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A Study to Evaluate Pertuzumab + Trastuzumab + Docetaxel vs. Placebo + Trastuzumab + Docetaxel in Previously Untreated HER2-Positive Metastatic Breast Cancer (CLEOPATRA)

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT00567190
Recruitment Status : Completed
First Posted : December 4, 2007
Results First Posted : September 13, 2012
Last Update Posted : December 13, 2019
Sponsor:
Collaborator:
Hoffmann-La Roche
Information provided by (Responsible Party):
Genentech, Inc.

Study Type Interventional
Study Design Allocation: Randomized;   Intervention Model: Parallel Assignment;   Masking: Triple (Participant, Investigator, Outcomes Assessor);   Primary Purpose: Treatment
Condition Metastatic Breast Cancer
Interventions Drug: Pertuzumab
Drug: Placebo
Drug: Trastuzumab
Drug: Docetaxel
Enrollment 808
Recruitment Details  
Pre-assignment Details A total of 1196 patients were screened for the study, of whom a total of 808 participants were randomized to one of the two treatment arms.
Arm/Group Title Pertuzumab + Trastuzumab + Docetaxel Placebo + Trastuzumab + Docetaxel
Hide Arm/Group Description Participants randomized to this arm received pertuzumab 420 milligrams (mg) intravenously (IV) once every 3 weeks (q3w) and trastuzumab 6 milligrams per kilogram (mg/kg) IV q3w, plus docetaxel 75 milligrams per square metre of body surface (mg/m^2) IV q3w (for at least 6 cycles; 1 cycle was 21 days). After Cycle 6, continuation of docetaxel treatment was at the discretion of the participant and treating physician. Participants remained in the treatment phase of the study until investigator-assessed radiographic or clinical evidence of disease progression, unmanageable toxicity, or study termination and were followed for survival until death, loss to follow-up, withdrawal of consent, or study termination. Participants randomized to this arm received placebo IV q3w and trastuzumab 6 mg/kg IV q3w, plus docetaxel 75 mg/m^2 IV q3w (for at least 6 cycles; 1 cycle was 21 days). After Cycle 6, continuation of docetaxel treatment was at the discretion of the participant and treating physician. Participants remained in the treatment phase of the study until investigator-assessed radiographic or clinical evidence of disease progression, unmanageable toxicity, or study termination and were followed for survival until death, loss to follow-up, withdrawal of consent, or study termination.
Period Title: Overall Study
Started [1] 402 406
Did Not Receive Any Study Treatment 2 2
Received at Least One Dose of Pertuzumab [2] 399 9 [3]
Received at Least One Dose of Placebo [4] 1 [5] 395
Crossover From Placebo to Pertuzumab 0 50 [6]
Completed [7] 119 73
Not Completed 283 333
Reason Not Completed
Death             235             280
Withdrew Consent or Lost to Follow-up             48             53
[1]
Intent-to-Treat (ITT) Population
[2]
Safety Population (Pertuzumab)
[3]
9 participants randomized to the Placebo arm actually received at least one dose of pertuzumab.
[4]
Safety Population (Placebo)
[5]
1 participant randomized to the Pertuzumab arm actually received placebo at every treatment cycle.
[6]
From July 2012, 50 participants randomized to Placebo arm crossed over to open-label pertuzumab.
[7]
Alive and in Survival Follow-up at End of Study
Arm/Group Title Pertuzumab + Trastuzumab + Docetaxel Placebo + Trastuzumab + Docetaxel Total
Hide Arm/Group Description Participants randomized to this arm received pertuzumab 420 milligrams (mg) intravenously (IV) once every 3 weeks (q3w) and trastuzumab 6 milligrams per kilogram (mg/kg) IV q3w, plus docetaxel 75 milligrams per square metre of body surface (mg/m^2) IV q3w (for at least 6 cycles; 1 cycle was 21 days). After Cycle 6, continuation of docetaxel treatment was at the discretion of the participant and treating physician. Participants remained in the treatment phase of the study until investigator-assessed radiographic or clinical evidence of disease progression, unmanageable toxicity, or study termination and were followed for survival until death, loss to follow-up, withdrawal of consent, or study termination. Participants randomized to this arm received placebo IV q3w and trastuzumab 6 mg/kg IV q3w, plus docetaxel 75 mg/m^2 IV q3w (for at least 6 cycles; 1 cycle was 21 days). After Cycle 6, continuation of docetaxel treatment was at the discretion of the participant and treating physician. Participants remained in the treatment phase of the study until investigator-assessed radiographic or clinical evidence of disease progression, unmanageable toxicity, or study termination and were followed for survival until death, loss to follow-up, withdrawal of consent, or study termination. Total of all reporting groups
Overall Number of Baseline Participants 402 406 808
Hide Baseline Analysis Population Description
ITT population
Age, Continuous  
Mean (Standard Deviation)
Unit of measure:  Years
Number Analyzed 402 participants 406 participants 808 participants
53.4  (10.94) 53.5  (11.35) 53.5  (11.14)
Sex: Female, Male  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 402 participants 406 participants 808 participants
Female
402
 100.0%
404
  99.5%
806
  99.8%
Male
0
   0.0%
2
   0.5%
2
   0.2%
Ethnicity (NIH/OMB)  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 402 participants 406 participants 808 participants
Hispanic or Latino
39
   9.7%
44
  10.8%
83
  10.3%
Not Hispanic or Latino
362
  90.0%
362
  89.2%
724
  89.6%
Unknown or Not Reported
1
   0.2%
0
   0.0%
1
   0.1%
Race (NIH/OMB)  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 402 participants 406 participants 808 participants
American Indian or Alaska Native
3
   0.7%
4
   1.0%
7
   0.9%
Asian
128
  31.8%
133
  32.8%
261
  32.3%
Native Hawaiian or Other Pacific Islander
0
   0.0%
0
   0.0%
0
   0.0%
Black or African American
10
   2.5%
20
   4.9%
30
   3.7%
White
245
  60.9%
235
  57.9%
480
  59.4%
More than one race
0
   0.0%
0
   0.0%
0
   0.0%
Unknown or Not Reported
16
   4.0%
14
   3.4%
30
   3.7%
Region  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 402 participants 406 participants 808 participants
Asia
125
  31.1%
128
  31.5%
253
  31.3%
Europe
154
  38.3%
152
  37.4%
306
  37.9%
North America
67
  16.7%
68
  16.7%
135
  16.7%
South America
56
  13.9%
58
  14.3%
114
  14.1%
Prior Treatment Status  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 402 participants 406 participants 808 participants
Adjuvant or Neo-Adjuvant Therapy
184
  45.8%
192
  47.3%
376
  46.5%
De Novo
218
  54.2%
214
  52.7%
432
  53.5%
Independent-Review Facility (IRF)-Determined Disease Status at Screening   [1] 
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 402 participants 406 participants 808 participants
Measurable Disease
343
  85.3%
336
  82.8%
679
  84.0%
Non-Measurable Disease
44
  10.9%
43
  10.6%
87
  10.8%
Not Evaluated
15
   3.7%
27
   6.7%
42
   5.2%
[1]
Measure Description: A participant was deemed to have measurable disease if they had at least 1 target lesion at screening. Target lesions (maximum of 5 per organ and 10 in total) were selected on the basis of their size (lesions with the longest diameter) and their suitability for accurate repeated measurements (either by imaging techniques or clinically). Any participants with non-target lesions only were deemed to have non-measurable disease. The IRF did not evaluate baseline tumor assessments for any participant without a post-baseline tumor assessment.
