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    Clinical Trial Results:
    A Randomized, Phase II Study Evaluating MK-1775 in Combination with Paclitaxel and Carboplatin versus Paclitaxel and Carboplatin Alone in Adult Patients with Platinum Sensitive p53 Mutant Ovarian Cancer

    Summary
    EudraCT number
    		 2011-002803-13
    Trial protocol
    		 DE   SE   HU   GB  
    Global end of trial date
    08 Aug 2016

    Results information
    Results version number
    		 v1(current)
    This version publication date
    06 Aug 2017
    First version publication date
    06 Aug 2017
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    1775-004
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT01357161
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Merck Sharp & Dohme Corp.
    Sponsor organisation address
    2000 Galloping Hill Road, Kenilworth, NJ, United States, 07033
    Public contact
    Clinical Trials Disclosure, Merck Sharp & Dohme Corp., ClinicalTrialsDisclosure@merck.com
    Scientific contact
    Clinical Trials Disclosure, Merck Sharp & Dohme Corp., ClinicalTrialsDisclosure@merck.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
    08 Aug 2016
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    08 Aug 2016
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    This was a study of the safety and efficacy of MK-1775 in combination with paclitaxel plus carboplatin in the treatment of ovarian, fallopian tube, and primary peritoneal tumors with the P53 mutation. In Part 1, a small group of participants received MK-1775 along with paclitaxel plus carboplatin to establish the tolerability of MK-1775 with this combination. In Part 2, participants were randomly assigned to receive either MK-1775 plus paclitaxel and carboplatin OR placebo plus paclitaxel and carboplatin to assess efficacy of MK-1775 compared to placebo. The primary hypothesis of the study (Part 2) was that administration of MK-1775 in combination with paclitaxel plus carboplatin in participants with platinum sensitive p53 mutant ovarian cancer would result in improvement in progression free survival (PFS) per enhanced Response Evaluation Criteria In Solid Tumors version 1.1 (enhanced RECIST 1.1) compared to participants treated with paclitaxel plus carboplatin alone.
    Protection of trial subjects
    This study was conducted in conformance with Good Clinical Practice standards and applicable country and/or local statutes and regulations regarding ethical committee review, informed consent, and the protection of human subjects participating in biomedical research.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    26 Jul 2011
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    No
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Brazil: 5
    Country: Number of subjects enrolled
    Canada: 34
    Country: Number of subjects enrolled
    Germany: 17
    Country: Number of subjects enrolled
    Hungary: 9
    Country: Number of subjects enrolled
    Israel: 3
    Country: Number of subjects enrolled
    Sweden: 12
    Country: Number of subjects enrolled
    Taiwan: 8
    Country: Number of subjects enrolled
    United Kingdom: 13
    Country: Number of subjects enrolled
    United States: 22
    Country: Number of subjects enrolled
    Russian Federation: 13
    Worldwide total number of subjects
    136
    EEA total number of subjects
    51
    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)
    94
    From 65 to 84 years
    42
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 -

    Pre-assignment
    Screening details
    		 Fifteen participants were enrolled in the open label run-in (Part 1) and 121 participants were enrolled separately in the double-blind comparison (Part 2) for a total of 136 participants.

    Period 1
    Period 1 title
    Overall Study (overall period)
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Subject, Investigator

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Part 1: MK-1775 225 mg + paclitaxel +carboplatin
    Arm description
    		 During the open-label run-in, participants received 225 mg MK-1775 twice daily (BID) starting on Day 1 of Cycle 1 (cycle=21 days) for a total of 5 doses. Participants received MK-1775 in combination with paclitaxel (175 mg/m2) and carboplatin (area under the curve [AUC] 5).
    Arm type
    		 Experimental

    Investigational medicinal product name
    MK-1775
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    MK-1775 capsules, orally twice a day (BID) for a total of 5 doses starting on Day 1 of each 3-week cycle

    Investigational medicinal product name
    paclitaxel
    Investigational medicinal product code
    Other name
    Taxol
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    paclitaxel, intravenous (IV) infusion on Day 1 of each 3-week cycle

    Investigational medicinal product name
    carboplatin
    Investigational medicinal product code
    Other name
    paraplatin
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    carboplatin, IV infusion on Day 1 of each 3-week cycle

    Arm title
    		 Part 2: MK-1775 225 mg + paclitaxel +carboplatin
    Arm description
    		 During Part 2, participants received 225 mg MK-1775 BID starting on Day 1 of each 21 day cycle for a total of 5 doses. Participants received MK-1775 in combination with paclitaxel (175 mg/m2) and carboplatin (AUC 5).
    Arm type
    		 Experimental

    Investigational medicinal product name
    MK-1775
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    MK-1775 capsules, orally twice a day (BID) for a total of 5 doses starting on Day 1 of each 3-week cycle

    Investigational medicinal product name
    paclitaxel
    Investigational medicinal product code
    Other name
    Taxol
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    paclitaxel, intravenous (IV) infusion on Day 1 of each 3-week cycle

    Investigational medicinal product name
    carboplatin
    Investigational medicinal product code
    Other name
    paraplatin
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    carboplatin, IV infusion on Day 1 of each 3-week cycle

    Arm title
    		 Part 2: Placebo + paclitaxel +carboplatin
    Arm description
    		 During Part 2, participants received matched placebo to MK-1775 BID starting on Day 1 of each 21 day cycle for a total of 5 doses. Participants received placebo in combination with paclitaxel (175 mg/m2) and carboplatin (AUC 5).
    Arm type
    		 Experimental

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    placebo capsule to MK-1775, orally BID for a total of 5 doses, starting on Day 1 of each 3-week cycle

    Investigational medicinal product name
    paclitaxel
    Investigational medicinal product code
    Other name
    Taxol
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    paclitaxel, intravenous (IV) infusion on Day 1 of each 3-week cycle

    Investigational medicinal product name
    carboplatin
    Investigational medicinal product code
    Other name
    paraplatin
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    carboplatin, IV infusion on Day 1 of each 3-week cycle

    Number of subjects in period 1
    		Part 1: MK-1775 225 mg + paclitaxel +carboplatin Part 2: MK-1775 225 mg + paclitaxel +carboplatin Part 2: Placebo + paclitaxel +carboplatin
    Started
    15
    59
    62
    Completed
    0
    0
    0
    Not completed
    15
    59
    62
         Adverse event, serious fatal
    5
    22
    19
         Physician decision
    1
    1
    4
         Consent withdrawn by subject
    1
    5
    4
         Study Terminated By Sponsor
    5
    29
    26
         Progressive Disease
    -
    1
    3
         Lost to follow-up
    3
    1
    6

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Part 1: MK-1775 225 mg + paclitaxel +carboplatin
    Reporting group description
    		 During the open-label run-in, participants received 225 mg MK-1775 twice daily (BID) starting on Day 1 of Cycle 1 (cycle=21 days) for a total of 5 doses. Participants received MK-1775 in combination with paclitaxel (175 mg/m2) and carboplatin (area under the curve [AUC] 5).

    Reporting group title
    Part 2: MK-1775 225 mg + paclitaxel +carboplatin
    Reporting group description
    		 During Part 2, participants received 225 mg MK-1775 BID starting on Day 1 of each 21 day cycle for a total of 5 doses. Participants received MK-1775 in combination with paclitaxel (175 mg/m2) and carboplatin (AUC 5).

    Reporting group title
    Part 2: Placebo + paclitaxel +carboplatin
    Reporting group description
    		 During Part 2, participants received matched placebo to MK-1775 BID starting on Day 1 of each 21 day cycle for a total of 5 doses. Participants received placebo in combination with paclitaxel (175 mg/m2) and carboplatin (AUC 5).

