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    Clinical Trial Results:
    Randomized, Double-Blind, Multicenter, Phase 3 Study Comparing Veliparib Plus Carboplatin and Paclitaxel Versus Placebo Plus Carboplatin and Paclitaxel in Previously Untreated Advanced or Metastatic Squamous Non-Small Cell Lung Cancer (NSCLC)

    Summary
    EudraCT number
    		 2013-005020-42
    Trial protocol
    		 SK   FI   LT   CZ   PT   HU   NO   SE   DE   AT   IT   IE   DK   NL   ES   GR   LV   PL   FR   HR   EE  
    Global end of trial date
    20 Nov 2019

    Results information
    Results version number
    		 v1(current)
    This version publication date
    03 Dec 2020
    First version publication date
    03 Dec 2020
    Other versions

    Trial information

    		 Close Top of page
    Trial identification
    Sponsor protocol code
    M11-089
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT02106546
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Abbvie Deutschland GmbH & Co.KG
    Sponsor organisation address
    AbbVie House, Vanwall Business Park, Maidenhead, Berkshire, United Kingdom, SL6-4UB
    Public contact
    Global Medical Services, AbbVie, 001 800-633-9110, abbvieclinicaltrials@abbvie.com
    Scientific contact
    Global Medical Services, AbbVie, 001 800-633-9110, abbvieclinicaltrials@abbvie.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
    20 Nov 2019
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    20 Nov 2019
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The primary objective of the study was to assess whether the addition of oral veliparib to carboplatin and paclitaxel (C/P) would improve overall survival (OS) compared to the addition of placebo to C/P in current smokers with previously untreated locally advanced and metastatic squamous NSCLC.
    Protection of trial subjects
    Subject read and understood the information provided about the study and gave written permission.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    10 Apr 2014
    Long term follow-up planned
    Yes
    Long term follow-up rationale
    		 Efficacy
    Long term follow-up duration
    		 4 Years
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Australia: 16
    Country: Number of subjects enrolled
    Austria: 5
    Country: Number of subjects enrolled
    Belarus: 45
    Country: Number of subjects enrolled
    Brazil: 28
    Country: Number of subjects enrolled
    Canada: 27
    Country: Number of subjects enrolled
    Croatia: 15
    Country: Number of subjects enrolled
    Czech Republic: 30
    Country: Number of subjects enrolled
    Denmark: 8
    Country: Number of subjects enrolled
    Egypt: 17
    Country: Number of subjects enrolled
    Estonia: 5
    Country: Number of subjects enrolled
    Finland: 6
    Country: Number of subjects enrolled
    France: 47
    Country: Number of subjects enrolled
    Germany: 10
    Country: Number of subjects enrolled
    Greece: 27
    Country: Number of subjects enrolled
    Hungary: 79
    Country: Number of subjects enrolled
    Ireland: 12
    Country: Number of subjects enrolled
    Israel: 13
    Country: Number of subjects enrolled
    Italy: 19
    Country: Number of subjects enrolled
    Latvia: 19
    Country: Number of subjects enrolled
    Lithuania: 9
    Country: Number of subjects enrolled
    Mexico: 7
    Country: Number of subjects enrolled
    Netherlands: 23
    Country: Number of subjects enrolled
    New Zealand: 2
    Country: Number of subjects enrolled
    Norway: 10
    Country: Number of subjects enrolled
    Poland: 17
    Country: Number of subjects enrolled
    Portugal: 19
    Country: Number of subjects enrolled
    Puerto Rico: 1
    Country: Number of subjects enrolled
    Russian Federation: 90
    Country: Number of subjects enrolled
    Serbia: 23
    Country: Number of subjects enrolled
    Slovakia: 11
    Country: Number of subjects enrolled
    South Africa: 18
    Country: Number of subjects enrolled
    Spain: 37
    Country: Number of subjects enrolled
    Sweden: 8
    Country: Number of subjects enrolled
    Switzerland: 12
    Country: Number of subjects enrolled
    Turkey: 43
    Country: Number of subjects enrolled
    Ukraine: 73
    Country: Number of subjects enrolled
    United Kingdom: 44
    Country: Number of subjects enrolled
    United States: 95
    Worldwide total number of subjects
    970
    EEA total number of subjects
    460
    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)
    517
    From 65 to 84 years
    453
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 A total of 218 sites in 37 countries enrolled participants with previously untreated advanced or metastatic squamous non-small cell lung cancer (NSCLC).

    Pre-assignment
    Screening details
    		 Participants were randomized 1:1 to 1 of 2 groups. Randomization was stratified by tumor stage (locally advanced vs metastatic), Eastern Cooperative Oncology Group performance score (0 vs 1), geographic region (Western Europe/Australia/Americas vs Eastern Europe/Russia), and smoking history (current smoker vs never smoked vs past smoker).

    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, Assessor

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Placebo + Carboplatin + Paclitaxel
    Arm description
    		 Participants received placebo orally twice a day (BID) on Days -2 to 5 (7 consecutive days) of each 21-day cycle and carboplatin at an area under the concentration-time curve (AUC) 6 mg/mL/min and paclitaxel 200 mg/m² by intravenous (IV) infusion on Day 1 of each 21-day cycle for up to a maximum 6 cycles of treatment, until treatment toxicity which, in the Investigator's opinion, prohibited further therapy, or until radiographic progression.
    Arm type
    		 Placebo

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    Capsules taken orally twice a day, 12 hours apart.

    Investigational medicinal product name
    Carboplatin
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Carboplatin administered intravenously over approximately 15 to 30 minutes at (AUC 6 mg/mL/min) immediately following paclitaxel infusion.

    Investigational medicinal product name
    Paclitaxel
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Paclitaxel administered intravenously over 3 hours at a dose of 200 mg/m².

    Arm title
    		 Veliparib + Carboplatin + Paclitaxel
    Arm description
    		 Participants received veliparib 120 mg orally twice daily (BID) on Days -2 to 5 (7 consecutive days) of each 21-day cycle and carboplatin at an AUC 6 mg/mL/min and paclitaxel 200 mg/m² by intravenous (IV) infusion on Day 1 of each 21-day cycle for up to a maximum 6 cycles of treatment, until treatment toxicity which, in the Investigator's opinion, prohibited further therapy, or until radiographic progression.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Veliparib
    Investigational medicinal product code
    Other name
    ABT-888
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    Capsules taken orally twice a day, 12 hours apart.

    Investigational medicinal product name
    Carboplatin
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Carboplatin administered intravenously over approximately 15 to 30 minutes at (AUC 6 mg/mL/min) immediately following paclitaxel infusion.

    Investigational medicinal product name
    Paclitaxel
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Paclitaxel administered intravenously over 3 hours at a dose of 200 mg/m².

    Number of subjects in period 1
    		Placebo + Carboplatin + Paclitaxel Veliparib + Carboplatin + Paclitaxel
    Started
    484
    486
    Received Treatment
    482
    485
    Completed
    268
    288
    Not completed
    216
    198
         Adverse Event Related to Progression
    25
    17
         Consent withdrawn by subject
    17
    16
         Other
    9
    7
         Progressive Disease
    81
    78
         Adverse Event Not Related to Progression
    82
    80
         Lost to follow-up
    2
    -

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Placebo + Carboplatin + Paclitaxel
    Reporting group description
    		 Participants received placebo orally twice a day (BID) on Days -2 to 5 (7 consecutive days) of each 21-day cycle and carboplatin at an area under the concentration-time curve (AUC) 6 mg/mL/min and paclitaxel 200 mg/m² by intravenous (IV) infusion on Day 1 of each 21-day cycle for up to a maximum 6 cycles of treatment, until treatment toxicity which, in the Investigator's opinion, prohibited further therapy, or until radiographic progression.