1.Primary Outcome
Title Progression-Free Survival (PFS) Determined by an Independent Review Facility
Hide Description PFS was defined as the time from randomization to first documented radiographical progressive disease (PD), as determined by an independent review facility (IRF) using RECIST version 1.0, or death from any cause (within 18 weeks of last tumor assessment), whichever occurred first (Kaplan-Meier method). For target lesions, PD was defined as at least a 20% increase in the sum of the longest diameter (LD) of target lesions, taking as reference the smallest sum of the LD recorded since treatment started or the appearance of ≥1 new lesion. For non-target lesions, PD was defined as the appearance of ≥1 new lesion or unequivocal progression of existing lesions. Participants without IRF-determined PD or who had not died within 18 weeks of their last IRF-determined, progression-free tumor assessment were censored at the date of the last IRF-reviewed, evaluable tumor assessment; those with no post-baseline tumor assessment and who had not died within 18 weeks of baseline were censored at 1 day.
Time Frame Tumor assessments every 9 weeks from randomization to IRF-determined PD or death from any cause, whichever occurred first, up to the primary completion date (up to 3 years, 3 months)
Hide Outcome Measure Data
Hide Analysis Population Description
Intent-to-Treat (ITT) Population: All randomized participants
Arm/Group Title Pertuzumab + Trastuzumab + Docetaxel Placebo + Trastuzumab + Docetaxel
Hide Arm/Group Description:
Participants randomized to this arm received pertuzumab 420 milligrams (mg) intravenously (IV) once every 3 weeks (q3w) and trastuzumab 6 milligrams per kilogram (mg/kg) IV q3w, plus docetaxel 75 milligrams per square metre of body surface (mg/m^2) IV q3w (for at least 6 cycles; 1 cycle was 21 days). After Cycle 6, continuation of docetaxel treatment was at the discretion of the participant and treating physician. Participants remained in the treatment phase of the study until investigator-assessed radiographic or clinical evidence of disease progression, unmanageable toxicity, or study termination and were followed for survival until death, loss to follow-up, withdrawal of consent, or study termination.
Participants randomized to this arm received placebo IV q3w and trastuzumab 6 mg/kg IV q3w, plus docetaxel 75 mg/m^2 IV q3w (for at least 6 cycles; 1 cycle was 21 days). After Cycle 6, continuation of docetaxel treatment was at the discretion of the participant and treating physician. Participants remained in the treatment phase of the study until investigator-assessed radiographic or clinical evidence of disease progression, unmanageable toxicity, or study termination and were followed for survival until death, loss to follow-up, withdrawal of consent, or study termination.
Overall Number of Participants Analyzed 402 406
Median (95% Confidence Interval)
Unit of Measure: Months
18.5
(15 to 23)
12.4
(10 to 13)
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Pertuzumab + Trastuzumab + Docetaxel, Placebo + Trastuzumab + Docetaxel
Comments The null hypothesis (H0) was that the survival distributions of PFS in the two treatments arms (pertuzumab vs. placebo) are the same. The alternative hypothesis (H1) was that the survival distribution of PFS in the experimental arm (pertuzumab) and control arm (placebo) are different.
Type of Statistical Test Superiority
Comments [Not Specified]
Statistical Test of Hypothesis P-Value <0.0001
Comments Tested at two-sided 5% significance level
Method Log Rank (stratified)
Comments Stratified by prior treatment status and region
Method of Estimation Estimation Parameter Cox Proportional Hazard
Estimated Value 0.62
Confidence Interval (2-Sided) 95%
0.51 to 0.75
Estimation Comments Hazard ratio is comparing Pertuzumab arm with Placebo arm.
Hide Statistical Analysis 2
Statistical Analysis Overview Comparison Group Selection Pertuzumab + Trastuzumab + Docetaxel, Placebo + Trastuzumab + Docetaxel
Comments The null hypothesis (H0) was that the survival distributions of PFS in the two treatments arms (pertuzumab vs. placebo) are the same. The alternative hypothesis (H1) was that the survival distribution of PFS in the experimental arm (pertuzumab) and control arm (placebo) are different.
Type of Statistical Test Superiority
Comments [Not Specified]
Statistical Test of Hypothesis P-Value <0.0001
Comments Tested at two-sided 5% significance level
Method Log Rank (unstratified)
Comments Unstratified
Method of Estimation Estimation Parameter Cox Proportional Hazard
Estimated Value 0.63
Confidence Interval (2-Sided) 95%
0.52 to 0.76
Estimation Comments Hazard ratio is comparing Pertuzumab arm with Placebo arm.
2.Secondary Outcome
Title Overall Survival
Hide Description Overall survival (OS) was the time from randomization to death from any cause, using Kaplan-Meier methodology. Survival data was collected every 18 weeks during the post-treatment follow-up period until death, loss to follow-up, or withdrawal of consent. Those who were alive, lost to follow up, or withdrew consent were censored at the latest date they participated in the study; those without post-baseline data were censored at 1 day. OS analyses were planned to take place at the primary completion date (First Interim), after 385 deaths (Event-Driven Final), and at the end of study (End-of-Study). A second interim OS analysis was planned due to a formal request from the European Medicines Agency. Median [range] time in weeks on study at each OS analysis (Pertuzumab vs. Placebo): First: 77.1 [0.7-165.3] vs. 73.1 [0.4-165.3]; Second: 117.1 [0.7-207.9] vs. 105.9 [0.4-207.9]; Event-Driven Final: 189.9 [0.7-304.1] vs. 140.5 [0.4-301.6]; End-of-Study: 201.8 [0.7-520.0] vs. 138.0 [0.4-514.7].
Time Frame From randomization to death from any cause, up to each respective analysis data cut-off date (see the Description field for the median time on study per treatment arm)
Hide Outcome Measure Data
Hide Analysis Population Description
ITT Population: All randomized participants
Arm/Group Title Pertuzumab + Trastuzumab + Docetaxel Placebo + Trastuzumab + Docetaxel
Hide Arm/Group Description:
Participants randomized to this arm received pertuzumab 420 milligrams (mg) intravenously (IV) once every 3 weeks (q3w) and trastuzumab 6 milligrams per kilogram (mg/kg) IV q3w, plus docetaxel 75 milligrams per square metre of body surface (mg/m^2) IV q3w (for at least 6 cycles; 1 cycle was 21 days). After Cycle 6, continuation of docetaxel treatment was at the discretion of the participant and treating physician. Participants remained in the treatment phase of the study until investigator-assessed radiographic or clinical evidence of disease progression, unmanageable toxicity, or study termination and were followed for survival until death, loss to follow-up, withdrawal of consent, or study termination.