    Reporting group values
    		 Part 1: MK-1775 225 mg + paclitaxel +carboplatin Part 2: MK-1775 225 mg + paclitaxel +carboplatin Part 2: Placebo + paclitaxel +carboplatin Total
    Number of subjects
    		 15 59 62 136
    Age categorical
    Units: Subjects
    Age Continuous
    Units: years
        arithmetic mean (standard deviation)
    		 58.2 ( 9.9 ) 58.3 ( 10.1 ) 60.4 ( 9.8 ) -
    Gender, Male/Female
    Units: Subjects
        Female
    		 15 59 62 136

    End points

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    End points reporting groups
    Reporting group title
    Part 1: MK-1775 225 mg + paclitaxel +carboplatin
    Reporting group description
    		 During the open-label run-in, participants received 225 mg MK-1775 twice daily (BID) starting on Day 1 of Cycle 1 (cycle=21 days) for a total of 5 doses. Participants received MK-1775 in combination with paclitaxel (175 mg/m2) and carboplatin (area under the curve [AUC] 5).

    Reporting group title
    Part 2: MK-1775 225 mg + paclitaxel +carboplatin
    Reporting group description
    		 During Part 2, participants received 225 mg MK-1775 BID starting on Day 1 of each 21 day cycle for a total of 5 doses. Participants received MK-1775 in combination with paclitaxel (175 mg/m2) and carboplatin (AUC 5).

    Reporting group title
    Part 2: Placebo + paclitaxel +carboplatin
    Reporting group description
    		 During Part 2, participants received matched placebo to MK-1775 BID starting on Day 1 of each 21 day cycle for a total of 5 doses. Participants received placebo in combination with paclitaxel (175 mg/m2) and carboplatin (AUC 5).

    Primary: Part 2: Median Progression-free survival (PFS) in weeks based on Enhanced Response Evaluation Criteria In Solid Tumors version 1.1 (enhanced RECIST 1.1) by Independent Radiology Review

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    End point title
    		 Part 2: Median Progression-free survival (PFS) in weeks based on Enhanced Response Evaluation Criteria In Solid Tumors version 1.1 (enhanced RECIST 1.1) by Independent Radiology Review [1]
    End point description
    PFS was defined as the time from randomization to progressive disease (based on blinded independent central radiologic review) or death, whichever occurred earlier. Tumor response was evaluated every 6 weeks during treatment by diagnostic anatomic imaging and objective response assessments were performed based on enhanced RECIST 1.1 criteria. According to enhanced RECIST 1.1, progressive disease was the appearance of one or more new lesions, OR an unambiguous increase in the sum of target lesion volumes with both 1) >20% increase in the sum of volumes (SOV) of all target lesions (taking as reference the nadir) and 2) greater than two times the variability of the measurements estimated by the sponsor and/or its designees. PFS was analyzed for all randomized Part 2 participants (Intent to Treat [ITT] Population) using the Kaplan-Meier method and median PFS was reported in weeks. Per protocol, Part 1 participants were not included in this analysis.
    End point type
    Primary
    End point timeframe
    Up to 57 months
    Notes
    [1] - 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: As pre-specified by the protocol, this endpoint reported data for only the Part 2 arms.
    End point values
    		 Part 2: MK-1775 225 mg + paclitaxel +carboplatin Part 2: Placebo + paclitaxel +carboplatin
    Number of subjects analysed
    59
    62
    Units: weeks
        median (confidence interval 95%)
    34.14 (29.86 to 43.14)
    31.86 (24.43 to 35.57)
    Statistical analysis title
    		 Part 2 PFS (enhanced RECIST): MK-1775 vs. Placebo
    Statistical analysis description
    A stratified [number of prior platinum based regimens (1 vs. 2 and 3), time since last platinum based therapy (<12 months vs. ≥12 months)] Cox proportional hazards model, with Efron method of tie handling, was used to assess the magnitude of the treatment difference between the treatment arms. The p-value from the score test was used in the significance test and the hazard ratio (MK-1775 versus Placebo) and its 95% confidence interval (CI) from the same Cox model was reported.
    Comparison groups
    Part 2: Placebo + paclitaxel +carboplatin v Part 2: MK-1775 225 mg + paclitaxel +carboplatin
    Number of subjects included in analysis
    121
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    		 = 0.08
    Method
    		 Cox proportional hazards model
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.63
    Confidence interval
         level
    		 80%
         sides
    2-sided
         lower limit
    		 0.45
         upper limit
    		 0.89

    Primary: Part 1: Number of participants with a dose limiting toxicity (DLT)

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    End point title
    		 Part 1: Number of participants with a dose limiting toxicity (DLT) [2] [3]
    End point description
    DLTs assessed during first 21-day cycle of Part 1 and defined as toxicities that met pre-defined severity criteria, were possibly, probably, or definitely related to triplet therapy, and could possibly result in a change in the given dose. Hematologic DLTs included Grade (Gr) 3 or Gr 4 neutropenia with fever >38.5°C and/or infection requiring antibiotic or anti-fungal treatment, and any Gr 4-5 hematological toxicity EXCEPT Gr 4 anemia, leukopenia, lymphopenia, neutropenia lasting <7 days, and thrombocytopenia lasting <4 days, except if a platelet transfusion was required. Non-hematologic DLT defined as any Gr 3, 4, or 5 nonhematologic toxicity EXCEPT: Gr 3 nausea, vomiting, diarrhea, or dehydration judged by Investigator and SPONSOR to occur in setting of inadequate compliance with supportive care measures and last for less than 48 hours, alopecia of any grade, inadequately treated hypersensitivity reactions, or clinically non-significant, treatable or reversible lab abnormalities.
    End point type
    Primary
    End point timeframe
    During Cycle 1 of Part 1 (first 21 days)
    Notes
    [2] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: No between-group statistical analyses were planned for this endpoint.
    [3] - 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: As pre-specified by the protocol, this endpoint reported data for only the Part 1 arm.
    End point values
    		 Part 1: MK-1775 225 mg + paclitaxel +carboplatin
    Number of subjects analysed
    12 [4]
    Units: participants
        Total
    3
        Febrile neutropenia
    1
        Neutropenia
    1
        Thrombocytopenia
    1
    Notes
    [4] - 3 participants excluded due to prohibited medication (1) and enrollment after interim analysis (2).
    No statistical analyses for this end point

    Primary: Parts 1 and 2: Percentage of participants that experienced an adverse event (AE)

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    End point title
    		 Parts 1 and 2: Percentage of participants that experienced an adverse event (AE)
    End point description
    An AE was defined as any unfavorable and unintended change in the structure, function, or chemistry of the body temporally associated with the use of the SPONSOR’s products, whether or not considered related to the use of the product. Any worsening (i.e., any clinically significant adverse change in frequency and/or intensity) of a preexisting condition which is temporally associated with the use of the SPONSOR’s product was also an AE. The percentage of participants that experienced at least one AE was reported for each treatment arm. All participants who received at least one dose of study treatment during Parts 1 and 2 were analyzed.
    End point type
    Primary
    End point timeframe
    Part 1: Day 1 through Post Study (286 days total). Part 2: Day 1 through Post Study (479 days total)
    End point values
    		 Part 1: MK-1775 225 mg + paclitaxel +carboplatin Part 2: MK-1775 225 mg + paclitaxel +carboplatin Part 2: Placebo + paclitaxel +carboplatin
    Number of subjects analysed
    15
    59
    60 [5]
    Units: percentage of participants
        number (not applicable)
    100
    100
    96.7
    Notes
    [5] - Two participants were randomized to the Part 2 placebo arm but were not treated.
    Statistical analysis title
    		 % with AEs: Part 2 MK-1775 vs. Placebo
    Statistical analysis description
    P-values and 95% CIs were calculated using the Miettinen and Nurminen method for between-treatment differences (MK-1775 vs. placebo) in the percentage of participants with events.
    Comparison groups
    Part 2: MK-1775 225 mg + paclitaxel +carboplatin v Part 2: Placebo + paclitaxel +carboplatin
    Number of subjects included in analysis
    119
    Analysis specification
    Pre-specified
    Analysis type
    Method
    Parameter type
    		 Difference in Percentages
    Point estimate
    3.3
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -2.9
         upper limit
    		 11.4

