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    Clinical Trial Results:
    A Double-Blind, Placebo-Controlled, Randomized, Multicenter Phase III Study Evaluating the Efficacy and Safety of Pertuzumab in Combination With Trastuzumab and Chemotherapy in Patients With HER2-Positive Metastatic Gastroesophageal Junction and Gastric Cancer

    Summary
    EudraCT number
    		 2012-003554-83
    Trial protocol
    		 ES   AT   DE   FI   NL   IT   BE   HU   BG   PL  
    Global end of trial date

    Results information
    Results version number
    		 v1
    This version publication date
    24 Dec 2017
    First version publication date
    24 Dec 2017
    Other versions
    		 v2

    Trial information

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    Trial identification
    Sponsor protocol code
    BO25114
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT01774786
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Hoffmann-La Roche
    Sponsor organisation address
    Grenzacherstrasse 124, CH, Basel, Switzerland, CH-4070
    Public contact
    Medical Communications, Hoffmann-La Roche, 41 8008218590, genentech@druginfo.com
    Scientific contact
    Medical Communications, Hoffmann-La Roche, 41 8008218590, genentech@druginfo.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
    Interim
    Date of interim/final analysis
    09 Dec 2016
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    09 Dec 2016
    Global end of trial reached?
    No
    General information about the trial
    Main objective of the trial
    The primary objective of this study was to compare overall survival in subjects treated with pertuzumab in addition to trastuzumab, fluoropyrimidine and cisplatin (TFP) versus subjects treated with placebo in addition to TFP.
    Protection of trial subjects
    All subjects (or authorized representatives) signed an informed consent form before participating in the study.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    10 Jun 2013
    Long term follow-up planned
    Yes
    Long term follow-up rationale
    		 Safety, Efficacy
    Long term follow-up duration
    		 5 Years
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    China: 163
    Country: Number of subjects enrolled
    Kazakhstan: 2
    Country: Number of subjects enrolled
    Korea, Republic of: 94
    Country: Number of subjects enrolled
    Malaysia: 2
    Country: Number of subjects enrolled
    Thailand: 8
    Country: Number of subjects enrolled
    Taiwan: 20
    Country: Number of subjects enrolled
    Japan: 80
    Country: Number of subjects enrolled
    Australia: 11
    Country: Number of subjects enrolled
    Austria: 3
    Country: Number of subjects enrolled
    Belgium: 3
    Country: Number of subjects enrolled
    Canada: 18
    Country: Number of subjects enrolled
    Switzerland: 8
    Country: Number of subjects enrolled
    Germany: 38
    Country: Number of subjects enrolled
    Spain: 51
    Country: Number of subjects enrolled
    Finland: 1
    Country: Number of subjects enrolled
    Italy: 44
    Country: Number of subjects enrolled
    Netherlands: 8
    Country: Number of subjects enrolled
    Turkey: 57
    Country: Number of subjects enrolled
    United States: 24
    Country: Number of subjects enrolled
    Bulgaria: 6
    Country: Number of subjects enrolled
    Brazil: 22
    Country: Number of subjects enrolled
    Croatia: 4
    Country: Number of subjects enrolled
    Hungary: 16
    Country: Number of subjects enrolled
    Mexico: 3
    Country: Number of subjects enrolled
    Macedonia, the former Yugoslav Republic of: 10
    Country: Number of subjects enrolled
    Panama: 2
    Country: Number of subjects enrolled
    Peru: 14
    Country: Number of subjects enrolled
    Poland: 31
    Country: Number of subjects enrolled
    Romania: 16
    Country: Number of subjects enrolled
    Russian Federation: 21
    Worldwide total number of subjects
    780
    EEA total number of subjects
    221
    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)
    475
    From 65 to 84 years
    304
    85 years and over
    1

    Subject disposition

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    Recruitment
    Recruitment details
    		 -

    Pre-assignment
    Screening details
    		 The analysis included data up to a clinical data cut-off date of 9 December 2016.

    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
    		 Investigator, Subject

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Pertuzumab + Trastuzumab + Chemotherapy
    Arm description
    		 Subjects will receive pertuzumab in combination with trastuzumab and chemotherapy (cisplatin and fluoropyrimidine [capecitabine or 5-fluorouracil]) for the first 6 treatment cycles (cycle length = 21 days). Subjects will continue to receive pertuzumab and trastuzumab until disease progression occurrence of unacceptable toxicity or withdrawal from the study for another reason.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Pertuzumab
    Investigational medicinal product code
    Other name
    Perjeta
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Subjects will receive pertuzumab 840 milligrams (mg) intravenously (IV) every 3 weeks (q3w) until disease progression, occurrence of unacceptable toxicity, or withdrawal from the study for another reason.

    Investigational medicinal product name
    Trastuzumab
    Investigational medicinal product code
    Other name
    Herceptin
    Pharmaceutical forms
    Powder for solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Subjects will receive 8 milligrams per kilogram (mg/kg) IV initial dose on Day 1, followed by 6 mg/kg IV q3w until disease progression, occurrence of unacceptable toxicity, or withdrawal from the study for another reason.

    Investigational medicinal product name
    5-Fluorouracil
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Subjects will receive 5-fluorouracil 800 milligrams per meter square (mg/m^2)/24 hour IV infusion for 120 hours (Days 1-5) q3w for 6 cycles.

    Investigational medicinal product name
    Capecitabine
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Subjects will receive capecitabine 1000 mg/m^2 orally twice daily, evening of Day 1 to morning of Day 15 (28 doses) q3w for 6 cycles.

    Investigational medicinal product name
    Cisplatin
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Subjects will receive cisplatin 80 mg/m^2 IV q3w for 6 cycles.

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Subjects will receive pertuzumab placebo IV q3w until disease progression, occurrence of unacceptable toxicity, or withdrawal from the study for another reason.

    Arm title
    		 Placebo + Trastuzumab + Chemotherapy
    Arm description
    		 Subjects will receive pertuzumab placebo in combination with trastuzumab and chemotherapy (cisplatin and fluoropyrimidine [capecitabine or 5-fluorouracil]) for the first 6 treatment cycles (cycle length = 21 days). Subjects will continue to receive pertuzumab placebo and trastuzumab until disease progression occurrence of unacceptable toxicity or withdrawal from the study for another reason.
    Arm type
    		 Placebo

    Investigational medicinal product name
    Pertuzumab
    Investigational medicinal product code
    Other name
    Perjeta
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Subjects will receive pertuzumab 840 mg intravenously (IV) every 3 weeks (q3w) until disease progression, occurrence of unacceptable toxicity, or withdrawal from the study for another reason.

    Investigational medicinal product name
    Trastuzumab
    Investigational medicinal product code
    Other name
    Herceptin
    Pharmaceutical forms
    Powder for solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Subjects will receive 8 mg/kg IV initial dose on Day 1, followed by 6 mg/kg IV q3w until disease progression, occurrence of unacceptable toxicity, or withdrawal from the study for another reason.

    Investigational medicinal product name
    Capecitabine
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Subjects will receive capecitabine 1000 mg/m^2 orally twice daily, evening of Day 1 to morning of Day 15 (28 doses) q3w for 6 cycles.

    Investigational medicinal product name
    5-Fluorouracil
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Subjects will receive 5-fluorouracil 800 milligrams per meter square (mg/m^2)/24 hour IV infusion for 120 hours (Days 1-5) q3w for 6 cycles.

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Subjects will receive pertuzumab placebo IV q3w until disease progression, occurrence of unacceptable toxicity, or withdrawal from the study for another reason.

    Investigational medicinal product name
    Cisplatin
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Subjects will receive cisplatin 80 mg/m^2 IV q3w for 6 cycles.

    Number of subjects in period 1
    		Pertuzumab + Trastuzumab + Chemotherapy Placebo + Trastuzumab + Chemotherapy
    Started
    388
    392
    Did Not Receive Study Drug
    4
    3
    Received One Dose of Pertuzumab by Error
    0
    1
    Received at Least One Dose of Study Drug
    385
    388
    Completed
    0
    0
    Not completed
    388
    392
         Between Treatment and Follow-up
    6
    2
         Ineligible for Study
    1
    3
         On Treatment
    55
    47
         Consent withdrawn by subject
    15
    12
         Physician decision
    1
    -
         Death
    242
    262
         Lost to follow-up
    3
    4
         In Follow-up
    65
    62

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Pertuzumab + Trastuzumab + Chemotherapy
    Reporting group description
    		 Subjects will receive pertuzumab in combination with trastuzumab and chemotherapy (cisplatin and fluoropyrimidine [capecitabine or 5-fluorouracil]) for the first 6 treatment cycles (cycle length = 21 days). Subjects will continue to receive pertuzumab and trastuzumab until disease progression occurrence of unacceptable toxicity or withdrawal from the study for another reason.

    Reporting group title
    Placebo + Trastuzumab + Chemotherapy
    Reporting group description
    		 Subjects will receive pertuzumab placebo in combination with trastuzumab and chemotherapy (cisplatin and fluoropyrimidine [capecitabine or 5-fluorouracil]) for the first 6 treatment cycles (cycle length = 21 days). Subjects will continue to receive pertuzumab placebo and trastuzumab until disease progression occurrence of unacceptable toxicity or withdrawal from the study for another reason.

    Reporting group values
    		 Pertuzumab + Trastuzumab + Chemotherapy Placebo + Trastuzumab + Chemotherapy Total
    Number of subjects
    		 388 392 780
    Age categorical
    Units: Subjects
        Adults (18-64 years)
    		 228 247 475
        From 65-84 years
    		 159 145 304
        85 years and over
    		 1 0 1
    Age Continuous
    Units: years
        arithmetic mean (standard deviation)
    		 60.9 ± 11.3 60.1 ± 10.7 -
    Sex: Female, Male
    Units: Subjects
        Female
    		 94 69 163
        Male
    		 294 323 617
    EORTC QLQ-C30 Scores at Baseline - Appetite Loss
    European Organisation for Research and Treatment of Cancer (EORTC) Quality of Life-Core 30 (QLQ-C30) Appetite Loss Symptom Scale score at baseline (Cycle 1, Day 1)
    Units: score on a scale
        arithmetic mean (standard deviation)
    		 26.68 ± 28.65 27.59 ± 29.96 -
    EORTC QLQ-C30 Scores at Baseline - Cognitive Functional Scale
    EORTC QLQ-C30 Cognitive Functional Scale score at baseline (Cycle 1, Day 1)
    Units: score on a scale
        arithmetic mean (standard deviation)
    		 87.95 ± 17.32 88.22 ± 16.18 -
    EORTC QLQ-C30 Scores at Baseline - Constipation Symptom Scale
    EORTC QLQ-C30 Constipation Symptom Scale score at baseline (Cycle 1, Day 1)
    Units: score on a scale
        arithmetic mean (standard deviation)
    		 20.43 ± 28.45 18.41 ± 27.13 -
    EORTC QLQ-C30 Scores at Baseline - Diarrhea Symptom Scale
    EORTC QLQ-C30 Diarrhea Symptom Scale score at baseline (Cycle 1, Day 1)
    Units: score on a scale
        arithmetic mean (standard deviation)
    		 8.87 ± 17.70 9.16 ± 18.87 -
    EORTC QLQ-C30 Scores at Baseline - Dyspnoea Symptom Scale
    EORTC QLQ-C30 Dyspnoea Symptom Scale score at baseline (Cycle 1, Day 1)
    Units: score on a scale
        arithmetic mean (standard deviation)
    		 12.07 ± 17.99 12.65 ± 20.20 -
    EORTC QLQ-C30 Scores at Baseline - Emotional Functional Scale
    EORTC QLQ-C30 Emotional Functional Scale score at baseline (Cycle 1, Day 1)
    Units: score on a scale
        arithmetic mean (standard deviation)
    		 76.90 ± 20.21 76.56 ± 19.84 -
    EORTC QLQ-C30 Scores at Baseline - Fatigue Symptom Scale
    EORTC QLQ-C30 Fatigue Symptom Scale score at baseline (Cycle 1, Day 1)
    Units: score on a scale
        arithmetic mean (standard deviation)
    		 31.96 ± 23.46 32.27 ± 21.92 -
    EORTC QLQ-C30 Scores at Baseline - Financial Difficulties Symptom Scale
    EORTC QLQ-C30 Financial Difficulties Symptom Scale score at baseline (Cycle 1, Day 1)
    Units: score on a scale
        arithmetic mean (standard deviation)
    		 26.67 ± 30.32 26.21 ± 29.78 -
    EORTC QLQ-C30 Scores at Baseline - Nausea and Vomiting Symptom Scale
    EORTC QLQ-C30 Nausea and Vomiting Symptom Scale score at baseline (Cycle 1, Day 1)
    Units: score on a scale
        arithmetic mean (standard deviation)
    		 11.14 ± 19.11 11.92 ± 18.76 -
    EORTC QLQ-C30 Scores at Baseline - Pain Symptom Scale
    EORTC QLQ-C30 Pain Symptom Scale score at baseline (Cycle 1, Day 1)
    Units: score on a scale
        arithmetic mean (standard deviation)
    		 23.92 ± 25.92 23.72 ± 24.82 -
    EORTC QLQ-C30 Scores at Baseline - Physical Functional Scale
    EORTC QLQ-C30 Physical Functional Scale score at baseline (Cycle 1, Day 1)
    Units: score on a scale
        arithmetic mean (standard deviation)
    		 80.86 ± 19.53 82.05 ± 18.32 -
    EORTC QLQ-C30 Scores at Baseline - Global Health Status Scale
    EORTC QLQ-C30 Global Health Status Scale score at baseline (Cycle 1, Day 1)
    Units: score on a scale
        arithmetic mean (standard deviation)
    		 59.77 ± 22.88 59.90 ± 22.11 -
    EORTC QLQ-C30 Scores at Baseline - Role Functional Scale
    EORTC QLQ-C30 Role Functional Scale score at baseline (Cycle 1, Day 1)
    Units: score on a scale
        arithmetic mean (standard deviation)
    		 77.06 ± 27.02 79.33 ± 25.12 -
    EORTC QLQ-C30 Scores at Baseline - Social Functional Scale
    EORTC QLQ-C30 Social Functional Scale score at baseline (Cycle 1, Day 1)
    Units: score on a scale
        arithmetic mean (standard deviation)
    		 77.96 ± 24.09 75.90 ± 24.69 -
    EORTC QLQ-C30 Scores at Baseline - Insomnia Symptom Scale
    EORTC QLQ-C30 Insomnia Symptom Scale score at baseline (Cycle 1, Day 1)
    Units: score on a scale
        arithmetic mean (standard deviation)
    		 22.94 ± 28.00 25.41 ± 28.81 -
    EORTC QLQ-STO22 Scores at Baseline - Anxiety
    European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire-Gastric Cancer Module (EORTC QLQ-STO22) Anxiety score at baseline (Cycle 1, Day 1)
    Units: score on a scale
        arithmetic mean (standard deviation)
    		 40.10 ± 25.85 40.48 ± 25.32 -
    EORTC QLQ-STO22 Scores at Baseline - Body Image
    EORTC QLQ-STO22 Body Image score at baseline (Cycle 1, Day 1)
    Units: score on a scale
        arithmetic mean (standard deviation)
    		 23.53 ± 28.40 23.68 ± 27.47 -
    EORTC QLQ-STO22 Scores at Baseline - Dry Mouth
    EORTC QLQ-STO22 Dry Mouth score at baseline (Cycle 1, Day 1)
    Units: score on a scale
        arithmetic mean (standard deviation)
    		 21.80 ± 25.07 23.32 ± 26.79 -
    EORTC QLQ-STO22 Scores at Baseline - Dysphagia
    EORTC QLQ-STO22 Dysphagia score at baseline (Cycle 1, Day 1)
    Units: score on a scale
        arithmetic mean (standard deviation)
    		 16.29 ± 21.46 14.15 ± 18.93 -
    EORTC QLQ-STO22 Scores at Baseline - Eating Restrictions
    EORTC QLQ-STO22 Eating Restrictions score at baseline (Cycle 1, Day 1)
    Units: score on a scale
        arithmetic mean (standard deviation)
    		 23.26 ± 21.78 22.33 ± 20.22 -
    EORTC QLQ-STO22 Scores at Baseline - Hair Loss
    EORTC QLQ-STO22 Hair Loss score at baseline (Cycle 1, Day 1)
    Units: score on a scale
        arithmetic mean (standard deviation)
    		 4.73 ± 13.28 4.04 ± 13.20 -
    EORTC QLQ-STO22 Scores at Baseline - Pain
    EORTC QLQ-STO22 Pain score at baseline (Cycle 1, Day 1)
    Units: score on a scale
        arithmetic mean (standard deviation)
    		 26.48 ± 21.34 26.47 ± 20.70 -
    EORTC QLQ-STO22 Scores at Baseline - Reflux Symptoms
    EORTC QLQ-STO22 Reflux Symptoms score at baseline (Cycle 1, Day 1)
    Units: score on a scale
        arithmetic mean (standard deviation)
    		 16.68 ± 19.03 17.34 ± 18.31 -
    EORTC QLQ-STO22 Scores at Baseline - Taste
    EORTC QLQ-STO22 Taste score at baseline (Cycle 1, Day 1)
    Units: score on a scale
        arithmetic mean (standard deviation)
    		 13.79 ± 23.99 16.22 ± 25.49 -

    End points

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    End points reporting groups
    Reporting group title
    Pertuzumab + Trastuzumab + Chemotherapy
    Reporting group description
    		 Subjects will receive pertuzumab in combination with trastuzumab and chemotherapy (cisplatin and fluoropyrimidine [capecitabine or 5-fluorouracil]) for the first 6 treatment cycles (cycle length = 21 days). Subjects will continue to receive pertuzumab and trastuzumab until disease progression occurrence of unacceptable toxicity or withdrawal from the study for another reason.