Participants randomized to this arm received placebo IV q3w and trastuzumab 6 mg/kg IV q3w, plus docetaxel 75 mg/m^2 IV q3w (for at least 6 cycles; 1 cycle was 21 days). After Cycle 6, continuation of docetaxel treatment was at the discretion of the participant and treating physician. Participants remained in the treatment phase of the study until investigator-assessed radiographic or clinical evidence of disease progression, unmanageable toxicity, or study termination and were followed for survival until death, loss to follow-up, withdrawal of consent, or study termination.
Overall Number of Participants Analyzed 402 406
Median (95% Confidence Interval)
Unit of Measure: Months
End-of-Study OS Analysis
57.1
(50 to 72)
40.8
(36 to 48)
Event-Driven Final OS Analysis
56.5 [1] 
(49 to NA)
40.8
(36 to 48)
Second Interim OS Analysis
NA [2] 
(42 to NA)
37.6 [1] 
(34 to NA)
First Interim OS Analysis
NA [3] 
(NA to NA)
NA [2] 
(30 to NA)
[1]
The upper limit of the 95% CI could not be determined because it was larger than the maximum follow-up time at data cutoff for the analysis.
[2]
The median and upper limit of the 95% CI could not be determined because they were larger than the maximum follow-up time at data cutoff for the analysis.
[3]
The median and lower and upper limits of the 95% CI could not be determined because they were larger than the maximum follow-up time at data cutoff for the analysis.
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Pertuzumab + Trastuzumab + Docetaxel, Placebo + Trastuzumab + Docetaxel
Comments End-of-Study OS Analysis: This end-of-study OS analysis is considered exploratory only as the confirmatory OS analysis for statistical interpretation had previously occurred at the second interim OS analysis.
Type of Statistical Test Superiority
Comments Exploratory
Statistical Test of Hypothesis P-Value <0.0001
Comments Exploratory
Method Log Rank (stratified)
Comments Stratified by prior treatment status and region.
Method of Estimation Estimation Parameter Cox Proportional Hazard
Estimated Value 0.69
Confidence Interval (2-Sided) 95%
0.58 to 0.82
Estimation Comments Hazard ratio is comparing Pertuzumab arm with Placebo arm.
Hide Statistical Analysis 2
Statistical Analysis Overview Comparison Group Selection Pertuzumab + Trastuzumab + Docetaxel, Placebo + Trastuzumab + Docetaxel
Comments Event-Driven Final OS Analysis: This final OS analysis was event-driven and planned to take place after a total of 385 deaths had occurred. It is considered exploratory only as the confirmatory OS analysis for statistical interpretation had previously occurred at the second interim OS analysis.
Type of Statistical Test Superiority
Comments Exploratory
Statistical Test of Hypothesis P-Value 0.0002
Comments Exploratory
Method Log Rank (stratified)
Comments Stratified by prior treatment status and region.
Method of Estimation Estimation Parameter Cox Proportional Hazard
Estimated Value 0.68
Confidence Interval (2-Sided) 95%
0.56 to 0.84
Estimation Comments Hazard ratio is comparing Pertuzumab arm with Placebo arm.
Hide Statistical Analysis 3
Statistical Analysis Overview Comparison Group Selection Pertuzumab + Trastuzumab + Docetaxel, Placebo + Trastuzumab + Docetaxel
Comments Second Interim OS Analysis: For this second interim OS analysis, the pre-defined O'Brien-Fleming stopping boundary for the Lan-DeMets α-spending function was: HR≤0.739, p≤0.0138.
Type of Statistical Test Superiority
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.0008
Comments The threshold for statistical significance was HR≤0.739, p≤0.0138.
Method Log Rank (stratified)
Comments Stratified by prior treatment status and region.
Method of Estimation Estimation Parameter Cox Proportional Hazard
Estimated Value 0.66
Confidence Interval (2-Sided) 95%
0.52 to 0.84
Estimation Comments Hazard ratio (HR) is comparing Pertuzumab arm with Placebo arm.
Hide Statistical Analysis 4
Statistical Analysis Overview Comparison Group Selection Pertuzumab + Trastuzumab + Docetaxel, Placebo + Trastuzumab + Docetaxel
Comments First Interim OS Analysis: For this first interim OS analysis, the pre-defined O'Brien-Fleming stopping boundary for the Lan-DeMets α-spending function was: HR≤0.603, p≤0.0012.
Type of Statistical Test Superiority
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.0050
Comments The threshold for statistical significance was HR≤0.603, p≤0.0012.
Method Log Rank (stratified)
Comments Stratified by prior treatment status and region.
Method of Estimation Estimation Parameter Cox Proportional Hazard
Estimated Value 0.64
Confidence Interval (2-Sided) 95%
0.47 to 0.88
Estimation Comments Hazard ratio (HR) is comparing pertuzumab with placebo arms.
3.Secondary Outcome
Title Progression-Free Survival (PFS) Determined by the Investigator
Hide Description PFS was defined as the time from randomization to first documented radiographical progressive disease (PD), as determined by the investigator using RECIST version 1.0, or death from any cause (within 18 weeks of last tumor assessment), whichever occurred first (Kaplan-Meier method). For target lesions, PD was defined as at least a 20% increase in the sum of the longest diameter (LD) of target lesions, taking as reference the smallest sum of the LD recorded since treatment started or the appearance of ≥1 new lesion. For non-target lesions, PD was defined as the appearance of ≥1 new lesion or unequivocal progression of existing lesions. Participants without PD or who had not died within 18 weeks of their last investigator-determined, progression-free tumor assessment were censored at the date of the last investigator tumor assessment; those with no post-baseline tumor assessment and who had not died within 18 weeks of baseline were censored at 1 day.
Time Frame Tumor assessments every 9 weeks from randomization to investigator-determined PD or death from any cause, whichever occurred first (median [range] time on study in pertuzumab vs. placebo arms: 201.8 [0.7-520.0] weeks vs. 138.0 [0.4-514.7] weeks)
Hide Outcome Measure Data
Hide Analysis Population Description
Intent-to-treat population: All randomized patients.
Arm/Group Title Pertuzumab + Trastuzumab + Docetaxel Placebo + Trastuzumab + Docetaxel
Hide Arm/Group Description:
Participants randomized to this arm received pertuzumab 420 milligrams (mg) intravenously (IV) once every 3 weeks (q3w) and trastuzumab 6 milligrams per kilogram (mg/kg) IV q3w, plus docetaxel 75 milligrams per square metre of body surface (mg/m^2) IV q3w (for at least 6 cycles; 1 cycle was 21 days). After Cycle 6, continuation of docetaxel treatment was at the discretion of the participant and treating physician. Participants remained in the treatment phase of the study until investigator-assessed radiographic or clinical evidence of disease progression, unmanageable toxicity, or study termination and were followed for survival until death, loss to follow-up, withdrawal of consent, or study termination.
Participants randomized to this arm received placebo IV q3w and trastuzumab 6 mg/kg IV q3w, plus docetaxel 75 mg/m^2 IV q3w (for at least 6 cycles; 1 cycle was 21 days). After Cycle 6, continuation of docetaxel treatment was at the discretion of the participant and treating physician. Participants remained in the treatment phase of the study until investigator-assessed radiographic or clinical evidence of disease progression, unmanageable toxicity, or study termination and were followed for survival until death, loss to follow-up, withdrawal of consent, or study termination.