    Primary: Parts 1 and 2: Percentage of participants that discontinued study treatment due to an AE

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    End point title
    		 Parts 1 and 2: Percentage of participants that discontinued study treatment due to an AE
    End point description
    An AE was defined as any unfavorable and unintended change in the structure, function, or chemistry of the body temporally associated with the use of the SPONSOR’s products, whether or not considered related to the use of the product. Any worsening (i.e., any clinically significant adverse change in frequency and/or intensity) of a preexisting condition which is temporally associated with the use of the SPONSOR’s product was also an AE. The percentage of participants that discontinued (DC) study treatment (paclitaxel, carboplatin, or MK-1775) due to an AE was reported for each treatment arm. All participants who received at least one dose of study treatment during Parts 1 and 2 were analyzed.
    End point type
    Primary
    End point timeframe
    Part 1: Day 1 through Post Study (286 days total). Part 2: Day 1 through Post Study (479 days total)
    End point values
    		 Part 1: MK-1775 225 mg + paclitaxel +carboplatin Part 2: MK-1775 225 mg + paclitaxel +carboplatin Part 2: Placebo + paclitaxel +carboplatin
    Number of subjects analysed
    15
    59
    60 [6]
    Units: percentage of participants
        number (not applicable)
    20
    20.3
    21.7
    Notes
    [6] - Two participants were randomized to the Part 2 placebo arm but were not treated.
    Statistical analysis title
    		 % DC due to AEs: Part 2 MK-1775 vs. Placebo
    Statistical analysis description
    P-values and 95% CIs were calculated using the Miettinen and Nurminen method for between-treatment differences (MK-1775 vs. placebo) in the percentage of participants with events.
    Comparison groups
    Part 2: MK-1775 225 mg + paclitaxel +carboplatin v Part 2: Placebo + paclitaxel +carboplatin
    Number of subjects included in analysis
    119
    Analysis specification
    Pre-specified
    Analysis type
    Method
    Parameter type
    		 Difference in Percentages
    Point estimate
    -1.3
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -16.2
         upper limit
    		 13.6

    Secondary: Part 1: Objective response rate (ORR) per Gynecological Cancer Intergroup (GCIG) criteria based on both RECIST 1.1 and cancer antigen 125 (CA-125) level by Independent Radiology Review

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    End point title
    		 Part 1: Objective response rate (ORR) per Gynecological Cancer Intergroup (GCIG) criteria based on both RECIST 1.1 and cancer antigen 125 (CA-125) level by Independent Radiology Review [7]
    End point description
    ORR was defined as the percentage of participants whose best response was confirmed partial response (PR) or complete response (CR) based both on imaging per RECIST 1.1 and on serum marker CA-125 level according to GCIC criteria. CR was defined by RECIST 1.1 as disappearance of all target lesions. Any pathological lymph nodes (whether target or non-target) must have had reduction in short axis to <10 mm. PR was defined by RECIST 1.1 as at least a 30% decrease in the sum of the diameters (SOD) of target lesions, taking as reference the baseline SOD. A response according to CA-125 had occurred if there was ≥50% reduction in CA-125 levels from a pretreatment sample. The response must have been confirmed and maintained for at least 28 days. Participants could be evaluated according to CA-125 only if they had a pretreatment sample that was ≥2 times the upper limit of normal and within 2 weeks prior to starting treatment. Only evaluable Part 1 participants were analyzed for this endpoint.
    End point type
    Secondary
    End point timeframe
    Up to 57 months
    Notes
    [7] - 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: As pre-specified by the protocol, this endpoint reported data for only the Part 1 arm.
    End point values
    		 Part 1: MK-1775 225 mg + paclitaxel +carboplatin
    Number of subjects analysed
    12 [8]
    Units: percentage of participants
        number (confidence interval 95%)
    75 (42.814 to 94.514)
    Notes
    [8] - 3 participants excluded due to prohibited medication (1) and enrollment after interim analysis (2).
    No statistical analyses for this end point

    Secondary: Part 2: Median PFS in weeks based on RECIST 1.1 by Independent Radiology Review

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    End point title
    		 Part 2: Median PFS in weeks based on RECIST 1.1 by Independent Radiology Review [9]
    End point description
    PFS was defined as the time from randomization to progressive disease (based on blinded independent central radiologic review) or death, whichever occurred earlier. Tumor response was evaluated every 6 weeks during treatment by diagnostic anatomic imaging and objective response assessments were performed based on RECIST 1.1 criteria. According to RECIST 1.1, progressive disease was the appearance of one or more new lesions, OR a ≥20% increase in the sum of target lesion diameters (SOD) taking as reference the nadir (smallest SOD recorded since treatment started). PFS was analyzed for all randomized participants in Part 2 using the Kaplan-Meier method and median PFS was reported in weeks. Per protocol, Part 1 participants were not included in this analysis.
    End point type
    Secondary
    End point timeframe
    Up to 57 months
    Notes
    [9] - 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: As pre-specified by the protocol, this endpoint reported data for only the Part 2 arms.
    End point values
    		 Part 2: MK-1775 225 mg + paclitaxel +carboplatin Part 2: Placebo + paclitaxel +carboplatin
    Number of subjects analysed
    59
    62
    Units: weeks
        median (confidence interval 95%)
    42.86 (35 to 48.86)
    34.86 (30.43 to 36.86)
    Statistical analysis title
    		 Part 2 PFS (RECIST): MK-1775 vs. Placebo
    Statistical analysis description
    A stratified [number of prior platinum based regimens (1 vs. 2 and 3), time since last platinum based therapy (<12 months vs. ≥12 months)] Cox proportional hazards model, with Efron method of tie handling, was used to assess the magnitude of the treatment difference between the treatment arms. The p-value from the score test was used in the significance test and the hazard ratio (MK-1775 versus Placebo) and its 95% CI from the same Cox model was reported.
    Comparison groups
    Part 2: MK-1775 225 mg + paclitaxel +carboplatin v Part 2: Placebo + paclitaxel +carboplatin
    Number of subjects included in analysis
    121
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    		 = 0.03
    Method
    		 Cox proportional hazards model
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.55
    Confidence interval
         level
    		 80%
         sides
    2-sided
         lower limit
    		 0.39
         upper limit
    		 0.79

    Secondary: Part 2: ORR per GCIG criteria based on both Enhanced RECIST 1.1 and CA125 level by Independent Radiology Review