    Reporting group title
    Veliparib + Carboplatin + Paclitaxel
    Reporting group description
    		 Participants received veliparib 120 mg orally twice daily (BID) on Days -2 to 5 (7 consecutive days) of each 21-day cycle and carboplatin at an AUC 6 mg/mL/min and paclitaxel 200 mg/m² by intravenous (IV) infusion on Day 1 of each 21-day cycle for up to a maximum 6 cycles of treatment, until treatment toxicity which, in the Investigator's opinion, prohibited further therapy, or until radiographic progression.

    Reporting group values
    		 Placebo + Carboplatin + Paclitaxel Veliparib + Carboplatin + Paclitaxel Total
    Number of subjects
    		 484 486 970
    Age categorical
    Units: Subjects
        < 65 years
    		 256 261 517
        ≥ 65 years
    		 228 225 453
    Age continuous
    Units: years
        median (full range (min-max))
    		 64.0 (33 to 84) 64.0 (36 to 83) -
    Gender categorical
    Units: Subjects
        Female
    		 100 75 175
        Male
    		 384 411 795
    Race
    Units: Subjects
        White
    		 477 471 948
        Black
    		 5 9 14
        Asian
    		 0 5 5
        Other
    		 2 1 3
    Geographic Region
    Units: Subjects
        Western Europe/Australia/Americas
    		 239 242 481
        Eastern Europe/Russia
    		 245 244 489
    Eastern Cooperative Oncology Group (ECOG) Performance Status (PS)
    ECOG performance status is used by doctors and researchers to assess how a participant's disease is progressing, assess how the disease affects the daily living activities of the participant and determine appropriate treatment and prognosis. 0 = Fully Active (Most Favorable Activity); 1 = Restricted activity but ambulatory; 2 = Ambulatory but unable to carry out work activities; 3 = Limited Self-Care; 4 = Completely Disabled, No self-care (Least Favorable Activity)
    Units: Subjects
        Grade 0 (fully active)
    		 165 166 331
        Grade 1 (restricted but ambulatory)
    		 319 320 639
    Smoking Status
    Units: Subjects
        Current smoker
    		 276 276 552
        Past smoker
    		 181 181 362
        Never smoked
    		 27 29 56
    Tumor Stage
    Units: Subjects
        Locally advanced
    		 112 114 226
        Metastatic
    		 372 372 744

    End points

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    End points reporting groups
    Reporting group title
    Placebo + Carboplatin + Paclitaxel
    Reporting group description
    		 Participants received placebo orally twice a day (BID) on Days -2 to 5 (7 consecutive days) of each 21-day cycle and carboplatin at an area under the concentration-time curve (AUC) 6 mg/mL/min and paclitaxel 200 mg/m² by intravenous (IV) infusion on Day 1 of each 21-day cycle for up to a maximum 6 cycles of treatment, until treatment toxicity which, in the Investigator's opinion, prohibited further therapy, or until radiographic progression.

    Reporting group title
    Veliparib + Carboplatin + Paclitaxel
    Reporting group description
    		 Participants received veliparib 120 mg orally twice daily (BID) on Days -2 to 5 (7 consecutive days) of each 21-day cycle and carboplatin at an AUC 6 mg/mL/min and paclitaxel 200 mg/m² by intravenous (IV) infusion on Day 1 of each 21-day cycle for up to a maximum 6 cycles of treatment, until treatment toxicity which, in the Investigator's opinion, prohibited further therapy, or until radiographic progression.

    Primary: Overall Survival in Current Smokers

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    End point title
    		 Overall Survival in Current Smokers
    End point description
    Overall survival (OS) was calculated as the time from the date that the participant was randomized to the date of death. All events of death were included, regardless of whether the event occurred while the participant was still taking study drug, or after the participant discontinued study drug. Participants who had not died prior to the analysis cut-off date were censored at the date they were last known to be alive, or on the cut-off date if survival data were known after the cut-off date. The distributions of OS on the two treatment arms were estimated using the Kaplan-Meier method. The data cut-off date for the analyses of primary and secondary efficacy endpoints was pre-specified as the date of the 400th death in current smokers and 667 events in the total ITT population. OS was analysed in the intent-to-treat (ITT) population (all randomized participants) who were current smokers
    End point type
    Primary
    End point timeframe
    From randomization to the primary analysis data cut-off date in 2017.
    End point values
    		 Placebo + Carboplatin + Paclitaxel Veliparib + Carboplatin + Paclitaxel
    Number of subjects analysed
    276 [1]
    276 [2]
    Units: months
        median (confidence interval 95%)
    11.1 (9.6 to 12.6)
    11.9 (10.5 to 13.5)
    Notes
    [1] - Current smokers
    [2] - Current smokers
    Statistical analysis title
    		 Primary Analysis of OS in Current Smokers
    Comparison groups
    Placebo + Carboplatin + Paclitaxel v Veliparib + Carboplatin + Paclitaxel
    Number of subjects included in analysis
    552
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [3]
    P-value
    		 = 0.266 [4]
    Method
    		 Stratified Log-rank
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.905
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.744
         upper limit
    		 1.101
    Notes
    [3] - Statistical significance was determined by a two-sided P-value ≤0.05. If the primary endpoint was not met, all analyses of secondary and other efficacy endpoints were to be performed in a descriptive manner and treated as exploratory, with P-values interpreted as nominal.
    [4] - Log-rank test stratified by tumor staging (locally advanced vs metastatic) and ECOG performance status (0 vs 1).

    Secondary: Overall Survival in All Participants - Primary Analysis

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    End point title
    		 Overall Survival in All Participants - Primary Analysis
    End point description
    Overall survival was calculated as the time from the date that the participant was randomized to the date of death. All events of death were included, regardless of whether the event occurred while the participant was still taking study drug, or after the participant discontinued study drug. Participants who had not died prior to the analysis cut-off date were censored at the date they were last known to be alive, or on the cut-off date if survival data were known after the cut-off date. The distributions of OS on the two treatment arms were estimated using the Kaplan-Meier method. The data cut-off date for the analyses of primary and secondary efficacy endpoints was pre-specified as the date of the 400th death in current smokers and 667 events in the total ITT population.
    End point type
    Secondary
    End point timeframe
    From randomization to the primary analysis data cut-off date in 2017.
    End point values
    		 Placebo + Carboplatin + Paclitaxel Veliparib + Carboplatin + Paclitaxel
    Number of subjects analysed
    484 [5]
    486 [6]
    Units: months
        median (confidence interval 95%)
    11.2 (10.1 to 12.6)
    12.2 (10.9 to 13.5)
    Notes
    [5] - Intent-to-treat population
    [6] - Intent-to-treat population
    Statistical analysis title
    		 Primary Analysis of OS in All Participants
    Comparison groups
    Placebo + Carboplatin + Paclitaxel v Veliparib + Carboplatin + Paclitaxel
    Number of subjects included in analysis
    970
    Analysis specification
    Pre-specified
    Analysis type
    		 other [7]
    P-value
    		 = 0.098 [8]
    Method
    		 Stratified Log-rank
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.889
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.767
         upper limit
    		 1.031
    Notes
    [7] - If the primary endpoint was not met, all analyses of secondary and other efficacy endpoints were to be performed in a descriptive manner and treated as exploratory, with P-values interpreted as nominal.
    [8] - Stratified by tumor staging (locally advanced vs metastatic), smoking status (current smokers vs past vs never smokers), and ECOG PS (0 vs 1).