Overall Number of Participants Analyzed 402 406
Median (95% Confidence Interval)
Unit of Measure: Months
18.7
(17 to 22)
12.4
(10 to 14)
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Pertuzumab + Trastuzumab + Docetaxel, Placebo + Trastuzumab + Docetaxel
Comments PFS by Investigator - Stratified
Type of Statistical Test Superiority
Comments [Not Specified]
Statistical Test of Hypothesis P-Value <0.0001
Comments [Not Specified]
Method Log Rank (stratified)
Comments Stratified by prior treatment status and region.
Method of Estimation Estimation Parameter Cox Proportional Hazard
Estimated Value 0.69
Confidence Interval (2-Sided) 95%
0.59 to 0.81
Estimation Comments Hazard ratio is comparing Pertuzumab arm with Placebo arm.
4.Secondary Outcome
Title Objective Response Determined by an Independent Review Facility
Hide Description An objective response was defined as the percentage of participants with confirmed best overall response of complete response (CR) or partial response (PR) determined by an independent review facility (IRF) using RECIST v1.0 on two consecutive occasions ≥4 weeks apart. For target lesions, CR: disappearance of all target lesions; PR: ≥30% decrease in the sum of the longest diameter (LD) of target lesions (baseline sum LD as reference); PD: ≥20% increase in the sum of the LD of target lesions (smallest sum of the LD recorded as reference) or appearance of ≥1 new lesion; SD: neither sufficient shrinkage to qualify for PR nor sufficient increase for PD. For non-target lesions, CR: disappearance of all non-target lesions; Incomplete/SD: persistence of ≥1 non-target lesions; PD: unequivocal progression of existing non-target lesions. 95% confidence intervals (CI) were calculated only for clinical responses using the Pearson-Clopper method.
Time Frame Tumor assessments every 9 weeks from Baseline until IRF-determined progressive disease (PD), death, or first administration of next line of anti-cancer therapy (whichever occurred first), up to the primary completion date (up to 3 years, 3 months)
Hide Outcome Measure Data
Hide Analysis Population Description
ITT Population: All randomized participants; only participants with IRF-determined measurable disease at baseline (i.e., ≥1 target lesion) were included in the analysis.
Arm/Group Title Pertuzumab + Trastuzumab + Docetaxel Placebo + Trastuzumab + Docetaxel
Hide Arm/Group Description:
Participants randomized to this arm received pertuzumab 420 milligrams (mg) intravenously (IV) once every 3 weeks (q3w) and trastuzumab 6 milligrams per kilogram (mg/kg) IV q3w, plus docetaxel 75 milligrams per square metre of body surface (mg/m^2) IV q3w (for at least 6 cycles; 1 cycle was 21 days). After Cycle 6, continuation of docetaxel treatment was at the discretion of the participant and treating physician. Participants remained in the treatment phase of the study until investigator-assessed radiographic or clinical evidence of disease progression, unmanageable toxicity, or study termination and were followed for survival until death, loss to follow-up, withdrawal of consent, or study termination.
Participants randomized to this arm received placebo IV q3w and trastuzumab 6 mg/kg IV q3w, plus docetaxel 75 mg/m^2 IV q3w (for at least 6 cycles; 1 cycle was 21 days). After Cycle 6, continuation of docetaxel treatment was at the discretion of the participant and treating physician. Participants remained in the treatment phase of the study until investigator-assessed radiographic or clinical evidence of disease progression, unmanageable toxicity, or study termination and were followed for survival until death, loss to follow-up, withdrawal of consent, or study termination.
Overall Number of Participants Analyzed 343 336
Measure Type: Number
Number (95% Confidence Interval)
Unit of Measure: Percentage of patients
Objective Response (CR + PR)
80.2
(75.6 to 84.3)
69.3
(64.1 to 74.2)
Complete Response (CR)
5.5
(3.4 to 8.5)
4.2
(2.3 to 6.9)
Partial Response (PR)
74.6
(69.7 to 79.2)
65.2
(59.8 to 70.3)
Stable Disease (SD)
14.6
(11.0 to 18.8)
20.8
(16.6 to 25.6)
Progressive Disease (PD)
3.8
(2.0 to 6.4)
8.3
(5.6 to 11.8)
Unable to Assess (UA)
0.6
(0.1 to 2.1)
0.6
(0.1 to 2.1)
Missing (No Assessment)
0.9 [1] 
(NA to NA)
0.9 [1] 
(NA to NA)
[1]
95% confidence intervals were calculated only for clinical responses.
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Pertuzumab + Trastuzumab + Docetaxel, Placebo + Trastuzumab + Docetaxel
Comments Difference in Objective Response (CR + PR) Between Arms
Type of Statistical Test Superiority
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.0011
Comments [Not Specified]
Method Mantel Haenszel
Comments Stratified by prior treatment status and region.
Method of Estimation Estimation Parameter Difference in Objective Response Rates
Estimated Value 10.83
Confidence Interval (2-Sided) 95%
4.2 to 17.5
Estimation Comments Difference in the objective response rates between arms is calculated as Pertuzumab arm minus Placebo arm. The 95% CI was calculated using the Hauck-Anderson method.
Hide Statistical Analysis 2
Statistical Analysis Overview Comparison Group Selection Pertuzumab + Trastuzumab + Docetaxel, Placebo + Trastuzumab + Docetaxel
Comments Odds Ratio for Objective Response (CR + PR)
Type of Statistical Test Superiority
Comments [Not Specified]
Method of Estimation Estimation Parameter Odds Ratio (OR)
Estimated Value 1.79
Confidence Interval (2-Sided) 95%
1.26 to 2.54
Estimation Comments [Not Specified]
5.Secondary Outcome
Title Duration of Objective Response Determined by an Independent Review Facility
Hide Description Duration of objective response (estimated using the Kaplan-Meier method) was defined as the time from the initial confirmed complete response (CR) or partial response (PR), the date of tumor assessment at which the CR/PR was first detected by the independent review facility (IRF) using RECIST version 1.0, until the date of IRF-determined progressive disease (PD), death from any cause within 18 weeks of the last tumor assessment, or first administration of next line of anti-cancer therapy (whichever occurred first). If the visit when the initial CR or PR was observed spanned multiple dates, the latest date was used. Only participants in the ITT analysis population with an IRF-determined objective response (CR or PR), observed prior to IRF-assessed PD, death or next line of anti-cancer therapy, were included in the analysis. Participants who did not progress or die after they had a confirmed response were censored at the date of their last IRF-evaluable tumor measurement.
Time Frame From initial IRF-confirmed objective response until IRF-determined progressive disease (PD), death, or first administration of next line of anti-cancer therapy (whichever occurred first), up to the primary completion date (up to 3 years, 3 months)
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ITT Population: All randomized participants; only participants with IRF-determined measurable disease at baseline (i.e., ≥1 target lesion) that had an objective response were included in the analysis.
