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The European Union Clinical Trials Register allows you to search for protocol and results information on:

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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
Subject Disposition
Baseline Characteristics
End Points
Adverse Events
More Information

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Trial information

Top of page

Sponsor protocol code

BO25114

ISRCTN number

-

US NCT number

NCT01774786

WHO universal trial number (UTN)

-

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

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

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

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

Efficacy, Safety

Long term follow-up duration

5 Years

Independent data monitoring committee (IDMC) involvement?

Yes

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

Top of page

Recruitment details

-

Screening details

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

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

Are arms mutually exclusive

Yes

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.

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

Top of page

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

Top of page

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

Top of page

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

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

Top of page

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)

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

Top of page

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

Top of page

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

Top of page

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

Top of page

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)

Top of page

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

Top of page

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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Timeframe for reporting adverse events

Baseline up to the 09 Dec 2016 data cutoff, approximately 3.5 years.

Assessment type

Non-systematic

Dictionary name

MedDRA

Dictionary version

19.1

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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Were there any global substantial amendments to the protocol? Yes

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.

Were there any global interruptions to the trial? No

Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.

None reported

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