    Secondary: Progression-Free Survival in Current Smokers

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    End point title
    		 Progression-Free Survival in Current Smokers
    End point description
    Progression-free survival (PFS) was calculated using Kaplan-Meier methods as the time from the date that the participant was randomized to the date the participant experienced an event of disease progression or to the date of death (all causes of mortality) if disease progression was not reached. Participants who did not have an event of progression or death prior to the analysis cut-off date were censored at the date of the last disease assessment before the cut-off date, or at the date of randomization if they did not have a post-baseline assessment. Disease progression was defined according to Response Evaluation Criteria in Solid Tumors (RECIST), version 1.1: At least a 20% increase in the sum of the longest diameter (LD) of target lesions, taking as reference the smallest sum LD recorded since the treatment started (baseline or after) with an absolute increase of at least 5 mm, unequivocal progression of existing non-target lesions, or the appearance of any new lesions.
    End point type
    Secondary
    End point timeframe
    From randomization to the primary analysis data cut-off date in 2017
    End point values
    		 Placebo + Carboplatin + Paclitaxel Veliparib + Carboplatin + Paclitaxel
    Number of subjects analysed
    276 [9]
    276 [10]
    Units: months
        median (confidence interval 95%)
    5.6 (5.4 to 5.7)
    5.6 (5.5 to 5.8)
    Notes
    [9] - Current smokers
    [10] - Current smokers
    Statistical analysis title
    		 Analysis of PFS in Current Smokers
    Comparison groups
    Placebo + Carboplatin + Paclitaxel v Veliparib + Carboplatin + Paclitaxel
    Number of subjects included in analysis
    552
    Analysis specification
    Pre-specified
    Analysis type
    		 other [11]
    P-value
    		 = 0.376 [12]
    Method
    		 Stratified Log-rank
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.918
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.763
         upper limit
    		 1.105
    Notes
    [11] - If the primary endpoint was not met, all analyses of secondary and other efficacy endpoints were to be performed in a descriptive manner and treated as exploratory, with P-values interpreted as nominal.
    [12] - Log-rank test stratified by tumor staging (locally advanced vs metastatic) and ECOG performance status (0 vs 1).

    Secondary: Progression-Free Survival in All Participants - Primary Analysis

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    End point title
    		 Progression-Free Survival in All Participants - Primary Analysis
    End point description
    Progression-free survival (PFS) was calculated using Kaplan-Meier methods as the time from the date that the participant was randomized to the date the participant experienced an event of disease progression or to the date of death (all causes of mortality) if disease progression was not reached. Participants who did not have an event of progression or death prior to the analysis cut-off date were censored at the date of the last disease assessment before the cut-off date, or at the date of randomization if they did not have a post-baseline assessment. Disease progression was defined according to Response Evaluation Criteria in Solid Tumors (RECIST), version 1.1: At least a 20% increase in the sum of the longest diameter (LD) of target lesions, taking as reference the smallest sum LD recorded since the treatment started (baseline or after) with an absolute increase of at least 5 mm, unequivocal progression of existing non-target lesions, or the appearance of any new lesions.
    End point type
    Secondary
    End point timeframe
    From randomization to the primary analysis data cut-off date in 2017.
    End point values
    		 Placebo + Carboplatin + Paclitaxel Veliparib + Carboplatin + Paclitaxel
    Number of subjects analysed
    484 [13]
    486 [14]
    Units: months
        median (confidence interval 95%)
    5.6 (5.5 to 5.7)
    5.6 (5.6 to 5.8)
    Notes
    [13] - Intent-to-treat population
    [14] - Intent-to-treat population
    Statistical analysis title
    		 Primary Analysis of PFS in All Participants
    Comparison groups
    Placebo + Carboplatin + Paclitaxel v Veliparib + Carboplatin + Paclitaxel
    Number of subjects included in analysis
    970
    Analysis specification
    Pre-specified
    Analysis type
    		 other [15]
    P-value
    		 = 0.132 [16]
    Method
    		 Stratified Log-rank
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.895
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.778
         upper limit
    		 1.031
    Notes
    [15] - If the primary endpoint was not met, all analyses of secondary and other efficacy endpoints were to be performed in a descriptive manner and treated as exploratory, with P-values interpreted as nominal.
    [16] - Stratified by tumor staging (locally advanced vs metastatic), smoking status (current smokers vs past vs never smokers), and ECOG PS (0 vs 1).

    Secondary: Objective Response Rate in Current Smokers

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    End point title
    		 Objective Response Rate in Current Smokers
    End point description
    Disease assessments were made using computed tomography (CT) scans of the full chest and abdomen and assessed by the investigator according to the Response Evaluation Criteria in Solid Tumors (RECIST) v1.1. Objective response rate (ORR) is defined as the percentage of participants a with complete or partial response, confirmed 4 weeks after the first documentation. Complete Response (CR): The disappearance of all target and non-target lesions, and no new lesions. Any pathological lymph nodes (whether target or non-target) must have reduction in short axis to < 10 mm. Partial Response (PR): At least a 30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum diameters, persistence of one or more non-target lesion(s) and/or maintenance of tumor marker level above the normal limits, or any new lesions.
    End point type
    Secondary
    End point timeframe
    Tumor assessments were performed on Day 1 of Cycle 3 and Cycle 5, every 6 weeks until 1 year after starting treatment, and then every 12 weeks until radiographic progression, additional cancer treatment, or death; median time on follow-up was 20 months.
    End point values
    		 Placebo + Carboplatin + Paclitaxel Veliparib + Carboplatin + Paclitaxel
    Number of subjects analysed
    276 [17]
    276 [18]
    Units: percentage of participants
        number (confidence interval 95%)
    34.8 (29.2 to 40.7)
    34.4 (28.8 to 40.4)
    Notes
    [17] - Current smokers
    [18] - Current smokers
    Statistical analysis title
    		 Analysis of ORR in Current Smokers
    Comparison groups
    Placebo + Carboplatin + Paclitaxel v Veliparib + Carboplatin + Paclitaxel
    Number of subjects included in analysis
    552
    Analysis specification
    Pre-specified
    Analysis type
    		 other [19]
    P-value
    		 = 0.92 [20]
    Method
    		 Cochran-Mantel-Haenszel
    Confidence interval
    Notes
    [19] - If the primary endpoint was not met, all analyses of secondary and other efficacy endpoints were to be performed in a descriptive manner and treated as exploratory, with P-values interpreted as nominal.
    [20] - Cochran-Mantel-Haenszel (CMH) test stratified by tumor staging (locally advanced versus metastatic) and ECOG performance status (0 versus 1).

