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    Clinical Trial Results:
    Randomised phase II Trial of olaparib, chemotherapy or olaparib and cediranib in patients with platinum–resistant ovarian cancer

    Summary
    EudraCT number
    		 2016-000559-28
    Trial protocol
    		 GB  
    Global end of trial date
    26 Oct 2023

    Results information
    Results version number
    		 v1(current)
    This version publication date
    09 Nov 2024
    First version publication date
    09 Nov 2024
    Other versions
    Summary report(s)
    		 OCTOVA results - BJC Manuscript publication

    Trial information

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    Trial identification
    Sponsor protocol code
    OCTO-062
    Additional study identifiers
    ISRCTN number
    		 ISRCTN14784018
    US NCT number
    		 NCT03117933
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    RGEA, University of Oxford
    Sponsor organisation address
    1st floor, Boundary Brook House, Churchill Drive, Headington , Oxford, United Kingdom, OX3 7GB
    Public contact
    Lisa Poulton, Oncology Clinical Trials Office (OCTO), +44 1865617075, octo-octova@oncology.ox.ac.uk
    Scientific contact
    Lisa Poulton, Oncology Clinical Trials Office (OCTO), +44 1865617075, octo-octova@oncology.ox.ac.uk
    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
    21 Mar 2022
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    10 Jul 2021
    Global end of trial reached?
    Yes
    Global end of trial date
    26 Oct 2023
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The main objective is to assess the efficacy of olaparib compared to weekly paclitaxel or the combination of olaparib and cediranib in patients with ovarian, fallopian tube, primary peritoneal cancer who have relapsed within 12 months of previous platinum therapy
    Protection of trial subjects
    The protocol was conducted in compliance with the UK Clinical Trials Regulations, the Principles of Good Clinical Practice (GCP) and the applicable policies of the sponsoring organisation. Together, these implement the ethical principles of the Declaration of Helsinki (1996) and the regulatory requirements for clinical trials of investigational medicinal products under the European Union Clinical Trials Directive.
    Background therapy
    		 None.
    Evidence for comparator
    		 Patients relapsing within 12 months of prior platinum therapy have a degree of platinum resistance, and therefore it is acceptable to consider the use of platinum sparing options, such as weekly taxol or Caelyx, in this group. Caelyx is often used earlier in the treatment pathway in combination with carboplatin, and therefore we chose weekly taxol as our comparator arm. A retrospective analysis demonstrated that weekly Taxol had similar efficacy in sporadic and BRCA-mutated relapsed ovarian cancer patients. The study, conducted in four cancer centres, analysed response and PFS following paclitaxel (3-weekly/weekly) monotherapy in BRCA-mutated relapsed ovarian cancer patients. There were 26 patients, 15 platinum-sensitive (58%) and 11 platinum-resistant (42%). The clinical benefit rate (complete or partial response, or stable disease) was 36%, with a median PFS of 21 weeks, which is consistent with the PFS of 4.7-5.3 months in the SaPPrOC study, in which patients with unknown BRCA status and platinum-resistant ovarian cancer received weekly Taxol.
    Actual start date of recruitment
    31 Jan 2017
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    United Kingdom: 139
    Worldwide total number of subjects
    139
    EEA total number of subjects
    0
    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)
    63
    From 65 to 84 years
    75
    85 years and over
    1

    Subject disposition

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    Recruitment
    Recruitment details
    		 Start of recruitment: 30 May 2017 End of recruitment: 10 January 2020 139 participants were recruited in total (46 to Arm A, 46 to Arm B and 47 to Arm C)

    Pre-assignment
    Screening details
    		 258 patients were screened for the trial. 119 patients were excluded; 36 patients declined participation, 83 patients were not eligible and one patient consented but passed away prior to end of screening.

    Period 1
    Period 1 title
    Part 1 (IMP administration) (overall period)
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Not blinded
    Blinding implementation details
    N/A

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Arm A
    Arm description
    		 IV weekly paclitaxel 80 mg/m2 on D1,8 & 15 every 28 days
    Arm type
    		 Active comparator

    Investigational medicinal product name
    Paclitaxel
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Injection/infusion, Solution for solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    80 mg/m2 administered weekly on on D1,8 & 15 every 28 days

    Arm title
    		 Arm B
    Arm description
    		 Olaparib tablets will be supplied as 100 & 150mg (to allow for dose adjustments). Tablet formulation, 300 mg twice daily PO, continuous dosing.
    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 twice daily PO, continuous dosing. Olaparib will be dispensed to patients on Day 1 and every 4 weeks thereafter until the patient completes the study, withdraws from the study or closure of the study.

    Arm title
    		 Arm C
    Arm description
    		 Olaparib 300mg bd with Cediranib 20mg bd. Cediranib will be supplied as 15mg and 20mg film coated tablets, to allow for dose adjustments. Patients will either receive 15mg or 20mg to avoid any dosing errors.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Cediranib + Olaparib
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Tablet formulation, 20 mg PO once daily, continuous. Cediranib will be dispensed to patients on Day 1 and every 4 weeks thereafter until the patient completes the study, withdraws from the study or closure of the study. 300 mg twice daily PO, continuous dosing. Olaparib will be dispensed to patients on Day 1 and every 4 weeks thereafter until the patient completes the study, withdraws from the study or closure of the study.

    Number of subjects in period 1
    		Arm A Arm B Arm C
    Started
    46
    46
    47
    Completed
    46
    46
    47

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Arm A
    Reporting group description
    		 IV weekly paclitaxel 80 mg/m2 on D1,8 & 15 every 28 days

    Reporting group title
    Arm B
    Reporting group description
    		 Olaparib tablets will be supplied as 100 & 150mg (to allow for dose adjustments). Tablet formulation, 300 mg twice daily PO, continuous dosing.

    Reporting group title
    Arm C
    Reporting group description
    		 Olaparib 300mg bd with Cediranib 20mg bd. Cediranib will be supplied as 15mg and 20mg film coated tablets, to allow for dose adjustments. Patients will either receive 15mg or 20mg to avoid any dosing errors.

    Reporting group values
    		 Arm A Arm B Arm C Total
    Number of subjects
    		 46 46 47 139
    Age categorical
    Units: Subjects
        In utero
    		 0
        Preterm newborn infants (gestational age < 37 wks)
    		 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)
    		 0
        From 65-84 years
    		 0
        85 years and over
    		 0
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    		 64 ( 11 ) 64 ( 10 ) 64 ( 10 ) -
    Gender categorical
    Units: Subjects
        Female
    		 46 46 47 139
        Male
    		 0 0 0 0
    PARP
    Poly ADP Ribose Polymerase
    Units: Subjects
        Yes
    		 10 10 11 31
        No
    		 36 36 36 108
    Angiogenic
    Units: Subjects
        Yes
    		 15 15 17 47
        No
    		 31 31 30 92
    BRCA
    Units: Subjects
        Yes
    		 11 15 16 42
        No
    		 35 31 31 97

    End points

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    End points reporting groups
    Reporting group title
    Arm A
    Reporting group description
    		 IV weekly paclitaxel 80 mg/m2 on D1,8 & 15 every 28 days

    Reporting group title
    Arm B
    Reporting group description
    		 Olaparib tablets will be supplied as 100 & 150mg (to allow for dose adjustments). Tablet formulation, 300 mg twice daily PO, continuous dosing.

    Reporting group title
    Arm C
    Reporting group description
    		 Olaparib 300mg bd with Cediranib 20mg bd. Cediranib will be supplied as 15mg and 20mg film coated tablets, to allow for dose adjustments. Patients will either receive 15mg or 20mg to avoid any dosing errors.

