / 178 (1.12%)
    2 / 76 (2.63%)
         occurrences all number
    4
    3
    Colitis
         subjects affected / exposed
    1 / 178 (0.56%)
    0 / 76 (0.00%)
         occurrences all number
    2
    0
    Dental caries
         subjects affected / exposed
    2 / 178 (1.12%)
    0 / 76 (0.00%)
         occurrences all number
    2
    0
    Dry mouth
         subjects affected / exposed
    4 / 178 (2.25%)
    1 / 76 (1.32%)
         occurrences all number
    8
    1
    Dysphagia
         subjects affected / exposed
    1 / 178 (0.56%)
    0 / 76 (0.00%)
         occurrences all number
    1
    0
    Faeces soft
         subjects affected / exposed
    1 / 178 (0.56%)
    0 / 76 (0.00%)
         occurrences all number
    1
    0
    Gastric mucosal hypertrophy
         subjects affected / exposed
    0 / 178 (0.00%)
    1 / 76 (1.32%)
         occurrences all number
    0
    1
    Food poisoning
         subjects affected / exposed
    0 / 178 (0.00%)
    1 / 76 (1.32%)
         occurrences all number
    0
    1
    Gastric ulcer
         subjects affected / exposed
    1 / 178 (0.56%)
    0 / 76 (0.00%)
         occurrences all number
    1
    0
    Gastritis
         subjects affected / exposed
    5 / 178 (2.81%)
    0 / 76 (0.00%)
         occurrences all number
    6
    0
    Gastrointestinal disorder
         subjects affected / exposed
    2 / 178 (1.12%)
    0 / 76 (0.00%)
         occurrences all number
    2
    0
    Gastrointestinal fistula
         subjects affected / exposed
    1 / 178 (0.56%)
    0 / 76 (0.00%)
         occurrences all number
    1
    0
    Gastrointestinal wall thickening
         subjects affected / exposed
    1 / 178 (0.56%)
    0 / 76 (0.00%)
         occurrences all number
    1
    0
    Gastrointestinal pain
         subjects affected / exposed
    1 / 178 (0.56%)
    0 / 76 (0.00%)
         occurrences all number
    1
    0
    Gingival pain
         subjects affected / exposed
    2 / 178 (1.12%)
    0 / 76 (0.00%)
         occurrences all number
    2
    0
    Haemorrhoids
         subjects affected / exposed
    4 / 178 (2.25%)
    0 / 76 (0.00%)
         occurrences all number
    5
    0
    Odynophagia
         subjects affected / exposed
    0 / 178 (0.00%)
    1 / 76 (1.32%)
         occurrences all number
    0
    2
    Irritable bowel syndrome
         subjects affected / exposed
    1 / 178 (0.56%)
    0 / 76 (0.00%)
         occurrences all number
    1
    0
    Hyperaesthesia teeth
         subjects affected / exposed
    1 / 178 (0.56%)
    0 / 76 (0.00%)
         occurrences all number
    1
    0
    Oesophageal pain
         subjects affected / exposed
    0 / 178 (0.00%)
    1 / 76 (1.32%)
         occurrences all number
    0
    1
    Oesophagitis
         subjects affected / exposed
    1 / 178 (0.56%)
    0 / 76 (0.00%)
         occurrences all number
    1
    0
    Oral pain
         subjects affected / exposed
    0 / 178 (0.00%)
    3 / 76 (3.95%)
         occurrences all number
    0
    3
    Pneumatosis intestinalis
         subjects affected / exposed
    1 / 178 (0.56%)
    0 / 76 (0.00%)
         occurrences all number
    1
    0
    Proctitis
         subjects affected / exposed
    1 / 178 (0.56%)
    0 / 76 (0.00%)
         occurrences all number
    1
    0
    Rectal haemorrhage
         subjects affected / exposed
    1 / 178 (0.56%)
    2 / 76 (2.63%)
         occurrences all number
    1
    2
    Tooth loss
         subjects affected / exposed
    1 / 178 (0.56%)
    0 / 76 (0.00%)
         occurrences all number
    1
    0
    Toothache
         subjects affected / exposed
    3 / 178 (1.69%)
    1 / 76 (1.32%)
         occurrences all number
    5
    1
    Hepatobiliary disorders
    Biliary colic
         subjects affected / exposed
    1 / 178 (0.56%)
    0 / 76 (0.00%)
         occurrences all number
    1
    0
    Hypertransaminasaemia
         subjects affected / exposed