Arm/Group Title Pertuzumab + Trastuzumab + Docetaxel Placebo + Trastuzumab + Docetaxel
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Participants randomized to this arm received pertuzumab 420 milligrams (mg) intravenously (IV) once every 3 weeks (q3w) and trastuzumab 6 milligrams per kilogram (mg/kg) IV q3w, plus docetaxel 75 milligrams per square metre of body surface (mg/m^2) IV q3w (for at least 6 cycles; 1 cycle was 21 days). After Cycle 6, continuation of docetaxel treatment was at the discretion of the participant and treating physician. Participants remained in the treatment phase of the study until investigator-assessed radiographic or clinical evidence of disease progression, unmanageable toxicity, or study termination and were followed for survival until death, loss to follow-up, withdrawal of consent, or study termination.
Participants randomized to this arm received placebo IV q3w and trastuzumab 6 mg/kg IV q3w, plus docetaxel 75 mg/m^2 IV q3w (for at least 6 cycles; 1 cycle was 21 days). After Cycle 6, continuation of docetaxel treatment was at the discretion of the participant and treating physician. Participants remained in the treatment phase of the study until investigator-assessed radiographic or clinical evidence of disease progression, unmanageable toxicity, or study termination and were followed for survival until death, loss to follow-up, withdrawal of consent, or study termination.
Overall Number of Participants Analyzed 275 233
Median (95% Confidence Interval)
Unit of Measure: Weeks
87.6
(71 to 106)
54.1
(46 to 64)
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Pertuzumab + Trastuzumab + Docetaxel, Placebo + Trastuzumab + Docetaxel
Comments [Not Specified]
Type of Statistical Test Superiority
Comments [Not Specified]
Method of Estimation Estimation Parameter Cox Proportional Hazard
Estimated Value 0.66
Confidence Interval (2-Sided) 95%
0.51 to 0.85
Estimation Comments [Not Specified]
6.Secondary Outcome
Title Time to Symptom Progression
Hide Description Time to symptom progression was defined as the time from randomization to the first symptom progression as measured by the Functional Assessment of Cancer Therapy-for patients with Breast Cancer (FACT-B) questionnaire with the Trial Outcomes Index-Physical/Functional/Breast (TOI-PFB) subscale. The FACT-B TOI-PFB subscale contains 24 items from 3 subsections of the FACT-B questionnaire: Physical well-being, functional well-being, and additional concerns for breast cancer patients (breast cancer subscale [BCS]). All items in the questionnaire were rated by the patient on a 5-point scale ranging from 0 ("not at all") to 4 ("very much"). The total score ranged from 0 to 96. A higher score indicates better perceived quality of life. A positive change score from baseline indicates improvement. Symptom progression was defined as a decrease from baseline of 5 points or more.
Time Frame Every 9 weeks from Baseline until investigator-determined progressive disease, up to the primary completion date (up to 3 years, 3 months)
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ITT population: All randomized participants; only female participants were included in the analysis.
Arm/Group Title Pertuzumab + Trastuzumab + Docetaxel Placebo + Trastuzumab + Docetaxel
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Participants randomized to this arm received pertuzumab 420 milligrams (mg) intravenously (IV) once every 3 weeks (q3w) and trastuzumab 6 milligrams per kilogram (mg/kg) IV q3w, plus docetaxel 75 milligrams per square metre of body surface (mg/m^2) IV q3w (for at least 6 cycles; 1 cycle was 21 days). After Cycle 6, continuation of docetaxel treatment was at the discretion of the participant and treating physician. Participants remained in the treatment phase of the study until investigator-assessed radiographic or clinical evidence of disease progression, unmanageable toxicity, or study termination and were followed for survival until death, loss to follow-up, withdrawal of consent, or study termination.
Participants randomized to this arm received placebo IV q3w and trastuzumab 6 mg/kg IV q3w, plus docetaxel 75 mg/m^2 IV q3w (for at least 6 cycles; 1 cycle was 21 days). After Cycle 6, continuation of docetaxel treatment was at the discretion of the participant and treating physician. Participants remained in the treatment phase of the study until investigator-assessed radiographic or clinical evidence of disease progression, unmanageable toxicity, or study termination and were followed for survival until death, loss to follow-up, withdrawal of consent, or study termination.
Overall Number of Participants Analyzed 402 404
Median (95% Confidence Interval)
Unit of Measure: Weeks
18.4
(18 to 27)
18.3
(18 to 27)
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Pertuzumab + Trastuzumab + Docetaxel, Placebo + Trastuzumab + Docetaxel
Comments [Not Specified]
Type of Statistical Test Superiority
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.7161
Comments Stratified by prior treatment status and region.
Method Log Rank (stratified)
Comments [Not Specified]
Method of Estimation Estimation Parameter Cox Proportional Hazard
Estimated Value 0.97
Confidence Interval (2-Sided) 95%
0.81 to 1.16
Estimation Comments Hazard ratio is comparing Pertuzumab arm with Placebo arm.
7.Secondary Outcome
Title Overall Number of Participants Who Experienced at Least One Adverse Event, Including Serious and Non-Serious Adverse Events, by Most Severe Intensity (According to NCI-CTCAE v3.0) During the Treatment Period
Hide Description Adverse event (AE) severity was assessed according to the National Cancer Institute Common Terminology Criteria for Adverse Events, Version 3.0 (NCI-CTCAE v3.0); if the AE was not specifically listed, the following grades of severity were used: Grade 1 = mild; Grade 2 = moderate; Grade 3 = severe; Grade 4 = life-threatening or disabling; and Grade 5 = death. Severe and serious are not synonymous. Severity refers to the intensity of an AE, whereas a serious AE must meet criteria set out in the protocol; both were independently assessed for each AE. Only the most severe intensity was counted for multiple occurrences of the same AE in one participant. AEs reported prior to first crossover treatment were included in the Placebo arm, and in the Crossover arm after that date, for participants who crossed over from placebo to pertuzumab. Median [range] time on study treatment per arm: Placebo: 49.3 [0.3-514.7] weeks; Pertuzumab: 75.7 [0.6-519.6] weeks; Crossover: 129.9 [0.3-322.3] weeks.
Time Frame Placebo arm: Baseline to last dose of study treatment +42 days (or crossover date); Pertuzumab arm: Baseline to last dose of study treatment +42 days; Crossover arm: Crossover date to last dose of study treatment +42 days (see Description - time per arm)
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Safety Population: All participants who received at least one dose of any study medication.
Arm/Group Title Placebo + Trastuzumab + Docetaxel Pertuzumab + Trastuzumab + Docetaxel Crossover From Placebo to Pertuzumab
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This is the placebo safety population, which includes participants who received study treatment with placebo at every cycle. Participants received placebo IV q3w and trastuzumab 6 mg/kg IV q3w, plus docetaxel 75 mg/m^2 IV q3w (for at least 6 cycles; 1 cycle was 21 days). After Cycle 6, continuation of docetaxel treatment was at the discretion of the participant and treating physician. Participants remained in the treatment phase of the study until investigator-assessed radiographic or clinical evidence of disease progression, unmanageable toxicity, or study termination and were followed for survival until death, loss to follow-up, withdrawal of consent, or study termination.
This is the pertuzumab safety population, which includes participants who received at least one dose of study treatment with pertuzumab. Participants received pertuzumab 420 milligrams (mg) intravenously (IV) once every 3 weeks (q3w) and trastuzumab 6 milligrams per kilogram (mg/kg) IV q3w, plus docetaxel 75 milligrams per square metre of body surface (mg/m^2) IV q3w (for at least 6 cycles; 1 cycle was 21 days). After Cycle 6, continuation of docetaxel treatment was at the discretion of the participant and treating physician. Participants remained in the treatment phase of the study until investigator-assessed radiographic or clinical evidence of disease progression, unmanageable toxicity, or study termination and were followed for survival until death, loss to follow-up, withdrawal of consent, or study termination.