    Primary: Progression free survival (PFS)

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    End point title
    		 Progression free survival (PFS)
    End point description
    End point type
    Primary
    End point timeframe
    Time from date of randomisation to RECIST-defined progression or death from any cause (whichever is first)
    End point values
    		 Arm A Arm B Arm C
    Number of subjects analysed
    46
    46
    47
    Units: month
        median (inter-quartile range (Q1-Q3))
    3.9 (1.9 to 9.1)
    3.7 (1.8 to 7.6)
    5.4 (2.3 to 9.6)
    Attachments
    		 KM plots
    Statistical analysis title
    		 Primary Outcome Analysis A vs B
    Comparison groups
    Arm A v Arm B
    Number of subjects included in analysis
    92
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.2 [1]
    Method
    		 Regression, Cox
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.89
    Confidence interval
         level
    		 60%
         sides
    2-sided
         lower limit
    		 0.72
         upper limit
    		 1.09
    Notes
    [1] - A one-sided p-value of <0.2 was considered
    Statistical analysis title
    		 Primary Outcome Analysis B vs C
    Comparison groups
    Arm B v Arm C
    Number of subjects included in analysis
    93
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.2
    Method
    		 Regression, Cox
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.73
    Confidence interval
         level
    		 60%
         sides
    2-sided
         lower limit
    		 0.59
         upper limit
    		 0.89

    Secondary: Overall survival

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    End point title
    		 Overall survival
    End point description
    End point type
    Secondary
    End point timeframe
    From randomisation to death at 18 months
    End point values
    		 Arm A Arm B Arm C
    Number of subjects analysed
    46
    46
    47
    Units: rate
        number (confidence interval 60%)
    0.41 (0.34 to 0.49)
    0.30 (0.24 to 0.38)
    0.32 (0.26 to 0.39)
    Attachments
    		 KM plots
    No statistical analyses for this end point

    Secondary: Object Response Rate

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    End point title
    		 Object Response Rate
    End point description
    ORR as determined by RECIST
    End point type
    Secondary
    End point timeframe
    12 months
    End point values
    		 Arm A Arm B Arm C
    Number of subjects analysed
    44
    43
    44
    Units: Response
        Response
    15
    7
    6
        Non-response
    29
    36
    38
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    From day one of treatment until the 28 day follow-up visit
    Assessment type
    		 Non-systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 NCI-CTCAE
    Dictionary version
    4.03
    Reporting groups
    Reporting group title
    Arm A: Paclitaxel
    Reporting group description
    		 -

    Reporting group title
    Arm B: Olaparib
    Reporting group description
    		 -

    Reporting group title
    Arm C: Olaparib+Cediranib
    Reporting group description
    		 -