    Secondary: Objective Response Rate in All Participants - Primary Analysis

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    End point title
    		 Objective Response Rate in All Participants - Primary Analysis
    End point description
    Disease assessments were made using computed tomography (CT) scans of the full chest and abdomen and assessed by the investigator according to RECIST v1.1. Objective response rate (ORR) is defined as the percentage of participants with a complete or partial response that was confirmed 4 weeks after the first documentation. Complete Response (CR): The disappearance of all target and non-target lesions, and no new lesions. Any pathological lymph nodes (whether target or non-target) must have reduction in short axis to < 10 mm. Partial Response (PR): At least a 30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum diameters, persistence of one or more non-target lesion(s) and/or maintenance of tumor marker level above the normal limits, or any new lesions.
    End point type
    Secondary
    End point timeframe
    Tumor assessments were performed on Day 1 of Cycle 3 and Cycle 5, every 6 weeks until 1 year after starting treatment, and then every 12 weeks until radiographic progression, additional cancer treatment, or death; median time on follow-up was 20 months.
    End point values
    		 Placebo + Carboplatin + Paclitaxel Veliparib + Carboplatin + Paclitaxel
    Number of subjects analysed
    484 [21]
    486 [22]
    Units: percentage of participants
        number (confidence interval 95%)
    37.2 (32.9 to 41.7)
    37.0 (32.7 to 41.5)
    Notes
    [21] - Intent-to-treat population
    [22] - Intent-to-treat population
    Statistical analysis title
    		 Analysis of ORR in All Participants
    Comparison groups
    Placebo + Carboplatin + Paclitaxel v Veliparib + Carboplatin + Paclitaxel
    Number of subjects included in analysis
    970
    Analysis specification
    Pre-specified
    Analysis type
    		 other [23]
    P-value
    		 = 0.963 [24]
    Method
    		 Cochran-Mantel-Haenszel
    Confidence interval
    Notes
    [23] - If the primary endpoint was not met, all analyses of secondary and other efficacy endpoints were to be performed in a descriptive manner and treated as exploratory, with P-values interpreted as nominal.
    [24] - Stratified by tumor stage (locally advanced vs metastatic), smoking status (current smokers vs past smokers vs never smoked), and ECOG PS (0 vs 1).

    Secondary: Overall Survival in All Participants - Final Analysis

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    End point title
    		 Overall Survival in All Participants - Final Analysis
    End point description
    Overall survival was calculated as the time from the date that the participant was randomized to the date of death. All events of death were included, regardless of whether the event occurred while the participant was still taking study drug, or after the participant discontinued study drug. Participants who had not died prior to the analysis cut-off date were censored at the date they were last known to be alive. The distributions of OS on the two treatment arms were estimated using the Kaplan-Meier method.
    End point type
    Secondary
    End point timeframe
    From randomization to the end of study
    End point values
    		 Placebo + Carboplatin + Paclitaxel Veliparib + Carboplatin + Paclitaxel
    Number of subjects analysed
    484 [25]
    486 [26]
    Units: months
        median (confidence interval 95%)
    11.2 (10.1 to 12.6)
    12.2 (10.9 to 13.5)
    Notes
    [25] - Intent-to-treat population
    [26] - Intent-to-treat population
    Statistical analysis title
    		 Final Analysis of OS in All Participants
    Comparison groups
    Placebo + Carboplatin + Paclitaxel v Veliparib + Carboplatin + Paclitaxel
    Number of subjects included in analysis
    970
    Analysis specification
    Pre-specified
    Analysis type
    		 other [27]
    P-value
    		 = 0.032 [28]
    Method
    		 Stratified Log-rank
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.853
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.747
         upper limit
    		 0.974
    Notes
    [27] - If the primary endpoint was not met, all analyses of secondary and other efficacy endpoints were to be performed in a descriptive manner and treated as exploratory, with P-values interpreted as nominal.
    [28] - Stratified by tumor staging (locally advanced vs metastatic), smoking status (current smokers vs past vs never smokers), and ECOG PS (0 vs 1).

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Deaths are reported from randomization until the end of follow-up; median time on study was 49.8 and 47.1 months in the placebo and veliparib arms respectively. AEs are reported from first dose of study drug until 30 days after last dose; max 181 days
    Adverse event reporting additional description
    Adverse event data are reported for all participants who received at least 1 dose of study drug (veliparib/placebo). One participant randomized to each arm who did not receive treatment and are not included in the safety analysis set died in addition to those in the table below.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    21.0
    Reporting groups
    Reporting group title
    Veliparib + Carboplatin + Paclitaxel
    Reporting group description
    		 Participants received veliparib 120 mg orally BID on Days -2 to 5 (7 consecutive days) of each 21-day cycle and carboplatin at an AUC 6 mg/mL/min and paclitaxel 200 mg/m² by IV infusion on Day 1 of each 21-day cycle for up to a maximum 6 cycles of treatment, until treatment toxicity which, in the Investigator's opinion, prohibited further therapy, or until radiographic progression.

    Reporting group title
    Placebo + Carboplatin + Paclitaxel
    Reporting group description
    		 Participants received placebo orally BID on Days -2 to 5 (7 consecutive days) of each 21-day cycle and carboplatin at an AUC 6 mg/mL/min and paclitaxel 200 mg/m² by IV infusion on Day 1 of each 21-day cycle for up to a maximum 6 cycles of treatment, until treatment toxicity which, in the Investigator's opinion, prohibited further therapy, or until radiographic progression.