    1 / 178 (0.56%)
    1 / 76 (1.32%)
         occurrences all number
    1
    1
    Hepatic pain
         subjects affected / exposed
    1 / 178 (0.56%)
    0 / 76 (0.00%)
         occurrences all number
    1
    0
    Skin and subcutaneous tissue disorders
    Dry skin
         subjects affected / exposed
    0 / 178 (0.00%)
    4 / 76 (5.26%)
         occurrences all number
    0
    4
    Palmar-plantar erythrodysaesthesia syndrome
         subjects affected / exposed
    1 / 178 (0.56%)
    27 / 76 (35.53%)
         occurrences all number
    1
    42
    Skin hyperpigmentation
         subjects affected / exposed
    1 / 178 (0.56%)
    4 / 76 (5.26%)
         occurrences all number
    1
    5
    Pruritus
         subjects affected / exposed
    5 / 178 (2.81%)
    5 / 76 (6.58%)
         occurrences all number
    8
    6
    Rash
         subjects affected / exposed
    13 / 178 (7.30%)
    9 / 76 (11.84%)
         occurrences all number
    17
    14
    Rash maculo-papular
         subjects affected / exposed
    1 / 178 (0.56%)
    4 / 76 (5.26%)
         occurrences all number
    1
    4
    Alopecia
         subjects affected / exposed
    11 / 178 (6.18%)
    12 / 76 (15.79%)
         occurrences all number
    11
    12
    Erythema
         subjects affected / exposed
    2 / 178 (1.12%)
    4 / 76 (5.26%)
         occurrences all number
    2
    4
    Nail discolouration
         subjects affected / exposed
    0 / 178 (0.00%)
    4 / 76 (5.26%)
         occurrences all number
    0
    4
    Nail disorder
         subjects affected / exposed
    1 / 178 (0.56%)
    6 / 76 (7.89%)
         occurrences all number
    1
    8
    Butterfly rash
         subjects affected / exposed
    0 / 178 (0.00%)
    1 / 76 (1.32%)
         occurrences all number
    0
    1
    Blister
         subjects affected / exposed
    0 / 178 (0.00%)
    3 / 76 (3.95%)
         occurrences all number
    0
    3
    Decubitus ulcer
         subjects affected / exposed
    1 / 178 (0.56%)
    0 / 76 (0.00%)
         occurrences all number
    1
    0
    Dermatitis
         subjects affected / exposed
    0 / 178 (0.00%)
    1 / 76 (1.32%)
         occurrences all number
    0
    1
    Dermatitis bullous
         subjects affected / exposed
    0 / 178 (0.00%)
    3 / 76 (3.95%)
         occurrences all number
    0
    3
    Dermatitis contact
         subjects affected / exposed
    1 / 178 (0.56%)
    0 / 76 (0.00%)
         occurrences all number
    1
    0
    Ecchymosis
         subjects affected / exposed
    1 / 178 (0.56%)
    0 / 76 (0.00%)
         occurrences all number
    1
    0
    Eczema
         subjects affected / exposed
    0 / 178 (0.00%)
    1 / 76 (1.32%)
         occurrences all number
    0
    1
    Eczema asteatotic
         subjects affected / exposed
    1 / 178 (0.56%)
    1 / 76 (1.32%)
         occurrences all number
    1
    1
    Hair disorder
         subjects affected / exposed
    0 / 178 (0.00%)
    1 / 76 (1.32%)
         occurrences all number
    0
    1
    Erythema nodosum
         subjects affected / exposed
    1 / 178 (0.56%)
    0 / 76 (0.00%)
         occurrences all number
    1
    0
    Hyperhidrosis
         subjects affected / exposed
    3 / 178 (1.69%)
    0 / 76 (0.00%)
         occurrences all number
    3
    0
    Hand dermatitis
         subjects affected / exposed
    0 / 178 (0.00%)
    1 / 76 (1.32%)
         occurrences all number
    0
    1
    Hyperkeratosis
         subjects affected / exposed
    0 / 178 (0.00%)
    1 / 76 (1.32%)
         occurrences all number
    0
    1
    Miliaria
         subjects affected / exposed
    0 / 178 (0.00%)
    1 / 76 (1.32%)
         occurrences all number
    0
    1
    Ingrowing nail
         subjects affected / exposed
    2 / 178 (1.12%)
    0 / 76 (0.00%)
         occurrences all number
    2
    0
    Nail pigmentation
         subjects affected / exposed
    0 / 178 (0.00%)