    Serious adverse events
    		 Arm A: Paclitaxel Arm B: Olaparib Arm C: Olaparib+Cediranib
    Total subjects affected by serious adverse events
         subjects affected / exposed
    20 / 46 (43.48%)
    16 / 46 (34.78%)
    13 / 47 (27.66%)
         number of deaths (all causes)
    27
    32
    32
         number of deaths resulting from adverse events
    0
    1
    0
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Basal cell carcinoma
         subjects affected / exposed
    0 / 46 (0.00%)
    0 / 46 (0.00%)
    1 / 47 (2.13%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Vascular disorders
    Deep vein thrombosis
         subjects affected / exposed
    0 / 46 (0.00%)
    0 / 46 (0.00%)
    1 / 47 (2.13%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Fatigue
         subjects affected / exposed
    1 / 46 (2.17%)
    0 / 46 (0.00%)
    0 / 47 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pyrexia
         subjects affected / exposed
    2 / 46 (4.35%)
    0 / 46 (0.00%)
    0 / 47 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Dyspnoea
         subjects affected / exposed
    1 / 46 (2.17%)
    0 / 46 (0.00%)
    0 / 47 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pleural effusion
         subjects affected / exposed
    3 / 46 (6.52%)
    0 / 46 (0.00%)
    0 / 47 (0.00%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pneumonitis
         subjects affected / exposed
    0 / 46 (0.00%)
    1 / 46 (2.17%)
    0 / 47 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pulmonary embolism
         subjects affected / exposed
    1 / 46 (2.17%)
    2 / 46 (4.35%)
    2 / 47 (4.26%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Psychiatric disorders
    Confusional state
         subjects affected / exposed
    1 / 46 (2.17%)
    0 / 46 (0.00%)
    0 / 47 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Investigations
    Liver function test abnormal
         subjects affected / exposed
    0 / 46 (0.00%)
    0 / 46 (0.00%)
    1 / 47 (2.13%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Troponin I increased
         subjects affected / exposed
    0 / 46 (0.00%)
    0 / 46 (0.00%)
    1 / 47 (2.13%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Hip fracture
         subjects affected / exposed
    1 / 46 (2.17%)
    0 / 46 (0.00%)
    0 / 47 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cardiac disorders
    Pericardial effusion
         subjects affected / exposed
    0 / 46 (0.00%)
    1 / 46 (2.17%)
    0 / 47 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Nervous system disorders
    Seizure
         subjects affected / exposed
    1 / 46 (2.17%)
    0 / 46 (0.00%)
    0 / 47 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    1 / 46 (2.17%)
    2 / 46 (4.35%)
    1 / 47 (2.13%)
         occurrences causally related to treatment / all
    0 / 1
    3 / 3
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Neutropenia
         subjects affected / exposed
    0 / 46 (0.00%)
    1 / 46 (2.17%)
    0 / 47 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Abdominal pain
         subjects affected / exposed
    2 / 46 (4.35%)
    2 / 46 (4.35%)
    0 / 47 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Ascites
         subjects affected / exposed
    2 / 46 (4.35%)
    0 / 46 (0.00%)
    0 / 47 (0.00%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Constipation
         subjects affected / exposed
    2 / 46 (4.35%)
    0 / 46 (0.00%)
    1 / 47 (2.13%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Diarrhoea
         subjects affected / exposed
    0 / 46 (0.00%)
    0 / 46 (0.00%)
    1 / 47 (2.13%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Nausea
         subjects affected / exposed
    0 / 46 (0.00%)
    1 / 46 (2.17%)
    1 / 47 (2.13%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Small intestinal obstruction
         subjects affected / exposed
    1 / 46 (2.17%)
    0 / 46 (0.00%)
    0 / 47 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Small intestinal perforation
         subjects affected / exposed
    0 / 46 (0.00%)
    1 / 46 (2.17%)
    0 / 47 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    Vomiting
         subjects affected / exposed
    5 / 46 (10.87%)
    3 / 46 (6.52%)
    1 / 47 (2.13%)
         occurrences causally related to treatment / all
    2 / 6
    2 / 3
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hepatobiliary disorders
    Cholecystitis
         subjects affected / exposed
    1 / 46 (2.17%)
    0 / 46 (0.00%)
    0 / 47 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hyperbilirubinaemia
         subjects affected / exposed
    0 / 46 (0.00%)
    0 / 46 (0.00%)
    1 / 47 (2.13%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Jaundice
         subjects affected / exposed
    0 / 46 (0.00%)
    0 / 46 (0.00%)
    1 / 47 (2.13%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Renal and urinary disorders
    Acute kidney injury
         subjects affected / exposed
    0 / 46 (0.00%)
    2 / 46 (4.35%)
    0 / 47 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Haematuria
         subjects affected / exposed
    0 / 46 (0.00%)
    1 / 46 (2.17%)
    0 / 47 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Infections and infestations
    Clostridium difficile colitis
         subjects affected / exposed
    1 / 46 (2.17%)
    0 / 46 (0.00%)
    0 / 47 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Clostridium difficile infection
         subjects affected / exposed
    0 / 46 (0.00%)
    0 / 46 (0.00%)
    1 / 47 (2.13%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cystitis
         subjects affected / exposed
    0 / 46 (0.00%)
    0 / 46 (0.00%)
    1 / 47 (2.13%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Diverticulitis
         subjects affected / exposed
    0 / 46 (0.00%)
    0 / 46 (0.00%)
    1 / 47 (2.13%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal infection
         subjects affected / exposed
    1 / 46 (2.17%)
    0 / 46 (0.00%)
    0 / 47 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Herpes zoster
         subjects affected / exposed
    0 / 46 (0.00%)
    1 / 46 (2.17%)
    0 / 47 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Infection
         subjects affected / exposed
    1 / 46 (2.17%)
    0 / 46 (0.00%)
    0 / 47 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Lower respiratory tract infection
         subjects affected / exposed
    0 / 46 (0.00%)
    2 / 46 (4.35%)
    1 / 47 (2.13%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pneumonia
         subjects affected / exposed
    1 / 46 (2.17%)
    0 / 46 (0.00%)
    1 / 47 (2.13%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Stoma site infection
         subjects affected / exposed
    0 / 46 (0.00%)
    0 / 46 (0.00%)
    1 / 47 (2.13%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Upper respiratory tract infection
         subjects affected / exposed
    1 / 46 (2.17%)
    0 / 46 (0.00%)
    0 / 47 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Urinary tract infection
         subjects affected / exposed
    0 / 46 (0.00%)
    0 / 46 (0.00%)
    1 / 47 (2.13%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Hypomagnesaemia
         subjects affected / exposed
    0 / 46 (0.00%)
    0 / 46 (0.00%)
    1 / 47 (2.13%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 0%
    Non-serious adverse events
    		 Arm A: Paclitaxel Arm B: Olaparib Arm C: Olaparib+Cediranib
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    44 / 46 (95.65%)
    44 / 46 (95.65%)
    45 / 47 (95.74%)
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Basal cell carcinoma
         subjects affected / exposed
    0 / 46 (0.00%)
    0 / 46 (0.00%)
    1 / 47 (2.13%)
         occurrences all number
    0
    0
    1
    Vascular disorders
    Deep vein thrombosis
         subjects affected / exposed
    0 / 46 (0.00%)
    1 / 46 (2.17%)
    1 / 47 (2.13%)
         occurrences all number
    0
    1
    1
    Embolism
         subjects affected / exposed
    1 / 46 (2.17%)
    0 / 46 (0.00%)
    0 / 47 (0.00%)
         occurrences all number
    1
    0
    0
    Flushing
         subjects affected / exposed
    1 / 46 (2.17%)
    1 / 46 (2.17%)
    1 / 47 (2.13%)
         occurrences all number
    1
    2
    1
    Hot flush
         subjects affected / exposed
    1 / 46 (2.17%)
    2 / 46 (4.35%)
    1 / 47 (2.13%)
         occurrences all number
    1
    2
    1
    Hypertension
         subjects affected / exposed
    4 / 46 (8.70%)
    5 / 46 (10.87%)
    14 / 47 (29.79%)
         occurrences all number
    8
    14
    22
    Hypotension
         subjects affected / exposed
    0 / 46 (0.00%)
    0 / 46 (0.00%)
    1 / 47 (2.13%)
         occurrences all number
    0
    0
    1
    Lymphoedema
         subjects affected / exposed
    0 / 46 (0.00%)
    0 / 46 (0.00%)
    2 / 47 (4.26%)
         occurrences all number
    0
    0
    2
    Pelvic venous thrombosis
         subjects affected / exposed
    1 / 46 (2.17%)
    0 / 46 (0.00%)
    0 / 47 (0.00%)
         occurrences all number
    1
    0
    0
    Thrombosis
         subjects affected / exposed
    1 / 46 (2.17%)
    0 / 46 (0.00%)
    1 / 47 (2.13%)
         occurrences all number
    1
    0
    1
    Surgical and medical procedures
    Ureteral stent insertion
         subjects affected / exposed
    0 / 46 (0.00%)
    1 / 46 (2.17%)
    0 / 47 (0.00%)
         occurrences all number
    0
    1
    0
    General disorders and administration site conditions
    asthenia
         subjects affected / exposed
    1 / 46 (2.17%)
    0 / 46 (0.00%)
    0 / 47 (0.00%)
         occurrences all number
    1
    0
    0
    Axillary pain
         subjects affected / exposed
    1 / 46 (2.17%)
    0 / 46 (0.00%)
    0 / 47 (0.00%)
         occurrences all number
    1
    0
    0
    Catheter site pain