    Serious adverse events
    		 Veliparib + Carboplatin + Paclitaxel Placebo + Carboplatin + Paclitaxel
    Total subjects affected by serious adverse events
         subjects affected / exposed
    155 / 485 (31.96%)
    164 / 482 (34.02%)
         number of deaths (all causes)
    435
    443
         number of deaths resulting from adverse events
    38
    44
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    MALIGNANT NEOPLASM PROGRESSION
         subjects affected / exposed
    8 / 485 (1.65%)
    13 / 482 (2.70%)
         occurrences causally related to treatment / all
    1 / 8
    0 / 13
         deaths causally related to treatment / all
    0 / 6
    0 / 9
    METASTASES TO CENTRAL NERVOUS SYSTEM
         subjects affected / exposed
    0 / 485 (0.00%)
    2 / 482 (0.41%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    METASTASES TO HEART
         subjects affected / exposed
    0 / 485 (0.00%)
    1 / 482 (0.21%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    METASTASES TO SPINE
         subjects affected / exposed
    1 / 485 (0.21%)
    0 / 482 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    NON-SMALL CELL LUNG CANCER
         subjects affected / exposed
    1 / 485 (0.21%)
    3 / 482 (0.62%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 3
         deaths causally related to treatment / all
    0 / 1
    0 / 3
    TUMOUR COMPRESSION
         subjects affected / exposed
    0 / 485 (0.00%)
    1 / 482 (0.21%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    TUMOUR PAIN
         subjects affected / exposed
    0 / 485 (0.00%)
    1 / 482 (0.21%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vascular disorders
    AORTIC THROMBOSIS
         subjects affected / exposed
    1 / 485 (0.21%)
    0 / 482 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    EMBOLISM
         subjects affected / exposed
    1 / 485 (0.21%)
    0 / 482 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    HYPOTENSION
         subjects affected / exposed
    2 / 485 (0.41%)
    0 / 482 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    ORTHOSTATIC HYPOTENSION
         subjects affected / exposed
    1 / 485 (0.21%)
    0 / 482 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    SUPERIOR VENA CAVA SYNDROME
         subjects affected / exposed
    2 / 485 (0.41%)
    1 / 482 (0.21%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    General disorders and administration site conditions
    ADVERSE DRUG REACTION
         subjects affected / exposed
    0 / 485 (0.00%)
    1 / 482 (0.21%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    CHEST PAIN
         subjects affected / exposed
    4 / 485 (0.82%)
    1 / 482 (0.21%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    DEATH
         subjects affected / exposed
    4 / 485 (0.82%)
    3 / 482 (0.62%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 3
         deaths causally related to treatment / all
    0 / 4
    0 / 3
    DISEASE PROGRESSION
         subjects affected / exposed
    1 / 485 (0.21%)
    1 / 482 (0.21%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 1
         deaths causally related to treatment / all
    1 / 1
    0 / 1
    FATIGUE
         subjects affected / exposed
    1 / 485 (0.21%)
    3 / 482 (0.62%)
         occurrences causally related to treatment / all
    1 / 1
    1 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    GENERAL PHYSICAL HEALTH DETERIORATION
         subjects affected / exposed
    1 / 485 (0.21%)
    3 / 482 (0.62%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    MULTIPLE ORGAN DYSFUNCTION SYNDROME
         subjects affected / exposed
    0 / 485 (0.00%)
    1 / 482 (0.21%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    1 / 1
    PAIN
         subjects affected / exposed
    0 / 485 (0.00%)
    2 / 482 (0.41%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    PERFORMANCE STATUS DECREASED
         subjects affected / exposed
    0 / 485 (0.00%)
    1 / 482 (0.21%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    PYREXIA
         subjects affected / exposed
    2 / 485 (0.41%)
    3 / 482 (0.62%)
         occurrences causally related to treatment / all
    0 / 2
    1 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Immune system disorders
    ANAPHYLACTIC REACTION
         subjects affected / exposed
    1 / 485 (0.21%)
    0 / 482 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    DRUG HYPERSENSITIVITY
         subjects affected / exposed
    3 / 485 (0.62%)
    7 / 482 (1.45%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 10
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Reproductive system and breast disorders
    OVARIAN MASS
         subjects affected / exposed
    0 / 485 (0.00%)
    1 / 482 (0.21%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    PROSTATITIS
         subjects affected / exposed
    1 / 485 (0.21%)
    0 / 482 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    TESTICULAR CYST
         subjects affected / exposed
    0 / 485 (0.00%)
    1 / 482 (0.21%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    ACUTE RESPIRATORY FAILURE
         subjects affected / exposed
    0 / 485 (0.00%)
    3 / 482 (0.62%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 3
    ALVEOLITIS
         subjects affected / exposed
    0 / 485 (0.00%)
    1 / 482 (0.21%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    ASPIRATION
         subjects affected / exposed
    1 / 485 (0.21%)
    0 / 482 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    ATELECTASIS
         subjects affected / exposed
    2 / 485 (0.41%)
    0 / 482 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    BRONCHIAL OBSTRUCTION
         subjects affected / exposed
    1 / 485 (0.21%)
    0 / 482 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    CHRONIC OBSTRUCTIVE PULMONARY DISEASE
         subjects affected / exposed
    1 / 485 (0.21%)
    2 / 482 (0.41%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    DYSPNOEA
         subjects affected / exposed
    4 / 485 (0.82%)
    6 / 482 (1.24%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 6
         deaths causally related to treatment / all
    0 / 1
    0 / 1
    HAEMOPTYSIS
         subjects affected / exposed
    7 / 485 (1.44%)
    3 / 482 (0.62%)
         occurrences causally related to treatment / all
    0 / 7
    1 / 3
         deaths causally related to treatment / all
    0 / 3
    1 / 1
    HYPOXIA
         subjects affected / exposed
    1 / 485 (0.21%)
    1 / 482 (0.21%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    LUNG INFILTRATION
         subjects affected / exposed
    0 / 485 (0.00%)
    1 / 482 (0.21%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    PLEURAL EFFUSION
         subjects affected / exposed
    8 / 485 (1.65%)
    4 / 482 (0.83%)
         occurrences causally related to treatment / all
    1 / 8
    0 / 4
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    PNEUMONIA ASPIRATION
         subjects affected / exposed
    1 / 485 (0.21%)
    0 / 482 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    PNEUMONITIS
         subjects affected / exposed
    1 / 485 (0.21%)
    0 / 482 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    PNEUMOTHORAX
         subjects affected / exposed
    2 / 485 (0.41%)
    1 / 482 (0.21%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    PNEUMOTHORAX SPONTANEOUS
         subjects affected / exposed
    1 / 485 (0.21%)
    0 / 482 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    PULMONARY EMBOLISM
         subjects affected / exposed
    5 / 485 (1.03%)
    6 / 482 (1.24%)
         occurrences causally related to treatment / all
    2 / 5
    1 / 6
         deaths causally related to treatment / all
    0 / 1
    0 / 1
    PULMONARY HAEMORRHAGE
         subjects affected / exposed
    2 / 485 (0.41%)
    3 / 482 (0.62%)
         occurrences causally related to treatment / all
    0 / 2
    1 / 3
         deaths causally related to treatment / all
    0 / 2
    1 / 2
    PULMONARY OEDEMA
         subjects affected / exposed
    0 / 485 (0.00%)
    1 / 482 (0.21%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    RESPIRATORY DISORDER
         subjects affected / exposed
    0 / 485 (0.00%)
    1 / 482 (0.21%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    RESPIRATORY DISTRESS
         subjects affected / exposed
    0 / 485 (0.00%)
    1 / 482 (0.21%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    RESPIRATORY FAILURE
         subjects affected / exposed
    2 / 485 (0.41%)
    3 / 482 (0.62%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 3
         deaths causally related to treatment / all