    1 / 76 (1.32%)
         occurrences all number
    0
    1
    Onychalgia
         subjects affected / exposed
    0 / 178 (0.00%)
    1 / 76 (1.32%)
         occurrences all number
    0
    1
    Onychoclasis
         subjects affected / exposed
    0 / 178 (0.00%)
    1 / 76 (1.32%)
         occurrences all number
    0
    1
    Onycholysis
         subjects affected / exposed
    0 / 178 (0.00%)
    1 / 76 (1.32%)
         occurrences all number
    0
    1
    Pain of skin
         subjects affected / exposed
    1 / 178 (0.56%)
    1 / 76 (1.32%)
         occurrences all number
    1
    1
    Onychomadesis
         subjects affected / exposed
    0 / 178 (0.00%)
    1 / 76 (1.32%)
         occurrences all number
    0
    1
    Papule
         subjects affected / exposed
    0 / 178 (0.00%)
    1 / 76 (1.32%)
         occurrences all number
    0
    1
    Panniculitis
         subjects affected / exposed
    0 / 178 (0.00%)
    1 / 76 (1.32%)
         occurrences all number
    0
    1
    Pigmentation disorder
         subjects affected / exposed
    0 / 178 (0.00%)
    2 / 76 (2.63%)
         occurrences all number
    0
    2
    Psoriasis
         subjects affected / exposed
    1 / 178 (0.56%)
    0 / 76 (0.00%)
         occurrences all number
    1
    0
    Rash erythematous
         subjects affected / exposed
    0 / 178 (0.00%)
    1 / 76 (1.32%)
         occurrences all number
    0
    2
    Skin erosion
         subjects affected / exposed
    0 / 178 (0.00%)
    1 / 76 (1.32%)
         occurrences all number
    0
    1
    Skin discolouration
         subjects affected / exposed
    0 / 178 (0.00%)
    2 / 76 (2.63%)
         occurrences all number
    0
    2
    Skin exfoliation
         subjects affected / exposed
    2 / 178 (1.12%)
    1 / 76 (1.32%)
         occurrences all number
    2
    1
    Skin fissures
         subjects affected / exposed
    0 / 178 (0.00%)
    1 / 76 (1.32%)
         occurrences all number
    0
    1
    Skin induration
         subjects affected / exposed
    0 / 178 (0.00%)
    1 / 76 (1.32%)
         occurrences all number
    0
    1
    Skin irritation
         subjects affected / exposed
    0 / 178 (0.00%)
    1 / 76 (1.32%)
         occurrences all number
    0
    1
    Skin lesion
         subjects affected / exposed
    1 / 178 (0.56%)
    1 / 76 (1.32%)
         occurrences all number
    1
    1
    Skin mass
         subjects affected / exposed
    1 / 178 (0.56%)
    0 / 76 (0.00%)
         occurrences all number
    1
    0
    Skin tightness
         subjects affected / exposed
    1 / 178 (0.56%)
    0 / 76 (0.00%)
         occurrences all number
    1
    0
    Skin toxicity
         subjects affected / exposed
    0 / 178 (0.00%)
    3 / 76 (3.95%)
         occurrences all number
    0
    3
    Skin ulcer
         subjects affected / exposed
    0 / 178 (0.00%)
    1 / 76 (1.32%)
         occurrences all number
    0
    2
    Renal and urinary disorders
    Chronic kidney disease
         subjects affected / exposed
    1 / 178 (0.56%)
    0 / 76 (0.00%)
         occurrences all number
    1
    0
    Calculus urinary
         subjects affected / exposed
    1 / 178 (0.56%)
    0 / 76 (0.00%)
         occurrences all number
    1
    0
    Acute kidney injury
         subjects affected / exposed
    4 / 178 (2.25%)
    0 / 76 (0.00%)
         occurrences all number
    4
    0
    Cystitis noninfective
         subjects affected / exposed
    2 / 178 (1.12%)
    0 / 76 (0.00%)
         occurrences all number
    2
    0
    Dysuria
         subjects affected / exposed
    8 / 178 (4.49%)
    1 / 76 (1.32%)
         occurrences all number
    9
    1
    Haematuria
         subjects affected / exposed
    2 / 178 (1.12%)
    0 / 76 (0.00%)
         occurrences all number
    2
    0
    Hydronephrosis
         subjects affected / exposed
    3 / 178 (1.69%)
    1 / 76 (1.32%)
         occurrences all number
    3