         subjects affected / exposed
    1 / 46 (2.17%)
    0 / 46 (0.00%)
    0 / 47 (0.00%)
         occurrences all number
    1
    0
    0
    Chest discomfort
         subjects affected / exposed
    1 / 46 (2.17%)
    0 / 46 (0.00%)
    1 / 47 (2.13%)
         occurrences all number
    1
    0
    1
    Chest pain
         subjects affected / exposed
    0 / 46 (0.00%)
    1 / 46 (2.17%)
    2 / 47 (4.26%)
         occurrences all number
    0
    1
    2
    Early satiety
         subjects affected / exposed
    0 / 46 (0.00%)
    1 / 46 (2.17%)
    1 / 47 (2.13%)
         occurrences all number
    0
    1
    1
    Facial pain
         subjects affected / exposed
    0 / 46 (0.00%)
    0 / 46 (0.00%)
    1 / 47 (2.13%)
         occurrences all number
    0
    0
    1
    Fatigue
         subjects affected / exposed
    32 / 46 (69.57%)
    26 / 46 (56.52%)
    32 / 47 (68.09%)
         occurrences all number
    73
    46
    61
    Influenza like illness
         subjects affected / exposed
    1 / 46 (2.17%)
    0 / 46 (0.00%)
    1 / 47 (2.13%)
         occurrences all number
    1
    0
    1
    Localised oedema
         subjects affected / exposed
    1 / 46 (2.17%)
    0 / 46 (0.00%)
    0 / 47 (0.00%)
         occurrences all number
    1
    0
    0
    Non-cardiac chest pain
         subjects affected / exposed
    0 / 46 (0.00%)
    0 / 46 (0.00%)
    1 / 47 (2.13%)
         occurrences all number
    0
    0
    1
    Oedema peripheral
         subjects affected / exposed
    3 / 46 (6.52%)
    1 / 46 (2.17%)
    1 / 47 (2.13%)
         occurrences all number
    3
    1
    1
    Pain
         subjects affected / exposed
    1 / 46 (2.17%)
    2 / 46 (4.35%)
    3 / 47 (6.38%)
         occurrences all number
    1
    2
    3
    Peripheral swelling
         subjects affected / exposed
    1 / 46 (2.17%)
    2 / 46 (4.35%)
    0 / 47 (0.00%)
         occurrences all number
    1
    2
    0
    Pyrexia
         subjects affected / exposed
    7 / 46 (15.22%)
    4 / 46 (8.70%)
    0 / 47 (0.00%)
         occurrences all number
    11
    4
    0
    Vaccination site pain
         subjects affected / exposed
    0 / 46 (0.00%)
    0 / 46 (0.00%)
    1 / 47 (2.13%)
         occurrences all number
    0
    1
    0
    Immune system disorders
    Seasonal allergy
         subjects affected / exposed
    0 / 46 (0.00%)
    1 / 46 (2.17%)
    0 / 47 (0.00%)
         occurrences all number
    0
    1
    0
    Reproductive system and breast disorders
    Pelvic haemorrhage
         subjects affected / exposed
    0 / 46 (0.00%)
    1 / 46 (2.17%)
    0 / 47 (0.00%)
         occurrences all number
    0
    1
    0
    Pelvic pain
         subjects affected / exposed
    0 / 46 (0.00%)
    0 / 46 (0.00%)
    1 / 47 (2.13%)
         occurrences all number
    0
    0
    1
    Vaginal discharge
         subjects affected / exposed
    0 / 46 (0.00%)
    1 / 46 (2.17%)
    1 / 47 (2.13%)
         occurrences all number
    0
    1
    1
    Vaginal haemorrhage
         subjects affected / exposed
    1 / 46 (2.17%)
    0 / 46 (0.00%)
    0 / 47 (0.00%)
         occurrences all number
    3
    0
    0
    Respiratory, thoracic and mediastinal disorders
    Chronic obstructive pulmonary disease
         subjects affected / exposed
    1 / 46 (2.17%)
    0 / 46 (0.00%)
    0 / 47 (0.00%)
         occurrences all number
    1
    0
    0
    Cough
         subjects affected / exposed
    8 / 46 (17.39%)
    13 / 46 (28.26%)
    8 / 47 (17.02%)
         occurrences all number
    10
    16
    10
    Diaphragmalgia
         subjects affected / exposed
    0 / 46 (0.00%)
    0 / 46 (0.00%)
    1 / 47 (2.13%)
         occurrences all number
    0
    0
    1
    Dysphonia
         subjects affected / exposed
    0 / 46 (0.00%)
    0 / 46 (0.00%)
    3 / 47 (6.38%)
         occurrences all number
    0
    0
    3
    Dyspnoea
         subjects affected / exposed
    11 / 46 (23.91%)
    15 / 46 (32.61%)
    10 / 47 (21.28%)
         occurrences all number
    21
    21
    13
    Dyspnoea exertional
         subjects affected / exposed
    1 / 46 (2.17%)
    0 / 46 (0.00%)
    0 / 47 (0.00%)
         occurrences all number
    1
    0
    0
    Epistaxis
         subjects affected / exposed
    3 / 46 (6.52%)
    0 / 46 (0.00%)
    0 / 47 (0.00%)
         occurrences all number
    4
    0
    0
    Hiccups
         subjects affected / exposed
    0 / 46 (0.00%)
    1 / 46 (2.17%)
    0 / 47 (0.00%)
         occurrences all number
    0
    1
    0
    Nasal congestion
         subjects affected / exposed
    3 / 46 (6.52%)
    1 / 46 (2.17%)
    0 / 47 (0.00%)
         occurrences all number
    3
    1
    0
    Oropharyngeal pain
         subjects affected / exposed
    2 / 46 (4.35%)
    2 / 46 (4.35%)
    1 / 47 (2.13%)
         occurrences all number
    2
    2
    1
    Pleural effusion
         subjects affected / exposed
    4 / 46 (8.70%)
    0 / 46 (0.00%)
    0 / 47 (0.00%)
         occurrences all number
    6
    0
    0
    Pneumonitis
         subjects affected / exposed
    1 / 46 (2.17%)
    1 / 46 (2.17%)
    0 / 47 (0.00%)
         occurrences all number
    1
    1
    0
    Productive cough
         subjects affected / exposed
    2 / 46 (4.35%)
    1 / 46 (2.17%)
    0 / 47 (0.00%)
         occurrences all number
    3
    1
    0
    Pulmonary embolism
         subjects affected / exposed
    5 / 46 (10.87%)
    4 / 46 (8.70%)
    6 / 47 (12.77%)
         occurrences all number
    5
    4
    7
    Rhinorrhoea
         subjects affected / exposed
    1 / 46 (2.17%)
    0 / 46 (0.00%)
    0 / 47 (0.00%)
         occurrences all number
    1
    0
    0
    Sinus congestion
         subjects affected / exposed
    0 / 46 (0.00%)
    0 / 46 (0.00%)
    1 / 47 (2.13%)
         occurrences all number
    0
    0
    1
    Sneezing
         subjects affected / exposed
    0 / 46 (0.00%)
    1 / 46 (2.17%)
    0 / 47 (0.00%)
         occurrences all number
    0
    1
    0
    Psychiatric disorders
    Anxiety
         subjects affected / exposed
    2 / 46 (4.35%)
    1 / 46 (2.17%)
    1 / 47 (2.13%)
         occurrences all number
    2
    1
    1
    Confusional state
         subjects affected / exposed
    2 / 46 (4.35%)
    0 / 46 (0.00%)
    0 / 47 (0.00%)
         occurrences all number
    2
    0
    0
    Depressed mood
         subjects affected / exposed
    1 / 46 (2.17%)
    0 / 46 (0.00%)
    0 / 47 (0.00%)
         occurrences all number
    1
    0
    0
    Depression
         subjects affected / exposed
    2 / 46 (4.35%)
    0 / 46 (0.00%)
    1 / 47 (2.13%)
         occurrences all number
    2
    0
    1
    Insomnia
         subjects affected / exposed
    3 / 46 (6.52%)
    2 / 46 (4.35%)
    0 / 47 (0.00%)
         occurrences all number
    3
    2
    0
    Irritability
         subjects affected / exposed
    1 / 46 (2.17%)
    0 / 46 (0.00%)
    0 / 47 (0.00%)
         occurrences all number
    1
    0
    0
    Panic attack
         subjects affected / exposed
    1 / 46 (2.17%)
    0 / 46 (0.00%)
    0 / 47 (0.00%)
         occurrences all number
    1
    0
    0
    Investigations
    Blood alkaline phosphatase increased
         subjects affected / exposed
    1 / 46 (2.17%)
    3 / 46 (6.52%)
    4 / 47 (8.51%)
         occurrences all number
    1
    3
    5
    Blood creatine increased
         subjects affected / exposed
    6 / 46 (13.04%)
    7 / 46 (15.22%)
    2 / 47 (4.26%)
         occurrences all number
    7
    8
    3
    Blood folate decreased
         subjects affected / exposed
    0 / 46 (0.00%)
    1 / 46 (2.17%)
    0 / 47 (0.00%)
         occurrences all number
    0
    1
    0
    Blood thyroid stimulating hormone increased
         subjects affected / exposed
    0 / 46 (0.00%)
    0 / 46 (0.00%)
    1 / 47 (2.13%)
         occurrences all number
    0
    0
    1
    Blood urea increased
         subjects affected / exposed
    0 / 46 (0.00%)
    1 / 46 (2.17%)
    0 / 47 (0.00%)
         occurrences all number
    0
    2
    0
    C-reactive protein increased
         subjects affected / exposed
    0 / 46 (0.00%)
    0 / 46 (0.00%)
    1 / 47 (2.13%)
         occurrences all number
    0
    0
    1
    Creatinine renal clearance decreased
         subjects affected / exposed
    1 / 46 (2.17%)
    0 / 46 (0.00%)
    0 / 47 (0.00%)
         occurrences all number
    1
    0
    0
    Gamma-glutamyltransferase increased
         subjects affected / exposed
    0 / 46 (0.00%)
    1 / 46 (2.17%)
    2 / 47 (4.26%)
         occurrences all number
    0
    1
    2
    Gastrointestinal stoma output decreased
         subjects affected / exposed
    1 / 46 (2.17%)
    0 / 46 (0.00%)
    0 / 47 (0.00%)
         occurrences all number
    1
    0
    0
    Gastrointestinal stoma output increased
         subjects affected / exposed
    1 / 46 (2.17%)
    0 / 46 (0.00%)
    0 / 47 (0.00%)
         occurrences all number
    1
    0
    0
    Glomerular filtration rate decreased
         subjects affected / exposed
    0 / 46 (0.00%)
    1 / 46 (2.17%)
    1 / 47 (2.13%)
         occurrences all number
    0
    2
    1
    Liver function test abnormal
         subjects affected / exposed
    0 / 46 (0.00%)
    0 / 46 (0.00%)
    1 / 47 (2.13%)
         occurrences all number
    0
    0
    1
    Lymphocyte count abnormal
         subjects affected / exposed
    1 / 46 (2.17%)
    0 / 46 (0.00%)
    0 / 47 (0.00%)
         occurrences all number
    1
    0
    0
    Mean cell volume increased
         subjects affected / exposed
    0 / 46 (0.00%)
    1 / 46 (2.17%)
    0 / 47 (0.00%)
         occurrences all number
    0
    1
    0
    Neutrophil count abnormal
         subjects affected / exposed
    1 / 46 (2.17%)
    0 / 46 (0.00%)
    0 / 47 (0.00%)
         occurrences all number
    1
    0
    0
    Paracentesis
         subjects affected / exposed
    0 / 46 (0.00%)