Fifty of 406 participants (12.3%) randomized to the placebo treatment arm whose disease had not progressed crossed over to an open-label pertuzumab treatment group between July 2012 and November 2018. Participants received pertuzumab administered as an IV loading dose of 840 mg at cycle 1 then 420 mg IV every q3w. Trastuzumab and docetaxel doses continued in accordance with the pre-crossover placebo treatment regimens and according to dosing specifications indicated in the study protocol. Participants remained in the treatment phase of the study until investigator-assessed radiographic or clinical evidence of disease progression, unmanageable toxicity, or study termination and were followed for survival until death, loss to follow-up, withdrawal of consent, or study termination.
Overall Number of Participants Analyzed 396 408 50
Measure Type: Count of Participants
Unit of Measure: Participants
At Least One Serious AE - All Grades
116
  29.3%
160
  39.2%
10
  20.0%
At Least One Non-Serious AE - All Grades
386
  97.5%
400
  98.0%
45
  90.0%
At Least One AE - All Grades
391
  98.7%
408
 100.0%
47
  94.0%
At Least One AE - Grade 1
368
  92.9%
386
  94.6%
44
  88.0%
At Least One AE - Grade 2
350
  88.4%
383
  93.9%
34
  68.0%
At Least One AE - Grade 3
229
  57.8%
264
  64.7%
11
  22.0%
At Least One AE - Grade 4
158
  39.9%
167
  40.9%
1
   2.0%
At Least One AE - Grade 5
12
   3.0%
8
   2.0%
1
   2.0%
8.Secondary Outcome
Title Overall Number of Adverse Events by Severity (NCI-CTCAE v3.0 All Grades and Grades 3 to 5) Per 100 Patient-Years of Exposure During the Treatment Period
Hide Description Adverse event (AE) severity, including serious and non-serious AEs, was assessed according to the NCI-CTCAE version 3.0; if the AE was not specifically listed, the following grades of severity were used: Grade 1 is mild; Grade 2 is moderate; Grade 3 is severe; Grade 4 is life-threatening or disabling; and Grade 5 is death. Multiple occurrences of the same AE in 1 participant were counted multiple times. Only AEs that started during the overall study treatment period were included. The cutoff date for inclusion of events and for calculation of patient-years was the date of the most recent follow-up of the participant, defined as the last available date during the treatment period, excluding pre-treatment and safety follow-up data. Confidence intervals were calculated assuming the number of events followed a Poisson distribution. Data reported prior to the date of first crossover treatment were included under the Placebo arm for participants who crossed over from placebo to pertuzumab.
Time Frame From Baseline to 42 days after the last dose of study treatment (total patient-years of exposure on study treatment in Placebo vs. Pertuzumab arms: 526.81 vs. 989.88 patient-years)
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Safety Population: All participants who received at least one dose of any study medication.
Arm/Group Title Placebo + Trastuzumab + Docetaxel Pertuzumab + Trastuzumab + Docetaxel
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This is the placebo safety population, which includes participants who received study treatment with placebo at every cycle. Participants received placebo IV q3w and trastuzumab 6 mg/kg IV q3This is the placebo safety population, which includes participants who received study treatment with placebo at every cycle. Participants received placebo IV q3w and trastuzumab 6 mg/kg IV q3w, plus docetaxel 75 mg/m^2 IV q3w (for at least 6 cycles; 1 cycle was 21 days). After Cycle 6, continuation of docetaxel treatment was at the discretion of the participant and treating physician. Participants remained in the treatment phase of the study until investigator-assessed radiographic or clinical evidence of disease progression, unmanageable toxicity, or study termination and were followed for survival until death, loss to follow-up, withdrawal of consent, or study termination.
This is the pertuzumab safety population, which includes participants who received at least one dose of study treatment with pertuzumab. Participants received pertuzumab 420 milligrams (mg) intravenously (IV) once every 3 weeks (q3w) and trastuzumab 6 milligrams per kilogram (mg/kg) IV q3w, plus docetaxel 75 milligrams per square metre of body surface (mg/m^2) IV q3w (for at least 6 cycles; 1 cycle was 21 days). After Cycle 6, continuation of docetaxel treatment was at the discretion of the participant and treating physician. Participants remained in the treatment phase of the study until investigator-assessed radiographic or clinical evidence of disease progression, unmanageable toxicity, or study termination and were followed for survival until death, loss to follow-up, withdrawal of consent, or study termination.
Overall Number of Participants Analyzed 396 408
Overall Number of Units Analyzed
Type of Units Analyzed: Adverse Events
9062 11908
Measure Type: Number
Number (90% Confidence Interval)
Unit of Measure: Events per 100 patient-years
All Grades Number Analyzed 9062 Adverse Events 11908 Adverse Events
1720.2
(1690.6 to 1750.2)
1203.0
(1184.9 to 1221.3)
Grades 3 to 5 Number Analyzed 1187 Adverse Events 1304 Adverse Events
225.3
(214.7 to 236.4)
131.7
(125.8 to 137.9)
9.Secondary Outcome
Title Cardiac-Related AEs to Monitor: Number of Participants Who Experienced at Least One Symptomatic Left Ventricular Dysfunction (LVD), Any LVD, or Serious AE Suggestive of Congestive Heart Failure by Severity During the Treatment Period
Hide Description Cardiac-related adverse events (AEs) to monitor during the study included investigator-assessed symptomatic left ventricular dysfunction (LVD), any LVD, or a serious adverse event (SAE) suggestive of congestive heart failure (CHF). All cardiac-related AEs were graded for severity according to NCI-CTCAE v3.0. Asymptomatic (Grades 1-2) and symptomatic (Grades 3-5) left ventricular systolic dysfunction (LVSD) both coded to the MedDRA preferred term LVD. Investigator-assessed events of symptomatic LVD were also graded for severity of symptoms according to Classes I (least severe) to IV (most severe) of the New York Heart Association (NYHA) Classification. SAEs suggestive of CHF were identified as serious events from the Standardized MedDRA Query (SMQ) (Wide) 'Cardiac Failure'. Median [range] time on study treatment per arm: Placebo: 49.3 [0.3-514.7] weeks; Pertuzumab: 75.7 [0.6-519.6] weeks; Crossover: 129.9 [0.3-322.3] weeks.
Time Frame Placebo arm: Baseline to last dose of study treatment +42 days (or crossover date); Pertuzumab arm: Baseline to last dose of study treatment +42 days; Crossover arm: Crossover date to last dose of study treatment +42 days (see Description - time per arm)
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Hide Analysis Population Description
Safety Population: All participants who received at least one dose of any study medication.