    0 / 1
    0 / 2
    Psychiatric disorders
    INSOMNIA
         subjects affected / exposed
    1 / 485 (0.21%)
    0 / 482 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Investigations
    BLOOD CREATININE INCREASED
         subjects affected / exposed
    1 / 485 (0.21%)
    0 / 482 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    1 / 1
    0 / 0
    GENERAL PHYSICAL CONDITION ABNORMAL
         subjects affected / exposed
    0 / 485 (0.00%)
    1 / 482 (0.21%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    FALL
         subjects affected / exposed
    1 / 485 (0.21%)
    1 / 482 (0.21%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    FEMORAL NECK FRACTURE
         subjects affected / exposed
    0 / 485 (0.00%)
    1 / 482 (0.21%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    PROCEDURAL PAIN
         subjects affected / exposed
    0 / 485 (0.00%)
    1 / 482 (0.21%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    SPINAL COMPRESSION FRACTURE
         subjects affected / exposed
    1 / 485 (0.21%)
    0 / 482 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    TOXICITY TO VARIOUS AGENTS
         subjects affected / exposed
    0 / 485 (0.00%)
    1 / 482 (0.21%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    ULNA FRACTURE
         subjects affected / exposed
    1 / 485 (0.21%)
    0 / 482 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac disorders
    ACUTE CORONARY SYNDROME
         subjects affected / exposed
    0 / 485 (0.00%)
    2 / 482 (0.41%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    ACUTE MYOCARDIAL INFARCTION
         subjects affected / exposed
    3 / 485 (0.62%)
    1 / 482 (0.21%)
         occurrences causally related to treatment / all
    2 / 3
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    ANGINA PECTORIS
         subjects affected / exposed
    1 / 485 (0.21%)
    1 / 482 (0.21%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    ARRHYTHMIA
         subjects affected / exposed
    1 / 485 (0.21%)
    0 / 482 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    ATRIAL FIBRILLATION
         subjects affected / exposed
    3 / 485 (0.62%)
    7 / 482 (1.45%)
         occurrences causally related to treatment / all
    0 / 3
    3 / 7
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    ATRIAL FLUTTER
         subjects affected / exposed
    0 / 485 (0.00%)
    1 / 482 (0.21%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    CARDIAC ARREST
         subjects affected / exposed
    2 / 485 (0.41%)
    2 / 482 (0.41%)
         occurrences causally related to treatment / all
    0 / 2
    1 / 2
         deaths causally related to treatment / all
    0 / 2
    1 / 2
    CARDIAC FAILURE
         subjects affected / exposed
    1 / 485 (0.21%)
    2 / 482 (0.41%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 1
    0 / 2
    CARDIAC FAILURE ACUTE
         subjects affected / exposed
    0 / 485 (0.00%)
    2 / 482 (0.41%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 2
    CARDIAC FAILURE CONGESTIVE
         subjects affected / exposed
    1 / 485 (0.21%)
    0 / 482 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    CARDIOVASCULAR INSUFFICIENCY
         subjects affected / exposed
    1 / 485 (0.21%)
    1 / 482 (0.21%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 1
         deaths causally related to treatment / all
    1 / 1
    0 / 1
    INTRACARDIAC MASS
         subjects affected / exposed
    1 / 485 (0.21%)
    0 / 482 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    MYOCARDIAL INFARCTION
         subjects affected / exposed
    1 / 485 (0.21%)
    1 / 482 (0.21%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    PERICARDIAL EFFUSION
         subjects affected / exposed
    1 / 485 (0.21%)
    2 / 482 (0.41%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    SINUS TACHYCARDIA
         subjects affected / exposed
    1 / 485 (0.21%)
    0 / 482 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    TACHYCARDIA
         subjects affected / exposed
    0 / 485 (0.00%)
    1 / 482 (0.21%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nervous system disorders
    CEREBRAL HAEMORRHAGE
         subjects affected / exposed
    0 / 485 (0.00%)
    1 / 482 (0.21%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    CEREBROVASCULAR ACCIDENT
         subjects affected / exposed
    3 / 485 (0.62%)
    0 / 482 (0.00%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    COGNITIVE DISORDER
         subjects affected / exposed
    0 / 485 (0.00%)
    1 / 482 (0.21%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    DIZZINESS
         subjects affected / exposed
    1 / 485 (0.21%)
    1 / 482 (0.21%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    HEMIPARESIS
         subjects affected / exposed
    0 / 485 (0.00%)
    1 / 482 (0.21%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    NEUROPATHY PERIPHERAL
         subjects affected / exposed
    1 / 485 (0.21%)
    0 / 482 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    PARTIAL SEIZURES
         subjects affected / exposed
    0 / 485 (0.00%)
    1 / 482 (0.21%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    PERIPHERAL SENSORY NEUROPATHY
         subjects affected / exposed
    1 / 485 (0.21%)
    1 / 482 (0.21%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    PRESYNCOPE
         subjects affected / exposed
    0 / 485 (0.00%)
    1 / 482 (0.21%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    SEIZURE
         subjects affected / exposed
    1 / 485 (0.21%)
    0 / 482 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    SYNCOPE
         subjects affected / exposed
    2 / 485 (0.41%)
    0 / 482 (0.00%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    TRANSIENT ISCHAEMIC ATTACK
         subjects affected / exposed
    2 / 485 (0.41%)
    1 / 482 (0.21%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    ANAEMIA
         subjects affected / exposed
    12 / 485 (2.47%)
    21 / 482 (4.36%)
         occurrences causally related to treatment / all
    5 / 18
    7 / 24
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    FEBRILE NEUTROPENIA
         subjects affected / exposed
    17 / 485 (3.51%)
    20 / 482 (4.15%)
         occurrences causally related to treatment / all
    10 / 18
    12 / 21
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    LEUKOPENIA
         subjects affected / exposed
    2 / 485 (0.41%)
    0 / 482 (0.00%)
         occurrences causally related to treatment / all
    2 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    NEUTROPENIA
         subjects affected / exposed
    8 / 485 (1.65%)
    12 / 482 (2.49%)
         occurrences causally related to treatment / all
    2 / 8
    3 / 12
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    PANCYTOPENIA
         subjects affected / exposed
    3 / 485 (0.62%)
    0 / 482 (0.00%)
         occurrences causally related to treatment / all
    1 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    THROMBOCYTOPENIA
         subjects affected / exposed
    3 / 485 (0.62%)
    4 / 482 (0.83%)
         occurrences causally related to treatment / all
    3 / 5
    2 / 5
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ear and labyrinth disorders
    VERTIGO
         subjects affected / exposed
    1 / 485 (0.21%)
    0 / 482 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal disorders
    ABDOMINAL PAIN
         subjects affected / exposed
    1 / 485 (0.21%)
    2 / 482 (0.41%)
         occurrences causally related to treatment / all
    1 / 1
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    ABDOMINAL PAIN UPPER
         subjects affected / exposed
    1 / 485 (0.21%)
    0 / 482 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    ASCITES
         subjects affected / exposed
    0 / 485 (0.00%)
    2 / 482 (0.41%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    CONSTIPATION
         subjects affected / exposed
    1 / 485 (0.21%)
    0 / 482 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    DIARRHOEA
         subjects affected / exposed
    2 / 485 (0.41%)
    5 / 482 (1.04%)
         occurrences causally related to treatment / all
    2 / 2
    3 / 5
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    DIVERTICULAR PERFORATION
         subjects affected / exposed
    1 / 485 (0.21%)
    0 / 482 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    DUODENAL ULCER
         subjects affected / exposed
    0 / 485 (0.00%)
    1 / 482 (0.21%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    DUODENAL ULCER PERFORATION
         subjects affected / exposed