    1 / 46 (2.17%)
    0 / 47 (0.00%)
         occurrences all number
    0
    1
    0
    Transaminases increased
         subjects affected / exposed
    0 / 46 (0.00%)
    2 / 46 (4.35%)
    5 / 47 (10.64%)
         occurrences all number
    0
    2
    5
    Troponin I increased
         subjects affected / exposed
    0 / 46 (0.00%)
    0 / 46 (0.00%)
    1 / 47 (2.13%)
         occurrences all number
    0
    0
    1
    Weight decreased
         subjects affected / exposed
    0 / 46 (0.00%)
    4 / 46 (8.70%)
    3 / 47 (6.38%)
         occurrences all number
    0
    4
    3
    White blood cell count increased
         subjects affected / exposed
    0 / 46 (0.00%)
    1 / 46 (2.17%)
    0 / 47 (0.00%)
         occurrences all number
    0
    1
    0
    White blood cell disorder
         subjects affected / exposed
    1 / 46 (2.17%)
    0 / 46 (0.00%)
    0 / 47 (0.00%)
         occurrences all number
    1
    0
    0
    Injury, poisoning and procedural complications
    Contusion
         subjects affected / exposed
    2 / 46 (4.35%)
    0 / 46 (0.00%)
    1 / 47 (2.13%)
         occurrences all number
    3
    0
    1
    Fall
         subjects affected / exposed
    1 / 46 (2.17%)
    0 / 46 (0.00%)
    0 / 47 (0.00%)
         occurrences all number
    1
    0
    0
    Hip fracture
         subjects affected / exposed
    1 / 46 (2.17%)
    0 / 46 (0.00%)
    0 / 47 (0.00%)
         occurrences all number
    1
    0
    0
    Infusion related reaction
         subjects affected / exposed
    1 / 46 (2.17%)
    0 / 46 (0.00%)
    0 / 47 (0.00%)
         occurrences all number
    1
    0
    0
    Joint injury
         subjects affected / exposed
    0 / 46 (0.00%)
    1 / 46 (2.17%)
    0 / 47 (0.00%)
         occurrences all number
    0
    1
    0
    Rib fracture
         subjects affected / exposed
    0 / 46 (0.00%)
    1 / 46 (2.17%)
    0 / 47 (0.00%)
         occurrences all number
    0
    1
    0
    Spinal column injury
         subjects affected / exposed
    1 / 46 (2.17%)
    0 / 46 (0.00%)
    0 / 47 (0.00%)
         occurrences all number
    1
    0
    0
    Stoma site pain
         subjects affected / exposed
    0 / 46 (0.00%)
    1 / 46 (2.17%)
    1 / 47 (2.13%)
         occurrences all number
    0
    1
    1
    Wound haemorrhage
         subjects affected / exposed
    1 / 46 (2.17%)
    0 / 46 (0.00%)
    0 / 47 (0.00%)
         occurrences all number
    1
    0
    0
    Cardiac disorders
    Pericardial effusion
         subjects affected / exposed
    0 / 46 (0.00%)
    1 / 46 (2.17%)
    0 / 47 (0.00%)
         occurrences all number
    0
    1
    0
    Sinus tachycardia
         subjects affected / exposed
    0 / 46 (0.00%)
    2 / 46 (4.35%)
    0 / 47 (0.00%)
         occurrences all number
    0
    2
    0
    Tachycardia
         subjects affected / exposed
    1 / 46 (2.17%)
    1 / 46 (2.17%)
    0 / 47 (0.00%)
         occurrences all number
    1
    1
    0
    Tinnitus
         subjects affected / exposed
    0 / 46 (0.00%)
    1 / 46 (2.17%)
    1 / 47 (2.13%)
         occurrences all number
    0
    1
    1
    Nervous system disorders
    Akathisia
         subjects affected / exposed
    1 / 46 (2.17%)
    0 / 46 (0.00%)
    0 / 47 (0.00%)
         occurrences all number
    2
    0
    0
    Ataxia
         subjects affected / exposed
    0 / 46 (0.00%)
    1 / 46 (2.17%)
    0 / 47 (0.00%)
         occurrences all number
    0
    1
    0
    Dizziness
         subjects affected / exposed
    3 / 46 (6.52%)
    5 / 46 (10.87%)
    2 / 47 (4.26%)
         occurrences all number
    4
    10
    2
    Dysgeusia
         subjects affected / exposed
    6 / 46 (13.04%)
    4 / 46 (8.70%)
    4 / 47 (8.51%)
         occurrences all number
    6
    4
    5
    Headache
         subjects affected / exposed
    7 / 46 (15.22%)
    5 / 46 (10.87%)
    6 / 47 (12.77%)
         occurrences all number
    13
    8
    9
    Lethargy
         subjects affected / exposed
    1 / 46 (2.17%)
    2 / 46 (4.35%)
    4 / 47 (8.51%)
         occurrences all number
    3
    2
    4
    Memory impairment
         subjects affected / exposed
    1 / 46 (2.17%)
    0 / 46 (0.00%)
    0 / 47 (0.00%)
         occurrences all number
    1
    0
    0
    Migraine
         subjects affected / exposed
    0 / 46 (0.00%)
    1 / 46 (2.17%)
    0 / 47 (0.00%)
         occurrences all number
    0
    1
    0
    Neuralgia
         subjects affected / exposed
    1 / 46 (2.17%)
    0 / 46 (0.00%)
    0 / 47 (0.00%)
         occurrences all number
    1
    0
    0
    Neuropathy peripheral
         subjects affected / exposed
    12 / 46 (26.09%)
    1 / 46 (2.17%)
    3 / 47 (6.38%)
         occurrences all number
    18
    1
    3
    Neurotoxicity
         subjects affected / exposed
    1 / 46 (2.17%)
    0 / 46 (0.00%)
    1 / 47 (2.13%)
         occurrences all number
    2
    0
    3
    Paraesthesia
         subjects affected / exposed
    1 / 46 (2.17%)
    0 / 46 (0.00%)
    0 / 47 (0.00%)
         occurrences all number
    1
    0
    0
    Peripheral sensory neuropathy
         subjects affected / exposed
    3 / 46 (6.52%)
    2 / 46 (4.35%)
    0 / 47 (0.00%)
         occurrences all number
    3
    2
    0
    Restless legs syndrome
         subjects affected / exposed
    1 / 46 (2.17%)
    0 / 46 (0.00%)
    0 / 47 (0.00%)
         occurrences all number
    1
    0
    0
    Seizure
         subjects affected / exposed
    1 / 46 (2.17%)
    0 / 46 (0.00%)
    0 / 47 (0.00%)
         occurrences all number
    1
    0
    0
    Tremor
         subjects affected / exposed
    0 / 46 (0.00%)
    0 / 46 (0.00%)
    1 / 47 (2.13%)
         occurrences all number
    0
    0
    1
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    18 / 46 (39.13%)
    13 / 46 (28.26%)
    11 / 47 (23.40%)
         occurrences all number
    29
    41
    31
    Leukocytosis
         subjects affected / exposed
    1 / 46 (2.17%)
    0 / 46 (0.00%)
    0 / 47 (0.00%)
         occurrences all number
    1
    0
    0
    Leukopenia
         subjects affected / exposed
    4 / 46 (8.70%)
    0 / 46 (0.00%)
    3 / 47 (6.38%)
         occurrences all number
    8
    0
    22
    Lymphopenia
         subjects affected / exposed
    2 / 46 (4.35%)
    2 / 46 (4.35%)
    0 / 47 (0.00%)
         occurrences all number
    8
    1
    0
    Neutropenia
         subjects affected / exposed
    4 / 46 (8.70%)
    3 / 46 (6.52%)
    4 / 47 (8.51%)
         occurrences all number
    10
    5
    19
    Neutrophilia
         subjects affected / exposed
    0 / 46 (0.00%)
    1 / 46 (2.17%)
    0 / 47 (0.00%)
         occurrences all number
    0
    1
    0
    Platelet disorder
         subjects affected / exposed
    1 / 46 (2.17%)
    0 / 46 (0.00%)
    0 / 47 (0.00%)
         occurrences all number
    1
    0
    0
    Thrombocytopenia
         subjects affected / exposed
    1 / 46 (2.17%)
    5 / 46 (10.87%)
    3 / 47 (6.38%)
         occurrences all number
    1
    6
    0
    Ear and labyrinth disorders
    Ear pain
         subjects affected / exposed
    1 / 46 (2.17%)
    0 / 46 (0.00%)
    0 / 47 (0.00%)
         occurrences all number
    1
    0
    0
    Hypoacusis
         subjects affected / exposed
    1 / 46 (2.17%)
    0 / 46 (0.00%)
    2 / 47 (4.26%)
         occurrences all number
    1
    0
    2
    Vertigo
         subjects affected / exposed
    1 / 46 (2.17%)
    0 / 46 (0.00%)
    0 / 47 (0.00%)
         occurrences all number
    1
    0
    0
    Eye disorders
    Cataract
         subjects affected / exposed
    1 / 46 (2.17%)
    0 / 46 (0.00%)
    0 / 47 (0.00%)
         occurrences all number
    1
    0
    0
    Dry eye
         subjects affected / exposed
    1 / 46 (2.17%)
    1 / 46 (2.17%)
    0 / 47 (0.00%)
         occurrences all number
    1
    1
    0
    Eyelid oedema
         subjects affected / exposed
    1 / 46 (2.17%)
    0 / 46 (0.00%)
    0 / 47 (0.00%)
         occurrences all number
    1
    0
    0
    Lacrimation increased
         subjects affected / exposed
    2 / 46 (4.35%)
    0 / 46 (0.00%)
    0 / 47 (0.00%)
         occurrences all number
    2
    0
    0
    Vision blurred
         subjects affected / exposed
    0 / 46 (0.00%)
    0 / 46 (0.00%)
    2 / 47 (4.26%)
         occurrences all number
    0
    0
    2
    Gastrointestinal disorders
    Abdominal distension
         subjects affected / exposed
    7 / 46 (15.22%)
    4 / 46 (8.70%)
    2 / 47 (4.26%)
         occurrences all number
    8
    4
    2
    Abdominal pain
         subjects affected / exposed
    16 / 46 (34.78%)
    16 / 46 (34.78%)
    21 / 47 (44.68%)
         occurrences all number
    29
    28
    27
    Anal incontinence
         subjects affected / exposed
    0 / 46 (0.00%)
    0 / 46 (0.00%)
    1 / 47 (2.13%)
         occurrences all number
    0
    0
    1
    Ascites
         subjects affected / exposed
    6 / 46 (13.04%)
    0 / 46 (0.00%)
    2 / 47 (4.26%)
         occurrences all number
    13
    0
    2
    Clostridium difficile colitis
         subjects affected / exposed
    1 / 46 (2.17%)
    0 / 46 (0.00%)
    0 / 47 (0.00%)
         occurrences all number
    1
    0
    0
    Constipation
         subjects affected / exposed
    18 / 46 (39.13%)
    14 / 46 (30.43%)
    17 / 47 (36.17%)
         occurrences all number
    30
    20
    24
    Diarrhoea
         subjects affected / exposed
    20 / 46 (43.48%)
    11 / 46 (23.91%)
    31 / 47 (65.96%)
         occurrences all number
    41
    14
    75
    Dry mouth
         subjects affected / exposed
    1 / 46 (2.17%)
    1 / 46 (2.17%)
    0 / 47 (0.00%)
         occurrences all number
    1
    1
    0
    Dry throat
         subjects affected / exposed
    0 / 46 (0.00%)
    1 / 46 (2.17%)
    0 / 47 (0.00%)
         occurrences all number
    0
    1
    0
    Dyspepsia