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    End point title
    		 Part 2: ORR per GCIG criteria based on both Enhanced RECIST 1.1 and CA125 level by Independent Radiology Review [10]
    End point description
    ORR defined as the percentage of participants with best response of confirmed PR or CR based both on imaging per enhanced RECIST 1.1 and on serum marker CA-125 level according to GCIC criteria. CR defined by enhanced RECIST 1.1 as disappearance of all target lesions. Any pathological lymph nodes (target or non-target) had reduction in short axis to <10 mm. PR defined by enhanced RECIST 1.1 as ≥30% decrease in SOV of target lesions, taking as reference baseline SOV. Response according to CA-125 had occurred if there was ≥50% reduction in CA-125 levels from pretreatment sample. Response must have been confirmed and maintained for ≥28 days. Participants could be evaluated according to CA-125 only if they had a pretreatment sample that was ≥2 times the upper limit of normal and within 2 weeks prior to starting treatment. All randomized participants in Part 2 were analyzed. Per protocol, Part 1 participants were not included in this analysis.
    End point type
    Secondary
    End point timeframe
    Up to 57 months
    Notes
    [10] - 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: As pre-specified by the protocol, this endpoint reported data for only the Part 2 arms.
    End point values
    		 Part 2: MK-1775 225 mg + paclitaxel +carboplatin Part 2: Placebo + paclitaxel +carboplatin
    Number of subjects analysed
    59
    62
    Units: percentage of participants
        number (confidence interval 95%)
    74.58 (61.6 to 85)
    69.35 (56.3 to 80.4)
    Statistical analysis title
    		 Part 2 ORR (enhanced RECIST): MK-1775 vs. Placebo
    Statistical analysis description
    Stratified Miettinen and Nurminen’s method with a two-sided p-Value for testing was used for comparison of the ORRs between the treatment groups in Part 2 portion of the study. A 95% CI for the difference in response rates was provided.
    Comparison groups
    Part 2: MK-1775 225 mg + paclitaxel +carboplatin v Part 2: Placebo + paclitaxel +carboplatin
    Number of subjects included in analysis
    121
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    		 = 0.5247
    Method
    		 Miettinen and Nurminen’s Method
    Parameter type
    		 Difference in Response Rate
    Point estimate
    5.2
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -10.9
         upper limit
    		 21.1

    Secondary: Part 2: Median Overall survival (OS) in months

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    End point title
    		 Part 2: Median Overall survival (OS) in months [11]
    End point description
    OS was defined as the time from randomization to death due to any cause, reported in months. Participants without documented death at the time of analysis were censored at the date last known to be alive. For this endpoint, all randomized participants in Part 2 were analyzed. Per protocol, Part 1 participants were not evaluated for OS. Median OS could not be calculated due to a small percentage of death events observed by the time of cut-off analysis date. A value of 9999 indicates that no data were calculated.
    End point type
    Secondary
    End point timeframe
    Up to 57 months
    Notes
    [11] - 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: As pre-specified by the protocol, this endpoint reported data for only the Part 2 arms.
    End point values
    		 Part 2: MK-1775 225 mg + paclitaxel +carboplatin Part 2: Placebo + paclitaxel +carboplatin
    Number of subjects analysed
    59
    62
    Units: months
        median (confidence interval 95%)
    9999 (20.34 to 9999)
    9999 (9999 to 9999)
    Statistical analysis title
    		 Part 2 OS: MK-1775 vs. Placebo
    Statistical analysis description
    A stratified [number of prior platinum based regimens (1 vs. 2 and 3), time since last platinum based therapy (<12 months vs. ≥12 months)] Cox proportional hazards model, with Efron method of tie handling, was used to assess the magnitude of the treatment difference between the treatment arms. The p-value from the score test was used in the significance test and the hazard ratio (MK-1775 versus Placebo) and its 95% CI from the same Cox model was reported.
    Comparison groups
    Part 2: MK-1775 225 mg + paclitaxel +carboplatin v Part 2: Placebo + paclitaxel +carboplatin
    Number of subjects included in analysis
    121
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    		 = 0.8
    Method
    		 Cox proportional hazards model
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    1.15
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.4
         upper limit
    		 3.34

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Part 1: Day 1 through Post Study (286 days total). Part 2: Day 1 through Post Study (479 days total)
    Adverse event reporting additional description
    Part 1: All participants who received at least one dose of study treatment during the open-label period (n=15). Part 2: All randomized participants who received at least one dose of study treatment (n=119). 2 participants were randomized to the Part 2 placebo arm but were not treated.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    19.0
    Reporting groups
    Reporting group title
    Part 1: MK-1775 225 mg + paclitaxel +carboplatin
    Reporting group description
    		 During the open-label run-in, participants received 225 mg MK-1775 BID starting on Day 1 of Cycle 1 (cycle=21 days) for a total of 5 doses. Participants received MK-1775 in combination with paclitaxel (175 mg/m2) and carboplatin (AUC 5).

    Reporting group title
    Part 2: Placebo + paclitaxel +carboplatin
    Reporting group description
    		 During Part 2, participants received matched placebo to MK-1775 BID starting on Day 1 of each 21 day cycle for a total of 5 doses. Participants received placebo in combination with paclitaxel (175 mg/m2) and carboplatin (AUC 5).

    Reporting group title
    Part 2: MK-1775 225 mg + paclitaxel +carboplatin
    Reporting group description
    		 During Part 2, participants received 225 mg MK-1775 BID starting on Day 1 of each 21 day cycle for a total of 5 doses. Participants received MK-1775 in combination with paclitaxel (175 mg/m2) and carboplatin (AUC 5).