    1
    Hydroureter
         subjects affected / exposed
    1 / 178 (0.56%)
    0 / 76 (0.00%)
         occurrences all number
    1
    0
    Leukocyturia
         subjects affected / exposed
    1 / 178 (0.56%)
    0 / 76 (0.00%)
         occurrences all number
    1
    0
    Micturition urgency
         subjects affected / exposed
    1 / 178 (0.56%)
    0 / 76 (0.00%)
         occurrences all number
    1
    0
    Pollakiuria
         subjects affected / exposed
    1 / 178 (0.56%)
    2 / 76 (2.63%)
         occurrences all number
    1
    2
    Nephrolithiasis
         subjects affected / exposed
    4 / 178 (2.25%)
    0 / 76 (0.00%)
         occurrences all number
    4
    0
    Renal colic
         subjects affected / exposed
    0 / 178 (0.00%)
    1 / 76 (1.32%)
         occurrences all number
    0
    1
    Renal failure
         subjects affected / exposed
    3 / 178 (1.69%)
    0 / 76 (0.00%)
         occurrences all number
    3
    0
    Ureteric obstruction
         subjects affected / exposed
    1 / 178 (0.56%)
    1 / 76 (1.32%)
         occurrences all number
    1
    1
    Urinary incontinence
         subjects affected / exposed
    1 / 178 (0.56%)
    1 / 76 (1.32%)
         occurrences all number
    1
    1
    Urinary tract disorder
         subjects affected / exposed
    1 / 178 (0.56%)
    0 / 76 (0.00%)
         occurrences all number
    1
    0
    Urinary tract obstruction
         subjects affected / exposed
    2 / 178 (1.12%)
    0 / 76 (0.00%)
         occurrences all number
    2
    0
    Musculoskeletal and connective tissue disorders
    Back pain
         subjects affected / exposed
    17 / 178 (9.55%)
    3 / 76 (3.95%)
         occurrences all number
    28
    3
    Arthralgia
         subjects affected / exposed
    18 / 178 (10.11%)
    6 / 76 (7.89%)
         occurrences all number
    35
    10
    Muscle spasms
         subjects affected / exposed
    12 / 178 (6.74%)
    0 / 76 (0.00%)
         occurrences all number
    21
    0
    Muscular weakness
         subjects affected / exposed
    2 / 178 (1.12%)
    4 / 76 (5.26%)
         occurrences all number
    2
    4
    Myalgia
         subjects affected / exposed
    9 / 178 (5.06%)
    2 / 76 (2.63%)
         occurrences all number
    18
    3
    Pain in extremity
         subjects affected / exposed
    10 / 178 (5.62%)
    6 / 76 (7.89%)
         occurrences all number
    13
    7
    Arthritis
         subjects affected / exposed
    1 / 178 (0.56%)
    0 / 76 (0.00%)
         occurrences all number
    1
    0
    Bone pain
         subjects affected / exposed
    1 / 178 (0.56%)
    3 / 76 (3.95%)
         occurrences all number
    1
    3
    Flank pain
         subjects affected / exposed
    4 / 178 (2.25%)
    3 / 76 (3.95%)
         occurrences all number
    5
    3
    Extremity contracture
         subjects affected / exposed
    1 / 178 (0.56%)
    0 / 76 (0.00%)
         occurrences all number
    1
    0
    Groin pain
         subjects affected / exposed
    1 / 178 (0.56%)
    0 / 76 (0.00%)
         occurrences all number
    2
    0
    Joint stiffness
         subjects affected / exposed
    1 / 178 (0.56%)
    0 / 76 (0.00%)
         occurrences all number
    1
    0
    Musculoskeletal pain
         subjects affected / exposed
    3 / 178 (1.69%)
    1 / 76 (1.32%)
         occurrences all number
    3
    1
    Musculoskeletal chest pain
         subjects affected / exposed
    1 / 178 (0.56%)
    1 / 76 (1.32%)
         occurrences all number
    1
    1
    Joint swelling
         subjects affected / exposed
    3 / 178 (1.69%)
    0 / 76 (0.00%)
         occurrences all number
    3
    0
    Neck pain
         subjects affected / exposed
    1 / 178 (0.56%)
    1 / 76 (1.32%)
         occurrences all number
    1
    1
    Osteopenia
         subjects affected / exposed
    1 / 178 (0.56%)
    0 / 76 (0.00%)
         occurrences all number