         subjects affected / exposed
    11 / 46 (23.91%)
    9 / 46 (19.57%)
    4 / 47 (8.51%)
         occurrences all number
    11
    11
    4
    Enteritis
         subjects affected / exposed
    0 / 46 (0.00%)
    0 / 46 (0.00%)
    1 / 47 (2.13%)
         occurrences all number
    0
    0
    1
    Faeces discoloured
         subjects affected / exposed
    1 / 46 (2.17%)
    1 / 46 (2.17%)
    0 / 47 (0.00%)
         occurrences all number
    1
    1
    0
    Flatulence
         subjects affected / exposed
    2 / 46 (4.35%)
    3 / 46 (6.52%)
    1 / 47 (2.13%)
         occurrences all number
    3
    3
    1
    Gastrointestinal haemorrhage
         subjects affected / exposed
    1 / 46 (2.17%)
    0 / 46 (0.00%)
    0 / 47 (0.00%)
         occurrences all number
    1
    0
    0
    Gastrooesophageal reflux disease
         subjects affected / exposed
    4 / 46 (8.70%)
    0 / 46 (0.00%)
    2 / 47 (4.26%)
         occurrences all number
    5
    0
    2
    Gingival pain
         subjects affected / exposed
    0 / 46 (0.00%)
    2 / 46 (4.35%)
    0 / 47 (0.00%)
         occurrences all number
    0
    2
    0
    Haemorrhoidal haemorrhage
         subjects affected / exposed
    0 / 46 (0.00%)
    0 / 46 (0.00%)
    1 / 47 (2.13%)
         occurrences all number
    0
    0
    1
    Haemorrhoids
         subjects affected / exposed
    1 / 46 (2.17%)
    0 / 46 (0.00%)
    1 / 47 (2.13%)
         occurrences all number
    1
    0
    1
    Intestinal obstruction
         subjects affected / exposed
    0 / 46 (0.00%)
    1 / 46 (2.17%)
    1 / 47 (2.13%)
         occurrences all number
    0
    1
    1
    Large intestinal obstruction
         subjects affected / exposed
    1 / 46 (2.17%)
    0 / 46 (0.00%)
    0 / 47 (0.00%)
         occurrences all number
    1
    0
    0
    Lip ulceration
         subjects affected / exposed
    1 / 46 (2.17%)
    0 / 46 (0.00%)
    0 / 47 (0.00%)
         occurrences all number
    1
    0
    0
    Lower gastrointestinal haemorrhage
         subjects affected / exposed
    0 / 46 (0.00%)
    1 / 46 (2.17%)
    0 / 47 (0.00%)
         occurrences all number
    0
    1
    0
    Mucositis
         subjects affected / exposed
    10 / 46 (21.74%)
    6 / 46 (13.04%)
    13 / 47 (27.66%)
         occurrences all number
    10
    6
    13
    Nausea
         subjects affected / exposed
    28 / 46 (60.87%)
    31 / 46 (67.39%)
    34 / 47 (72.34%)
         occurrences all number
    63
    52
    69
    Oesophagitis
         subjects affected / exposed
    1 / 46 (2.17%)
    0 / 46 (0.00%)
    0 / 47 (0.00%)
         occurrences all number
    1
    0
    0
    Proctalgia
         subjects affected / exposed
    0 / 46 (0.00%)
    1 / 46 (2.17%)
    0 / 47 (0.00%)
         occurrences all number
    0
    1
    0
    Rectal discharge
         subjects affected / exposed
    2 / 46 (4.35%)
    1 / 46 (2.17%)
    0 / 47 (0.00%)
         occurrences all number
    2
    2
    0
    Rectal haemorrhage
         subjects affected / exposed
    1 / 46 (2.17%)
    1 / 46 (2.17%)
    2 / 47 (4.26%)
         occurrences all number
    2
    2
    4
    Retching
         subjects affected / exposed
    0 / 46 (0.00%)
    0 / 46 (0.00%)
    1 / 47 (2.13%)
         occurrences all number
    0
    0
    1
    Small intestinal obstruction
         subjects affected / exposed
    1 / 46 (2.17%)
    0 / 46 (0.00%)
    0 / 47 (0.00%)
         occurrences all number
    1
    0
    0
    Small intestinal perforation
         subjects affected / exposed
    0 / 46 (0.00%)
    1 / 46 (2.17%)
    0 / 47 (0.00%)
         occurrences all number
    0
    2
    0
    Vomiting
         subjects affected / exposed
    23 / 46 (50.00%)
    16 / 46 (34.78%)
    25 / 47 (53.19%)
         occurrences all number
    41
    25
    51
    Hepatobiliary disorders
    Cholecystitis
         subjects affected / exposed
    1 / 46 (2.17%)
    0 / 46 (0.00%)
    0 / 47 (0.00%)
         occurrences all number
    1
    0
    0
    Hyperbilirubinaemia
         subjects affected / exposed
    0 / 46 (0.00%)
    1 / 46 (2.17%)
    1 / 47 (2.13%)
         occurrences all number
    0
    1
    2
    Jaundice
         subjects affected / exposed
    0 / 46 (0.00%)
    0 / 46 (0.00%)
    1 / 47 (2.13%)
         occurrences all number
    0
    0
    1
    Skin and subcutaneous tissue disorders
    Alopecia
         subjects affected / exposed
    23 / 46 (50.00%)
    1 / 46 (2.17%)
    3 / 47 (6.38%)
         occurrences all number
    35
    1
    4
    Dry skin
         subjects affected / exposed
    2 / 46 (4.35%)
    2 / 46 (4.35%)
    3 / 47 (6.38%)
         occurrences all number
    2
    2
    3
    Ephelides
         subjects affected / exposed
    0 / 46 (0.00%)
    0 / 46 (0.00%)
    1 / 47 (2.13%)
         occurrences all number
    0
    0
    1
    Itching
         subjects affected / exposed
    0 / 46 (0.00%)
    1 / 46 (2.17%)
    0 / 47 (0.00%)
         occurrences all number
    0
    2
    0
    Nail discolouration
         subjects affected / exposed
    1 / 46 (2.17%)
    0 / 46 (0.00%)
    1 / 47 (2.13%)
         occurrences all number
    1
    0
    1
    Nail disorder
         subjects affected / exposed
    2 / 46 (4.35%)
    0 / 46 (0.00%)
    0 / 47 (0.00%)
         occurrences all number
    2
    0
    0
    Nail ridging
         subjects affected / exposed
    1 / 46 (2.17%)
    1 / 46 (2.17%)
    0 / 47 (0.00%)
         occurrences all number
    1
    1
    0
    Night sweats
         subjects affected / exposed
    1 / 46 (2.17%)
    0 / 46 (0.00%)
    1 / 47 (2.13%)
         occurrences all number
    2
    0
    1
    Onychoclasis
         subjects affected / exposed
    1 / 46 (2.17%)
    0 / 46 (0.00%)
    0 / 47 (0.00%)
         occurrences all number
    1
    0
    0
    Onychomadesis
         subjects affected / exposed
    0 / 46 (0.00%)
    2 / 46 (4.35%)
    0 / 47 (0.00%)
         occurrences all number
    0
    2
    0
    Pain of skin
         subjects affected / exposed
    0 / 46 (0.00%)
    0 / 46 (0.00%)
    1 / 47 (2.13%)
         occurrences all number
    0
    0
    1
    Palmar-plantar erythrodysaesthesia syndrome
         subjects affected / exposed
    1 / 46 (2.17%)
    0 / 46 (0.00%)
    3 / 47 (6.38%)
         occurrences all number
    1
    0
    3
    Pruritus
         subjects affected / exposed
    0 / 46 (0.00%)
    0 / 46 (0.00%)
    4 / 47 (8.51%)
         occurrences all number
    0
    0
    5
    Rash
         subjects affected / exposed
    6 / 46 (13.04%)
    2 / 46 (4.35%)
    5 / 47 (10.64%)
         occurrences all number
    10
    3
    5
    Skin induration
         subjects affected / exposed
    0 / 46 (0.00%)
    0 / 46 (0.00%)
    1 / 47 (2.13%)
         occurrences all number
    0
    0
    1
    Skin reaction
         subjects affected / exposed
    1 / 46 (2.17%)
    0 / 46 (0.00%)
    0 / 47 (0.00%)
         occurrences all number
    1
    0
    0
    Swollen tongue
         subjects affected / exposed
    1 / 46 (2.17%)
    0 / 46 (0.00%)
    0 / 47 (0.00%)
         occurrences all number
    1
    0
    0
    Renal and urinary disorders
    Acute kidney injury
         subjects affected / exposed
    3 / 46 (6.52%)
    4 / 46 (8.70%)
    0 / 47 (0.00%)
         occurrences all number
    3
    5
    0
    Dysuria
         subjects affected / exposed
    1 / 46 (2.17%)
    3 / 46 (6.52%)
    3 / 47 (6.38%)
         occurrences all number
    1
    3
    3
    Haematuria
         subjects affected / exposed
    0 / 46 (0.00%)
    2 / 46 (4.35%)
    2 / 47 (4.26%)
         occurrences all number
    0
    2
    2
    Hydronephrosis
         subjects affected / exposed
    1 / 46 (2.17%)
    0 / 46 (0.00%)
    0 / 47 (0.00%)
         occurrences all number
    1
    0
    0
    Lower urinary tract symptoms
         subjects affected / exposed
    0 / 46 (0.00%)
    1 / 46 (2.17%)
    0 / 47 (0.00%)
         occurrences all number
    0
    1
    0
    Micturition urgency
         subjects affected / exposed
    1 / 46 (2.17%)
    1 / 46 (2.17%)
    0 / 47 (0.00%)
         occurrences all number
    1
    1
    0
    Nocturia
         subjects affected / exposed
    0 / 46 (0.00%)
    0 / 46 (0.00%)
    2 / 47 (4.26%)
         occurrences all number
    0
    0
    2
    Pollakiuria
         subjects affected / exposed
    3 / 46 (6.52%)
    0 / 46 (0.00%)
    1 / 47 (2.13%)
         occurrences all number
    3
    0
    1
    Polyuria
         subjects affected / exposed
    0 / 46 (0.00%)
    1 / 46 (2.17%)
    0 / 47 (0.00%)
         occurrences all number
    0
    1
    0
    Proteinuria
         subjects affected / exposed
    0 / 46 (0.00%)
    0 / 46 (0.00%)
    3 / 47 (6.38%)
         occurrences all number
    0
    0
    5
    Renal impairment
         subjects affected / exposed
    0 / 46 (0.00%)
    1 / 46 (2.17%)
    1 / 47 (2.13%)
         occurrences all number
    0
    1
    1
    Urethral pain
         subjects affected / exposed
    0 / 46 (0.00%)
    0 / 46 (0.00%)
    1 / 47 (2.13%)
         occurrences all number
    0
    0
    1
    Urinary incontinence
         subjects affected / exposed
    0 / 46 (0.00%)
    2 / 46 (4.35%)
    1 / 47 (2.13%)
         occurrences all number
    0
    2
    1
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    8 / 46 (17.39%)
    4 / 46 (8.70%)
    4 / 47 (8.51%)
         occurrences all number
    15
    5
    5
    Arthritis
         subjects affected / exposed
    0 / 46 (0.00%)
    0 / 46 (0.00%)
    1 / 47 (2.13%)
         occurrences all number
    0
    0
    2
    Back pain
         subjects affected / exposed
    4 / 46 (8.70%)
    6 / 46 (13.04%)
    5 / 47 (10.64%)
         occurrences all number
    4
    7
    6
    Bone pain
         subjects affected / exposed
    0 / 46 (0.00%)
    2 / 46 (4.35%)
    0 / 47 (0.00%)
         occurrences all number
    0
    2
    0
    Flank pain