    Serious adverse events
    		 Part 1: MK-1775 225 mg + paclitaxel +carboplatin Part 2: Placebo + paclitaxel +carboplatin Part 2: MK-1775 225 mg + paclitaxel +carboplatin
    Total subjects affected by serious adverse events
         subjects affected / exposed
    9 / 15 (60.00%)
    12 / 60 (20.00%)
    24 / 59 (40.68%)
         number of deaths (all causes)
    1
    0
    1
         number of deaths resulting from adverse events
    0
    0
    1
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Acute myeloid leukaemia
         subjects affected / exposed
    1 / 15 (6.67%)
    0 / 60 (0.00%)
    0 / 59 (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
    Malignant neoplasm progression
         subjects affected / exposed
    0 / 15 (0.00%)
    0 / 60 (0.00%)
    1 / 59 (1.69%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    Vascular disorders
    Hypotension
         subjects affected / exposed
    0 / 15 (0.00%)
    0 / 60 (0.00%)
    1 / 59 (1.69%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Thrombosis
         subjects affected / exposed
    0 / 15 (0.00%)
    0 / 60 (0.00%)
    1 / 59 (1.69%)
         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
    Adverse drug reaction
         subjects affected / exposed
    0 / 15 (0.00%)
    1 / 60 (1.67%)
    0 / 59 (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
    Asthenia
         subjects affected / exposed
    0 / 15 (0.00%)
    1 / 60 (1.67%)
    0 / 59 (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
    General physical health deterioration
         subjects affected / exposed
    0 / 15 (0.00%)
    0 / 60 (0.00%)
    2 / 59 (3.39%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    3 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Influenza like illness
         subjects affected / exposed
    1 / 15 (6.67%)
    0 / 60 (0.00%)
    0 / 59 (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
    Multi-organ failure
         subjects affected / exposed
    1 / 15 (6.67%)
    0 / 60 (0.00%)
    0 / 59 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    Pyrexia
         subjects affected / exposed
    0 / 15 (0.00%)
    1 / 60 (1.67%)
    1 / 59 (1.69%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Immune system disorders
    Drug hypersensitivity
         subjects affected / exposed
    0 / 15 (0.00%)
    2 / 60 (3.33%)
    2 / 59 (3.39%)
         occurrences causally related to treatment / all
    0 / 0
    2 / 2
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    0 / 15 (0.00%)
    0 / 60 (0.00%)
    1 / 59 (1.69%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pulmonary embolism
         subjects affected / exposed
    1 / 15 (6.67%)
    0 / 60 (0.00%)
    2 / 59 (3.39%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Psychiatric disorders
    Mental status changes
         subjects affected / exposed
    0 / 15 (0.00%)
    0 / 60 (0.00%)
    1 / 59 (1.69%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Investigations
    Blood magnesium decreased
         subjects affected / exposed
    0 / 15 (0.00%)
    0 / 60 (0.00%)
    1 / 59 (1.69%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Medical observation
         subjects affected / exposed
    1 / 15 (6.67%)
    0 / 60 (0.00%)
    0 / 59 (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
    Platelet count decreased
         subjects affected / exposed
    1 / 15 (6.67%)
    0 / 60 (0.00%)
    0 / 59 (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
    Injury, poisoning and procedural complications
    Transfusion reaction
         subjects affected / exposed
    1 / 15 (6.67%)
    0 / 60 (0.00%)
    0 / 59 (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
    Sinus tachycardia
         subjects affected / exposed
    1 / 15 (6.67%)
    0 / 60 (0.00%)
    0 / 59 (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
    Nervous system disorders
    Loss of consciousness
         subjects affected / exposed
    0 / 15 (0.00%)
    0 / 60 (0.00%)
    1 / 59 (1.69%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Syncope
         subjects affected / exposed
    0 / 15 (0.00%)
    1 / 60 (1.67%)
    1 / 59 (1.69%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    0 / 15 (0.00%)
    0 / 60 (0.00%)
    1 / 59 (1.69%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Febrile neutropenia
         subjects affected / exposed
    3 / 15 (20.00%)
    2 / 60 (3.33%)
    13 / 59 (22.03%)
         occurrences causally related to treatment / all
    3 / 3
    2 / 2
    16 / 16
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Neutropenia
         subjects affected / exposed
    3 / 15 (20.00%)
    1 / 60 (1.67%)
    2 / 59 (3.39%)
         occurrences causally related to treatment / all
    3 / 3
    1 / 1
    4 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    Thrombocytopenia
         subjects affected / exposed
    1 / 15 (6.67%)
    1 / 60 (1.67%)
    0 / 59 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Abdominal pain
         subjects affected / exposed
    0 / 15 (0.00%)
    1 / 60 (1.67%)
    0 / 59 (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
    Diarrhoea
         subjects affected / exposed
    2 / 15 (13.33%)
    1 / 60 (1.67%)
    1 / 59 (1.69%)
         occurrences causally related to treatment / all
    2 / 2
    1 / 2
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Ileus
         subjects affected / exposed
    0 / 15 (0.00%)
    0 / 60 (0.00%)
    1 / 59 (1.69%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Intestinal obstruction
         subjects affected / exposed
    0 / 15 (0.00%)
    0 / 60 (0.00%)
    1 / 59 (1.69%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Nausea
         subjects affected / exposed
    0 / 15 (0.00%)
    1 / 60 (1.67%)
    0 / 59 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Small intestinal obstruction
         subjects affected / exposed
    0 / 15 (0.00%)
    0 / 60 (0.00%)
    1 / 59 (1.69%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Subileus
         subjects affected / exposed
    0 / 15 (0.00%)
    0 / 60 (0.00%)
    1 / 59 (1.69%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Vomiting
         subjects affected / exposed
    1 / 15 (6.67%)
    1 / 60 (1.67%)
    2 / 59 (3.39%)
         occurrences causally related to treatment / all
    1 / 1
    1 / 1
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Skin and subcutaneous tissue disorders
    Acute febrile neutrophilic dermatosis
         subjects affected / exposed
    0 / 15 (0.00%)
    1 / 60 (1.67%)
    0 / 59 (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
    Renal and urinary disorders
    Haematuria
         subjects affected / exposed
    0 / 15 (0.00%)
    1 / 60 (1.67%)
    0 / 59 (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
    Renal failure acute
         subjects affected / exposed
    0 / 15 (0.00%)
    1 / 60 (1.67%)
    0 / 59 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Infections and infestations
    Cellulitis
         subjects affected / exposed
    1 / 15 (6.67%)
    0 / 60 (0.00%)
    0 / 59 (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 / 15 (0.00%)
    0 / 60 (0.00%)
    1 / 59 (1.69%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Neutropenic sepsis
         subjects affected / exposed
    0 / 15 (0.00%)
    0 / 60 (0.00%)
    1 / 59 (1.69%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pneumonia
         subjects affected / exposed
    0 / 15 (0.00%)
    0 / 60 (0.00%)
    1 / 59 (1.69%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Urinary tract infection