    Reporting group title
    Placebo + Trastuzumab + Chemotherapy
    Reporting group description
    		 Subjects will receive pertuzumab placebo in combination with trastuzumab and chemotherapy (cisplatin and fluoropyrimidine [capecitabine or 5-fluorouracil]) for the first 6 treatment cycles (cycle length = 21 days). Subjects will continue to receive pertuzumab placebo and trastuzumab until disease progression occurrence of unacceptable toxicity or withdrawal from the study for another reason.

    Primary: Overall Survival

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    End point title
    		 Overall Survival
    End point description
    Overall survival (OS) was defined as the time from randomization to death from any cause. The intent-to-treat (ITT) population included all randomized subjects, regardless of whether study medication was received.
    End point type
    Primary
    End point timeframe
    Baseline up to death (up to the 09 Dec 2016 data cutoff, approximately 3.5 years)
    End point values
    		 Pertuzumab + Trastuzumab + Chemotherapy Placebo + Trastuzumab + Chemotherapy
    Number of subjects analysed
    388
    392
    Units: Months
        median (confidence interval 95%)
    17.5 (16.2 to 19.3)
    14.2 (12.9 to 15.5)
    Statistical analysis title
    		 Statistical Analysis
    Statistical analysis description
    The null hypothesis is that the survival distribution of OS is the same in the two treatment arms.
    Comparison groups
    Pertuzumab + Trastuzumab + Chemotherapy v Placebo + Trastuzumab + Chemotherapy
    Number of subjects included in analysis
    780
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [1]
    P-value
    		 = 0.0565 [2]
    Method
    		 Stratified Log-Rank
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.84
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.71
         upper limit
    		 1
    Notes
    [1] - The study was designed to have 80% power to show a significant difference with respect to the primary endpoint.
    [2] - The actual p-value significance threshold required for OS was 0.0452, after alpha spent at the interim analysis was taken into account.

    Secondary: Progression-Free Survival, as Determined by the Investigator According to Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST v1.1) Criteria

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    End point title
    		 Progression-Free Survival, as Determined by the Investigator According to Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST v1.1) Criteria
    End point description
    Progression-free survival (PFS) is defined as the time from randomization to the first occurrence of disease progression, as determined by the investigator using RECIST v1.1, or death from any cause. Disease progression: at least a 20% increase in the sum of diameters of target lesions, taking as reference the smallest sum on study, including baseline; an absolute increase of at least 5 millimeters (mm) in the sum of diameters of target lesions; the appearance of one or more new lesions. The intent-to-treat (ITT) population included all randomized subjects, regardless of whether study medication was received.
    End point type
    Secondary
    End point timeframe
    Baseline up to death or disease progression, whichever occurs first (up to the 09 Dec 2016 data cutoff, approximately 3.5 years)
    End point values
    		 Pertuzumab + Trastuzumab + Chemotherapy Placebo + Trastuzumab + Chemotherapy
    Number of subjects analysed
    388
    392
    Units: months
        median (confidence interval 95%)
    8.5 (8.2 to 9.7)
    7.0 (6.4 to 8.2)
    Statistical analysis title
    		 Stratified Cox Regression
    Comparison groups
    Pertuzumab + Trastuzumab + Chemotherapy v Placebo + Trastuzumab + Chemotherapy
    Number of subjects included in analysis
    780
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [3]
    Method
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.73
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.62
         upper limit
    		 0.86
    Notes
    [3] - Given the hierarchical testing procedure and non-statistical significant OS result, confirmatory statistical significance of PFS based on the Log-Rank test p-value cannot be concluded.

    Secondary: Percentage of Subjects With Overall Objective Response, as Determined by the Investigator According to RECIST v1.1 Criteria

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    End point title
    		 Percentage of Subjects With Overall Objective Response, as Determined by the Investigator According to RECIST v1.1 Criteria
    End point description
    Overall objective response (partial response [PR] or complete response [CR]) occurring on two consecutive occasions ≥ 4 weeks apart, as determined by the investigator using RECIST v1.1. PR: at least a 30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum of diameters. CR: disappearance of all target lesions. Measurable disease is defined as tumor lesions measured in at least one dimension (longest diameter in plane of measurement) with a minimum size of: 10 mm by computed tomography (CT) or magnetic resonance imaging (MRI) scan; 10 mm caliper measurement by clinical examination; 20 mm by chest X-ray. For a malignant lymph node to be considered pathologically enlarged and measurable, it must be greater than or equal to (≥) 15 mm in short axis when assessed by CT scan. The analysis population included subjects with measurable disease at baseline.
    End point type
    Secondary
    End point timeframe
    Baseline up to death or disease progression, whichever occurs first (up to the 09 Dec 2016 data cutoff, approximately 3.5 years)
    End point values
    		 Pertuzumab + Trastuzumab + Chemotherapy Placebo + Trastuzumab + Chemotherapy
    Number of subjects analysed
    351
    352
    Units: Percentage of subjects
        number (not applicable)
    56.7
    48.3
    No statistical analyses for this end point

    Secondary: Duration of Objective Response, as Determined by Investigator According to RECIST v1.1 Criteria

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    End point title
    		 Duration of Objective Response, as Determined by Investigator According to RECIST v1.1 Criteria
    End point description
    Duration of objective response is defined as the time from the first occurrence of a documented objective response to documented disease progression, as determined by the investigator using RECIST v1.1, or death from any cause during the study. Overall objective response: PR or CR occurring on two consecutive occasions ≥ 4 weeks apart. PR: at least a 30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum of diameters. CR: disappearance of all target lesions. Disease progression: at least a 20% increase in the sum of diameters of target lesions, taking as reference the smallest sum on study, including baseline; an absolute increase of at least 5 mm in the sum of diameters of target lesions; the appearance of one or more new lesions. Data are reported for subjects with measurable disease at baseline who achieved a documented objective response.
    End point type
    Secondary
    End point timeframe
    Baseline up to death or disease progression, whichever occurs first (up to the 09 Dec 2016 data cutoff, approximately 3.5 years)
    End point values
    		 Pertuzumab + Trastuzumab + Chemotherapy Placebo + Trastuzumab + Chemotherapy
    Number of subjects analysed
    199
    170
    Units: months
        median (confidence interval 95%)
    10.2 (8.4 to 10.7)
    8.4 (6.8 to 8.7)
    No statistical analyses for this end point

    Secondary: Percentage of Subjects With Clinical Benefit, as Determined by the Investigator According to RECIST v1.1 Criteria

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    End point title
    		 Percentage of Subjects With Clinical Benefit, as Determined by the Investigator According to RECIST v1.1 Criteria
    End point description
    Clinical benefit rate is defined as best response of CR or PR or stable disease for 6 weeks or longer, as determined by the investigator using RECIST v1.1. CR: disappearance of all target lesions. PR: at least a 30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum of diameters. Stable Disease: neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for disease progression, taking as reference the smallest sum diameters while on study. The analysis population included subjects with measurable disease at baseline.
    End point type
    Secondary
    End point timeframe
    Baseline up to death or disease progression, whichever occurs first (up to the 09 Dec 2016 data cutoff, approximately 3.5 years)
    End point values
    		 Pertuzumab + Trastuzumab + Chemotherapy Placebo + Trastuzumab + Chemotherapy
    Number of subjects analysed
    351
    352
    Units: percentage of subjects
        number (not applicable)
    84.6
    81.3
    No statistical analyses for this end point

    Secondary: Percentage of Subjects With Adverse Events

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    End point title
    		 Percentage of Subjects With Adverse Events
    End point description
    An adverse event is any untoward medical occurrence in a clinical investigation subject administered a pharmaceutical product, regardless of causal attribution. The safety population included all subjects who received any amount of any study medication.
    End point type
    Secondary
    End point timeframe
    Baseline up to the 09 Dec 2016 data cutoff, approximately 3.5 years
    End point values
    		 Pertuzumab + Trastuzumab + Chemotherapy Placebo + Trastuzumab + Chemotherapy
    Number of subjects analysed
    385
    388
    Units: percentage of subjects
        number (not applicable)
    99.0
    99.2
    No statistical analyses for this end point

    Secondary: Percentage of Subjects With Left Ventricular Systolic Dysfunction (LVSD, Symptomatic or Asymptomatic)

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    End point title
    		 Percentage of Subjects With Left Ventricular Systolic Dysfunction (LVSD, Symptomatic or Asymptomatic)
    End point description
    Left ventricular systolic dysfunction may either be asymptomatic or have symptoms of heart failure. It is characterized by dilation of the left ventricle and vasoconstriction. The safety population included all subjects who received any amount of any study medication.
    End point type
    Secondary
    End point timeframe
    Baseline up to the 09 Dec 2016 data cutoff, approximately 3.5 years
    End point values
    		 Pertuzumab + Trastuzumab + Chemotherapy Placebo + Trastuzumab + Chemotherapy
    Number of subjects analysed
    385
    388
    Units: percentage of subjects
    number (not applicable)
        Symptomatic LVSD
    0.5
    0.3
        Asymptomatic LVSD
    4.7
    4.4
    No statistical analyses for this end point

    Secondary: Change from Baseline in European Organization for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire-Core 30 (QLQ-C30) Score