    1
    0
    Periarthritis
         subjects affected / exposed
    1 / 178 (0.56%)
    0 / 76 (0.00%)
         occurrences all number
    1
    0
    Osteoporosis
         subjects affected / exposed
    2 / 178 (1.12%)
    0 / 76 (0.00%)
         occurrences all number
    2
    0
    Spinal pain
         subjects affected / exposed
    1 / 178 (0.56%)
    0 / 76 (0.00%)
         occurrences all number
    1
    0
    Rotator cuff syndrome
         subjects affected / exposed
    1 / 178 (0.56%)
    0 / 76 (0.00%)
         occurrences all number
    2
    0
    Tendonitis
         subjects affected / exposed
    1 / 178 (0.56%)
    0 / 76 (0.00%)
         occurrences all number
    1
    0
    Infections and infestations
    Upper respiratory tract infection
         subjects affected / exposed
    16 / 178 (8.99%)
    8 / 76 (10.53%)
         occurrences all number
    19
    9
    Urinary tract infection
         subjects affected / exposed
    21 / 178 (11.80%)
    4 / 76 (5.26%)
         occurrences all number
    26
    4
    Bronchitis
         subjects affected / exposed
    10 / 178 (5.62%)
    2 / 76 (2.63%)
         occurrences all number
    12
    2
    Acute sinusitis
         subjects affected / exposed
    1 / 178 (0.56%)
    0 / 76 (0.00%)
         occurrences all number
    1
    0
    Candida infection
         subjects affected / exposed
    0 / 178 (0.00%)
    1 / 76 (1.32%)
         occurrences all number
    0
    1
    Catheter site infection
         subjects affected / exposed
    0 / 178 (0.00%)
    1 / 76 (1.32%)
         occurrences all number
    0
    1
    Conjunctivitis
         subjects affected / exposed
    1 / 178 (0.56%)
    2 / 76 (2.63%)
         occurrences all number
    1
    3
    Cellulitis
         subjects affected / exposed
    1 / 178 (0.56%)
    2 / 76 (2.63%)
         occurrences all number
    1
    2
    Diverticulitis
         subjects affected / exposed
    2 / 178 (1.12%)
    0 / 76 (0.00%)
         occurrences all number
    2
    0
    Cystitis
         subjects affected / exposed
    5 / 178 (2.81%)
    1 / 76 (1.32%)
         occurrences all number
    5
    2
    Ear infection
         subjects affected / exposed
    2 / 178 (1.12%)
    0 / 76 (0.00%)
         occurrences all number
    2
    0
    Eye infection
         subjects affected / exposed
    1 / 178 (0.56%)
    0 / 76 (0.00%)
         occurrences all number
    2
    0
    Escherichia infection
         subjects affected / exposed
    1 / 178 (0.56%)
    0 / 76 (0.00%)
         occurrences all number
    1
    0
    Erysipelas
         subjects affected / exposed
    0 / 178 (0.00%)
    1 / 76 (1.32%)
         occurrences all number
    0
    1
    Folliculitis
         subjects affected / exposed
    1 / 178 (0.56%)
    2 / 76 (2.63%)
         occurrences all number
    1
    2
    Fungal infection
         subjects affected / exposed
    1 / 178 (0.56%)
    0 / 76 (0.00%)
         occurrences all number
    1
    0
    Gastroenteritis
         subjects affected / exposed
    2 / 178 (1.12%)
    0 / 76 (0.00%)
         occurrences all number
    2
    0
    Gastroenteritis viral
         subjects affected / exposed
    4 / 178 (2.25%)
    0 / 76 (0.00%)
         occurrences all number
    4
    0
    Gastrointestinal infection
         subjects affected / exposed
    1 / 178 (0.56%)
    0 / 76 (0.00%)
         occurrences all number
    1
    0
    Gingivitis
         subjects affected / exposed
    2 / 178 (1.12%)
    0 / 76 (0.00%)
         occurrences all number
    4
    0
    Herpes simplex
         subjects affected / exposed
    0 / 178 (0.00%)
    2 / 76 (2.63%)
         occurrences all number
    0
    2
    Herpes simplex reactivation
         subjects affected / exposed
    1 / 178 (0.56%)
    0 / 76 (0.00%)
         occurrences all number
    1
    0
    Herpes virus infection
         subjects affected / exposed
    1 / 178 (0.56%)
    0 / 76 (0.00%)