    0 / 485 (0.00%)
    1 / 482 (0.21%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    DYSPHAGIA
         subjects affected / exposed
    0 / 485 (0.00%)
    1 / 482 (0.21%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    ENTERITIS
         subjects affected / exposed
    0 / 485 (0.00%)
    1 / 482 (0.21%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    FAECES DISCOLOURED
         subjects affected / exposed
    0 / 485 (0.00%)
    1 / 482 (0.21%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    GASTRIC HAEMORRHAGE
         subjects affected / exposed
    0 / 485 (0.00%)
    1 / 482 (0.21%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    GASTRIC ULCER
         subjects affected / exposed
    0 / 485 (0.00%)
    1 / 482 (0.21%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    GASTRITIS
         subjects affected / exposed
    0 / 485 (0.00%)
    1 / 482 (0.21%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    GASTRITIS EROSIVE
         subjects affected / exposed
    1 / 485 (0.21%)
    0 / 482 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    GASTROINTESTINAL HAEMORRHAGE
         subjects affected / exposed
    0 / 485 (0.00%)
    1 / 482 (0.21%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    GASTROINTESTINAL PERFORATION
         subjects affected / exposed
    1 / 485 (0.21%)
    0 / 482 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    NAUSEA
         subjects affected / exposed
    0 / 485 (0.00%)
    4 / 482 (0.83%)
         occurrences causally related to treatment / all
    0 / 0
    4 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    OESOPHAGEAL STENOSIS
         subjects affected / exposed
    0 / 485 (0.00%)
    1 / 482 (0.21%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    SMALL INTESTINAL OBSTRUCTION
         subjects affected / exposed
    0 / 485 (0.00%)
    1 / 482 (0.21%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    TONGUE OEDEMA
         subjects affected / exposed
    1 / 485 (0.21%)
    0 / 482 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    VOMITING
         subjects affected / exposed
    0 / 485 (0.00%)
    3 / 482 (0.62%)
         occurrences causally related to treatment / all
    0 / 0
    3 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatobiliary disorders
    HEPATITIS ACUTE
         subjects affected / exposed
    1 / 485 (0.21%)
    0 / 482 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    PORTAL VEIN THROMBOSIS
         subjects affected / exposed
    0 / 485 (0.00%)
    1 / 482 (0.21%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal and urinary disorders
    ACUTE KIDNEY INJURY
         subjects affected / exposed
    2 / 485 (0.41%)
    0 / 482 (0.00%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    AZOTAEMIA
         subjects affected / exposed
    0 / 485 (0.00%)
    1 / 482 (0.21%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    NEPHROLITHIASIS
         subjects affected / exposed
    0 / 485 (0.00%)
    1 / 482 (0.21%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    RENAL COLIC
         subjects affected / exposed
    0 / 485 (0.00%)
    1 / 482 (0.21%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    RENAL IMPAIRMENT
         subjects affected / exposed
    1 / 485 (0.21%)
    0 / 482 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    URINARY RETENTION
         subjects affected / exposed
    1 / 485 (0.21%)
    1 / 482 (0.21%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    ARTHRALGIA
         subjects affected / exposed
    0 / 485 (0.00%)
    1 / 482 (0.21%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    BACK PAIN
         subjects affected / exposed
    2 / 485 (0.41%)
    3 / 482 (0.62%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    BONE PAIN
         subjects affected / exposed
    0 / 485 (0.00%)
    1 / 482 (0.21%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    FLANK PAIN
         subjects affected / exposed
    0 / 485 (0.00%)
    1 / 482 (0.21%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    INTERVERTEBRAL DISC PROTRUSION
         subjects affected / exposed
    1 / 485 (0.21%)
    0 / 482 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    MUSCULAR WEAKNESS
         subjects affected / exposed
    0 / 485 (0.00%)
    2 / 482 (0.41%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    MUSCULOSKELETAL CHEST PAIN
         subjects affected / exposed
    0 / 485 (0.00%)
    1 / 482 (0.21%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    PAIN IN EXTREMITY
         subjects affected / exposed
    1 / 485 (0.21%)
    1 / 482 (0.21%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    PATHOLOGICAL FRACTURE
         subjects affected / exposed
    0 / 485 (0.00%)
    1 / 482 (0.21%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infections and infestations
    ANAL ABSCESS
         subjects affected / exposed
    1 / 485 (0.21%)
    0 / 482 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    BACTERAEMIA
         subjects affected / exposed
    1 / 485 (0.21%)
    0 / 482 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    BRONCHITIS
         subjects affected / exposed
    2 / 485 (0.41%)
    0 / 482 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    CLOSTRIDIUM DIFFICILE COLITIS
         subjects affected / exposed
    1 / 485 (0.21%)
    0 / 482 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    DIVERTICULITIS
         subjects affected / exposed
    1 / 485 (0.21%)
    0 / 482 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    EMPYEMA
         subjects affected / exposed
    0 / 485 (0.00%)
    1 / 482 (0.21%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    ENTEROCOLITIS INFECTIOUS
         subjects affected / exposed
    0 / 485 (0.00%)
    1 / 482 (0.21%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    GASTROENTERITIS
         subjects affected / exposed
    2 / 485 (0.41%)
    1 / 482 (0.21%)
         occurrences causally related to treatment / all
    0 / 2
    1 / 1
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    INFECTION
         subjects affected / exposed
    0 / 485 (0.00%)
    2 / 482 (0.41%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    LOWER RESPIRATORY TRACT INFECTION
         subjects affected / exposed
    3 / 485 (0.62%)
    7 / 482 (1.45%)
         occurrences causally related to treatment / all
    1 / 3
    1 / 7
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    LUNG ABSCESS
         subjects affected / exposed
    0 / 485 (0.00%)
    2 / 482 (0.41%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    LUNG INFECTION
         subjects affected / exposed
    3 / 485 (0.62%)
    0 / 482 (0.00%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    MESENTERIC ABSCESS
         subjects affected / exposed
    1 / 485 (0.21%)
    0 / 482 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    NEUTROPENIC SEPSIS
         subjects affected / exposed
    0 / 485 (0.00%)
    2 / 482 (0.41%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    ORAL CANDIDIASIS
         subjects affected / exposed
    1 / 485 (0.21%)
    0 / 482 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    OSTEOMYELITIS
         subjects affected / exposed
    0 / 485 (0.00%)
    1 / 482 (0.21%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    PNEUMONIA
         subjects affected / exposed
    23 / 485 (4.74%)
    19 / 482 (3.94%)
         occurrences causally related to treatment / all
    4 / 24
    4 / 21
         deaths causally related to treatment / all
    0 / 3
    1 / 2
    PNEUMONIA BACTERIAL
         subjects affected / exposed
    0 / 485 (0.00%)
    1 / 482 (0.21%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    PNEUMONIA KLEBSIELLA
         subjects affected / exposed
    1 / 485 (0.21%)
    0 / 482 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    PNEUMONIA STAPHYLOCOCCAL
         subjects affected / exposed
    1 / 485 (0.21%)
    0 / 482 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    PULMONARY SEPSIS
         subjects affected / exposed
    1 / 485 (0.21%)
    1 / 482 (0.21%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    0 / 1
    PYELONEPHRITIS
         subjects affected / exposed
    1 / 485 (0.21%)
    0 / 482 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    RESPIRATORY TRACT INFECTION
         subjects affected / exposed
    4 / 485 (0.82%)
    5 / 482 (1.04%)
         occurrences causally related to treatment / all
    1 / 4
    1 / 5
         deaths causally related to treatment / all
    0 / 0
    1 / 1
    SEPSIS
         subjects affected / exposed
    4 / 485 (0.82%)
    2 / 482 (0.41%)