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    End point title
    		 Change from Baseline in European Organization for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire-Core 30 (QLQ-C30) Score
    End point description
    The EORTC QLQ-C30 included global health status, functional scales (physical, role, emotional, cognitive, and social), symptom scales (fatigue, nausea/vomiting, and pain) and single items (dyspnoea, insomnia, appetite loss, constipation, diarrhea, and financial difficulties). Most questions used a 4-point scale (1 'Not at all' to 4 'Very much'; 2 questions used 7-point scale [1 'very poor' to 7 'Excellent']). Scores were averaged and transformed to 0 - 100 scale, whereby higher scores indicate greater functioning, greater quality of life, or a greater degree of symptoms, with changes of 5 - 10 points considered to be a minimally important difference to participants. A positive value means an increase, while a negative value means a decrease, in score at the indicated time-point relative to the score at baseline (Cycle 1, Day 1). Subjects in ITT population with both a baseline and at least 1 post-treatment assessment are included.
    End point type
    Secondary
    End point timeframe
    Day 1 of each 21-day treatment cycle up to 28 and 60-90 days after Day 1 of last treatment cycle (up to approximately 3.5 years)
    End point values
    		 Pertuzumab + Trastuzumab + Chemotherapy Placebo + Trastuzumab + Chemotherapy
    Number of subjects analysed
    388
    392
    Units: score on a scale
    arithmetic mean (standard deviation)
        Appetite Loss: Cycle 2
    6.57 ± 33.18
    0.97 ± 35.86
        Appetite Loss: Cycle 3
    3.63 ± 36.19
    3.81 ± 36.76
        Appetite Loss: Cycle 4
    5.24 ± 34.20
    0.79 ± 34.33
        Appetite Loss: Cycle 5
    4.55 ± 36.50
    2.90 ± 35.85
        Appetite Loss: Cycle 6
    3.94 ± 36.07
    -0.39 ± 36.86
        Appetite Loss: Cycle 7
    2.07 ± 38.05
    1.61 ± 35.98
        Appetite Loss: Cycle 8
    -2.42 ± 33.81
    -3.69 ± 34.20
        Appetite Loss: Cycle 9
    -6.67 ± 31.92
    -4.76 ± 31.67
        Appetite Loss: Cycle 10
    -8.06 ± 32.52
    -6.63 ± 28.48
        Appetite Loss: Cycle 11
    -9.36 ± 33.19
    -9.68 ± 27.38
        Appetite Loss: Cycle 12
    -9.22 ± 33.73
    -9.05 ± 28.51
        Appetite Loss: Cycle 13
    -10.17 ± 31.10
    -10.81 ± 29.18
        Appetite Loss: Cycle 14
    -12.10 ± 31.96
    -12.09 ± 30.32
        Appetite Loss: Cycle 15
    -8.21 ± 32.96
    -9.18 ± 29.81
        Appetite Loss: Cycle 16
    -6.03 ± 33.07
    -10.59 ± 28.74
        Appetite Loss: Cycle 17
    -6.55 ± 29.29
    -9.91 ± 29.05
        Appetite Loss: Cycle 18
    -4.90 ± 31.25
    -14.08 ± 27.98
        Appetite Loss: Cycle 19
    -8.33 ± 31.34
    -13.13 ± 28.57
        Appetite Loss: Cycle 20
    -3.97 ± 31.65
    -13.23 ± 29.66
        Appetite Loss: Cycle 21
    -5.91 ± 31.01
    -14.20 ± 32.76
        Appetite Loss: Cycle 22
    -4.98 ± 34.45
    -16.31 ± 29.38
        Appetite Loss: Cycle 23
    -6.35 ± 36.84
    -11.36 ± 35.90
        Appetite Loss: Cycle 24
    -7.78 ± 33.82
    -13.33 ± 30.00
        Appetite Loss: Cycle 25
    -7.05 ± 35.14
    -12.04 ± 31.02
        Appetite Loss: Cycle 26
    -7.48 ± 34.87
    -12.50 ± 32.52
        Appetite Loss: Cycle 27
    -10.08 ± 33.76
    -9.20 ± 28.03
        Appetite Loss: Cycle 28
    -10.00 ± 32.20
    -11.54 ± 29.73
        Appetite Loss: Post-treatment Visit 1
    7.30 ± 36.86
    2.64 ± 33.14
        Appetite Loss: Post-treatment Visit 2
    -0.33 ± 33.83
    4.55 ± 34.53
        Cognitive Functional Scale: Cycle 2
    -1.90 ± 17.82
    -1.81 ± 16.93
        Cognitive Functional Scale: Cycle 3
    -0.83 ± 17.11
    -3.17 ± 18.30
        Cognitive Functional Scale: Cycle 4
    -2.04 ± 17.78
    -2.99 ± 19.28
        Cognitive Functional Scale: Cycle 5
    -3.04 ± 19.09
    -4.59 ± 19.59
        Cognitive Functional Scale: Cycle 6
    -5.10 ± 19.23
    -3.84 ± 19.00
        Cognitive Functional Scale: Cycle 7
    -4.34 ± 19.52
    -4.31 ± 19.09
        Cognitive Functional Scale: Cycle 8
    -3.15 ± 17.90
    -3.30 ± 17.59
        Cognitive Functional Scale: Cycle 9
    -2.22 ± 18.53
    -4.59 ± 18.53
        Cognitive Functional Scale: Cycle 10
    -3.32 ± 19.44
    -3.11 ± 18.50
        Cognitive Functional Scale: Cycle 11
    -2.83 ± 18.44
    -3.44 ± 17.06
        Cognitive Functional Scale: Cycle 12
    -3.35 ± 20.00
    -2.52 ± 18.16
        Cognitive Functional Scale: Cycle 13
    -1.79 ± 19.04
    -3.60 ± 17.89
        Cognitive Functional Scale: Cycle 14
    -1.98 ± 19.00
    -2.29 ± 17.56
        Cognitive Functional Scale: Cycle 15
    -1.15 ± 18.47
    -2.38 ± 16.05
        Cognitive Functional Scale: Cycle 16
    -2.73 ± 17.16
    -2.55 ± 17.16
        Cognitive Functional Scale: Cycle 17
    -2.53 ± 17.21
    -1.13 ± 15.44
        Cognitive Functional Scale: Cycle 18
    -2.78 ± 18.18
    0.47 ± 16.42
        Cognitive Functional Scale: Cycle 19
    -1.04 ± 18.07
    0.00 ± 14.62
        Cognitive Functional Scale: Cycle 20
    -2.18 ± 19.67
    0.79 ± 15.68
        Cognitive Functional Scale: Cycle 21
    -2.11 ± 20.56
    0.62 ± 16.50
        Cognitive Functional Scale: Cycle 22
    -4.73 ± 18.98
    -0.71 ± 18.04
        Cognitive Functional Scale: Cycle 23
    -2.38 ± 19.60
    1.14 ± 17.75
        Cognitive Functional Scale: Cycle 24
    -2.78 ± 19.69
    1.25 ± 16.18
        Cognitive Functional Scale: Cycle 25
    -5.45 ± 16.41
    -0.93 ± 18.66
        Cognitive Functional Scale: Cycle 26
    -2.38 ± 16.32
    -1.56 ± 18.63
        Cognitive Functional Scale: Cycle 27
    -3.88 ± 18.84
    -1.15 ± 18.33
        Cognitive Functional Scale: Cycle 28
    -3.75 ± 15.78
    0.00 ± 20.00
        Cognitive Functional Scale: Post-treatment Visit 1
    -9.13 ± 21.90
    -9.16 ± 20.02
        Cognitive Functional Scale: Post-treatment Visit 2
    -8.42 ± 20.22
    -11.21 ± 22.48
        Constipation Symptom Scale: Cycle 2
    -5.39 ± 27.05
    0.29 ± 27.23
        Constipation Symptom Scale: Cycle 3
    -7.48 ± 28.98
    -2.11 ± 27.65
        Constipation Symptom Scale: Cycle 4
    -5.32 ± 29.21
    -3.73 ± 28.26
        Constipation Symptom Scale: Cycle 5
    -5.94 ± 29.15
    -1.28 ± 27.64
        Constipation Symptom Scale: Cycle 6
    -7.13 ± 29.65
    -2.33 ± 30.24
        Constipation Symptom Scale: Cycle 7
    -8.13 ± 30.11
    -4.09 ± 29.06
        Constipation Symptom Scale: Cycle 8
    -8.05 ± 30.90
    -4.45 ± 27.32
        Constipation Symptom Scale: Cycle 9
    -10.00 ± 27.10
    -5.61 ± 26.74
        Constipation Symptom Scale: Cycle 10
    -9.32 ± 29.56
    -7.43 ± 26.81
        Constipation Symptom Scale: Cycle 11
    -9.16 ± 29.60
    -6.88 ± 27.84
        Constipation Symptom Scale: Cycle 12
    -10.27 ± 29.04
    -7.25 ± 25.39
        Constipation Symptom Scale: Cycle 13
    -11.19 ± 29.55
    -5.76 ± 26.27
        Constipation Symptom Scale: Cycle 14
    -11.60 ± 27.11
    -6.21 ± 26.00
        Constipation Symptom Scale: Cycle 15
    -10.51 ± 26.59
    -7.14 ± 24.52
        Constipation Symptom Scale: Cycle 16
    -8.62 ± 24.91
    -7.45 ± 25.39
        Constipation Symptom Scale: Cycle 17
    -8.33 ± 24.30
    -5.86 ± 18.59
        Constipation Symptom Scale: Cycle 18
    -7.52 ± 22.93
    -6.57 ± 26.20
        Constipation Symptom Scale: Cycle 19
    -3.47 ± 25.81
    -3.03 ± 25.97
        Constipation Symptom Scale: Cycle 20
    -3.97 ± 26.08
    -4.76 ± 26.68
        Constipation Symptom Scale: Cycle 21
    -3.80 ± 29.23
    -9.26 ± 25.42
        Constipation Symptom Scale: Cycle 22
    -4.98 ± 28.58
    -8.51 ± 27.34
        Constipation Symptom Scale: Cycle 23
    -6.35 ± 28.62
    -8.33 ± 26.04
        Constipation Symptom Scale: Cycle 24
    -7.78 ± 27.01
    -10.00 ± 26.37
        Constipation Symptom Scale: Cycle 25
    -7.05 ± 29.77
    -9.26 ± 28.30
        Constipation Symptom Scale: Cycle 26
    -6.12 ± 30.94
    -6.25 ± 23.09
        Constipation Symptom Scale: Cycle 27
    -7.75 ± 28.95
    -10.34 ± 26.88
        Constipation Symptom Scale: Cycle 28
    -6.67 ± 26.37
    -6.41 ± 21.12
        Constipation Symptom Scale: Post-treatment Visit 1
    -6.78 ± 31.45
    -4.62 ± 26.19
        Constipation Symptom Scale: Post-treatment Visit 2
    -6.93 ± 28.41
    -0.91 ± 31.11
        Diarrhea Symptom Scale: Cycle 2
    15.12 ± 30.42
    5.20 ± 23.79
        Diarrhea Symptom Scale: Cycle 3
    14.64 ± 27.71
    4.99 ± 26.10
        Diarrhea Symptom Scale: Cycle 4
    14.13 ± 27.15
    4.63 ± 24.07
        Diarrhea Symptom Scale: Cycle 5
    13.17 ± 25.47
    4.99 ± 23.70
        Diarrhea Symptom Scale: Cycle 6
    14.81 ± 27.01
    2.47 ± 23.76
        Diarrhea Symptom Scale: Cycle 7
    12.26 ± 23.74
    2.92 ± 23.44
        Diarrhea Symptom Scale: Cycle 8
    8.91 ± 23.56
    2.61 ± 23.53
        Diarrhea Symptom Scale: Cycle 9
    6.83 ± 23.76
    2.04 ± 21.25
        Diarrhea Symptom Scale: Cycle 10
    6.63 ± 23.97
    0.60 ± 20.91
        Diarrhea Symptom Scale: Cycle 11
    5.26 ± 21.80
    2.60 ± 20.36
        Diarrhea Symptom Scale: Cycle 12
    3.98 ± 22.30
    1.92 ± 19.97
        Diarrhea Symptom Scale: Cycle 13
    4.29 ± 24.27
    1.50 ± 19.27
        Diarrhea Symptom Scale: Cycle 14
    3.95 ± 24.45
    0.98 ± 20.15
        Diarrhea Symptom Scale: Cycle 15
    3.33 ± 23.79
    1.02 ± 19.42
        Diarrhea Symptom Scale: Cycle 16
    5.46 ± 21.06
    3.14 ± 15.10
        Diarrhea Symptom Scale: Cycle 17
    2.68 ± 21.05
    2.25 ± 14.94
        Diarrhea Symptom Scale: Cycle 18
    3.59 ± 21.95
    3.29 ± 17.95
        Diarrhea Symptom Scale: Cycle 19
    3.82 ± 19.86
    2.02 ± 16.41
        Diarrhea Symptom Scale: Cycle 20
    5.95 ± 19.47
    3.70 ± 17.05
        Diarrhea Symptom Scale: Cycle 21
    3.80 ± 23.26
    1.85 ± 16.40
        Diarrhea Symptom Scale: Cycle 22
    6.97 ± 24.98
    4.26 ± 17.88
        Diarrhea Symptom Scale: Cycle 23
    6.88 ± 21.72
    8.33 ± 20.49
        Diarrhea Symptom Scale: Cycle 24
    7.22 ± 22.21
    3.33 ± 16.54
        Diarrhea Symptom Scale: Cycle 25
    8.97 ± 23.91
    2.78 ± 14.64
        Diarrhea Symptom Scale: Cycle 26
    5.44 ± 21.89
    5.21 ± 20.93
        Diarrhea Symptom Scale: Cycle 27
    3.88 ± 22.07
    3.45 ± 16.29
        Diarrhea Symptom Scale: Cycle 28
    7.50 ± 27.72
    2.56 ± 16.12
        Diarrhea Symptom Scale: Post-treatment Visit 1
    8.14 ± 26.00
    1.98 ± 24.35
        Diarrhea Symptom Scale: Post-treatment Visit 2
    7.26 ± 25.65
    4.24 ± 29.65
        Dyspnoea Symptom Scale: Cycle 2
    -0.50 ± 19.04
    0.29 ± 19.72
        Dyspnoea Symptom Scale: Cycle 3
    -0.31 ± 20.18
    -0.32 ± 20.38
        Dyspnoea Symptom Scale: Cycle 4
    1.23 ± 20.31
    1.81 ± 21.08
        Dyspnoea Symptom Scale: Cycle 5
    2.58 ± 20.62
    1.39 ± 21.18
        Dyspnoea Symptom Scale: Cycle 6
    3.20 ± 23.79
    0.39 ± 20.55
        Dyspnoea Symptom Scale: Cycle 7
    0.00 ± 21.94
    0.59 ± 20.07
        Dyspnoea Symptom Scale: Cycle 8
    -0.14 ± 21.99
    0.93 ± 20.56
        Dyspnoea Symptom Scale: Cycle 9
    -1.12 ± 20.51
    0.17 ± 18.95
        Dyspnoea Symptom Scale: Cycle 10
    -0.54 ± 21.56
    1.00 ± 16.99
        Dyspnoea Symptom Scale: Cycle 11
    -2.16 ± 19.58
    -1.29 ± 17.77
        Dyspnoea Symptom Scale: Cycle 12
    -2.53 ± 19.75
    -0.71 ± 18.95
        Dyspnoea Symptom Scale: Cycle 13
    -1.43 ± 20.34
    -1.20 ± 16.77
        Dyspnoea Symptom Scale: Cycle 14
    -1.98 ± 19.00
    -2.61 ± 17.98
        Dyspnoea Symptom Scale: Cycle 15
    -2.84 ± 21.26
    2.72 ± 18.95
        Dyspnoea Symptom Scale: Cycle 16
    -1.45 ± 20.42
    1.18 ± 18.86
        Dyspnoea Symptom Scale: Cycle 17
    -1.82 ± 20.61
    0.90 ± 19.87
        Dyspnoea Symptom Scale: Cycle 18
    -0.98 ± 20.15
    -2.35 ± 18.10
        Dyspnoea Symptom Scale: Cycle 19
    -1.74 ± 20.73
    0.51 ± 18.15
        Dyspnoea Symptom Scale: Cycle 20
    -1.19 ± 20.98
    -1.06 ± 16.90
        Dyspnoea Symptom Scale: Cycle 21
    1.27 ± 22.29
    -0.62 ± 19.95
        Dyspnoea Symptom Scale: Cycle 22
    -1.99 ± 22.38
    0.71 ± 14.73
        Dyspnoea Symptom Scale: Cycle 23
    -1.59 ± 21.94
    1.52 ± 14.30
        Dyspnoea Symptom Scale: Cycle 24
    1.11 ± 22.10
    -1.67 ± 12.96
        Dyspnoea Symptom Scale: Cycle 25
    0.64 ± 21.38
    -3.70 ± 15.49
        Dyspnoea Symptom Scale: Cycle 26
    0.00 ± 22.57
    1.04 ± 23.16
        Dyspnoea Symptom Scale: Cycle 27
    0.78 ± 21.19
    3.45 ± 22.44
        Dyspnoea Symptom Scale: Cycle 28
    1.67 ± 21.28
    3.85 ± 17.20
        Dyspnoea Symptom Scale: Post-treatment Visit 1
    6.97 ± 26.98
    6.77 ± 23.82
        Dyspnoea Symptom Scale: Post-treatment Visit 2
    3.30 ± 23.81
    9.39 ± 26.76
        Emotional Functional Scale: Cycle 2
    3.53 ± 16.84
    3.05 ± 18.49
        Emotional Functional Scale: Cycle 3
    2.65 ± 18.63
    3.96 ± 19.95
        Emotional Functional Scale: Cycle 4
    3.10 ± 21.11
    3.67 ± 20.44
        Emotional Functional Scale: Cycle 5
    2.62 ± 19.97
    2.74 ± 21.72
        Emotional Functional Scale: Cycle 6
    1.01 ± 19.64
    4.93 ± 21.00
        Emotional Functional Scale: Cycle 7
    1.72 ± 21.09
    4.41 ± 20.18
        Emotional Functional Scale: Cycle:8
    3.43 ± 20.66
    5.66 ± 19.63
        Emotional Functional Scale: Cycle 9
    4.72 ± 20.10
    4.78 ± 19.45
        Emotional Functional Scale: Cycle 10
    3.72 ± 21.76
    6.74 ± 18.13
        Emotional Functional Scale: Cycle 11
    5.85 ± 19.64
    4.96 ± 19.21
        Emotional Functional Scale: Cycle 12
    4.93 ± 21.38
    5.24 ± 19.14
        Emotional Functional Scale: Cycle 13
    5.00 ± 23.07
    5.18 ± 17.95
        Emotional Functional Scale: Cycle 14
    5.93 ± 22.90
    6.29 ± 19.03
        Emotional Functional Scale: Cycle 15
    6.03 ± 22.13
    5.19 ± 19.61
        Emotional Functional Scale: Cycle 16
    5.17 ± 23.20
    5.29 ± 20.81
        Emotional Functional Scale: Cycle 17
    6.01 ± 23.55
    6.31 ± 18.70
        Emotional Functional Scale: Cycle 18
    3.68 ± 24.11
    5.87 ± 19.39
        Emotional Functional Scale: Cycle 19
    4.69 ± 26.01
    5.56 ± 18.68
        Emotional Functional Scale: Cycle 20
    3.47 ± 26.92
    5.42 ± 17.91
        Emotional Functional Scale: Cycle 21
    4.54 ± 26.55
    6.48 ± 22.00
        Emotional Functional Scale: Cycle 22
    5.35 ± 28.67
    6.91 ± 18.66
        Emotional Functional Scale: Cycle 23
    5.82 ± 28.42
    6.63 ± 21.00
        Emotional Functional Scale: Cycle 24
    5.28 ± 26.22
    8.54 ± 19.57
        Emotional Functional Scale: Cycle 25
    5.93 ± 25.48
    8.80 ± 20.89
        Emotional Functional Scale: Cycle 26
    5.44 ± 27.77
    5.99 ± 16.15
        Emotional Functional Scale: Cycle 27
    7.56 ± 28.34
    5.75 ± 18.51
        Emotional Functional Scale: Cycle 28
    7.08 ± 25.43
    7.05 ± 18.96
        Emotional Functional Scale: Post-treatment Visit 1
    -5.48 ± 23.16
    -3.92 ± 23.28
        Emotional Functional Scale: Post-treatment Visit 2
    -2.64 ± 23.33
    -4.47 ± 23.34
        Fatigue Symptom Scale: Cycle 2
    3.13 ± 19.80
    2.32 ± 21.57
        Fatigue Symptom Scale: Cycle 3
    1.41 ± 22.65
    3.19 ± 22.97
        Fatigue Symptom Scale: Cycle 4
    2.77 ± 23.14
    1.58 ± 24.04
        Fatigue Symptom Scale: Cycle 5
    3.87 ± 25.75
    3.05 ± 24.29
        Fatigue Symptom Scale: Cycle 6
    4.37 ± 25.64
    2.62 ± 23.68
        Fatigue Symptom Scale: Cycle 7
    2.36 ± 26.79
    0.97 ± 23.44
        Fatigue Symptom Scale: Cycle 8
    -0.19 ± 25.00
    -1.18 ± 22.74
        Fatigue Symptom Scale: Cycle 9
    -2.38 ± 22.69
    -2.01 ± 22.84
        Fatigue Symptom Scale: Cycle 10
    -3.41 ± 24.69
    -3.08 ± 22.41
        Fatigue Symptom Scale: Cycle 11
    -4.35 ± 22.66
    -3.44 ± 21.21
        Fatigue Symptom Scale: Cycle 12
    -3.14 ± 24.56
    -4.60 ± 24.39
        Fatigue Symptom Scale: Cycle 13
    -4.57 ± 23.31
    -4.50 ± 21.47
        Fatigue Symptom Scale: Cycle 14
    -6.75 ± 24.32
    -6.54 ± 22.89
        Fatigue Symptom Scale: Cycle 15
    -5.47 ± 24.68
    -4.99 ± 22.40
        Fatigue Symptom Scale: Cycle 16
    -3.54 ± 24.81
    -6.93 ± 21.89
        Fatigue Symptom Scale: Cycle 17
    -4.27 ± 25.50
    -3.45 ± 21.91
        Fatigue Symptom Scale: Cycle 18
    -4.14 ± 24.42
    -8.92 ± 20.54
        Fatigue Symptom Scale: Cycle 19
    -5.32 ± 27.83
    -9.01 ± 20.71
        Fatigue Symptom Scale: Cycle 20
    -5.56 ± 26.64
    -6.53 ± 21.83
        Fatigue Symptom Scale: Cycle 21
    -3.94 ± 25.97
    -7.41 ± 23.45
        Fatigue Symptom Scale: Cycle 22
    -1.49 ± 25.58
    -10.64 ± 22.22
        Fatigue Symptom Scale: Cycle 23
    -5.82 ± 25.23
    -9.60 ± 28.01
        Fatigue Symptom Scale: Cycle 24
    -1.67 ± 27.05
    -12.50 ± 24.29
        Fatigue Symptom Scale: Cycle 25
    -4.70 ± 26.16
    -12.35 ± 22.03
        Fatigue Symptom Scale: Cycle 26
    -4.99 ± 24.85
    -11.46 ± 22.84
        Fatigue Symptom Scale: Cycle 27
    -6.98 ± 23.76
    -5.36 ± 23.87
        Fatigue Symptom Scale: Cycle 28
    -6.39 ± 18.98
    -4.70 ± 26.14
        Fatigue Symptom Scale: Post-treatment Visit 1
    10.02 ± 28.48
    5.25 ± 24.00
        Fatigue Symptom Scale: Post-treatment Visit 2
    7.70 ± 27.65
    9.70 ± 25.01
        Financial Difficulties Symptom Scale: Cycle 2
    -0.90 ± 26.85
    -2.46 ± 25.46
        Financial Difficulties Symptom Scale: Cycle 3
    0.31 ± 27.62
    0.00 ± 26.33
        Financial Difficulties Symptom Scale: Cycle 4
    0.89 ± 25.95
    0.11 ± 25.10
        Financial Difficulties Symptom Scale: Cycle 5
    1.75 ± 27.71
    2.58 ± 26.46
        Financial Difficulties Symptom Scale: Cycle 6
    1.11 ± 27.62
    0.92 ± 26.36
        Financial Difficulties Symptom Scale: Cycle 7
    1.11 ± 31.08
    0.30 ± 26.41
        Financial Difficulties Symptom Scale: Cycle 8
    1.15 ± 30.21
    0.47 ± 25.27
        Financial Difficulties Symptom Scale: Cycle 9
    1.11 ± 29.78
    -0.51 ± 24.75