         subjects affected / exposed
    0 / 46 (0.00%)
    2 / 46 (4.35%)
    1 / 47 (2.13%)
         occurrences all number
    0
    2
    1
    Groin pain
         subjects affected / exposed
    2 / 46 (4.35%)
    1 / 46 (2.17%)
    1 / 47 (2.13%)
         occurrences all number
    2
    1
    1
    Intervertebral disc protrusion
         subjects affected / exposed
    0 / 46 (0.00%)
    0 / 46 (0.00%)
    1 / 47 (2.13%)
         occurrences all number
    0
    0
    1
    Joint swelling
         subjects affected / exposed
    2 / 46 (4.35%)
    0 / 46 (0.00%)
    0 / 47 (0.00%)
         occurrences all number
    2
    0
    0
    Muscle spasms
         subjects affected / exposed
    2 / 46 (4.35%)
    1 / 46 (2.17%)
    5 / 47 (10.64%)
         occurrences all number
    2
    1
    6
    Muscular weakness
         subjects affected / exposed
    1 / 46 (2.17%)
    1 / 46 (2.17%)
    0 / 47 (0.00%)
         occurrences all number
    1
    1
    0
    Musculoskeletal chest pain
         subjects affected / exposed
    2 / 46 (4.35%)
    0 / 46 (0.00%)
    0 / 47 (0.00%)
         occurrences all number
    2
    0
    0
    Musculoskeletal discomfort
         subjects affected / exposed
    1 / 46 (2.17%)
    0 / 46 (0.00%)
    0 / 47 (0.00%)
         occurrences all number
    2
    0
    0
    Musculoskeletal pain
         subjects affected / exposed
    5 / 46 (10.87%)
    2 / 46 (4.35%)
    0 / 47 (0.00%)
         occurrences all number
    5
    4
    0
    Musculoskeletal stiffness
         subjects affected / exposed
    1 / 46 (2.17%)
    0 / 46 (0.00%)
    2 / 47 (4.26%)
         occurrences all number
    1
    0
    2
    Myalgia
         subjects affected / exposed
    4 / 46 (8.70%)
    0 / 46 (0.00%)
    3 / 47 (6.38%)
         occurrences all number
    5
    0
    3
    Neck pain
         subjects affected / exposed
    1 / 46 (2.17%)
    1 / 46 (2.17%)
    2 / 47 (4.26%)
         occurrences all number
    1
    1
    2
    Pain in extremity
         subjects affected / exposed
    5 / 46 (10.87%)
    3 / 46 (6.52%)
    7 / 47 (14.89%)
         occurrences all number
    7
    3
    9
    Tendon pain
         subjects affected / exposed
    1 / 46 (2.17%)
    0 / 46 (0.00%)
    0 / 47 (0.00%)
         occurrences all number
    1
    0
    0
    Infections and infestations
    Bacteraemia
         subjects affected / exposed
    0 / 46 (0.00%)
    0 / 46 (0.00%)
    1 / 47 (2.13%)
         occurrences all number
    0
    0
    1
    Cellulitis
         subjects affected / exposed
    2 / 46 (4.35%)
    1 / 46 (2.17%)
    0 / 47 (0.00%)
         occurrences all number
    3
    1
    0
    Clostridium difficile infection
         subjects affected / exposed
    0 / 46 (0.00%)
    0 / 46 (0.00%)
    1 / 47 (2.13%)
         occurrences all number
    0
    0
    1
    Cystitis
         subjects affected / exposed
    0 / 46 (0.00%)
    0 / 46 (0.00%)
    3 / 47 (6.38%)
         occurrences all number
    0
    0
    3
    Diverticulitis
         subjects affected / exposed
    0 / 46 (0.00%)
    0 / 46 (0.00%)
    1 / 47 (2.13%)
         occurrences all number
    0
    0
    1
    Eye infection
         subjects affected / exposed
    0 / 46 (0.00%)
    1 / 46 (2.17%)
    0 / 47 (0.00%)
         occurrences all number
    0
    1
    0
    Fungal infection
         subjects affected / exposed
    1 / 46 (2.17%)
    0 / 46 (0.00%)
    0 / 47 (0.00%)
         occurrences all number
    1
    0
    0
    Gastrointestinal infection
         subjects affected / exposed
    1 / 46 (2.17%)
    0 / 46 (0.00%)
    0 / 47 (0.00%)
         occurrences all number
    1
    0
    0
    Gingivitis
         subjects affected / exposed
    0 / 46 (0.00%)
    1 / 46 (2.17%)
    0 / 47 (0.00%)
         occurrences all number
    0
    1
    0
    Herpes zoster
         subjects affected / exposed
    1 / 46 (2.17%)
    2 / 46 (4.35%)
    1 / 47 (2.13%)
         occurrences all number
    1
    3
    1
    Hordeolum
         subjects affected / exposed
    1 / 46 (2.17%)
    0 / 46 (0.00%)
    0 / 47 (0.00%)
         occurrences all number
    1
    0
    0
    Infection
         subjects affected / exposed
    1 / 46 (2.17%)
    0 / 46 (0.00%)
    1 / 47 (2.13%)
         occurrences all number
    1
    0
    1
    Influenza
         subjects affected / exposed
    2 / 46 (4.35%)
    0 / 46 (0.00%)
    0 / 47 (0.00%)
         occurrences all number
    2
    0
    0
    Liver function test increased
         subjects affected / exposed
    0 / 46 (0.00%)
    1 / 46 (2.17%)
    0 / 47 (0.00%)
         occurrences all number
    0
    1
    0
    Lower respiratory tract infection
         subjects affected / exposed
    7 / 46 (15.22%)
    4 / 46 (8.70%)
    5 / 47 (10.64%)
         occurrences all number
    9
    4
    5
    Nasopharyngitis
         subjects affected / exposed
    1 / 46 (2.17%)
    1 / 46 (2.17%)
    5 / 47 (10.64%)
         occurrences all number
    1
    1
    6
    Omphalitis
         subjects affected / exposed
    1 / 46 (2.17%)
    0 / 46 (0.00%)
    1 / 47 (2.13%)
         occurrences all number
    1
    0
    1
    Onychomycosis
         subjects affected / exposed
    0 / 46 (0.00%)
    0 / 46 (0.00%)
    1 / 47 (2.13%)
         occurrences all number
    0
    0
    1
    Oral candidiasis
         subjects affected / exposed
    3 / 46 (6.52%)
    1 / 46 (2.17%)
    1 / 47 (2.13%)
         occurrences all number
    3
    1
    1
    Oral herpes
         subjects affected / exposed
    1 / 46 (2.17%)
    1 / 46 (2.17%)
    1 / 47 (2.13%)
         occurrences all number
    1
    1
    1
    Paronychia
         subjects affected / exposed
    1 / 46 (2.17%)
    0 / 46 (0.00%)
    1 / 47 (2.13%)
         occurrences all number
    2
    0
    1
    Pneumonia
         subjects affected / exposed
    1 / 46 (2.17%)
    0 / 46 (0.00%)
    2 / 47 (4.26%)
         occurrences all number
    1
    0
    3
    Respiratory tract infection
         subjects affected / exposed
    0 / 46 (0.00%)
    1 / 46 (2.17%)
    0 / 47 (0.00%)
         occurrences all number
    0
    1
    0
    Sepsis
         subjects affected / exposed
    1 / 46 (2.17%)
    0 / 46 (0.00%)
    1 / 47 (2.13%)
         occurrences all number
    1
    0
    1
    Sinusitis
         subjects affected / exposed
    1 / 46 (2.17%)
    0 / 46 (0.00%)
    0 / 47 (0.00%)
         occurrences all number
    1
    0
    0
    Skin infection
         subjects affected / exposed
    1 / 46 (2.17%)
    0 / 46 (0.00%)
    0 / 47 (0.00%)
         occurrences all number
    1
    0
    0
    Stoma site infection
         subjects affected / exposed
    0 / 46 (0.00%)
    0 / 46 (0.00%)
    1 / 47 (2.13%)
         occurrences all number
    0
    0
    1
    Tooth abscess
         subjects affected / exposed
    0 / 46 (0.00%)
    0 / 46 (0.00%)
    1 / 47 (2.13%)
         occurrences all number
    0
    0
    1
    Tooth infection
         subjects affected / exposed
    0 / 46 (0.00%)
    0 / 46 (0.00%)
    1 / 47 (2.13%)
         occurrences all number
    0
    0
    2
    Upper respiratory tract infection
         subjects affected / exposed
    4 / 46 (8.70%)
    1 / 46 (2.17%)
    1 / 47 (2.13%)
         occurrences all number
    5
    1
    1
    Urinary tract infection
         subjects affected / exposed
    7 / 46 (15.22%)
    6 / 46 (13.04%)
    8 / 47 (17.02%)
         occurrences all number
    9
    8
    11
    Vaginal infection
         subjects affected / exposed
    0 / 46 (0.00%)
    0 / 46 (0.00%)
    1 / 47 (2.13%)
         occurrences all number
    0
    0
    1
    Metabolism and nutrition disorders
    Decreased appetite
         subjects affected / exposed
    16 / 46 (34.78%)
    11 / 46 (23.91%)
    16 / 47 (34.04%)
         occurrences all number
    20
    22
    33
    Dehydration
         subjects affected / exposed
    0 / 46 (0.00%)
    3 / 46 (6.52%)
    2 / 47 (4.26%)
         occurrences all number
    0
    3
    3
    Hypercalcaemia
         subjects affected / exposed
    1 / 46 (2.17%)
    0 / 46 (0.00%)
    0 / 47 (0.00%)
         occurrences all number
    1
    0
    0
    Hyperkalaemia
         subjects affected / exposed
    1 / 46 (2.17%)
    1 / 46 (2.17%)
    0 / 47 (0.00%)
         occurrences all number
    1
    1
    0
    Hypernatraemia
         subjects affected / exposed
    0 / 46 (0.00%)
    0 / 46 (0.00%)
    1 / 47 (2.13%)
         occurrences all number
    0
    0
    1
    Hypoalbuminaemia
         subjects affected / exposed
    2 / 46 (4.35%)
    0 / 46 (0.00%)
    0 / 47 (0.00%)
         occurrences all number
    2
    0
    0
    Hypocalcaemia
         subjects affected / exposed
    2 / 46 (4.35%)
    1 / 46 (2.17%)
    1 / 47 (2.13%)
         occurrences all number
    2
    1
    1
    Hypokalaemia
         subjects affected / exposed
    3 / 46 (6.52%)
    3 / 46 (6.52%)
    2 / 47 (4.26%)
         occurrences all number
    10
    3
    3
    Hypomagnesaemia
         subjects affected / exposed
    8 / 46 (17.39%)
    5 / 46 (10.87%)
    8 / 47 (17.02%)
         occurrences all number
    12
    6
    16
    Hyponatraemia
         subjects affected / exposed
    4 / 46 (8.70%)
    0 / 46 (0.00%)
    2 / 47 (4.26%)
         occurrences all number
    4
    0
    6
    Hypophagia
         subjects affected / exposed
    1 / 46 (2.17%)
    0 / 46 (0.00%)
    0 / 47 (0.00%)
         occurrences all number
    1
    0
    0
    Hypophosphataemia
         subjects affected / exposed
    1 / 46 (2.17%)
    0 / 46 (0.00%)
    0 / 47 (0.00%)
         occurrences all number
    1
    0
    0
    Hypoproteinaemia
         subjects affected / exposed
    1 / 46 (2.17%)
    0 / 46 (0.00%)
    0 / 47 (0.00%)
         occurrences all number
    1
    0
    0
    Vitamin D deficiency
         subjects affected / exposed
    0 / 46 (0.00%)
    0 / 46 (0.00%)
    1 / 47 (2.13%)
         occurrences all number
    0
    0
    1