Arm/Group Title Placebo + Trastuzumab + Docetaxel Pertuzumab + Trastuzumab + Docetaxel Crossover From Placebo to Pertuzumab
Hide Arm/Group Description:
This is the placebo safety population, which includes participants who received study treatment with placebo at every cycle. Participants received placebo IV q3w and trastuzumab 6 mg/kg IV q3This is the placebo safety population, which includes participants who received study treatment with placebo at every cycle. Participants received placebo IV q3w and trastuzumab 6 mg/kg IV q3w, plus docetaxel 75 mg/m^2 IV q3w (for at least 6 cycles; 1 cycle was 21 days). After Cycle 6, continuation of docetaxel treatment was at the discretion of the participant and treating physician. Participants remained in the treatment phase of the study until investigator-assessed radiographic or clinical evidence of disease progression, unmanageable toxicity, or study termination and were followed for survival until death, loss to follow-up, withdrawal of consent, or study termination.
This is the pertuzumab safety population, which includes participants who received at least one dose of study treatment with pertuzumab. Participants received pertuzumab 420 milligrams (mg) intravenously (IV) once every 3 weeks (q3w) and trastuzumab 6 milligrams per kilogram (mg/kg) IV q3w, plus docetaxel 75 milligrams per square metre of body surface (mg/m^2) IV q3w (for at least 6 cycles; 1 cycle was 21 days). After Cycle 6, continuation of docetaxel treatment was at the discretion of the participant and treating physician. Participants remained in the treatment phase of the study until investigator-assessed radiographic or clinical evidence of disease progression, unmanageable toxicity, or study termination and were followed for survival until death, loss to follow-up, withdrawal of consent, or study termination.
Fifty of 406 participants (12.3%) randomized to the placebo treatment arm whose disease had not progressed crossed over to an open-label pertuzumab treatment group between July 2012 and November 2018. Participants received pertuzumab administered as an IV loading dose of 840 mg at cycle 1 then 420 mg IV every q3w. Trastuzumab and docetaxel doses continued in accordance with the pre-crossover placebo treatment regimens and according to dosing specifications indicated in the study protocol. Participants remained in the treatment phase of the study until investigator-assessed radiographic or clinical evidence of disease progression, unmanageable toxicity, or study termination and were followed for survival until death, loss to follow-up, withdrawal of consent, or study termination.
Overall Number of Participants Analyzed 396 408 50
Measure Type: Count of Participants
Unit of Measure: Participants
Symptomatic LVD(Investigator)-All NYHA Classes
7
   1.8%
6
   1.5%
1
   2.0%
Symptomatic LVD(Investigator)-NYHA Classes III/IV
4
   1.0%
4
   1.0%
1
   2.0%
Any LVD - All NCI-CTCAE Grades
34
   8.6%
32
   7.8%
3
   6.0%
Any LVD - NCI-CTCAE Grade ≥3
13
   3.3%
6
   1.5%
2
   4.0%
SAE Suggestive of CHF - All NCI-CTCAE Grades
8
   2.0%
8
   2.0%
1
   2.0%
SAE Suggestive of CHF - NCI-CTCAE Grade ≥3
7
   1.8%
7
   1.7%
1
   2.0%
10.Secondary Outcome
Title Number of Participants Who Experienced at Least One Adverse Event to Monitor (Excluding Cardiac-Related AEs) by Severity During the Treatment Period
Hide Description The clinical diagnoses listed in this table, excluding cardiac safety (summarized separately), were also selected as adverse events (AEs) to monitor based on clinical and nonclinical data for pertuzumab and the safety profile established for trastuzumab, monoclonal antibodies in general, and potential effects associated with HER receptor inhibition. Search strategies were defined by single or aggregate MedDRA Preferred Terms (PT) through Standardized MedDRA Queries (SMQ), where possible, or based on Roche AE Group Terms (AEGT). Diarrhoea AEs: High-Level Term (HLT) 'Diarrhoea (excl. infective)' and PT 'Diarrhoea infectious'. Leukopenic and Febrile Neutropenic Infections: AEs from 'Infections & Infestations' with start ≤14 days after start date of Grade ≥3 AEs in SMQ(narrow) 'Leukopenia' or PT 'Febrile neutropenia', respectively. Median [range] time on study treatment per arm: Placebo: 49.3 [0.3-514.7] weeks; Pertuzumab: 75.7 [0.6-519.6] weeks; Crossover: 129.9 [0.3-322.3] weeks.
Time Frame Placebo arm: Baseline to last dose of study treatment +42 days (or crossover date); Pertuzumab arm: Baseline to last dose of study treatment +42 days; Crossover arm: Crossover date to last dose of study treatment +42 days (see Description - time per arm)
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Hide Analysis Population Description
Safety Population: All participants who received at least one dose of any study medication.
Arm/Group Title Placebo + Trastuzumab + Docetaxel Pertuzumab + Trastuzumab + Docetaxel Crossover From Placebo to Pertuzumab
Hide Arm/Group Description:
This is the placebo safety population, which includes participants who received study treatment with placebo at every cycle. Participants received placebo IV q3w and trastuzumab 6 mg/kg IV q3This is the placebo safety population, which includes participants who received study treatment with placebo at every cycle. Participants received placebo IV q3w and trastuzumab 6 mg/kg IV q3w, plus docetaxel 75 mg/m^2 IV q3w (for at least 6 cycles; 1 cycle was 21 days). After Cycle 6, continuation of docetaxel treatment was at the discretion of the participant and treating physician. Participants remained in the treatment phase of the study until investigator-assessed radiographic or clinical evidence of disease progression, unmanageable toxicity, or study termination and were followed for survival until death, loss to follow-up, withdrawal of consent, or study termination.
This is the pertuzumab safety population, which includes participants who received at least one dose of study treatment with pertuzumab. Participants received pertuzumab 420 milligrams (mg) intravenously (IV) once every 3 weeks (q3w) and trastuzumab 6 milligrams per kilogram (mg/kg) IV q3w, plus docetaxel 75 milligrams per square metre of body surface (mg/m^2) IV q3w (for at least 6 cycles; 1 cycle was 21 days). After Cycle 6, continuation of docetaxel treatment was at the discretion of the participant and treating physician. Participants remained in the treatment phase of the study until investigator-assessed radiographic or clinical evidence of disease progression, unmanageable toxicity, or study termination and were followed for survival until death, loss to follow-up, withdrawal of consent, or study termination.
Fifty of 406 participants (12.3%) randomized to the placebo treatment arm whose disease had not progressed crossed over to an open-label pertuzumab treatment group between July 2012 and November 2018. Participants received pertuzumab administered as an IV loading dose of 840 mg at cycle 1 then 420 mg IV every q3w. Trastuzumab and docetaxel doses continued in accordance with the pre-crossover placebo treatment regimens and according to dosing specifications indicated in the study protocol. Participants remained in the treatment phase of the study until investigator-assessed radiographic or clinical evidence of disease progression, unmanageable toxicity, or study termination and were followed for survival until death, loss to follow-up, withdrawal of consent, or study termination.