        Financial Difficulties Symptom Scale: Cycle 10
    0.90 ± 30.10
    -2.42 ± 24.30
        Financial Difficulties Symptom Scale: Cycle 11
    0.39 ± 29.37
    -0.22 ± 24.84
        Financial Difficulties Symptom Scale: Cycle 12
    -1.05 ± 28.91
    -0.97 ± 26.39
        Financial Difficulties Symptom Scale: Cycle 13
    -0.95 ± 28.82
    0.30 ± 24.82
        Financial Difficulties Symptom Scale: Cycle 14
    -1.73 ± 29.74
    -0.98 ± 25.02
        Financial Difficulties Symptom Scale: Cycle 15
    -1.81 ± 28.96
    1.36 ± 26.18
        Financial Difficulties Symptom Scale: Cycle 16
    -3.16 ± 30.13
    0.39 ± 25.97
        Financial Difficulties Symptom Scale: Cycle 17
    -3.87 ± 29.59
    1.35 ± 27.28
        Financial Difficulties Symptom Scale: Cycle 18
    -2.29 ± 27.46
    2.35 ± 26.02
        Financial Difficulties Symptom Scale: Cycle 19
    -0.35 ± 28.41
    -0.51 ± 27.73
        Financial Difficulties Symptom Scale: Cycle 20
    1.19 ± 29.47
    1.59 ± 27.71
        Financial Difficulties Symptom Scale: Cycle 21
    1.27 ± 28.96
    -4.94 ± 27.78
        Financial Difficulties Symptom Scale: Cycle 22
    2.49 ± 26.79
    -4.26 ± 23.69
        Financial Difficulties Symptom Scale: Cycle 23
    -0.53 ± 26.43
    -2.27 ± 29.11
        Financial Difficulties Symptom Scale: Cycle 24
    1.11 ± 24.52
    -5.83 ± 26.03
        Financial Difficulties Symptom Scale: Cycle 25
    3.21 ± 27.42
    -4.63 ± 25.39
        Financial Difficulties Symptom Scale: Cycle 26
    2.72 ± 28.74
    -2.22 ± 26.16
        Financial Difficulties Symptom Scale: Cycle 27
    -3.10 ± 23.92
    1.15 ± 24.37
        Financial Difficulties Symptom Scale: Cycle 28
    -1.67 ± 23.81
    -1.28 ± 24.00
        Financial Difficulties: Post-treatment Visit 1
    1.70 ± 29.66
    1.33 ± 26.21
        Financial Difficulties: Post-treatment Visit 2
    1.98 ± 26.17
    4.24 ± 31.32
        Nausea And Vomiting Symptom Scale: Cycle 2
    5.85 ± 22.65
    4.08 ± 22.25
        Nausea And Vomiting Symptom Scale: Cycle 3
    5.12 ± 23.62
    5.06 ± 21.14
        Nausea And Vomiting Symptom Scale: Cycle 4
    4.10 ± 21.85
    3.56 ± 23.76
        Nausea And Vomiting Symptom Scale: Cycle 5
    5.13 ± 22.58
    5.15 ± 23.81
        Nausea And Vomiting Symptom Scale: Cycle 6
    4.11 ± 23.36
    2.59 ± 21.24
        Nausea And Vomiting Symptom Scale: Cycle 7
    2.07 ± 23.58
    2.49 ± 22.31
        Nausea And Vomiting Symptom Scale: Cycle 8
    -0.86 ± 20.80
    -0.77 ± 20.21
        Nausea And Vomiting Symptom Scale: Cycle 9
    -2.54 ± 20.85
    -2.98 ± 19.78
        Nausea And Vomiting Symptom Scale: Cycle 10
    -4.30 ± 18.81
    -2.81 ± 20.57
        Nausea And Vomiting Symptom Scale: Cycle 11
    -3.51 ± 18.01
    -3.66 ± 20.04
        Nausea And Vomiting Symptom Scale: Cycle 12
    -3.04 ± 18.07
    -3.45 ± 20.34
        Nausea And Vomiting Symptom Scale: Cycle 13
    -4.02 ± 16.29
    -3.60 ± 19.25
        Nausea And Vomiting Symptom Scale: Cycle 14
    -3.46 ± 19.54
    -5.72 ± 18.54
        Nausea And Vomiting Symptom Scale: Cycle 15
    -3.59 ± 16.34
    -3.91 ± 16.55
        Nausea And Vomiting Symptom Scale: Cycle 16
    -0.43 ± 20.32
    -2.55 ± 20.00
        Nausea And Vomiting Symptom Scale: Cycle 17
    -0.60 ± 17.46
    -3.15 ± 16.48
        Nausea And Vomiting Symptom Scale: Cycle 18
    -0.65 ± 16.90
    -3.52 ± 18.24
        Nausea And Vomiting Symptom Scale: Cycle 19
    -0.87 ± 18.32
    -4.04 ± 19.62
        Nausea And Vomiting Symptom Scale: Cycle 20
    -1.79 ± 18.48
    -3.97 ± 17.89
        Nausea And Vomiting Symptom Scale: Cycle 21
    -1.05 ± 20.03
    -6.48 ± 19.80
        Nausea And Vomiting Symptom Scale: Cycle 22
    -3.48 ± 19.14
    -8.16 ± 18.99
        Nausea And Vomiting Symptom Scale: Cycle 23
    -4.23 ± 17.70
    -6.44 ± 24.70
        Nausea And Vomiting Symptom Scale: Cycle 24
    -4.72 ± 16.26
    -7.92 ± 17.70
        Nausea And Vomiting Symptom Scale: Cycle 25
    -4.17 ± 20.84
    -7.41 ± 19.29
        Nausea And Vomiting Symptom Scale: Cycle 26
    -3.40 ± 24.29
    -9.38 ± 19.37
        Nausea And Vomiting Symptom Scale: Cycle 27
    -5.04 ± 22.58
    -7.47 ± 20.70
        Nausea And Vomiting Symptom Scale: Cycle 28
    -1.25 ± 20.11
    -6.41 ± 17.69
        Nausea/Vomiting Scale: Post-treatment Visit 1
    4.68 ± 22.20
    4.13 ± 23.91
        Nausea/Vomiting Scale: Post-treatment Visit 2
    4.29 ± 23.05
    2.73 ± 21.60
        Pain Symptom Scale: Cycle 2
    -6.80 ± 24.69
    -6.38 ± 23.58
        Pain Symptom Scale: Cycle 3
    -9.89 ± 25.16
    -7.23 ± 25.78
        Pain Symptom Scale: Cycle 4
    -10.26 ± 24.78
    -7.46 ± 26.06
        Pain Symptom Scale: Cycle 5
    -8.86 ± 25.88
    -6.25 ± 25.42
        Pain Symptom Scale: Cycle 6
    -8.95 ± 25.73
    -7.33 ± 24.85
        Pain Symptom Scale: Cycle 7
    -10.95 ± 26.13
    -7.46 ± 24.79
        Pain Symptom Scale: Cycle 8
    -9.97 ± 25.80
    -8.53 ± 22.86
        Pain Symptom Scale: Cycle 9
    -9.29 ± 24.83
    -7.82 ± 22.98
        Pain Symptom Scale: Cycle 10
    -9.41 ± 26.10
    -8.13 ± 22.75
        Pain Symptom Scale: Cycle 11
    -10.33 ± 25.77
    -6.34 ± 22.97
        Pain Symptom Scale: Cycle 12
    -10.27 ± 23.10
    -5.24 ± 25.29
        Pain Symptom Scale: Cycle 13
    -10.28 ± 25.79
    -4.80 ± 20.27
        Pain Symptom Scale: Cycle 14
    -10.49 ± 25.49
    -5.56 ± 23.37
        Pain Symptom Scale: Cycle 15
    -11.15 ± 22.86
    -3.74 ± 22.77
        Pain Symptom Scale: Cycle 16
    -9.91 ± 22.94
    -4.71 ± 23.66
        Pain Symptom Scale: Cycle 17
    -7.59 ± 25.00
    -5.63 ± 22.63
        Pain Symptom Scale: Cycle 18
    -8.82 ± 23.42
    -8.22 ± 20.68
        Pain Symptom Scale: Cycle 19
    -8.16 ± 25.13
    -5.05 ± 21.48
        Pain Symptom Scale: Cycle 20
    -6.94 ± 25.90
    -6.08 ± 19.24
        Pain Symptom Scale: Cycle 21
    -9.92 ± 27.15
    -6.48 ± 23.44
        Pain Symptom Scale: Cycle 22
    -7.71 ± 26.96
    -8.51 ± 19.62
        Pain Symptom Scale: Cycle 23
    -10.85 ± 22.03
    -7.95 ± 26.29
        Pain Symptom Scale: Cycle 24
    -10.00 ± 24.39
    -10.00 ± 17.21
        Pain Symptom Scale: Cycle 25
    -9.94 ± 24.09
    -12.96 ± 19.96
        Pain Symptom Scale: Cycle 26
    -10.54 ± 22.49
    -8.33 ± 18.45
        Pain Symptom Scale: Cycle 27
    -11.24 ± 22.34
    -5.75 ± 21.95
        Pain Symptom Scale: Cycle 28
    -10.42 ± 27.91
    -9.62 ± 19.54
        Pain Symptom Scale: Post-treatment Visit 1
    1.13 ± 27.27
    2.06 ± 28.70
        Pain Symptom Scale: Post-treatment Visit 2
    -1.49 ± 28.39
    5.45 ± 29.96
        Physical Functional Scale: Cycle 2
    -3.58 ± 14.56
    -3.01 ± 15.34
        Physical Functional Scale: Cycle 3
    -2.99 ± 17.19
    -3.92 ± 17.03
        Physical Functional Scale: Cycle 4
    -3.28 ± 18.87
    -3.50 ± 17.99
        Physical Functional Scale: Cycle 5
    -3.10 ± 19.35
    -4.62 ± 17.62
        Physical Functional Scale: Cycle 6
    -5.00 ± 20.30
    -3.84 ± 18.65
        Physical Functional Scale: Cycle 7
    -3.66 ± 20.75
    -3.79 ± 19.82
        Physical Functional Scale: Cycle 8
    -2.24 ± 21.14
    -1.56 ± 18.55
        Physical Functional Scale: Cycle 9
    -1.59 ± 20.21
    -0.75 ± 18.44
        Physical Functional Scale: Cycle 10
    0.11 ± 19.93
    -0.27 ± 17.16
        Physical Functional Scale: Cycle 11
    0.35 ± 19.43
    0.27 ± 17.09
        Physical Functional Scale: Cycle 12
    -1.05 ± 20.06
    0.89 ± 16.35
        Physical Functional Scale: Cycle 13
    -0.80 ± 20.65
    0.27 ± 17.41
        Physical Functional Scale: Cycle 14
    -0.02 ± 20.14
    1.70 ± 18.09
        Physical Functional Scale: Cycle 15
    0.41 ± 18.91
    -0.95 ± 17.99
        Physical Functional Scale: Cycle 16
    -1.08 ± 19.85
    -0.08 ± 18.18
        Physical Functional Scale: Cycle 17
    -0.46 ± 19.43
    -0.81 ± 17.55
        Physical Functional Scale: Cycle 18
    0.13 ± 19.74
    0.75 ± 16.85
        Physical Functional Scale: Cycle 19
    1.39 ± 19.82
    1.31 ± 14.38
        Physical Functional Scale: Cycle 20
    0.71 ± 21.08
    0.85 ± 16.74
        Physical Functional Scale: Cycle 21
    0.42 ± 22.20
    0.25 ± 18.18
        Physical Functional Scale: Cycle 22
    -2.79 ± 21.90
    1.42 ± 16.79
        Physical Functional Scale: Cycle 23
    -1.48 ± 21.47
    0.61 ± 19.60
        Physical Functional Scale: Cycle 24
    -2.67 ± 22.27
    3.00 ± 16.47
        Physical Functional Scale: Cycle 25
    -2.18 ± 20.61
    4.81 ± 15.91
        Physical Functional Scale: Cycle 26
    -1.90 ± 20.09
    -1.88 ± 20.69
        Physical Functional Scale: Cycle 27
    0.16 ± 18.66
    -3.68 ± 19.40
        Physical Functional Scale: Cycle 28
    -1.17 ± 17.79
    -2.82 ± 18.97
        Physical Functional Scale: Post-treatment Visit 1
    -11.37 ± 23.67
    -7.51 ± 20.53
        Physical Functional Scale: Post-treatment Visit 2
    -11.49 ± 24.31
    -11.82 ± 20.27
        Global Health Status Scale: Cycle 2
    1.81 ± 23.35
    4.29 ± 23.42
        Global Health Status Scale: Cycle 3
    1.56 ± 25.05
    2.86 ± 25.03
        Global Health Status Scale: Cycle 4
    1.39 ± 25.26
    4.15 ± 23.79
        Global Health Status Scale: Cycle 5
    1.17 ± 25.70
    3.92 ± 23.05
        Global Health Status Scale: Cycle 6
    0.68 ± 27.89
    3.61 ± 23.13
        Global Health Status Scale: Cycle 7
    1.83 ± 27.81
    3.33 ± 22.77
        Global Health Status Scale: Cycle 8
    3.06 ± 27.09
    5.18 ± 23.18
        Global Health Status Scale: Cycle 9
    4.39 ± 26.25
    4.68 ± 22.99
        Global Health Status Scale: Cycle 10
    4.80 ± 25.35
    5.07 ± 22.77
        Global Health Status Scale: Cycle 11
    5.78 ± 26.62
    3.82 ± 23.75
        Global Health Status Scale: Cycle 12
    3.11 ± 24.89
    5.34 ± 24.47
        Global Health Status Scale: Cycle 13
    3.51 ± 23.82
    3.83 ± 23.78
        Global Health Status Scale: Cycle 14
    5.97 ± 23.09
    4.82 ± 24.86
        Global Health Status Scale: Cycle 15
    4.26 ± 25.98
    1.70 ± 24.46
        Global Health Status Scale: Cycle 16
    3.12 ± 25.16
    3.04 ± 23.77
        Global Health Status Scale: Cycle 17
    2.93 ± 24.84
    3.83 ± 24.84
        Global Health Status Scale: Cycle 18
    3.02 ± 23.88
    2.58 ± 27.08
        Global Health Status Scale: Cycle 19
    3.25 ± 26.39
    3.97 ± 25.43
        Global Health Status Scale: Cycle 20
    5.12 ± 24.20
    4.89 ± 25.69
        Global Health Status Scale: Cycle 21
    5.38 ± 23.87
    5.40 ± 24.72
        Global Health Status Scale: Cycle 22
    3.79 ± 22.56
    3.19 ± 25.57
        Global Health Status Scale: Cycle 23
    4.03 ± 23.85
    4.07 ± 27.18
        Global Health Status Scale: Cycle 24
    4.24 ± 22.66
    2.92 ± 30.58
        Global Health Status Scale: Cycle 25
    3.59 ± 22.38
    8.10 ± 25.39
        Global Health Status Scale: Cycle 26
    7.27 ± 24.55
    5.47 ± 26.91
        Global Health Status Scale: Cycle 27
    7.54 ± 23.19
    1.72 ± 28.38
        Global Health Status Scale: Cycle 28
    4.49 ± 22.69
    4.81 ± 28.98
        Global Health Status Scale: Post-treatment Visit 1
    -7.24 ± 27.24
    -6.14 ± 24.97
        Global Health Status Scale: Post-treatment Visit 2
    -2.72 ± 27.46
    -5.68 ± 26.57
        Role Functional Scale: Cycle 2
    -3.78 ± 24.99
    -2.82 ± 24.35
        Role Functional Scale: Cycle 3
    -3.62 ± 25.96
    -4.55 ± 28.00
        Role Functional Scale: Cycle 4
    -4.64 ± 27.69
    -5.99 ± 26.87
        Role Functional Scale: Cycle 5
    -4.72 ± 27.68
    -7.41 ± 27.25
        Role Functional Scale: Cycle 6
    -6.13 ± 28.94
    -6.03 ± 28.51
        Role Functional Scale: Cycle 7
    -4.82 ± 29.75
    -5.34 ± 26.31
        Role Functional Scale: Cycle 8
    -1.85 ± 28.87
    -2.38 ± 26.41
        Role Functional Scale: Cycle 9
    -1.19 ± 28.57
    -2.47 ± 27.29
        Role Functional Scale: Cycle 10
    -1.79 ± 28.10
    0.90 ± 25.97
        Role Functional Scale: Cycle 11
    -0.78 ± 28.34
    -2.69 ± 24.94
        Role Functional Scale: Cycle 12
    -1.05 ± 27.28
    0.24 ± 24.07
        Role Functional Scale: Cycle 13
    -2.01 ± 26.61
    -2.40 ± 24.91
        Role Functional Scale: Cycle 14
    -0.86 ± 27.27
    -1.31 ± 25.66
        Role Functional Scale: Cycle 15
    -1.03 ± 27.51
    -3.23 ± 25.40
        Role Functional Scale: Cycle 16
    -3.16 ± 28.73
    -2.35 ± 25.48
        Role Functional Scale: Cycle 17
    -1.04 ± 26.69
    -3.38 ± 25.88
        Role Functional Scale: Cycle 18
    -0.16 ± 27.10
    0.23 ± 26.05
        Role Functional Scale: Cycle 19
    1.04 ± 27.55
    -0.25 ± 23.48
        Role Functional Scale: Cycle 20
    -1.19 ± 30.04
    0.79 ± 23.46
        Role Functional Scale: Cycle 21
    -0.84 ± 28.98
    0.00 ± 27.47
        Role Functional Scale: Cycle 22
    -2.24 ± 27.96
    1.06 ± 22.63
        Role Functional Scale: Cycle 23
    -3.44 ± 30.11
    1.14 ± 25.01
        Role Functional Scale: Cycle 24
    -4.44 ± 29.73
    2.08 ± 24.22
        Role Functional Scale: Cycle 25
    -3.53 ± 29.21
    4.63 ± 26.91
        Role Functional Scale: Cycle 26
    -1.36 ± 28.02
    0.52 ± 26.60
        Role Functional Scale: Cycle 27
    -1.55 ± 30.82
    -4.02 ± 29.77
        Role Functional Scale: Cycle 28
    -0.42 ± 27.86
    -3.85 ± 29.56
        Role Functional Scale: Post-Treatment Visit 1
    -14.61 ± 30.41
    -9.49 ± 28.64
        Role Functional Scale: Post-Treatment Visit 2
    -10.73 ± 31.94
    -15.45 ± 31.82
        Social Functional Scale: Cycle 2
    -3.45 ± 24.07
    -0.44 ± 23.09
        Social Functional Scale: Cycle 3
    -4.62 ± 25.25
    -2.07 ± 25.35
        Social Functional Scale: Cycle 4
    -2.59 ± 25.08
    -1.70 ± 26.58
        Social Functional Scale: Cycle 5
    -5.54 ± 27.03
    -3.26 ± 27.24
        Social Functional Scale: Cycle 6
    -5.72 ± 27.87
    -1.04 ± 27.20
        Social Functional Scale: Cycle 7
    -2.69 ± 27.13
    -0.15 ± 26.00
        Social Functional Scale: Cycle 8
    -1.72 ± 26.93
    1.08 ± 26.49
        Social Functional Scale: Cycle 9
    0.56 ± 27.59
    0.77 ± 25.11
        Social Functional Scale: Cycle 10
    -0.81 ± 27.31
    2.31 ± 25.75
        Social Functional Scale: Cycle 11
    0.58 ± 27.35
    1.94 ± 24.39
        Social Functional Scale: Cycle 12
    0.52 ± 28.59
    2.40 ± 24.70
        Social Functional Scale: Cycle 13
    0.83 ± 25.31
    2.10 ± 25.73
        Social Functional Scale: Cycle 14
    1.98 ± 26.71
    2.12 ± 24.89
        Social Functional Scale: Cycle 15
    1.79 ± 27.24
    0.00 ± 27.08
        Social Functional Scale: Cycle 16
    -0.72 ± 25.76
    0.39 ± 25.84
        Social Functional Scale: Cycle 17
    -0.45 ± 26.51
    1.58 ± 24.39
        Social Functional Scale: Cycle 18
    -0.98 ± 25.99
    2.11 ± 26.42
        Social Functional Scale: Cycle 19
    2.26 ± 26.56
    3.28 ± 21.53
        Social Functional Scale: Cycle 20
    1.59 ± 27.09
    0.79 ± 22.88
        Social Functional Scale: Cycle 21
    1.27 ± 28.09
    5.86 ± 22.00
        Social Functional Scale: Cycle 22
    1.24 ± 27.72
    2.84 ± 24.16
        Social Functional Scale: Cycle 23
    6.08 ± 27.32
    1.89 ± 22.51
        Social Functional Scale: Cycle 24
    5.83 ± 25.64
    4.17 ± 24.39
        Social Functional Scale: Cycle 25
    1.60 ± 27.27
    2.78 ± 23.40
        Social Functional Scale: Cycle 26
    3.74 ± 26.19
    1.56 ± 24.45
        Social Functional Scale: Cycle 27
    5.81 ± 24.37
    -1.72 ± 26.85
        Social Functional Scale: Cycle 28
    6.25 ± 23.48
    -0.64 ± 24.26
        Social Functional Scale: Post-Treatment Visit 1
    -9.13 ± 26.47
    -3.80 ± 28.74
        Social Functional Scale: Post-Treatment Visit 2
    -5.45 ± 28.49
    -8.48 ± 28.98
        Insomnia Symptom Scale: Cycle 2
    -0.69 ± 26.82
    -0.39 ± 28.27
        Insomnia Symptom Scale: Cycle 3
    -3.53 ± 27.03
    -3.48 ± 30.14
        Insomnia Symptom Scale: Cycle 4
    -2.88 ± 28.14
    -3.62 ± 30.40
        Insomnia Symptom Scale: Cycle 5
    -2.21 ± 29.27
    -2.66 ± 30.17
        Insomnia Symptom Scale: Cycle 6
    -2.94 ± 28.63
    -5.58 ± 32.53
        Insomnia Symptom Scale: Cycle 7
    -4.56 ± 28.42
    -4.82 ± 32.98
        Insomnia Symptom Scale: Cycle 8
    -6.13 ± 27.72
    -6.45 ± 30.75
        Insomnia Symptom Scale: Cycle 9
    -8.97 ± 25.69
    -6.12 ± 30.32
        Insomnia Symptom Scale: Cycle 10
    -8.24 ± 26.69
    -4.42 ± 28.79
        Insomnia Symptom Scale: Cycle 11
    -8.97 ± 28.19
    -5.81 ± 27.69
        Insomnia Symptom Scale: Cycle 12
    -8.81 ± 27.67
    -6.43 ± 26.49
        Insomnia Symptom Scale: Cycle 13
    -10.17 ± 26.71
    -5.11 ± 24.29
        Insomnia Symptom Scale: Cycle 14
    -9.14 ± 26.84
    -7.84 ± 24.45
        Insomnia Symptom Scale: Cycle 15
    -9.74 ± 28.89
    -5.10 ± 21.59
        Insomnia Symptom Scale: Cycle 16
    -8.91 ± 26.14
    -4.31 ± 26.62
        Insomnia Symptom Scale: Cycle 17
    -11.01 ± 26.62
    -5.41 ± 26.48
        Insomnia Symptom Scale: Cycle 18
    -8.82 ± 28.12
    -8.45 ± 20.09
        Insomnia Symptom Scale: Cycle 19
    -11.46 ± 29.35
    -7.58 ± 22.49
        Insomnia Symptom Scale: Cycle 20
    -10.32 ± 27.37
    -5.29 ± 25.55
        Insomnia Symptom Scale: Cycle 21
    -11.81 ± 27.24
    -4.94 ± 27.02
        Insomnia Symptom Scale: Cycle 22
    -10.95 ± 31.46
    -7.80 ± 19.92
        Insomnia Symptom Scale: Cycle 23
    -10.58 ± 34.82
    -6.06 ± 23.04
        Insomnia Symptom Scale: Cycle 24
    -9.44 ± 31.94
    -7.50 ± 21.99
        Insomnia Symptom Scale: Cycle 25
    -10.26 ± 28.42
    -8.33 ± 26.87
        Insomnia Symptom Scale: Cycle 26
    -9.52 ± 32.63
    -4.17 ± 20.30
        Insomnia Symptom Scale: Cycle 27
    -13.18 ± 30.11
    -4.60 ± 19.36
        Insomnia Symptom Scale: Cycle 28
    -11.67 ± 31.62
    -1.28 ± 22.07
        Insomnia Symptom Scale: Post-Treatment Visit 1
    2.81 ± 29.19
    -1.32 ± 30.81
        Insomnia Symptom Scale: Post-Treatment Visit 2
    5.67 ± 29.23
    3.03 ± 31.13
    No statistical analyses for this end point