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    02 Aug 2017
    The amendment concerned a number of changes to the protocol and patient materials. ‘Patients with increased risk of thrombotic events or who have a history of thrombotic events’ was removed from the trial exclusion criteria. The exclusion criterion relating to cardiac function (ECHO) was also clarified to reflect the cardiac function requirements detailed in the drug management section of the protocol for patients on Arm C (olaparib and cediranib). The requirement to fast when taking olaparib was removed from the protocol based on updated information in the olaparib IB. The amendment also concerned removal of PK sampling and changes to drug modification in response to toxicity. The olaparib investigator brochure Edition 14 was also submitted to act as the updated RSI.
    21 Sep 2017
    Updated olaparib label (removing fasting language)
    13 Mar 2018
    The amendment concerned a number of changes to the protocol and patient materials. The requirement to wait 6 months after administration of bevacizumab was reduced to 6 weeks (1 half-life). The screening Hb requirement was reduced to 9g/dL from 10g/dL. The exclusion criterion relating to cardiac risk of 'Prior treatment with anthracyclines' has been refined to exclude liposomal doxorubicin. The requirement for a patient receiving paclitaxel to be assessed by a doctor has been reduced to once a cycle, as per standard of care. Similarly research nurses may review AEs at other treatment visits as per local site policy.The cediranib investigator brochure Edition 20 was submitted to the MHRA to act as the reference safety information for the trial.
    21 Jun 2018
    Addition of new site.
    05 Oct 2018
    The amendment concerned a number of changes to the protocol and patient materials. The inclusion criteria was updated to include BRCA wildtype patients.The guidance for management of rotator cuff injury was removed from the protocol as this adverse event has been removed from the list of possible cediranib/olaparib combination toxicities in the current cediranib investigator brochure approved for the study (Edition 20). Two sites included in the original IRAS were removed prior to activation, Guy’s and St Thomas and Birmingham due to feasibility issues.
    20 Aug 2019
    The amendment concerned a number of changes to the protocol and patient materials. Scans were reduced to 12 weekly once participants had been on treatment for 12 months. A third dose reduction was also proposed for olaparib of 150mg BD. A requirement for patients to start treatment within 8 days of randomisation was also added to the protocol. Guidance on concomitant use of a new class of anti-coagulant, novel oral anticoagulants (NOACs) was added, as use of these NOACs was becoming more frequent amongst this patient population. Clarification was also made to the trial inclusion criterion 12, adverse event reporting and the trial schedule of events. The latest version of the olaparib investigator brochure, Edition 17, was submitted to the MHRA as the reference safety information for the study.
    16 Apr 2020
    A change of PI at UCLH.
    18 Jun 2021
    The amendment concerned clarification of the end of trial definition. The protocol was also updated to include a section on management of patients remaining on treatment past 18 months and the safety assessments that are required. The olaparib investigator brochure Edition 20 was submitted to the MHRA as the updated reference safety information for the trial.
    13 Oct 2021
    The amendment concerned a change of PI at a participating site. The protocol was also updated to clarify the requirements for CT scans for participants that continue on trial beyond 18 months of treatment.
    22 Jun 2022
    The olaparib investigator brochure Edition 21 was submitted to the MHRA as the updated reference safety information for the trial. The Patient Information sheet was updated to reflect the adverse drug reactions.

    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

    Online references
    http://www.ncbi.nlm.nih.gov/pubmed/38245661
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