         occurrences causally related to treatment / all
    2 / 4
    0 / 2
         deaths causally related to treatment / all
    1 / 1
    0 / 0
    SEPTIC EMBOLUS
         subjects affected / exposed
    0 / 485 (0.00%)
    1 / 482 (0.21%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    SEPTIC SHOCK
         subjects affected / exposed
    4 / 485 (0.82%)
    2 / 482 (0.41%)
         occurrences causally related to treatment / all
    0 / 4
    1 / 2
         deaths causally related to treatment / all
    0 / 2
    1 / 1
    SINUSITIS
         subjects affected / exposed
    0 / 485 (0.00%)
    1 / 482 (0.21%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    SUBCUTANEOUS ABSCESS
         subjects affected / exposed
    0 / 485 (0.00%)
    1 / 482 (0.21%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    UPPER RESPIRATORY TRACT INFECTION
         subjects affected / exposed
    0 / 485 (0.00%)
    1 / 482 (0.21%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    URINARY TRACT INFECTION
         subjects affected / exposed
    1 / 485 (0.21%)
    1 / 482 (0.21%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    URINARY TRACT INFECTION ENTEROCOCCAL
         subjects affected / exposed
    0 / 485 (0.00%)
    1 / 482 (0.21%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    DECREASED APPETITE
         subjects affected / exposed
    1 / 485 (0.21%)
    1 / 482 (0.21%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    DEHYDRATION
         subjects affected / exposed
    3 / 485 (0.62%)
    2 / 482 (0.41%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    ELECTROLYTE IMBALANCE
         subjects affected / exposed
    1 / 485 (0.21%)
    0 / 482 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    HYPERCALCAEMIA
         subjects affected / exposed
    1 / 485 (0.21%)
    3 / 482 (0.62%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    HYPERGLYCAEMIA
         subjects affected / exposed
    2 / 485 (0.41%)
    0 / 482 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    HYPERURICAEMIA
         subjects affected / exposed
    1 / 485 (0.21%)
    0 / 482 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    HYPOGLYCAEMIA
         subjects affected / exposed
    1 / 485 (0.21%)
    0 / 482 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    HYPOKALAEMIA
         subjects affected / exposed
    1 / 485 (0.21%)
    1 / 482 (0.21%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    HYPONATRAEMIA
         subjects affected / exposed
    1 / 485 (0.21%)
    1 / 482 (0.21%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Veliparib + Carboplatin + Paclitaxel Placebo + Carboplatin + Paclitaxel
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    441 / 485 (90.93%)
    438 / 482 (90.87%)
    Investigations
    WEIGHT DECREASED
         subjects affected / exposed
    26 / 485 (5.36%)
    36 / 482 (7.47%)
         occurrences all number
    29
    42
    Nervous system disorders
    DIZZINESS
         subjects affected / exposed
    26 / 485 (5.36%)
    24 / 482 (4.98%)
         occurrences all number
    30
    26
    DYSGEUSIA
         subjects affected / exposed
    22 / 485 (4.54%)
    26 / 482 (5.39%)
         occurrences all number
    22
    29
    NEUROPATHY PERIPHERAL
         subjects affected / exposed
    43 / 485 (8.87%)
    43 / 482 (8.92%)
         occurrences all number
    57
    58
    PARAESTHESIA
         subjects affected / exposed
    27 / 485 (5.57%)
    43 / 482 (8.92%)
         occurrences all number
    29
    57
    PERIPHERAL SENSORY NEUROPATHY
         subjects affected / exposed
    153 / 485 (31.55%)
    148 / 482 (30.71%)
         occurrences all number
    217
    220
    Blood and lymphatic system disorders
    ANAEMIA
         subjects affected / exposed
    157 / 485 (32.37%)
    146 / 482 (30.29%)
         occurrences all number
    254
    232
    LEUKOPENIA
         subjects affected / exposed
    53 / 485 (10.93%)
    34 / 482 (7.05%)
         occurrences all number
    86
    46
    LYMPHOPENIA
         subjects affected / exposed
    25 / 485 (5.15%)
    18 / 482 (3.73%)
         occurrences all number
    37
    22
    NEUTROPENIA
         subjects affected / exposed
    152 / 485 (31.34%)
    133 / 482 (27.59%)
         occurrences all number
    259
    227
    THROMBOCYTOPENIA
         subjects affected / exposed
    92 / 485 (18.97%)
    98 / 482 (20.33%)
         occurrences all number
    173
    185
    General disorders and administration site conditions
    ASTHENIA
         subjects affected / exposed
    71 / 485 (14.64%)
    72 / 482 (14.94%)
         occurrences all number
    114
    118
    FATIGUE
         subjects affected / exposed
    100 / 485 (20.62%)
    105 / 482 (21.78%)
         occurrences all number
    134
    143
    OEDEMA PERIPHERAL
         subjects affected / exposed
    25 / 485 (5.15%)
    23 / 482 (4.77%)
         occurrences all number
    30
    24
    PYREXIA
         subjects affected / exposed
    32 / 485 (6.60%)
    34 / 482 (7.05%)
         occurrences all number
    37
    44
    Gastrointestinal disorders
    CONSTIPATION
         subjects affected / exposed
    74 / 485 (15.26%)
    84 / 482 (17.43%)
         occurrences all number
    90
    98
    DIARRHOEA
         subjects affected / exposed
    83 / 485 (17.11%)
    76 / 482 (15.77%)
         occurrences all number
    110
    91
    NAUSEA
         subjects affected / exposed
    116 / 485 (23.92%)
    112 / 482 (23.24%)
         occurrences all number
    142
    146
    VOMITING
         subjects affected / exposed
    44 / 485 (9.07%)
    51 / 482 (10.58%)
         occurrences all number
    61
    65
    Respiratory, thoracic and mediastinal disorders
    COUGH
         subjects affected / exposed
    62 / 485 (12.78%)
    69 / 482 (14.32%)
         occurrences all number
    71
    73
    DYSPNOEA
         subjects affected / exposed
    70 / 485 (14.43%)
    55 / 482 (11.41%)
         occurrences all number
    77
    61
    Skin and subcutaneous tissue disorders
    ALOPECIA
         subjects affected / exposed
    232 / 485 (47.84%)
    220 / 482 (45.64%)
         occurrences all number
    268
    245
    RASH
         subjects affected / exposed
    12 / 485 (2.47%)
    25 / 482 (5.19%)
         occurrences all number
    13
    32
    Psychiatric disorders
    INSOMNIA
         subjects affected / exposed
    32 / 485 (6.60%)
    38 / 482 (7.88%)
         occurrences all number
    36
    40
    Musculoskeletal and connective tissue disorders
    ARTHRALGIA
         subjects affected / exposed
    65 / 485 (13.40%)
    66 / 482 (13.69%)
         occurrences all number
    77
    97
    MYALGIA
         subjects affected / exposed
    56 / 485 (11.55%)
    43 / 482 (8.92%)
         occurrences all number
    83
    59
    PAIN IN EXTREMITY
         subjects affected / exposed
    46 / 485 (9.48%)
    40 / 482 (8.30%)
         occurrences all number
    58
    45
    Metabolism and nutrition disorders
    DECREASED APPETITE
         subjects affected / exposed
    68 / 485 (14.02%)
    77 / 482 (15.98%)
         occurrences all number
    84
    88
    HYPERGLYCAEMIA
         subjects affected / exposed
    33 / 485 (6.80%)
    36 / 482 (7.47%)
         occurrences all number
    49
    61
    HYPOKALAEMIA
         subjects affected / exposed
    19 / 485 (3.92%)
    27 / 482 (5.60%)
         occurrences all number
    21
    34
    HYPOMAGNESAEMIA
         subjects affected / exposed
    33 / 485 (6.80%)
    29 / 482 (6.02%)
         occurrences all number
    48
    35

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    07 May 2014
    Updated inclusion/exclusion criteria and updated requirements for physical examination to include neurological evaluation and hearing assessment at Screening and C2D1 – C6D1, in agreement with regulatory feedback.
    10 Jul 2014
    Updated inclusion/exclusion criteria, moved duration of response (DOR) from a secondary endpoint to a tertiary endpoint, and clarified that confirmed response was required as part of ORR analysis in agreement with regulatory feedback.
    02 Feb 2016
    The primary endpoint was amended to OS in current smokers with OS of all subjects as a secondary endpoint (as Phase 2 data suggested that veliparib benefit may be most evident in smokers). Corresponding changes were also made to the sample size calculation and timing of efficacy and futility interim analysis to align with primary endpoint change.

    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
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    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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