    Secondary: Change from Baseline in EORTC QLQ-Gastric Cancer Module (EORTC QLQ-STO22) Questionnaire Score

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    End point title
    		 Change from Baseline in EORTC QLQ-Gastric Cancer Module (EORTC QLQ-STO22) Questionnaire Score
    End point description
    The EORTC QLQ-STO22 is a gastric cancer quality of life questionnaire. There are 22 questions concerning disease, treatment related symptoms, side effects, dysphagia, nutritional aspects, and questions about the emotional problems of gastric cancer (dysphagia, pain, reflux, eating restrictions, anxiety, dry mouth, body image, and hair loss). The questions are grouped into five scales and 4 single items which are related to the symptoms of the disease. Most questions used 4-point scale (1 'Not at all' to 4 'Very much'; 1 question was a yes or no answer). A linear transformation was used to standardize all scores and single-items to a scale of 0 to 100; higher score=better level of functioning or greater degree of symptoms. Positive value means increase, while negative value means decrease, in score at indicated time-point relative to score at baseline (Cycle 1, Day 1). Subjects in ITT population with both a baseline and at least 1 post-treatment assessment are included.
    End point type
    Secondary
    End point timeframe
    Day 1 of each 21-day treatment cycle up to 28 and 60-90 days after Day 1 of last treatment cycle (up to approximately 3.5 years)
    End point values
    		 Pertuzumab + Trastuzumab + Chemotherapy Placebo + Trastuzumab + Chemotherapy
    Number of subjects analysed
    388
    392
    Units: score on a scale
    arithmetic mean (standard deviation)
        Anxiety: Cycle 2
    -2.58 ± 21.72
    -4.11 ± 21.19
        Anxiety: Cycle 3
    -4.14 ± 22.45
    -3.87 ± 23.19
        Anxiety: Cycle 4
    -4.52 ± 23.01
    -7.25 ± 23.16
        Anxiety: Cycle 5
    -4.10 ± 22.94
    -7.39 ± 24.36
        Anxiety: Cycle 6
    -4.54 ± 23.97
    -8.42 ± 25.21
        Anxiety: Cycle 7
    -6.40 ± 24.00
    -10.40 ± 24.37
        Anxiety: Cycle 8
    -9.00 ± 23.17
    -11.92 ± 24.50
        Anxiety: Cycle 9
    -10.09 ± 23.30
    -11.43 ± 23.24
        Anxiety: Cycle 10
    -11.17 ± 25.05
    -12.64 ± 22.09
        Anxiety: Cycle 11
    -10.78 ± 23.47
    -12.09 ± 21.84
        Anxiety: Cycle 12
    -12.62 ± 26.24
    -13.16 ± 23.11
        Anxiety: Cycle 13
    -13.32 ± 25.93
    -13.33 ± 22.47
        Anxiety: Cycle 14
    -14.32 ± 26.49
    -12.43 ± 23.59
        Anxiety: Cycle 15
    -13.42 ± 26.64
    -10.65 ± 25.74
        Anxiety: Cycle 16
    -12.75 ± 26.87
    -12.57 ± 23.89
        Anxiety: Cycle 17
    -13.41 ± 27.30
    -12.79 ± 21.01
        Anxiety: Cycle 18
    -13.53 ± 28.05
    -12.38 ± 22.90
        Anxiety: Cycle 19
    -14.50 ± 27.41
    -12.48 ± 20.08
        Anxiety: Cycle 20
    -15.34 ± 29.21
    -12.37 ± 23.73
        Anxiety: Cycle 21
    -16.03 ± 28.84
    -14.47 ± 25.00
        Anxiety: Cycle 22
    -13.30 ± 30.77
    -15.46 ± 23.83
        Anxiety: Cycle 23
    -17.28 ± 30.64
    -14.47 ± 29.55
        Anxiety: Cycle 24
    -16.11 ± 30.65
    -17.09 ± 23.76
        Anxiety: Cycle 25
    -16.03 ± 29.47
    -17.78 ± 23.68
        Anxiety: Cycle 26
    -19.73 ± 30.28
    -13.26 ± 22.11
        Anxiety: Cycle 27
    -21.71 ± 29.89
    -12.70 ± 20.67
        Anxiety: Cycle 28
    -22.51 ± 29.34
    -12.89 ± 22.38
        Anxiety: Post-treatment Monitoring Visit 1
    -0.73 ± 25.18
    -4.73 ± 27.21
        Anxiety: Post-treatment Monitoring Visit 2
    -4.04 ± 28.24
    -3.98 ± 25.02
        Body Image: Cycle 2
    1.33 ± 28.19
    1.20 ± 26.44
        Body Image: Cycle 3
    1.48 ± 29.06
    3.88 ± 28.03
        Body Image: Cycle 4
    4.20 ± 28.51
    1.15 ± 27.19
        Body Image: Cycle 5
    2.86 ± 30.91
    1.06 ± 25.74
        Body Image: Cycle 6
    0.75 ± 30.11
    2.78 ± 28.48
        Body Image: Cycle 7
    -0.56 ± 28.94
    0.29 ± 25.53
        Body Image: Cycle 8
    -1.74 ± 29.83
    0.00 ± 26.30
        Body Image: Cycle 9
    -3.58 ± 28.74
    -0.69 ± 24.52
        Body Image: Cycle 10
    -5.07 ± 30.15
    -3.25 ± 24.55
        Body Image: Cycle 11
    -4.62 ± 30.24
    -1.53 ± 25.46
        Body Image: Cycle 12
    -5.31 ± 31.92
    -2.66 ± 27.04
        Body Image: Cycle 13
    -4.73 ± 30.23
    -2.73 ± 25.99
        Body Image: Cycle 14
    -5.43 ± 29.70
    -4.62 ± 24.05
        Body Image: Cycle 15
    -3.08 ± 30.63
    -2.43 ± 27.03
        Body Image: Cycle 16
    -1.74 ± 32.99
    -1.19 ± 26.10
        Body Image: Cycle 17
    -2.70 ± 32.76
    -2.28 ± 21.75
        Body Image: Cycle 18
    -2.64 ± 30.44
    -5.71 ± 23.38
        Body Image: Cycle 19
    -2.81 ± 33.57
    -5.21 ± 20.76
        Body Image: Cycle 20
    -3.97 ± 30.79
    -5.38 ± 22.74
        Body Image: Cycle 21
    1.69 ± 30.15
    -8.18 ± 26.07
        Body Image: Cycle 22
    -1.49 ± 32.01
    -10.87 ± 22.28
        Body Image: Cycle 23
    -5.82 ± 24.35
    -8.53 ± 29.18
        Body Image: Cycle 24
    -0.56 ± 31.25
    -11.11 ± 23.36
        Body Image: Cycle 25
    -3.21 ± 28.97
    -11.43 ± 24.18
        Body Image: Cycle 26
    -4.76 ± 29.66
    -6.45 ± 18.09
        Body Image: Cycle 27
    0.78 ± 24.65
    -7.14 ± 21.00
        Body Image: Cycle 28
    -4.27 ± 26.69
    -4.00 ± 24.19
        Body Image: Post-treatment Monitoring Visit 1
    2.48 ± 31.57
    3.42 ± 29.31
        Body Image: Post-treatment Monitoring Visit 2
    2.36 ± 35.40
    6.35 ± 27.38
        Dry Mouth: Cycle 2
    7.72 ± 28.70
    3.00 ± 25.43
        Dry Mouth: Cycle 3
    6.10 ± 28.65
    4.87 ± 27.33
        Dry Mouth: Cycle 4
    4.76 ± 29.40
    2.66 ± 31.06
        Dry Mouth: Cycle 5
    2.47 ± 29.67
    2.57 ± 28.68
        Dry Mouth: Cycle 6
    2.96 ± 30.14
    1.19 ± 27.65
        Dry Mouth: Cycle 7
    -1.96 ± 28.82
    0.44 ± 28.54
        Dry Mouth: Cycle 8
    -2.43 ± 28.68
    -2.66 ± 26.27
        Dry Mouth: Cycle 9
    -3.70 ± 25.70
    -4.32 ± 24.74
        Dry Mouth: Cycle 10
    -6.27 ± 25.04
    -3.46 ± 23.53
        Dry Mouth: Cycle 11
    -7.69 ± 25.46
    -1.96 ± 26.56
        Dry Mouth: Cycle 12
    -8.18 ± 24.22
    -4.35 ± 26.36
        Dry Mouth: Cycle 13
    -9.69 ± 24.08
    -8.48 ± 26.50
        Dry Mouth: Cycle 14
    -8.33 ± 24.60
    -3.63 ± 29.78
        Dry Mouth: Cycle 15
    -7.89 ± 22.20
    -7.29 ± 26.58
        Dry Mouth: Cycle 16
    -6.32 ± 24.44
    -8.33 ± 27.80
        Dry Mouth: Cycle 17
    -7.44 ± 23.12
    -3.20 ± 24.32
        Dry Mouth: Cycle 18
    -5.56 ± 24.86
    -8.10 ± 28.62
        Dry Mouth: Cycle 19
    -5.90 ± 24.18
    -7.69 ± 25.53
        Dry Mouth: Cycle 20
    -6.35 ± 26.62
    -9.68 ± 27.25
        Dry Mouth: Cycle 21
    -7.17 ± 24.27
    -9.43 ± 20.02
        Dry Mouth: Cycle 22
    -3.98 ± 26.29
    -8.70 ± 23.76
        Dry Mouth: Cycle 23
    -7.94 ± 23.73
    -3.88 ± 25.42
        Dry Mouth: Cycle 24
    -6.67 ± 25.15
    -9.40 ± 28.56
        Dry Mouth: Cycle 25
    -8.33 ± 22.75
    -9.52 ± 28.66
        Dry Mouth: Cycle 26
    -2.72 ± 23.41
    -7.53 ± 26.82
        Dry Mouth: Cycle 27
    -6.98 ± 21.28
    -7.14 ± 27.75
        Dry Mouth: Cycle 28
    -8.55 ± 21.24
    -8.00 ± 22.11
        Dry Mouth: Post-treatment Monitoring Visit 1
    0.19 ± 28.70
    2.38 ± 31.58
        Dry Mouth: Post-treatment Monitoring Visit 2
    -1.35 ± 30.09
    1.89 ± 25.95
        Dysphagia: Cycle 2
    -2.27 ± 17.64
    -0.53 ± 19.32
        Dysphagia: Cycle 3
    -3.39 ± 18.57
    -2.15 ± 19.67
        Dysphagia: Cycle 4
    -2.94 ± 18.93
    -1.08 ± 18.79
        Dysphagia: Cycle 5
    -3.22 ± 19.92
    -1.83 ± 18.99
        Dysphagia: Cycle 6
    -4.20 ± 18.99
    -2.25 ± 18.70
        Dysphagia: Cycle 7
    -4.83 ± 20.56
    -1.97 ± 19.94
        Dysphagia: Cycle 8
    -5.96 ± 18.80
    -3.29 ± 18.48
        Dysphagia: Cycle 9
    -6.17 ± 18.21
    -3.86 ± 18.49
        Dysphagia: Cycle 10
    -6.03 ± 17.37
    -4.61 ± 16.87
        Dysphagia: Cycle 11
    -6.25 ± 17.09
    -2.83 ± 17.03
        Dysphagia: Cycle 12
    -7.06 ± 17.65
    -4.19 ± 15.84
        Dysphagia: Cycle 13
    -6.93 ± 18.71
    -3.54 ± 17.61
        Dysphagia: Cycle 14
    -8.01 ± 18.53
    -4.95 ± 18.22
        Dysphagia: Cycle 15
    -6.45 ± 17.38
    -2.14 ± 18.69
        Dysphagia: Cycle 16
    -4.41 ± 18.29
    -3.70 ± 21.08
        Dysphagia: Cycle 17
    -5.36 ± 16.87
    -3.20 ± 14.99
        Dysphagia: Cycle 18
    -4.90 ± 16.44
    -3.33 ± 19.78
        Dysphagia: Cycle 19
    -4.40 ± 17.10
    -3.59 ± 14.31
        Dysphagia: Cycle 20
    -2.51 ± 16.21
    -3.76 ± 15.83
        Dysphagia: Cycle 21
    -3.80 ± 19.24
    -2.10 ± 17.84
        Dysphagia: Cycle 22
    -3.65 ± 20.41
    -4.83 ± 15.65
        Dysphagia: Cycle 23
    -4.23 ± 18.87
    -3.88 ± 17.63
        Dysphagia: Cycle 24
    -5.00 ± 18.35
    -3.70 ± 13.08
        Dysphagia: Cycle 25
    -5.98 ± 19.61
    -2.22 ± 16.79
        Dysphagia: Cycle 26
    -5.67 ± 20.43
    -2.87 ± 16.22
        Dysphagia: Cycle 27
    -5.68 ± 20.91
    -4.37 ± 12.22
        Dysphagia: Cycle 28
    -8.26 ± 19.86
    -3.56 ± 11.44
        Dysphagia: Post-treatment Monitoring Visit 1
    0.44 ± 24.15
    2.83 ± 22.63
        Dysphagia: Post-treatment Monitoring Visit 2
    -2.81 ± 24.40
    3.25 ± 19.81
        Eating Restrictions: Cycle 2
    -1.41 ± 19.36
    -1.54 ± 19.62
        Eating Restrictions: Cycle 3
    -1.04 ± 21.09
    -2.20 ± 20.94
        Eating Restrictions: Cycle 4
    -2.24 ± 20.81
    -1.39 ± 23.36
        Eating Restrictions: Cycle 5
    -1.39 ± 22.10
    -0.09 ± 23.31
        Eating Restrictions: Cycle 6
    -1.35 ± 22.77
    -3.32 ± 23.14
        Eating Restrictions: Cycle 7
    -2.45 ± 22.68
    -2.67 ± 21.66
        Eating Restrictions: Cycle 8
    -4.29 ± 22.70
    -5.56 ± 19.87
        Eating Restrictions: Cycle 9
    -6.99 ± 21.16
    -6.48 ± 19.69
        Eating Restrictions: Cycle 10
    -7.06 ± 21.32
    -5.89 ± 19.30
        Eating Restrictions: Cycle 11
    -8.22 ± 21.25
    -5.05 ± 19.98
        Eating Restrictions: Cycle 12
    -7.74 ± 21.16
    -6.34 ± 19.87
        Eating Restrictions: Cycle 13
    -8.55 ± 20.41
    -8.41 ± 19.57
        Eating Restrictions: Cycle 14
    -8.62 ± 19.16
    -8.58 ± 21.16
        Eating Restrictions: Cycle 15
    -6.85 ± 20.92
    -5.56 ± 21.21
        Eating Restrictions: Cycle 16
    -5.77 ± 22.01
    -6.94 ± 20.36
        Eating Restrictions: Cycle 17
    -5.56 ± 21.95
    -7.42 ± 17.76
        Eating Restrictions: Cycle 18
    -7.27 ± 20.40
    -6.90 ± 21.14
        Eating Restrictions: Cycle 19
    -7.03 ± 21.78
    -5.38 ± 18.07
        Eating Restrictions: Cycle 20
    -4.56 ± 21.03
    -4.44 ± 16.72
        Eating Restrictions: Cycle 21
    -5.80 ± 22.58
    -5.03 ± 19.97
        Eating Restrictions: Cycle 22
    -3.65 ± 21.79
    -6.16 ± 16.80
        Eating Restrictions: Cycle 23
    -3.70 ± 22.74
    -5.23 ± 20.25
        Eating Restrictions: Cycle 24
    -5.00 ± 20.77
    -7.91 ± 15.76
        Eating Restrictions: Cycle 25
    -5.77 ± 21.10
    -5.95 ± 16.61
        Eating Restrictions: Cycle 26
    -6.80 ± 21.22
    -2.42 ± 22.89
        Eating Restrictions: Cycle 27
    -5.62 ± 23.48
    -3.87 ± 10.26
        Eating Restrictions: Cycle 28
    -7.91 ± 21.79
    -5.00 ± 11.02
        Eating Restrictions: Post-treatment Visit 1
    1.52 ± 24.48
    0.94 ± 24.70
        Eating Restrictions: Post-treatment Visit 2
    -2.10 ± 25.32
    0.94 ± 21.46
        Hair Loss: Cycle 2
    0.20 ± 14.85
    1.27 ± 16.59
        Hair Loss: Cycle 3
    4.34 ± 17.51
    4.52 ± 18.71
        Hair Loss: Cycle 4
    5.40 ± 18.46
    6.53 ± 20.99
        Hair Loss: Cycle 5
    6.12 ± 19.38
    7.18 ± 19.49
        Hair Loss: Cycle 6
    6.93 ± 18.87
    10.07 ± 22.94
        Hair Loss: Cycle 7
    5.72 ± 19.91
    9.26 ± 22.92
        Hair Loss: Cycle 8
    5.00 ± 18.96
    7.38 ± 23.05
        Hair Loss: Cycle 9
    2.38 ± 17.43
    6.46 ± 21.06
        Hair Loss: Cycle 10
    0.64 ± 16.88
    4.22 ± 19.51
        Hair Loss: Cycle 11
    -0.10 ± 17.02
    2.54 ± 17.51
        Hair Loss: Cycle 12
    0.21 ± 19.70
    1.96 ± 15.72
        Hair Loss: Cycle 13
    0.36 ± 18.91
    2.29 ± 15.46
        Hair Loss: Cycle 14
    -1.37 ± 17.59
    1.83 ± 15.15
        Hair Loss: Cycle 15
    -0.39 ± 15.65
    1.58 ± 12.65
        Hair Loss: Cycle 16
    -1.47 ± 17.47
    1.42 ± 13.91
        Hair Loss: Cycle 17
    -1.07 ± 17.75
    0.23 ± 12.57
        Hair Loss: Cycle 18
    -1.68 ± 17.58
    -0.71 ± 13.14
        Hair Loss: Cycle 19
    -0.90 ± 18.12
    0.51 ± 14.12
        Hair Loss: Cycle 20
    -0.20 ± 19.21
    -1.61 ± 12.70
        Hair Loss: Cycle 21
    -1.07 ± 19.43
    -1.57 ± 8.81
        Hair Loss: Cycle 22
    -0.50 ± 16.66
    -3.26 ± 11.98
        Hair Loss: Cycle 23
    -0.54 ± 16.79
    -1.19 ± 11.28
        Hair Loss: Cycle 24
    -1.39 ± 17.44
    1.71 ± 16.13
        Hair Loss: Cycle 25
    -1.96 ± 18.75
    -0.95 ± 9.85
        Hair Loss: Cycle 26
    -1.02 ± 19.37
    -0.54 ± 10.08
        Hair Loss: Cycle 27
    -3.10 ± 15.96
    -0.60 ± 10.62
        Hair Loss: Cycle 28
    -4.70 ± 20.57
    -1.33 ± 10.67
        Hair Loss: Post-Treatment Monitoring Visit 1
    4.98 ± 19.73
    4.51 ± 20.39
        Hair Loss: Post-Treatment Monitoring Visit 2
    15.82 ± 25.35
    22.22 ± 30.81
        Pain: Cycle 2
    -4.63 ± 20.30
    -5.86 ± 19.15
        Pain: Cycle 3
    -6.96 ± 20.37
    -5.86 ± 20.68
        Pain: Cycle 4
    -6.45 ± 21.47
    -7.48 ± 21.23
        Pain: Cycle 5
    -7.28 ± 20.95
    -6.89 ± 22.10
        Pain: Cycle 6
    -7.24 ± 20.84
    -7.22 ± 21.62
        Pain: Cycle 7
    -9.52 ± 21.18
    -6.62 ± 21.63
        Pain: Cycle 8
    -10.53 ± 21.62
    -8.16 ± 20.11
        Pain: Cycle 9
    -10.08 ± 19.60
    -8.98 ± 20.29
        Pain: Cycle 10
    -10.63 ± 19.23
    -8.59 ± 20.38
        Pain: Cycle 11
    -11.65 ± 19.35
    -8.01 ± 18.97
        Pain: Cycle 12
    -11.76 ± 19.87
    -7.19 ± 19.11
        Pain: Cycle 13
    -11.92 ± 18.93
    -9.24 ± 19.79
        Pain: Cycle 14
    -11.66 ± 19.51
    -9.82 ± 19.91
        Pain: Cycle 15
    -11.15 ± 18.16
    -8.51 ± 20.94
        Pain: Cycle 16
    -8.72 ± 18.02
    -10.52 ± 21.30
        Pain: Cycle 17
    -8.88 ± 18.17
    -9.93 ± 17.27
        Pain: Cycle 18
    -8.31 ± 18.33
    -11.19 ± 18.16
        Pain: Cycle 19
    -6.63 ± 17.25
    -10.38 ± 14.51
        Pain: Cycle 20
    -5.72 ± 19.98
    -10.35 ± 16.65
        Pain: Cycle 21
    -8.19 ± 18.27
    -7.55 ± 16.77
        Pain: Cycle 22
    -9.08 ± 18.10
    -9.42 ± 16.72
        Pain: Cycle 23
    -9.66 ± 20.75
    -8.53 ± 19.96
        Pain: Cycle 24
    -9.86 ± 21.56
    -8.76 ± 15.53
        Pain: Cycle 25
    -10.58 ± 19.88
    -8.10 ± 18.69
        Pain: Cycle 26
    -9.01 ± 17.99
    -9.41 ± 17.58
        Pain: Cycle 27
    -12.02 ± 17.28
    -9.23 ± 14.58
        Pain: Cycle 28
    -11.54 ± 18.20
    -7.33 ± 13.46
        Pain: Post-Treatment Monitoring Visit 1
    -1.70 ± 23.07
    -2.99 ± 23.86
        Pain: Post-Treatment Monitoring Visit 2
    -7.49 ± 24.09
    -0.03 ± 22.04
        Reflux Symptoms: Cycle 2
    -0.13 ± 16.33
    -1.99 ± 18.03
        Reflux Symptoms: Cycle 3
    -0.52 ± 18.95
    -2.28 ± 19.53
        Reflux Symptoms: Cycle 4
    -0.98 ± 19.18
    -1.90 ± 19.93
        Reflux Symptoms: Cycle 5
    -1.92 ± 18.98
    -1.72 ± 20.10
        Reflux Symptoms: Cycle 6
    -2.90 ± 20.42
    -3.59 ± 19.04
        Reflux Symptoms: Cycle 7
    -4.18 ± 18.36
    -3.20 ± 20.21
        Reflux Symptoms: Cycle 8
    -4.96 ± 19.39
    -5.74 ± 19.53
        Reflux Symptoms: Cycle 9
    -5.02 ± 18.97
    -5.18 ± 19.81
        Reflux Symptoms: Cycle 10
    -6.12 ± 17.81
    -6.48 ± 18.55
        Reflux Symptoms: Cycle 11
    -6.44 ± 18.74
    -6.03 ± 18.07
        Reflux Symptoms: Cycle 12
    -4.82 ± 18.00
    -7.49 ± 16.99
        Reflux Symptoms: Cycle 13
    -6.42 ± 17.09
    -6.77 ± 18.19
        Reflux Symptoms: Cycle 14
    -5.39 ± 18.24
    -7.37 ± 17.45
        Reflux Symptoms: Cycle 15
    -5.00 ± 16.66
    -4.98 ± 18.72
        Reflux Symptoms: Cycle 16
    -3.07 ± 18.39
    -4.89 ± 22.31
        Reflux Symptoms: Cycle 17
    -3.35 ± 18.38
    -4.57 ± 20.44
        Reflux Symptoms: Cycle 18
    -2.94 ± 18.36
    -6.51 ± 20.33
        Reflux Symptoms: Cycle 19
    -2.43 ± 16.38
    -6.15 ± 18.43
        Reflux Symptoms: Cycle 20
    -1.85 ± 18.32
    -5.38 ± 18.63
        Reflux Symptoms: Cycle 21
    -1.83 ± 18.44
    -4.19 ± 17.73
        Reflux Symptoms: Cycle 22
    -3.81 ± 19.30
    -7.00 ± 19.65
        Reflux Symptoms: Cycle 23
    -5.11 ± 17.03
    -6.98 ± 19.70
        Reflux Symptoms: Cycle 24
    -4.07 ± 19.30
    -7.98 ± 18.19
        Reflux Symptoms: Cycle 25
    -5.56 ± 18.86
    -5.71 ± 16.69
        Reflux Symptoms: Cycle 26
    -4.99 ± 20.67
    -4.30 ± 21.98
        Reflux Symptoms: Cycle 27
    -7.75 ± 20.51
    -6.75 ± 16.10
        Reflux Symptoms: Cycle 28
    -7.12 ± 18.64
    -4.44 ± 11.56
        Reflux Symptoms: Post-Treatment Visit 1
    0.88 ± 20.01
    -0.45 ± 22.92
        Reflux Symptoms: Post-Treatment Visit 2
    0.56 ± 18.67
    -1.47 ± 22.28
        Taste: Cycle 2
    12.09 ± 28.78
    6.61 ± 26.94
        Taste: Cycle 3
    16.72 ± 32.11
    9.99 ± 30.16
        Taste: Cycle 4
    18.43 ± 34.70
    11.07 ± 31.93
        Taste: Cycle 5
    17.61 ± 32.93
    11.85 ± 30.25
        Taste: Cycle 6
    17.97 ± 31.20
    11.82 ± 32.21
        Taste: Cycle 7
    16.25 ± 33.51
    9.19 ± 31.09
        Taste: Cycle 8
    11.64 ± 29.81
    3.29 ± 28.13
        Taste: Cycle 9
    9.22 ± 28.25
    1.73 ± 26.30
        Taste: Cycle 10
    7.93 ± 26.41
    1.63 ± 28.79
        Taste: Cycle 11
    4.96 ± 26.72
    2.61 ± 26.91
        Taste: Cycle 12
    5.27 ± 24.82
    0.24 ± 24.66
        Taste: Cycle 13
    4.08 ± 25.53
    -0.91 ± 25.33
        Taste: Cycle 14
    0.49 ± 25.66
    -5.28 ± 24.37
        Taste: Cycle 15
    3.08 ± 24.36
    -1.04 ± 26.25
        Taste: Cycle 16
    5.51 ± 27.90
    -3.57 ± 20.71
        Taste: Cycle 17
    4.80 ± 24.96
    -3.65 ± 23.28
        Taste: Cycle 18
    3.59 ± 23.87
    -4.29 ± 23.34
        Taste: Cycle 19
    3.13 ± 25.17
    -4.62 ± 15.45
        Taste: Cycle 20
    5.56 ± 27.78
    -3.76 ± 18.21
        Taste: Cycle 21
    6.33 ± 27.26
    -5.03 ± 17.78
        Taste: Cycle 22
    9.45 ± 30.04
    -4.35 ± 16.64
        Taste: Cycle 23
    8.99 ± 30.06
    0.00 ± 23.00
        Taste: Cycle 24
    7.78 ± 28.37
    -5.13 ± 19.55
        Taste: Cycle 25
    3.21 ± 28.97
    -4.76 ± 18.33
        Taste: Cycle 26
    4.08 ± 34.45
    -3.23 ± 21.70
        Taste: Cycle 27
    4.65 ± 29.62
    -3.57 ± 20.96
        Taste: Cycle 28
    3.42 ± 21.35
    -6.67 ± 25.46
        Taste: Post-Treatment Monitoring Visit 1
    12.76 ± 34.59
    9.06 ± 33.56
        Taste: Post-Treatment Monitoring Visit 2
    8.42 ± 31.35
    6.67 ± 28.64
    No statistical analyses for this end point