         subjects affected / exposed
    0 / 15 (0.00%)
    1 / 60 (1.67%)
    1 / 59 (1.69%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Dehydration
         subjects affected / exposed
    0 / 15 (0.00%)
    1 / 60 (1.67%)
    0 / 59 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hyperglycaemia
         subjects affected / exposed
    1 / 15 (6.67%)
    0 / 60 (0.00%)
    0 / 59 (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
    Hyponatraemia
         subjects affected / exposed
    1 / 15 (6.67%)
    0 / 60 (0.00%)
    1 / 59 (1.69%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Part 1: MK-1775 225 mg + paclitaxel +carboplatin Part 2: Placebo + paclitaxel +carboplatin Part 2: MK-1775 225 mg + paclitaxel +carboplatin
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    15 / 15 (100.00%)
    57 / 60 (95.00%)
    59 / 59 (100.00%)
    Vascular disorders
    Embolism
         subjects affected / exposed
    0 / 15 (0.00%)
    1 / 60 (1.67%)
    3 / 59 (5.08%)
         occurrences all number
    0
    1
    3
    Flushing
         subjects affected / exposed
    4 / 15 (26.67%)
    4 / 60 (6.67%)
    1 / 59 (1.69%)
         occurrences all number
    5
    7
    3
    Hypertension
         subjects affected / exposed
    5 / 15 (33.33%)
    3 / 60 (5.00%)
    2 / 59 (3.39%)
         occurrences all number
    7
    8
    2
    Hypotension
         subjects affected / exposed
    1 / 15 (6.67%)
    1 / 60 (1.67%)
    1 / 59 (1.69%)
         occurrences all number
    1
    1
    1
    Lymphoedema
         subjects affected / exposed
    0 / 15 (0.00%)
    0 / 60 (0.00%)
    3 / 59 (5.08%)
         occurrences all number
    0
    0
    3
    General disorders and administration site conditions
    Asthenia
         subjects affected / exposed
    2 / 15 (13.33%)
    2 / 60 (3.33%)
    9 / 59 (15.25%)
         occurrences all number
    2
    3
    16
    Chills
         subjects affected / exposed
    3 / 15 (20.00%)
    4 / 60 (6.67%)
    3 / 59 (5.08%)
         occurrences all number
    5
    7
    3
    Face oedema
         subjects affected / exposed
    1 / 15 (6.67%)
    0 / 60 (0.00%)
    0 / 59 (0.00%)
         occurrences all number
    1
    0
    0
    Fatigue
         subjects affected / exposed
    13 / 15 (86.67%)
    33 / 60 (55.00%)
    32 / 59 (54.24%)
         occurrences all number
    17
    37
    54
    Influenza like illness
         subjects affected / exposed
    0 / 15 (0.00%)
    1 / 60 (1.67%)
    3 / 59 (5.08%)
         occurrences all number
    0
    1
    3
    Injection site granuloma
         subjects affected / exposed
    1 / 15 (6.67%)
    0 / 60 (0.00%)
    0 / 59 (0.00%)
         occurrences all number
    1
    0
    0
    Localised oedema
         subjects affected / exposed
    1 / 15 (6.67%)
    1 / 60 (1.67%)
    1 / 59 (1.69%)
         occurrences all number
    1
    1
    1
    Malaise
         subjects affected / exposed
    3 / 15 (20.00%)
    4 / 60 (6.67%)
    1 / 59 (1.69%)
         occurrences all number
    4
    5
    1
    Mucosal inflammation
         subjects affected / exposed
    1 / 15 (6.67%)
    3 / 60 (5.00%)
    3 / 59 (5.08%)
         occurrences all number
    1
    3
    3
    Oedema peripheral
         subjects affected / exposed
    1 / 15 (6.67%)
    3 / 60 (5.00%)
    9 / 59 (15.25%)
         occurrences all number
    3
    3
    12
    Peripheral swelling
         subjects affected / exposed
    1 / 15 (6.67%)
    0 / 60 (0.00%)
    3 / 59 (5.08%)
         occurrences all number
    1
    0
    3
    Pyrexia
         subjects affected / exposed
    7 / 15 (46.67%)
    6 / 60 (10.00%)
    6 / 59 (10.17%)
         occurrences all number
    8
    6
    7
    Immune system disorders
    Drug hypersensitivity
         subjects affected / exposed
    2 / 15 (13.33%)
    6 / 60 (10.00%)
    6 / 59 (10.17%)
         occurrences all number
    4
    8
    16
    Hypersensitivity
         subjects affected / exposed
    1 / 15 (6.67%)
    4 / 60 (6.67%)
    3 / 59 (5.08%)
         occurrences all number
    1
    5
    4
    Reproductive system and breast disorders
    Breast oedema
         subjects affected / exposed
    1 / 15 (6.67%)
    0 / 60 (0.00%)
    0 / 59 (0.00%)
         occurrences all number
    1
    0
    0
    Breast pain
         subjects affected / exposed
    1 / 15 (6.67%)
    0 / 60 (0.00%)
    0 / 59 (0.00%)
         occurrences all number
    2
    0
    0
    Pelvic pain
         subjects affected / exposed
    1 / 15 (6.67%)
    0 / 60 (0.00%)
    1 / 59 (1.69%)
         occurrences all number
    2
    0
    1
    Vaginal discharge
         subjects affected / exposed
    1 / 15 (6.67%)
    0 / 60 (0.00%)
    1 / 59 (1.69%)
         occurrences all number
    1
    0
    1
    Respiratory, thoracic and mediastinal disorders
    Bronchospasm
         subjects affected / exposed
    1 / 15 (6.67%)
    1 / 60 (1.67%)
    0 / 59 (0.00%)
         occurrences all number
    1
    1
    0
    Cough
         subjects affected / exposed
    3 / 15 (20.00%)
    6 / 60 (10.00%)
    8 / 59 (13.56%)
         occurrences all number
    4
    10
    10
    Dysphonia
         subjects affected / exposed
    0 / 15 (0.00%)
    2 / 60 (3.33%)
    3 / 59 (5.08%)
         occurrences all number
    0
    2
    3
    Dyspnoea
         subjects affected / exposed
    4 / 15 (26.67%)
    8 / 60 (13.33%)
    15 / 59 (25.42%)
         occurrences all number
    6
    10
    23
    Epistaxis
         subjects affected / exposed
    0 / 15 (0.00%)
    4 / 60 (6.67%)
    4 / 59 (6.78%)
         occurrences all number
    0
    4
    4
    Oropharyngeal pain
         subjects affected / exposed
    2 / 15 (13.33%)
    4 / 60 (6.67%)
    4 / 59 (6.78%)
         occurrences all number
    4
    5
    4
    Psychiatric disorders
    Agitation
         subjects affected / exposed
    1 / 15 (6.67%)
    2 / 60 (3.33%)
    3 / 59 (5.08%)
         occurrences all number
    1
    2
    3
    Anxiety
         subjects affected / exposed
    2 / 15 (13.33%)
    3 / 60 (5.00%)
    2 / 59 (3.39%)
         occurrences all number
    2
    4
    3
    Depression
         subjects affected / exposed
    3 / 15 (20.00%)
    1 / 60 (1.67%)
    1 / 59 (1.69%)
         occurrences all number
    3
    1
    1
    Insomnia
         subjects affected / exposed
    2 / 15 (13.33%)
    8 / 60 (13.33%)
    10 / 59 (16.95%)
         occurrences all number
    3
    8
    13
    Restlessness
         subjects affected / exposed
    0 / 15 (0.00%)
    1 / 60 (1.67%)
    3 / 59 (5.08%)
         occurrences all number
    0
    1
    3
    Investigations
    Alanine aminotransferase increased
         subjects affected / exposed
    3 / 15 (20.00%)
    3 / 60 (5.00%)
    6 / 59 (10.17%)
         occurrences all number
    3
    3
    6
    Aspartate aminotransferase increased
         subjects affected / exposed
    2 / 15 (13.33%)
    1 / 60 (1.67%)
    4 / 59 (6.78%)
         occurrences all number
    2
    1
    4
    Blood alkaline phosphatase increased
         subjects affected / exposed
    0 / 15 (0.00%)
    0 / 60 (0.00%)
    3 / 59 (5.08%)
         occurrences all number
    0
    0
    3
    Cardiac murmur
         subjects affected / exposed
    1 / 15 (6.67%)
    0 / 60 (0.00%)
    0 / 59 (0.00%)
         occurrences all number
    1
    0
    0
    Electrocardiogram QT prolonged
         subjects affected / exposed
    2 / 15 (13.33%)
    0 / 60 (0.00%)
    0 / 59 (0.00%)
         occurrences all number
    2
    0
    0
    Haemoglobin decreased
         subjects affected / exposed
    1 / 15 (6.67%)