         occurrences all number
    1
    0
    Influenza
         subjects affected / exposed
    8 / 178 (4.49%)
    0 / 76 (0.00%)
         occurrences all number
    8
    0
    Infected bite
         subjects affected / exposed
    0 / 178 (0.00%)
    1 / 76 (1.32%)
         occurrences all number
    0
    1
    Herpes zoster
         subjects affected / exposed
    1 / 178 (0.56%)
    2 / 76 (2.63%)
         occurrences all number
    1
    3
    Mastitis
         subjects affected / exposed
    1 / 178 (0.56%)
    0 / 76 (0.00%)
         occurrences all number
    1
    0
    Localised infection
         subjects affected / exposed
    0 / 178 (0.00%)
    1 / 76 (1.32%)
         occurrences all number
    0
    2
    Lice infestation
         subjects affected / exposed
    1 / 178 (0.56%)
    0 / 76 (0.00%)
         occurrences all number
    1
    0
    Mucosal infection
         subjects affected / exposed
    2 / 178 (1.12%)
    0 / 76 (0.00%)
         occurrences all number
    2
    0
    Nail infection
         subjects affected / exposed
    0 / 178 (0.00%)
    1 / 76 (1.32%)
         occurrences all number
    0
    2
    Nasopharyngitis
         subjects affected / exposed
    8 / 178 (4.49%)
    2 / 76 (2.63%)
         occurrences all number
    10
    2
    Oesophageal candidiasis
         subjects affected / exposed
    1 / 178 (0.56%)
    0 / 76 (0.00%)
         occurrences all number
    1
    0
    Oral herpes
         subjects affected / exposed
    1 / 178 (0.56%)
    1 / 76 (1.32%)
         occurrences all number
    1
    1
    Oral candidiasis
         subjects affected / exposed
    2 / 178 (1.12%)
    0 / 76 (0.00%)
         occurrences all number
    2
    0
    Onychomycosis
         subjects affected / exposed
    1 / 178 (0.56%)
    1 / 76 (1.32%)
         occurrences all number
    1
    1
    Paronychia
         subjects affected / exposed
    0 / 178 (0.00%)
    2 / 76 (2.63%)
         occurrences all number
    0
    2
    Pharyngitis
         subjects affected / exposed
    1 / 178 (0.56%)
    0 / 76 (0.00%)
         occurrences all number
    1
    0
    Pneumonia
         subjects affected / exposed
    1 / 178 (0.56%)
    0 / 76 (0.00%)
         occurrences all number
    3
    0
    Rash pustular
         subjects affected / exposed
    1 / 178 (0.56%)
    0 / 76 (0.00%)
         occurrences all number
    1
    0
    Pyuria
         subjects affected / exposed
    1 / 178 (0.56%)
    0 / 76 (0.00%)
         occurrences all number
    1
    0
    Rhinitis
         subjects affected / exposed
    1 / 178 (0.56%)
    1 / 76 (1.32%)
         occurrences all number
    1
    1
    Respiratory tract infection
         subjects affected / exposed
    2 / 178 (1.12%)
    0 / 76 (0.00%)
         occurrences all number
    2
    0
    Sinusitis
         subjects affected / exposed
    5 / 178 (2.81%)
    0 / 76 (0.00%)
         occurrences all number
    6
    0
    Tooth infection
         subjects affected / exposed
    1 / 178 (0.56%)
    0 / 76 (0.00%)
         occurrences all number
    1
    0
    Tooth abscess
         subjects affected / exposed
    1 / 178 (0.56%)
    0 / 76 (0.00%)
         occurrences all number
    1
    0
    Skin infection
         subjects affected / exposed
    0 / 178 (0.00%)
    2 / 76 (2.63%)
         occurrences all number
    0
    2
    Vaginal infection
         subjects affected / exposed
    1 / 178 (0.56%)
    1 / 76 (1.32%)
         occurrences all number
    1
    1
    Viral upper respiratory tract infection
         subjects affected / exposed
    1 / 178 (0.56%)
    0 / 76 (0.00%)
         occurrences all number
    1
    0
    Metabolism and nutrition disorders
    Decreased appetite
         subjects affected / exposed
    26 / 178 (14.61%)
    9 / 76 (11.84%)
         occurrences all number
    30
    9
    Hypoalbuminaemia
         subjects affected / exposed
    10 / 178 (5.62%)
    4 / 76 (5.26%)