    Secondary: Maximum Serum Concentrations (Cmax) of Pertuzumab

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    End point title
    		 Maximum Serum Concentrations (Cmax) of Pertuzumab [4]
    End point description
    The pharmacokinetic analysis included all subjects who were treated with study medication and who had at least one measurable concentration of pertuzumab or trastuzumab. Data are reported for evaluable subjects.
    End point type
    Secondary
    End point timeframe
    Pre-dose (0-6 hours [Hr] before infusion) on Day 1 (D1) of Cycles (Cy) 1, 2, 3, 4, 6, 8; 0.5 Hr after end of 30-60 minutes infusion on D1 of Cy 1, 2, 4, 8; at 28 & 60-90 days after D1 of last Cy (up approximately 3.5 years) (1 cycle = 21 days)
    Notes
    [4] - 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: This endpoint is only applicable to the Pertuzumab arm of the study; no data was collected from subjects in the Placebo arm for this endpoint.
    End point values
    		 Pertuzumab + Trastuzumab + Chemotherapy
    Number of subjects analysed
    374
    Units: micrograms per milliliter (μg/mL)
    arithmetic mean (standard deviation)
        Cycle 1
    258 ± 90.3
        Cycle 4
    341 ± 111
        Cycle 8
    371 ± 127
    No statistical analyses for this end point

    Secondary: Cmax of Trastuzumab

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    End point title
    		 Cmax of Trastuzumab
    End point description
    The pharmacokinetic analysis included all subjects who were treated with study medication and who had at least one measurable concentration of pertuzumab or trastuzumab. Data are reported for evaluable subjects.
    End point type
    Secondary
    End point timeframe
    Pre-dose (0-6 hours [Hr] before infusion) on Day 1 (D1) of Cycles (Cy) 1, 2, 3, 4, 6, 8; 0.5 Hr after end of 30-60 minutes infusion on D1 of Cy 1, 2, 4, 8; at 28 & 60-90 days after D1 of last Cy (up approximately 3.5 years) (1 cycle = 21 days)
    End point values
    		 Pertuzumab + Trastuzumab + Chemotherapy Placebo + Trastuzumab + Chemotherapy
    Number of subjects analysed
    372
    375
    Units: μg/mL
    arithmetic mean (standard deviation)
        Cycle 1
    142 ± 86.8
    139 ± 58.6
        Cycle 4
    127 ± 50.9
    129 ± 58.1
        Cycle 8
    130 ± 50.8
    147 ± 90.2
    No statistical analyses for this end point