    1 / 60 (1.67%)
    1 / 59 (1.69%)
         occurrences all number
    1
    2
    3
    Lymphocyte count decreased
         subjects affected / exposed
    0 / 15 (0.00%)
    0 / 60 (0.00%)
    3 / 59 (5.08%)
         occurrences all number
    0
    0
    6
    Neutrophil count decreased
         subjects affected / exposed
    2 / 15 (13.33%)
    9 / 60 (15.00%)
    12 / 59 (20.34%)
         occurrences all number
    8
    34
    30
    Platelet count decreased
         subjects affected / exposed
    5 / 15 (33.33%)
    6 / 60 (10.00%)
    8 / 59 (13.56%)
         occurrences all number
    9
    20
    23
    Weight decreased
         subjects affected / exposed
    1 / 15 (6.67%)
    1 / 60 (1.67%)
    2 / 59 (3.39%)
         occurrences all number
    1
    1
    2
    White blood cell count decreased
         subjects affected / exposed
    5 / 15 (33.33%)
    6 / 60 (10.00%)
    7 / 59 (11.86%)
         occurrences all number
    9
    15
    17
    Injury, poisoning and procedural complications
    Contusion
         subjects affected / exposed
    1 / 15 (6.67%)
    3 / 60 (5.00%)
    2 / 59 (3.39%)
         occurrences all number
    1
    3
    2
    Fall
         subjects affected / exposed
    1 / 15 (6.67%)
    1 / 60 (1.67%)
    0 / 59 (0.00%)
         occurrences all number
    1
    1
    0
    Spinal fracture
         subjects affected / exposed
    1 / 15 (6.67%)
    0 / 60 (0.00%)
    0 / 59 (0.00%)
         occurrences all number
    1
    0
    0
    Tooth fracture
         subjects affected / exposed
    1 / 15 (6.67%)
    0 / 60 (0.00%)
    0 / 59 (0.00%)
         occurrences all number
    1
    0
    0
    Cardiac disorders
    Palpitations
         subjects affected / exposed
    1 / 15 (6.67%)
    3 / 60 (5.00%)
    3 / 59 (5.08%)
         occurrences all number
    1
    3
    4
    Sinus tachycardia
         subjects affected / exposed
    1 / 15 (6.67%)
    2 / 60 (3.33%)
    3 / 59 (5.08%)
         occurrences all number
    1
    2
    3
    Tachycardia
         subjects affected / exposed
    1 / 15 (6.67%)
    2 / 60 (3.33%)
    5 / 59 (8.47%)
         occurrences all number
    1
    2
    5
    Nervous system disorders
    Dizziness
         subjects affected / exposed
    4 / 15 (26.67%)
    7 / 60 (11.67%)
    8 / 59 (13.56%)
         occurrences all number
    4
    11
    15
    Dysgeusia
         subjects affected / exposed
    6 / 15 (40.00%)
    7 / 60 (11.67%)
    9 / 59 (15.25%)
         occurrences all number
    9
    15
    11
    Headache
         subjects affected / exposed
    2 / 15 (13.33%)
    8 / 60 (13.33%)
    10 / 59 (16.95%)
         occurrences all number
    3
    11
    11
    Neuropathy peripheral
         subjects affected / exposed
    2 / 15 (13.33%)
    9 / 60 (15.00%)
    8 / 59 (13.56%)
         occurrences all number
    2
    11
    9
    Paraesthesia
         subjects affected / exposed
    0 / 15 (0.00%)
    7 / 60 (11.67%)
    3 / 59 (5.08%)
         occurrences all number
    0
    9
    3
    Peripheral sensory neuropathy
         subjects affected / exposed
    5 / 15 (33.33%)
    8 / 60 (13.33%)
    12 / 59 (20.34%)
         occurrences all number
    9
    9
    21
    Polyneuropathy
         subjects affected / exposed
    0 / 15 (0.00%)
    4 / 60 (6.67%)
    6 / 59 (10.17%)
         occurrences all number
    0
    5
    10
    Presyncope
         subjects affected / exposed
    1 / 15 (6.67%)
    0 / 60 (0.00%)
    0 / 59 (0.00%)
         occurrences all number
    1
    0
    0
    Restless legs syndrome
         subjects affected / exposed
    0 / 15 (0.00%)
    1 / 60 (1.67%)
    3 / 59 (5.08%)
         occurrences all number
    0
    1
    4
    Syncope
         subjects affected / exposed
    0 / 15 (0.00%)
    1 / 60 (1.67%)
    4 / 59 (6.78%)
         occurrences all number
    0
    1
    5
    Tremor
         subjects affected / exposed
    0 / 15 (0.00%)
    1 / 60 (1.67%)
    3 / 59 (5.08%)
         occurrences all number
    0
    1
    3
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    6 / 15 (40.00%)
    19 / 60 (31.67%)
    31 / 59 (52.54%)
         occurrences all number
    12
    36
    68
    Leukopenia
         subjects affected / exposed
    2 / 15 (13.33%)
    12 / 60 (20.00%)
    9 / 59 (15.25%)
         occurrences all number
    2
    23
    25
    Lymph node pain
         subjects affected / exposed
    1 / 15 (6.67%)
    0 / 60 (0.00%)
    0 / 59 (0.00%)
         occurrences all number
    1
    0
    0
    Neutropenia
         subjects affected / exposed
    7 / 15 (46.67%)
    24 / 60 (40.00%)
    24 / 59 (40.68%)
         occurrences all number
    16
    58
    52
    Thrombocytopenia
         subjects affected / exposed
    3 / 15 (20.00%)
    16 / 60 (26.67%)
    21 / 59 (35.59%)
         occurrences all number
    3
    31
    64
    Ear and labyrinth disorders
    Ear pain
         subjects affected / exposed
    1 / 15 (6.67%)
    1 / 60 (1.67%)
    5 / 59 (8.47%)
         occurrences all number
    1
    1
    5
    Vertigo
         subjects affected / exposed
    1 / 15 (6.67%)
    2 / 60 (3.33%)
    2 / 59 (3.39%)
         occurrences all number
    1
    2
    5
    Eye disorders
    Diplopia
         subjects affected / exposed
    1 / 15 (6.67%)
    0 / 60 (0.00%)
    0 / 59 (0.00%)
         occurrences all number
    2
    0
    0
    Vision blurred
         subjects affected / exposed
    0 / 15 (0.00%)
    2 / 60 (3.33%)
    4 / 59 (6.78%)
         occurrences all number
    0
    3
    4
    Visual acuity reduced
         subjects affected / exposed
    1 / 15 (6.67%)
    0 / 60 (0.00%)
    0 / 59 (0.00%)
         occurrences all number
    1
    0
    0
    Gastrointestinal disorders
    Abdominal pain
         subjects affected / exposed
    3 / 15 (20.00%)
    14 / 60 (23.33%)
    9 / 59 (15.25%)
         occurrences all number
    3
    15
    11
    Abdominal pain upper
         subjects affected / exposed
    3 / 15 (20.00%)
    2 / 60 (3.33%)
    4 / 59 (6.78%)
         occurrences all number
    3
    4
    9
    Constipation
         subjects affected / exposed
    5 / 15 (33.33%)
    23 / 60 (38.33%)
    17 / 59 (28.81%)
         occurrences all number
    5
    29
    26
    Diarrhoea
         subjects affected / exposed
    13 / 15 (86.67%)
    22 / 60 (36.67%)
    44 / 59 (74.58%)
         occurrences all number
    34
    39
    138
    Dyspepsia
         subjects affected / exposed
    3 / 15 (20.00%)
    4 / 60 (6.67%)
    6 / 59 (10.17%)
         occurrences all number
    5
    5
    8
    Dysphagia
         subjects affected / exposed
    2 / 15 (13.33%)
    1 / 60 (1.67%)
    1 / 59 (1.69%)
         occurrences all number
    2
    1
    1
    Flatulence
         subjects affected / exposed
    1 / 15 (6.67%)
    0 / 60 (0.00%)
    1 / 59 (1.69%)
         occurrences all number
    1
    0
    1
    Gastric haemorrhage
         subjects affected / exposed
    1 / 15 (6.67%)
    0 / 60 (0.00%)
    0 / 59 (0.00%)
         occurrences all number
    1
    0
    0
    Gastrooesophageal reflux disease
         subjects affected / exposed
    1 / 15 (6.67%)
    0 / 60 (0.00%)
    0 / 59 (0.00%)
         occurrences all number
    1
    0
    0
    Haemorrhoids
         subjects affected / exposed
    3 / 15 (20.00%)
    1 / 60 (1.67%)
    1 / 59 (1.69%)
         occurrences all number
    3
    1
    2
    Nausea
         subjects affected / exposed
    13 / 15 (86.67%)
    36 / 60 (60.00%)
    46 / 59 (77.97%)
         occurrences all number
    27
    67
    103
    Odynophagia
         subjects affected / exposed
    1 / 15 (6.67%)