         occurrences all number
    13
    4
    Hypokalaemia
         subjects affected / exposed
    12 / 178 (6.74%)
    3 / 76 (3.95%)
         occurrences all number
    16
    4
    Hypomagnesaemia
         subjects affected / exposed
    10 / 178 (5.62%)
    1 / 76 (1.32%)
         occurrences all number
    19
    1
    Hyponatraemia
         subjects affected / exposed
    9 / 178 (5.06%)
    2 / 76 (2.63%)
         occurrences all number
    14
    2
    Diabetes mellitus
         subjects affected / exposed
    1 / 178 (0.56%)
    0 / 76 (0.00%)
         occurrences all number
    1
    0
    Dehydration
         subjects affected / exposed
    2 / 178 (1.12%)
    3 / 76 (3.95%)
         occurrences all number
    4
    4
    Appetite disorder
         subjects affected / exposed
    1 / 178 (0.56%)
    1 / 76 (1.32%)
         occurrences all number
    1
    1
    Glucose tolerance impaired
         subjects affected / exposed
    1 / 178 (0.56%)
    1 / 76 (1.32%)
         occurrences all number
    1
    2
    Hypercalcaemia
         subjects affected / exposed
    3 / 178 (1.69%)
    0 / 76 (0.00%)
         occurrences all number
    4
    0
    Hyperamylasaemia
         subjects affected / exposed
    1 / 178 (0.56%)
    0 / 76 (0.00%)
         occurrences all number
    1
    0
    Gout
         subjects affected / exposed
    1 / 178 (0.56%)
    0 / 76 (0.00%)
         occurrences all number
    3
    0
    Hyperkalaemia
         subjects affected / exposed
    2 / 178 (1.12%)
    2 / 76 (2.63%)
         occurrences all number
    3
    3
    Hyperglycaemia
         subjects affected / exposed
    5 / 178 (2.81%)
    0 / 76 (0.00%)
         occurrences all number
    7
    0
    Hypercreatininaemia
         subjects affected / exposed
    1 / 178 (0.56%)
    0 / 76 (0.00%)
         occurrences all number
    1
    0
    Hypermagnesaemia
         subjects affected / exposed
    0 / 178 (0.00%)
    1 / 76 (1.32%)
         occurrences all number
    0
    1
    Hypernatraemia
         subjects affected / exposed
    1 / 178 (0.56%)
    0 / 76 (0.00%)
         occurrences all number
    1
    0
    Hyperphosphataemia
         subjects affected / exposed
    1 / 178 (0.56%)
    0 / 76 (0.00%)
         occurrences all number
    1
    0
    Hypertriglyceridaemia
         subjects affected / exposed
    1 / 178 (0.56%)
    0 / 76 (0.00%)
         occurrences all number
    1
    0
    Hyperuricaemia
         subjects affected / exposed
    0 / 178 (0.00%)
    2 / 76 (2.63%)
         occurrences all number
    0
    2
    Hypocalcaemia
         subjects affected / exposed
    5 / 178 (2.81%)
    1 / 76 (1.32%)
         occurrences all number
    6
    1
    Hypochloraemia
         subjects affected / exposed
    1 / 178 (0.56%)
    0 / 76 (0.00%)
         occurrences all number
    1
    0
    Hypoglycaemia
         subjects affected / exposed
    1 / 178 (0.56%)
    0 / 76 (0.00%)
         occurrences all number
    4
    0
    Vitamin D deficiency
         subjects affected / exposed
    2 / 178 (1.12%)
    0 / 76 (0.00%)
         occurrences all number
    2
    0
    Steroid diabetes
         subjects affected / exposed
    0 / 178 (0.00%)
    1 / 76 (1.32%)
         occurrences all number
    0
    1
    Hypophosphataemia
         subjects affected / exposed
    3 / 178 (1.69%)
    0 / 76 (0.00%)
         occurrences all number
    4
    0

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    29 Sep 2017
    Primary objective and endpoint changed from PFS to ORR and recruitment changed to close once a minimum of 250 patients were randomized instead of 411 as initially planned.

    Interruptions (globally)
    Were there any global interruptions to the trial? No

    Limitations and caveats
    Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.
    None reported
    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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