    Secondary: Minimum Serum Concentration (Cmin) of Pertuzumab

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    End point title
    		 Minimum Serum Concentration (Cmin) of Pertuzumab [5]
    End point description
    The pharmacokinetic analysis included all subjects who were treated with study medication and who had at least one measurable concentration of pertuzumab or trastuzumab. Data are reported for evaluable subjects.
    End point type
    Secondary
    End point timeframe
    Pre-dose (0-6 hours [Hr] before infusion) on Day 1 (D1) of Cycles (Cy) 1, 2, 3, 4, 6, 8; 0.5 Hr after end of 30-60 minutes infusion on D1 of Cy 1, 2, 4, 8; at 28 & 60-90 days after D1 of last Cy (up approximately 3.5 years) (1 cycle = 21 days)
    Notes
    [5] - 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: This endpoint is only applicable to the Pertuzumab arm of the study; no data was collected from subjects in the Placebo arm for this endpoint.
    End point values
    		 Pertuzumab + Trastuzumab + Chemotherapy
    Number of subjects analysed
    374
    Units: μg/mL
    arithmetic mean (standard deviation)
        Cycle 4
    90.4 ± 42.4
        Cycle 6
    114 ± 51.8
        Cycle 8
    142 ± 67.9
    No statistical analyses for this end point

    Secondary: Cmin of Trastuzumab

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    End point title
    		 Cmin of Trastuzumab
    End point description
    The pharmacokinetic analysis included all subjects who were treated with study medication and who had at least one measurable concentration of pertuzumab or trastuzumab. Data are reported for evaluable subjects.
    End point type
    Secondary
    End point timeframe
    Pre-dose (0-6 hours [Hr] before infusion) on Day 1 (D1) of Cycles (Cy) 1, 2, 3, 4, 6, 8; 0.5 Hr after end of 30-60 minutes infusion on D1 of Cy 1, 2, 4, 8; at 28 & 60-90 days after D1 of last Cy (up approximately 3.5 years) (1 cycle = 21 days)
    End point values
    		 Pertuzumab + Trastuzumab + Chemotherapy Placebo + Trastuzumab + Chemotherapy
    Number of subjects analysed
    372
    375
    Units: μg/mL
    arithmetic mean (standard deviation)
        Cycle 4
    22.9 ± 12.7
    24.1 ± 19.0
        Cycle 6
    26.3 ± 14.8
    29.8 ± 21.9
        Cycle 8
    32.7 ± 15.0
    37.4 ± 20.3
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Baseline up to the 09 Dec 2016 data cutoff, approximately 3.5 years.
    Assessment type
    		 Non-systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    19.1
    Reporting groups
    Reporting group title
    Placebo + Trastuzumab + Chemotherapy
    Reporting group description
    		 Subjects will receive pertuzumab placebo in combination with trastuzumab and chemotherapy (cisplatin and fluoropyrimidine [capecitabine or 5-fluorouracil]) for the first 6 treatment cycles (cycle length = 21 days). Subjects will continue to receive pertuzumab placebo and trastuzumab until disease progression occurrence of unacceptable toxicity or withdrawal from the study for another reason.

    Reporting group title
    Pertuzumab + Trastuzumab + Chemotherapy
    Reporting group description
    		 Subjects will receive pertuzumab in combination with trastuzumab and chemotherapy (cisplatin and fluoropyrimidine [capecitabine or 5-fluorouracil]) for the first 6 treatment cycles (cycle length = 21 days). Subjects will continue to receive pertuzumab and trastuzumab until disease progression occurrence of unacceptable toxicity or withdrawal from the study for another reason.