    0 / 60 (0.00%)
    0 / 59 (0.00%)
         occurrences all number
    1
    0
    0
    Oesophageal pain
         subjects affected / exposed
    1 / 15 (6.67%)
    0 / 60 (0.00%)
    0 / 59 (0.00%)
         occurrences all number
    1
    0
    0
    Oral dysaesthesia
         subjects affected / exposed
    1 / 15 (6.67%)
    0 / 60 (0.00%)
    0 / 59 (0.00%)
         occurrences all number
    2
    0
    0
    Proctalgia
         subjects affected / exposed
    1 / 15 (6.67%)
    2 / 60 (3.33%)
    0 / 59 (0.00%)
         occurrences all number
    2
    2
    0
    Rectal haemorrhage
         subjects affected / exposed
    1 / 15 (6.67%)
    0 / 60 (0.00%)
    1 / 59 (1.69%)
         occurrences all number
    2
    0
    2
    Stomatitis
         subjects affected / exposed
    1 / 15 (6.67%)
    6 / 60 (10.00%)
    8 / 59 (13.56%)
         occurrences all number
    1
    7
    9
    Vomiting
         subjects affected / exposed
    13 / 15 (86.67%)
    16 / 60 (26.67%)
    37 / 59 (62.71%)
         occurrences all number
    33
    19
    78
    Skin and subcutaneous tissue disorders
    Alopecia
         subjects affected / exposed
    11 / 15 (73.33%)
    40 / 60 (66.67%)
    32 / 59 (54.24%)
         occurrences all number
    11
    40
    33
    Dermatitis
         subjects affected / exposed
    1 / 15 (6.67%)
    0 / 60 (0.00%)
    0 / 59 (0.00%)
         occurrences all number
    1
    0
    0
    Dermatitis acneiform
         subjects affected / exposed
    1 / 15 (6.67%)
    1 / 60 (1.67%)
    0 / 59 (0.00%)
         occurrences all number
    1
    1
    0
    Dermatitis allergic
         subjects affected / exposed
    2 / 15 (13.33%)
    0 / 60 (0.00%)
    0 / 59 (0.00%)
         occurrences all number
    3
    0
    0
    Hyperhidrosis
         subjects affected / exposed
    2 / 15 (13.33%)
    2 / 60 (3.33%)
    1 / 59 (1.69%)
         occurrences all number
    2
    3
    1
    Pruritus
         subjects affected / exposed
    3 / 15 (20.00%)
    7 / 60 (11.67%)
    6 / 59 (10.17%)
         occurrences all number
    5
    9
    6
    Rash
         subjects affected / exposed
    1 / 15 (6.67%)
    5 / 60 (8.33%)
    2 / 59 (3.39%)
         occurrences all number
    2
    5
    2
    Rash maculo-papular
         subjects affected / exposed
    3 / 15 (20.00%)
    4 / 60 (6.67%)
    4 / 59 (6.78%)
         occurrences all number
    8
    4
    7
    Skin lesion
         subjects affected / exposed
    1 / 15 (6.67%)
    0 / 60 (0.00%)
    0 / 59 (0.00%)
         occurrences all number
    2
    0
    0
    Renal and urinary disorders
    Dysuria
         subjects affected / exposed
    2 / 15 (13.33%)
    1 / 60 (1.67%)
    2 / 59 (3.39%)
         occurrences all number
    3
    1
    4
    Haematuria
         subjects affected / exposed
    1 / 15 (6.67%)
    2 / 60 (3.33%)
    0 / 59 (0.00%)
         occurrences all number
    2
    2
    0
    Pollakiuria
         subjects affected / exposed
    2 / 15 (13.33%)
    1 / 60 (1.67%)
    2 / 59 (3.39%)
         occurrences all number
    2
    1
    2
    Urinary incontinence
         subjects affected / exposed
    1 / 15 (6.67%)
    3 / 60 (5.00%)
    0 / 59 (0.00%)
         occurrences all number
    2
    3
    0
    Urinary tract pain
         subjects affected / exposed
    2 / 15 (13.33%)
    0 / 60 (0.00%)
    1 / 59 (1.69%)
         occurrences all number
    3
    0
    1
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    5 / 15 (33.33%)
    16 / 60 (26.67%)
    15 / 59 (25.42%)
         occurrences all number
    11
    23
    20
    Back pain
         subjects affected / exposed
    4 / 15 (26.67%)
    2 / 60 (3.33%)
    5 / 59 (8.47%)
         occurrences all number
    5
    2
    5
    Flank pain
         subjects affected / exposed
    0 / 15 (0.00%)
    0 / 60 (0.00%)
    3 / 59 (5.08%)
         occurrences all number
    0
    0
    3
    Musculoskeletal pain
         subjects affected / exposed
    1 / 15 (6.67%)
    1 / 60 (1.67%)
    0 / 59 (0.00%)
         occurrences all number
    1
    1
    0
    Myalgia
         subjects affected / exposed
    1 / 15 (6.67%)
    11 / 60 (18.33%)
    15 / 59 (25.42%)
         occurrences all number
    1
    17
    20
    Pain in extremity
         subjects affected / exposed
    1 / 15 (6.67%)
    5 / 60 (8.33%)
    6 / 59 (10.17%)
         occurrences all number
    2
    8
    8
    Infections and infestations
    Fungal skin infection
         subjects affected / exposed
    1 / 15 (6.67%)
    0 / 60 (0.00%)
    0 / 59 (0.00%)
         occurrences all number
    1
    0
    0
    Nasopharyngitis
         subjects affected / exposed
    2 / 15 (13.33%)
    3 / 60 (5.00%)
    0 / 59 (0.00%)
         occurrences all number
    2
    3
    0
    Oral herpes
         subjects affected / exposed
    1 / 15 (6.67%)
    1 / 60 (1.67%)
    1 / 59 (1.69%)
         occurrences all number
    1
    1
    1
    Pyelonephritis
         subjects affected / exposed
    1 / 15 (6.67%)
    0 / 60 (0.00%)
    0 / 59 (0.00%)
         occurrences all number
    1
    0
    0
    Rhinitis
         subjects affected / exposed
    0 / 15 (0.00%)
    1 / 60 (1.67%)
    3 / 59 (5.08%)
         occurrences all number
    0
    1
    3
    Upper respiratory tract infection
         subjects affected / exposed
    0 / 15 (0.00%)
    4 / 60 (6.67%)
    3 / 59 (5.08%)
         occurrences all number
    0
    4
    3
    Urinary tract infection
         subjects affected / exposed
    3 / 15 (20.00%)
    5 / 60 (8.33%)
    7 / 59 (11.86%)
         occurrences all number
    6
    7
    9
    Metabolism and nutrition disorders
    Decreased appetite
         subjects affected / exposed
    8 / 15 (53.33%)
    11 / 60 (18.33%)
    11 / 59 (18.64%)
         occurrences all number
    10
    17
    18
    Dehydration
         subjects affected / exposed
    5 / 15 (33.33%)
    3 / 60 (5.00%)
    4 / 59 (6.78%)
         occurrences all number
    6
    8
    10
    Glucose tolerance impaired
         subjects affected / exposed
    5 / 15 (33.33%)
    0 / 60 (0.00%)
    0 / 59 (0.00%)
         occurrences all number
    15
    0
    0
    Hypocalcaemia
         subjects affected / exposed
    2 / 15 (13.33%)
    1 / 60 (1.67%)
    0 / 59 (0.00%)
         occurrences all number
    3
    1
    0
    Hypokalaemia
         subjects affected / exposed
    3 / 15 (20.00%)
    0 / 60 (0.00%)
    8 / 59 (13.56%)
         occurrences all number
    5
    0
    12
    Hypomagnesaemia
         subjects affected / exposed
    6 / 15 (40.00%)
    9 / 60 (15.00%)
    11 / 59 (18.64%)
         occurrences all number
    11
    9
    16
    Hyponatraemia
         subjects affected / exposed
    2 / 15 (13.33%)
    1 / 60 (1.67%)
    3 / 59 (5.08%)
         occurrences all number
    2
    1
    3

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    18 Apr 2012
    Amendment 01 (AM1) was implemented primarily to update an inclusion criterion to include participants with primary peritoneal and fallopian tube cancers.
    10 Jun 2013
    AM5 was implemented primarily to clarify the requirement of CA-125 during the follow up period.
    02 Oct 2013
    AM8 was implemented primarily to re-calculate sample size to expand from 80 to 120 participants for Part 2 of the study and re-estimate the power accordingly. The recruitment timelines were extended 6 more months and 15 sites were added as a result of the change. The change was made without unblinding the trial data.

    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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