    Serious adverse events
    		 Placebo + Trastuzumab + Chemotherapy Pertuzumab + Trastuzumab + Chemotherapy
    Total subjects affected by serious adverse events
         subjects affected / exposed
    152 / 388 (39.18%)
    175 / 385 (45.45%)
         number of deaths (all causes)
    262
    240
         number of deaths resulting from adverse events
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Rectosigmoid cancer stage 0
         subjects affected / exposed
    0 / 388 (0.00%)
    1 / 385 (0.26%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Myelodysplastic syndrome
         subjects affected / exposed
    1 / 388 (0.26%)
    0 / 385 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Second primary malignancy
         subjects affected / exposed
    1 / 388 (0.26%)
    0 / 385 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Tumour haemorrhage
         subjects affected / exposed
    0 / 388 (0.00%)
    4 / 385 (1.04%)
         occurrences causally related to treatment / all
    0 / 0
    2 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vascular disorders
    Aortic aneurysm
         subjects affected / exposed
    1 / 388 (0.26%)
    0 / 385 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Deep vein thrombosis
         subjects affected / exposed
    0 / 388 (0.00%)
    3 / 385 (0.78%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Embolism
         subjects affected / exposed
    1 / 388 (0.26%)
    2 / 385 (0.52%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Haemodynamic instability
         subjects affected / exposed
    1 / 388 (0.26%)
    0 / 385 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    1 / 1
    0 / 0
    Hypertensive crisis
         subjects affected / exposed
    0 / 388 (0.00%)
    1 / 385 (0.26%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypovolaemic shock
         subjects affected / exposed
    1 / 388 (0.26%)
    0 / 385 (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
    1 / 388 (0.26%)
    0 / 385 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Iliac artery occlusion
         subjects affected / exposed
    1 / 388 (0.26%)
    0 / 385 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Orthostatic hypotension
         subjects affected / exposed
    0 / 388 (0.00%)
    1 / 385 (0.26%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Peripheral ischaemia
         subjects affected / exposed
    0 / 388 (0.00%)
    1 / 385 (0.26%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Subclavian vein thrombosis
         subjects affected / exposed
    1 / 388 (0.26%)
    0 / 385 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Thrombosis
         subjects affected / exposed
    0 / 388 (0.00%)
    1 / 385 (0.26%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Varicose vein
         subjects affected / exposed
    0 / 388 (0.00%)
    1 / 385 (0.26%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Venous thrombosis limb
         subjects affected / exposed
    0 / 388 (0.00%)
    1 / 385 (0.26%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Asthenia
         subjects affected / exposed
    1 / 388 (0.26%)
    5 / 385 (1.30%)
         occurrences causally related to treatment / all
    1 / 1
    5 / 8
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Death
         subjects affected / exposed
    9 / 388 (2.32%)
    8 / 385 (2.08%)
         occurrences causally related to treatment / all
    1 / 9
    0 / 8
         deaths causally related to treatment / all
    1 / 9
    0 / 8
    Chest pain
         subjects affected / exposed
    1 / 388 (0.26%)
    0 / 385 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Fatigue
         subjects affected / exposed
    0 / 388 (0.00%)
    4 / 385 (1.04%)
         occurrences causally related to treatment / all
    0 / 0
    4 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    General physical health deterioration
         subjects affected / exposed
    0 / 388 (0.00%)
    1 / 385 (0.26%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Hypothermia
         subjects affected / exposed
    0 / 388 (0.00%)
    1 / 385 (0.26%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Malaise
         subjects affected / exposed
    1 / 388 (0.26%)
    0 / 385 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Mucosal inflammation
         subjects affected / exposed
    3 / 388 (0.77%)
    4 / 385 (1.04%)
         occurrences causally related to treatment / all
    3 / 3
    4 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Non-cardiac chest pain
         subjects affected / exposed
    1 / 388 (0.26%)
    0 / 385 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Multiple organ dysfunction syndrome
         subjects affected / exposed
    2 / 388 (0.52%)
    0 / 385 (0.00%)
         occurrences causally related to treatment / all
    2 / 2
    0 / 0
         deaths causally related to treatment / all
    1 / 1
    0 / 0
    Pneumatosis
         subjects affected / exposed
    0 / 388 (0.00%)
    1 / 385 (0.26%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pyrexia
         subjects affected / exposed
    1 / 388 (0.26%)
    2 / 385 (0.52%)
         occurrences causally related to treatment / all
    0 / 1
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Immune system disorders
    Cytokine release syndrome
         subjects affected / exposed
    0 / 388 (0.00%)
    1 / 385 (0.26%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypersensitivity
         subjects affected / exposed
    0 / 388 (0.00%)
    1 / 385 (0.26%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Acute respiratory distress syndrome
         subjects affected / exposed
    2 / 388 (0.52%)
    0 / 385 (0.00%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Bronchospasm
         subjects affected / exposed
    0 / 388 (0.00%)
    1 / 385 (0.26%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Epistaxis
         subjects affected / exposed
    0 / 388 (0.00%)
    1 / 385 (0.26%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Dyspnoea
         subjects affected / exposed
    1 / 388 (0.26%)
    2 / 385 (0.52%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Hypoxia
         subjects affected / exposed
    1 / 388 (0.26%)
    0 / 385 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lung disorder
         subjects affected / exposed
    0 / 388 (0.00%)
    1 / 385 (0.26%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumothorax
         subjects affected / exposed
    1 / 388 (0.26%)
    0 / 385 (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
    2 / 388 (0.52%)
    6 / 385 (1.56%)
         occurrences causally related to treatment / all
    2 / 2
    2 / 6
         deaths causally related to treatment / all
    1 / 1
    0 / 1
    Respiratory failure
         subjects affected / exposed
    2 / 388 (0.52%)
    0 / 385 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Psychiatric disorders
    Delirium
         subjects affected / exposed
    0 / 388 (0.00%)
    1 / 385 (0.26%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Depression
         subjects affected / exposed
    1 / 388 (0.26%)
    0 / 385 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Product issues
    Device dislocation
         subjects affected / exposed
    2 / 388 (0.52%)
    0 / 385 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Device occlusion
         subjects affected / exposed
    0 / 388 (0.00%)
    1 / 385 (0.26%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Investigations
    Aspartate aminotransferase increased
         subjects affected / exposed
    1 / 388 (0.26%)
    0 / 385 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Alanine aminotransferase increased
         subjects affected / exposed
    1 / 388 (0.26%)
    0 / 385 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Blood bilirubin increased
         subjects affected / exposed
    0 / 388 (0.00%)
    1 / 385 (0.26%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Blood creatine phosphokinase increased
         subjects affected / exposed
    0 / 388 (0.00%)
    1 / 385 (0.26%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Blood creatinine increased
         subjects affected / exposed
    2 / 388 (0.52%)
    1 / 385 (0.26%)
         occurrences causally related to treatment / all
    2 / 2
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Creatinine renal clearance decreased
         subjects affected / exposed
    0 / 388 (0.00%)
    1 / 385 (0.26%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Weight decreased
         subjects affected / exposed
    0 / 388 (0.00%)
    1 / 385 (0.26%)
         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
    Anastomotic stenosis
         subjects affected / exposed
    0 / 388 (0.00%)
    1 / 385 (0.26%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Craniocerebral injury
         subjects affected / exposed
    0 / 388 (0.00%)
    1 / 385 (0.26%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Fall
         subjects affected / exposed
    0 / 388 (0.00%)
    2 / 385 (0.52%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Femoral neck fracture
         subjects affected / exposed
    1 / 388 (0.26%)
    0 / 385 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Fracture
         subjects affected / exposed
    0 / 388 (0.00%)
    2 / 385 (0.52%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal anastomotic leak
         subjects affected / exposed
    1 / 388 (0.26%)
    0 / 385 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Head injury
         subjects affected / exposed
    0 / 388 (0.00%)
    1 / 385 (0.26%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infusion related reaction
         subjects affected / exposed
    2 / 388 (0.52%)
    2 / 385 (0.52%)
         occurrences causally related to treatment / all
    2 / 2
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hip fracture
         subjects affected / exposed
    1 / 388 (0.26%)
    0 / 385 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Injury
         subjects affected / exposed
    0 / 388 (0.00%)
    1 / 385 (0.26%)
         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
    0 / 388 (0.00%)
    1 / 385 (0.26%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Limb injury
         subjects affected / exposed
    0 / 388 (0.00%)
    1 / 385 (0.26%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Subarachnoid haemorrhage
         subjects affected / exposed
    1 / 388 (0.26%)
    0 / 385 (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 myocardial infarction
         subjects affected / exposed
    0 / 388 (0.00%)
    4 / 385 (1.04%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 3
    Atrial fibrillation
         subjects affected / exposed
    1 / 388 (0.26%)
    0 / 385 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Atrial septal defect acquired
         subjects affected / exposed
    0 / 388 (0.00%)
    1 / 385 (0.26%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Atrioventricular block complete
         subjects affected / exposed
    1 / 388 (0.26%)
    0 / 385 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac arrest
         subjects affected / exposed
    1 / 388 (0.26%)
    1 / 385 (0.26%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Cardiac failure
         subjects affected / exposed
    1 / 388 (0.26%)
    2 / 385 (0.52%)
         occurrences causally related to treatment / all
    1 / 1
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac ventricular thrombosis
         subjects affected / exposed
    0 / 388 (0.00%)
    1 / 385 (0.26%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Intracardiac thrombus
         subjects affected / exposed
    0 / 388 (0.00%)
    1 / 385 (0.26%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Myocardial infarction
         subjects affected / exposed
    1 / 388 (0.26%)
    2 / 385 (0.52%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Myocarditis
         subjects affected / exposed
    1 / 388 (0.26%)
    0 / 385 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Prinzmetal angina
         subjects affected / exposed
    0 / 388 (0.00%)
    1 / 385 (0.26%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nervous system disorders
    Anticholinergic syndrome
         subjects affected / exposed
    0 / 388 (0.00%)
    1 / 385 (0.26%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cerebral haemorrhage
         subjects affected / exposed
    1 / 388 (0.26%)
    0 / 385 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Cerebral infarction
         subjects affected / exposed
    1 / 388 (0.26%)
    0 / 385 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cerebral ischaemia
         subjects affected / exposed
    0 / 388 (0.00%)
    1 / 385 (0.26%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cerebrovascular accident
         subjects affected / exposed
    3 / 388 (0.77%)
    0 / 385 (0.00%)
         occurrences causally related to treatment / all
    1 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Dizziness
         subjects affected / exposed
    0 / 388 (0.00%)
    1 / 385 (0.26%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hydrocephalus
         subjects affected / exposed
    1 / 388 (0.26%)
    0 / 385 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ischaemic cerebral infarction
         subjects affected / exposed
    1 / 388 (0.26%)
    0 / 385 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ischaemic stroke
         subjects affected / exposed
    1 / 388 (0.26%)
    1 / 385 (0.26%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Loss of consciousness
         subjects affected / exposed
    0 / 388 (0.00%)
    1 / 385 (0.26%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Neuropathy peripheral
         subjects affected / exposed
    0 / 388 (0.00%)
    1 / 385 (0.26%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Presyncope
         subjects affected / exposed
    0 / 388 (0.00%)
    1 / 385 (0.26%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Seizure
         subjects affected / exposed
    0 / 388 (0.00%)
    1 / 385 (0.26%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Syncope
         subjects affected / exposed
    0 / 388 (0.00%)
    2 / 385 (0.52%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    16 / 388 (4.12%)
    8 / 385 (2.08%)
         occurrences causally related to treatment / all
    13 / 18
    6 / 11
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Febrile neutropenia
         subjects affected / exposed
    10 / 388 (2.58%)
    6 / 385 (1.56%)
         occurrences causally related to treatment / all
    8 / 10
    6 / 6
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Neutropenia
         subjects affected / exposed
    3 / 388 (0.77%)
    3 / 385 (0.78%)
         occurrences causally related to treatment / all
    3 / 3
    4 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Disseminated intravascular coagulation
         subjects affected / exposed
    1 / 388 (0.26%)
    0 / 385 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pancytopenia
         subjects affected / exposed
    3 / 388 (0.77%)
    0 / 385 (0.00%)
         occurrences causally related to treatment / all
    3 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Thrombocytopenia
         subjects affected / exposed
    1 / 388 (0.26%)
    2 / 385 (0.52%)
         occurrences causally related to treatment / all
    1 / 1
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ear and labyrinth disorders
    Tinnitus
         subjects affected / exposed
    1 / 388 (0.26%)
    0 / 385 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Abdominal pain
         subjects affected / exposed
    2 / 388 (0.52%)
    3 / 385 (0.78%)
         occurrences causally related to treatment / all
    0 / 2
    1 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Abdominal pain upper
         subjects affected / exposed
    1 / 388 (0.26%)
    0 / 385 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Colitis
         subjects affected / exposed
    3 / 388 (0.77%)
    0 / 385 (0.00%)
         occurrences causally related to treatment / all
    2 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Constipation
         subjects affected / exposed
    1 / 388 (0.26%)
    0 / 385 (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
    20 / 388 (5.15%)
    17 / 385 (4.42%)
         occurrences causally related to treatment / all
    18 / 21
    20 / 20
         deaths causally related to treatment / all
    1 / 1
    0 / 0
    Duodenal stenosis
         subjects affected / exposed
    0 / 388 (0.00%)
    1 / 385 (0.26%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Dysphagia
         subjects affected / exposed
    1 / 388 (0.26%)
    4 / 385 (1.04%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Enteritis
         subjects affected / exposed
    0 / 388 (0.00%)
    1 / 385 (0.26%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Enterocolitis
         subjects affected / exposed
    4 / 388 (1.03%)
    0 / 385 (0.00%)
         occurrences causally related to treatment / all
    3 / 4
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastric haemorrhage
         subjects affected / exposed
    2 / 388 (0.52%)
    6 / 385 (1.56%)
         occurrences causally related to treatment / all
    0 / 2
    1 / 7
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastric perforation
         subjects affected / exposed
    2 / 388 (0.52%)
    2 / 385 (0.52%)
         occurrences causally related to treatment / all
    2 / 2
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Gastric stenosis
         subjects affected / exposed
    0 / 388 (0.00%)
    1 / 385 (0.26%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastric ulcer
         subjects affected / exposed
    1 / 388 (0.26%)
    1 / 385 (0.26%)
         occurrences causally related to treatment / all
    1 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal disorder
         subjects affected / exposed
    1 / 388 (0.26%)
    0 / 385 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Gastrointestinal haemorrhage
         subjects affected / exposed
    3 / 388 (0.77%)
    0 / 385 (0.00%)
         occurrences causally related to treatment / all
    1 / 4
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal obstruction
         subjects affected / exposed
    1 / 388 (0.26%)
    0 / 385 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal inflammation
         subjects affected / exposed
    1 / 388 (0.26%)
    1 / 385 (0.26%)
         occurrences causally related to treatment / all
    1 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal perforation
         subjects affected / exposed
    1 / 388 (0.26%)
    0 / 385 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal ulcer
         subjects affected / exposed
    1 / 388 (0.26%)
    0 / 385 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrooesophageal reflux disease
         subjects affected / exposed
    1 / 388 (0.26%)
    0 / 385 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Haematemesis
         subjects affected / exposed
    1 / 388 (0.26%)
    0 / 385 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Haemorrhoids
         subjects affected / exposed
    0 / 388 (0.00%)
    1 / 385 (0.26%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ileus paralytic
         subjects affected / exposed
    0 / 388 (0.00%)
    1 / 385 (0.26%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ileus
         subjects affected / exposed
    0 / 388 (0.00%)
    2 / 385 (0.52%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Intestinal mass
         subjects affected / exposed
    1 / 388 (0.26%)
    0 / 385 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Intestinal obstruction
         subjects affected / exposed
    1 / 388 (0.26%)
    0 / 385 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lower gastrointestinal haemorrhage
         subjects affected / exposed
    2 / 388 (0.52%)
    0 / 385 (0.00%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Melaena
         subjects affected / exposed
    0 / 388 (0.00%)
    2 / 385 (0.52%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nausea
         subjects affected / exposed
    7 / 388 (1.80%)
    7 / 385 (1.82%)
         occurrences causally related to treatment / all
    7 / 9
    7 / 7
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Obstruction gastric
         subjects affected / exposed
    5 / 388 (1.29%)
    2 / 385 (0.52%)
         occurrences causally related to treatment / all
    1 / 7
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Oesophageal haemorrhage
         subjects affected / exposed
    1 / 388 (0.26%)
    1 / 385 (0.26%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Stomatitis
         subjects affected / exposed
    2 / 388 (0.52%)
    2 / 385 (0.52%)
         occurrences causally related to treatment / all
    2 / 2
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Upper gastrointestinal haemorrhage
         subjects affected / exposed
    4 / 388 (1.03%)
    3 / 385 (0.78%)
         occurrences causally related to treatment / all
    1 / 4
    1 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vomiting
         subjects affected / exposed
    13 / 388 (3.35%)
    7 / 385 (1.82%)
         occurrences causally related to treatment / all
    12 / 17
    5 / 8
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatobiliary disorders
    Cholecystitis
         subjects affected / exposed
    0 / 388 (0.00%)
    1 / 385 (0.26%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cholecystitis acute
         subjects affected / exposed
    3 / 388 (0.77%)
    1 / 385 (0.26%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatic function abnormal
         subjects affected / exposed
    1 / 388 (0.26%)
    0 / 385 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Skin and subcutaneous tissue disorders
    Actinic keratosis
         subjects affected / exposed
    0 / 388 (0.00%)
    1 / 385 (0.26%)
         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
    4 / 388 (1.03%)
    7 / 385 (1.82%)
         occurrences causally related to treatment / all
    4 / 4
    6 / 7
         deaths causally related to treatment / all
    0 / 0
    1 / 2
    Hydronephrosis
         subjects affected / exposed
    1 / 388 (0.26%)
    0 / 385 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal failure
         subjects affected / exposed
    3 / 388 (0.77%)
    2 / 385 (0.52%)
         occurrences causally related to treatment / all
    2 / 3
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal impairment
         subjects affected / exposed
    2 / 388 (0.52%)
    1 / 385 (0.26%)
         occurrences causally related to treatment / all
    2 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Endocrine disorders
    Autoimmune thyroiditis
         subjects affected / exposed
    0 / 388 (0.00%)
    1 / 385 (0.26%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Inappropriate antidiuretic hormone secretion
         subjects affected / exposed
    1 / 388 (0.26%)
    1 / 385 (0.26%)
         occurrences causally related to treatment / all
    1 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pseudoaldosteronism
         subjects affected / exposed
    0 / 388 (0.00%)
    1 / 385 (0.26%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Gouty arthritis
         subjects affected / exposed
    1 / 388 (0.26%)
    0 / 385 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Back pain
         subjects affected / exposed
    1 / 388 (0.26%)
    0 / 385 (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 / 388 (0.00%)
    1 / 385 (0.26%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infections and infestations
    Abdominal infection
         subjects affected / exposed
    1 / 388 (0.26%)
    0 / 385 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Arthritis bacterial
         subjects affected / exposed
    0 / 388 (0.00%)
    1 / 385 (0.26%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bacteraemia
         subjects affected / exposed
    1 / 388 (0.26%)
    2 / 385 (0.52%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Biliary sepsis
         subjects affected / exposed
    1 / 388 (0.26%)
    0 / 385 (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
    0 / 388 (0.00%)
    1 / 385 (0.26%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cellulitis
         subjects affected / exposed
    0 / 388 (0.00%)
    1 / 385 (0.26%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Device related infection
         subjects affected / exposed
    0 / 388 (0.00%)
    3 / 385 (0.78%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Device related sepsis
         subjects affected / exposed
    0 / 388 (0.00%)
    1 / 385 (0.26%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Diarrhoea infectious
         subjects affected / exposed
    0 / 388 (0.00%)
    1 / 385 (0.26%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastroenteritis
         subjects affected / exposed
    2 / 388 (0.52%)
    0 / 385 (0.00%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatitis B
         subjects affected / exposed
    1 / 388 (0.26%)
    0 / 385 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infection
         subjects affected / exposed
    3 / 388 (0.77%)
    0 / 385 (0.00%)
         occurrences causally related to treatment / all
    1 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Liver abscess
         subjects affected / exposed
    2 / 388 (0.52%)
    1 / 385 (0.26%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lung infection
         subjects affected / exposed
    4 / 388 (1.03%)
    2 / 385 (0.52%)
         occurrences causally related to treatment / all
    3 / 4
    1 / 2
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Parotitis
         subjects affected / exposed
    1 / 388 (0.26%)
    0 / 385 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Peritonitis
         subjects affected / exposed
    0 / 388 (0.00%)
    1 / 385 (0.26%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonia
         subjects affected / exposed
    9 / 388 (2.32%)
    11 / 385 (2.86%)
         occurrences causally related to treatment / all
    2 / 9
    5 / 12
         deaths causally related to treatment / all
    0 / 1
    0 / 3
    Pneumonia Klebsiella
         subjects affected / exposed
    1 / 388 (0.26%)
    0 / 385 (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
    1 / 388 (0.26%)
    0 / 385 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Sepsis
         subjects affected / exposed
    2 / 388 (0.52%)
    7 / 385 (1.82%)
         occurrences causally related to treatment / all
    2 / 2
    4 / 7
         deaths causally related to treatment / all
    1 / 1
    3 / 4
    Septic shock
         subjects affected / exposed
    4 / 388 (1.03%)
    3 / 385 (0.78%)
         occurrences causally related to treatment / all
    3 / 4
    1 / 3
         deaths causally related to treatment / all
    3 / 3
    0 / 0
    Urinary tract infection
         subjects affected / exposed
    0 / 388 (0.00%)
    1 / 385 (0.26%)
         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
    2 / 388 (0.52%)
    3 / 385 (0.78%)
         occurrences causally related to treatment / all
    0 / 2
    1 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Urosepsis
         subjects affected / exposed
    1 / 388 (0.26%)
    0 / 385 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Metabolism and nutrition disorders
    Cachexia
         subjects affected / exposed
    0 / 388 (0.00%)
    2 / 385 (0.52%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Decreased appetite
         subjects affected / exposed
    9 / 388 (2.32%)
    17 / 385 (4.42%)
         occurrences causally related to treatment / all
    9 / 9
    15 / 18
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Dehydration
         subjects affected / exposed
    9 / 388 (2.32%)
    9 / 385 (2.34%)
         occurrences causally related to treatment / all
    7 / 9
    9 / 10
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Diabetes mellitus
         subjects affected / exposed
    1 / 388 (0.26%)
    0 / 385 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Failure to thrive
         subjects affected / exposed
    1 / 388 (0.26%)
    0 / 385 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Diabetes mellitus inadequate control
         subjects affected / exposed
    1 / 388 (0.26%)
    0 / 385 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hyperglycaemia
         subjects affected / exposed
    1 / 388 (0.26%)
    0 / 385 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypernatraemia
         subjects affected / exposed
    0 / 388 (0.00%)
    1 / 385 (0.26%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypocalcaemia
         subjects affected / exposed
    1 / 388 (0.26%)
    2 / 385 (0.52%)
         occurrences causally related to treatment / all
    0 / 1
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypokalaemia
         subjects affected / exposed
    1 / 388 (0.26%)
    7 / 385 (1.82%)
         occurrences causally related to treatment / all
    1 / 1
    6 / 8
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypomagnesaemia
         subjects affected / exposed
    2 / 388 (0.52%)
    2 / 385 (0.52%)
         occurrences causally related to treatment / all
    1 / 2
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hyponatraemia
         subjects affected / exposed
    2 / 388 (0.52%)
    2 / 385 (0.52%)
         occurrences causally related to treatment / all
    1 / 2
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Malnutrition
         subjects affected / exposed
    1 / 388 (0.26%)
    1 / 385 (0.26%)
         occurrences causally related to treatment / all
    0 / 2
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Placebo + Trastuzumab + Chemotherapy Pertuzumab + Trastuzumab + Chemotherapy
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    375 / 388 (96.65%)
    373 / 385 (96.88%)
    Investigations
    Blood creatinine increased
         subjects affected / exposed
    22 / 388 (5.67%)
    28 / 385 (7.27%)
         occurrences all number
    31
    34
    Creatinine renal clearance decreased
         subjects affected / exposed
    51 / 388 (13.14%)
    70 / 385 (18.18%)
         occurrences all number
    62
    86
    Weight decreased
         subjects affected / exposed
    49 / 388 (12.63%)
    74 / 385 (19.22%)
         occurrences all number
    51
    75
    Injury, poisoning and procedural complications
    Infusion related reaction
         subjects affected / exposed
    23 / 388 (5.93%)
    45 / 385 (11.69%)
         occurrences all number
    26
    50
    Vascular disorders
    Hypertension
         subjects affected / exposed
    20 / 388 (5.15%)
    20 / 385 (5.19%)
         occurrences all number
    21
    20
    Nervous system disorders
    Dizziness
         subjects affected / exposed
    31 / 388 (7.99%)
    30 / 385 (7.79%)
         occurrences all number
    39
    34
    Neuropathy peripheral
         subjects affected / exposed
    29 / 388 (7.47%)
    32 / 385 (8.31%)
         occurrences all number
    30
    36
    Dysgeusia
         subjects affected / exposed
    34 / 388 (8.76%)
    37 / 385 (9.61%)
         occurrences all number
    35
    46
    Peripheral sensory neuropathy
         subjects affected / exposed
    34 / 388 (8.76%)
    29 / 385 (7.53%)
         occurrences all number
    35
    33
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    140 / 388 (36.08%)
    151 / 385 (39.22%)
         occurrences all number
    178
    182
    Leukopenia
         subjects affected / exposed
    69 / 388 (17.78%)
    77 / 385 (20.00%)
         occurrences all number
    107
    136
    Neutropenia
         subjects affected / exposed
    202 / 388 (52.06%)
    200 / 385 (51.95%)
         occurrences all number
    293
    327
    Thrombocytopenia
         subjects affected / exposed
    73 / 388 (18.81%)
    60 / 385 (15.58%)
         occurrences all number
    97
    98
    General disorders and administration site conditions
    Asthenia
         subjects affected / exposed
    61 / 388 (15.72%)
    56 / 385 (14.55%)
         occurrences all number
    78
    75
    Chills
         subjects affected / exposed
    17 / 388 (4.38%)
    36 / 385 (9.35%)
         occurrences all number
    19
    36
    Fatigue
         subjects affected / exposed
    122 / 388 (31.44%)
    138 / 385 (35.84%)
         occurrences all number
    163
    171
    Mucosal inflammation
         subjects affected / exposed
    34 / 388 (8.76%)
    43 / 385 (11.17%)
         occurrences all number
    40
    61
    Oedema
         subjects affected / exposed
    19 / 388 (4.90%)
    20 / 385 (5.19%)
         occurrences all number
    32
    33
    Oedema peripheral
         subjects affected / exposed
    32 / 388 (8.25%)
    24 / 385 (6.23%)
         occurrences all number
    35
    25
    Pyrexia
         subjects affected / exposed
    57 / 388 (14.69%)
    55 / 385 (14.29%)
         occurrences all number
    66
    75
    Gastrointestinal disorders
    Abdominal distension
         subjects affected / exposed
    19 / 388 (4.90%)
    23 / 385 (5.97%)
         occurrences all number
    24
    34
    Abdominal pain
         subjects affected / exposed
    50 / 388 (12.89%)
    42 / 385 (10.91%)
         occurrences all number
    55
    59
    Abdominal pain upper
         subjects affected / exposed
    23 / 388 (5.93%)
    27 / 385 (7.01%)
         occurrences all number
    25
    31
    Constipation
         subjects affected / exposed
    83 / 388 (21.39%)
    53 / 385 (13.77%)
         occurrences all number
    104
    61
    Dyspepsia
         subjects affected / exposed
    29 / 388 (7.47%)
    22 / 385 (5.71%)
         occurrences all number
    37
    24
    Diarrhoea
         subjects affected / exposed
    122 / 388 (31.44%)
    225 / 385 (58.44%)
         occurrences all number
    165
    333
    Dysphagia
         subjects affected / exposed
    32 / 388 (8.25%)
    25 / 385 (6.49%)
         occurrences all number
    38
    31
    Nausea
         subjects affected / exposed
    216 / 388 (55.67%)
    223 / 385 (57.92%)
         occurrences all number
    308
    308
    Stomatitis
         subjects affected / exposed
    67 / 388 (17.27%)
    80 / 385 (20.78%)
         occurrences all number
    84
    100
    Vomiting
         subjects affected / exposed
    120 / 388 (30.93%)
    142 / 385 (36.88%)
         occurrences all number
    166
    194
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    20 / 388 (5.15%)
    21 / 385 (5.45%)
         occurrences all number
    28
    23
    Dyspnoea
         subjects affected / exposed
    13 / 388 (3.35%)
    20 / 385 (5.19%)
         occurrences all number
    17
    23
    Hiccups
         subjects affected / exposed
    37 / 388 (9.54%)
    33 / 385 (8.57%)
         occurrences all number
    45
    37
    Skin and subcutaneous tissue disorders
    Alopecia
         subjects affected / exposed
    25 / 388 (6.44%)
    21 / 385 (5.45%)
         occurrences all number
    26
    24
    Dry skin
         subjects affected / exposed
    18 / 388 (4.64%)
    31 / 385 (8.05%)
         occurrences all number
    21
    38
    Rash
         subjects affected / exposed
    13 / 388 (3.35%)
    26 / 385 (6.75%)
         occurrences all number
    15
    28
    Palmar-plantar erythrodysaesthesia syndrome
         subjects affected / exposed
    98 / 388 (25.26%)
    85 / 385 (22.08%)
         occurrences all number
    109
    91
    Pruritus
         subjects affected / exposed
    14 / 388 (3.61%)
    33 / 385 (8.57%)
         occurrences all number
    22
    40
    Skin hyperpigmentation
         subjects affected / exposed
    22 / 388 (5.67%)
    17 / 385 (4.42%)
         occurrences all number
    22
    17
    Psychiatric disorders
    Insomnia
         subjects affected / exposed
    44 / 388 (11.34%)
    32 / 385 (8.31%)
         occurrences all number
    46
    42
    Infections and infestations
    Upper respiratory tract infection
         subjects affected / exposed
    12 / 388 (3.09%)
    22 / 385 (5.71%)
         occurrences all number
    15
    26
    Metabolism and nutrition disorders
    Decreased appetite
         subjects affected / exposed
    158 / 388 (40.72%)
    170 / 385 (44.16%)
         occurrences all number
    217
    233
    Hypoalbuminaemia
         subjects affected / exposed
    19 / 388 (4.90%)
    20 / 385 (5.19%)
         occurrences all number
    21
    24
    Hypocalcaemia
         subjects affected / exposed
    22 / 388 (5.67%)
    22 / 385 (5.71%)
         occurrences all number
    25
    27
    Hypokalaemia
         subjects affected / exposed
    46 / 388 (11.86%)
    72 / 385 (18.70%)
         occurrences all number
    56
    86
    Hypomagnesaemia
         subjects affected / exposed
    21 / 388 (5.41%)
    30 / 385 (7.79%)
         occurrences all number
    22
    37
    Hyponatraemia
         subjects affected / exposed
    28 / 388 (7.22%)
    16 / 385 (4.16%)
         occurrences all number
    28
    18

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    04 Mar 2014
    The period for contraception use was extended from 6 to 7 months following the last dose of study treatment. The safety reporting period for pregnancy (occurring during/after trastuzumab treatment) was updated from 6 to 7 months.

    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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