Overall Number of Participants Analyzed 396 408 50
Measure Type: Count of Participants
Unit of Measure: Participants
Diarrhoea (HLT+PT) - All Grades
191
  48.2%
280
  68.6%
25
  50.0%
Diarrhoea (HLT+PT) - Grade ≥3
20
   5.1%
40
   9.8%
1
   2.0%
Rash (AEGT) - All Grades
155
  39.1%
213
  52.2%
18
  36.0%
Rash (AEGT) - Grade ≥3
6
   1.5%
15
   3.7%
0
   0.0%
Leukopenia (SMQ-narrow) - All Grades
231
  58.3%
257
  63.0%
1
   2.0%
Leukopenia (SMQ-narrow) - Grade ≥3
211
  53.3%
238
  58.3%
0
   0.0%
Leukopenic Infection (PTs) - All Grades
38
   9.6%
53
  13.0%
0
   0.0%
Leukopenic Infection (PTs) - Grade ≥3
9
   2.3%
18
   4.4%
0
   0.0%
Febrile Neutropenic Infection (PTs) - All Grades
3
   0.8%
14
   3.4%
0
   0.0%
Febrile Neutropenic Infection (PTs) - Grade ≥3
1
   0.3%
6
   1.5%
0
   0.0%
Anaphylaxis and Hypersensitivity (AEGT)-All Grades
37
   9.3%
48
  11.8%
1
   2.0%
Anaphylaxis and Hypersensitivity (AEGT)-Grade ≥3
10
   2.5%
9
   2.2%
0
   0.0%
Interstitial Lung Disease (SMQ-narrow) -All Grades
6
   1.5%
10
   2.5%
1
   2.0%
Interstitial Lung Disease (SMQ-narrow) -Grade ≥3
2
   0.5%
3
   0.7%
0
   0.0%
QT Prolongation (SMQ-wide) - All Grades
5
   1.3%
16
   3.9%
0
   0.0%
QT Prolongation (SMQ-wide) - Grade ≥3
1
   0.3%
7
   1.7%
0
   0.0%
Mucositis (AEGT) - All Grades
154
  38.9%
208
  51.0%
12
  24.0%
Mucositis (AEGT) - Grade ≥3
8
   2.0%
14
   3.4%
0
   0.0%
Drug-Related Hepatic Disorder(SMQ-wide)-All Grades
43
  10.9%
47
  11.5%
0
   0.0%
Drug-Related Hepatic Disorder (SMQ-wide)-Grade ≥3
5
   1.3%
8
   2.0%
0
   0.0%
11.Secondary Outcome
Title Overall Number of Participants Who Experienced at Least One Adverse Event Leading to Discontinuation of Any or All Study Medication
Hide Description Participants could continue study treatment with pertuzumab/placebo plus trastuzumab when docetaxel was discontinued due to an adverse event (AE). Discontinuation of pertuzumab/placebo or trastuzumab due to an AE led to discontinuation of all study medication. The number of participants who discontinued any study medication due to an AE includes those who discontinued all study medication and those who discontinued docetaxel only and then continued on targeted therapy (note: some of these participants may have subsequently discontinued all treatment due to a separate AE). Multiple occurrences of the same adverse event in 1 participant was counted only once. AEs reported prior to first crossover treatment were included in the Placebo arm, and after that date in the Crossover arm, for those who crossed over from placebo to pertuzumab. Median [range] time on study treatment per arm: Placebo: 49.3 [0.3-514.7] weeks; Pertuzumab: 75.7 [0.6-519.6] weeks; Crossover: 129.9 [0.3-322.3] weeks.
Time Frame Placebo arm: Baseline to last dose of study treatment +42 days (or crossover date); Pertuzumab arm: Baseline to last dose of study treatment +42 days; Crossover arm: Crossover date to last dose of study treatment +42 days (see Description - time per arm)
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Hide Analysis Population Description
Safety Population: All participants who received at least one dose of any study medication.
Arm/Group Title Placebo + Trastuzumab + Docetaxel Pertuzumab + Trastuzumab + Docetaxel Crossover From Placebo to Pertuzumab
Hide Arm/Group Description:
This is the placebo safety population, which includes participants who received study treatment with placebo at every cycle. Participants received placebo IV q3w and trastuzumab 6 mg/kg IV q3This is the placebo safety population, which includes participants who received study treatment with placebo at every cycle. Participants received placebo IV q3w and trastuzumab 6 mg/kg IV q3w, plus docetaxel 75 mg/m^2 IV q3w (for at least 6 cycles; 1 cycle was 21 days). After Cycle 6, continuation of docetaxel treatment was at the discretion of the participant and treating physician. Participants remained in the treatment phase of the study until investigator-assessed radiographic or clinical evidence of disease progression, unmanageable toxicity, or study termination and were followed for survival until death, loss to follow-up, withdrawal of consent, or study termination.
This is the pertuzumab safety population, which includes participants who received at least one dose of study treatment with pertuzumab. Participants received pertuzumab 420 milligrams (mg) intravenously (IV) once every 3 weeks (q3w) and trastuzumab 6 milligrams per kilogram (mg/kg) IV q3w, plus docetaxel 75 milligrams per square metre of body surface (mg/m^2) IV q3w (for at least 6 cycles; 1 cycle was 21 days). After Cycle 6, continuation of docetaxel treatment was at the discretion of the participant and treating physician. Participants remained in the treatment phase of the study until investigator-assessed radiographic or clinical evidence of disease progression, unmanageable toxicity, or study termination and were followed for survival until death, loss to follow-up, withdrawal of consent, or study termination.
Fifty of 406 participants (12.3%) randomized to the placebo treatment arm whose disease had not progressed crossed over to an open-label pertuzumab treatment group between July 2012 and November 2018. Participants received pertuzumab administered as an IV loading dose of 840 mg at cycle 1 then 420 mg IV every q3w. Trastuzumab and docetaxel doses continued in accordance with the pre-crossover placebo treatment regimens and according to dosing specifications indicated in the study protocol. Participants remained in the treatment phase of the study until investigator-assessed radiographic or clinical evidence of disease progression, unmanageable toxicity, or study termination and were followed for survival until death, loss to follow-up, withdrawal of consent, or study termination.
Overall Number of Participants Analyzed 396 408 50
Measure Type: Count of Participants
Unit of Measure: Participants
AE Leading to Discontinuation-Any Study Medication
114
  28.8%
131
  32.1%
5
  10.0%
AE Leading to Discontinuation-All Study Medication
24
   6.1%
39
   9.6%
4
   8.0%
12.Secondary Outcome
Title Overall Number of Participants Who Experienced at Least One Adverse Event That Resulted in Interruption or Modification of Any Study Medication
Hide Description Pertuzumab, trastuzumab, and docetaxel administration could have been delayed to assess or treat adverse events (AEs). Docetaxel dose reduction was allowed for myelosuppression, hepatic dysfunction, and other toxicities. No dose reduction was allowed for pertuzumab or trastuzumab. Multiple occurrences of the same adverse event in one participant was counted only once. AEs reported prior to first crossover treatment were included in the Placebo arm, and after that date in the Crossover arm, for participants who crossed over from placebo to pertuzumab. Median [range] time on study treatment per arm: Placebo: 49.3 [0.3-514.7] weeks; Pertuzumab: 75.7 [0.6-519.6] weeks; Crossover: 129.9 [0.3-322.3] weeks
Time Frame Placebo arm: Baseline to last dose of study treatment +42 days (or crossover date); Pertuzumab arm: Baseline to last dose of study treatment +42 days; Crossover arm: Crossover date to last dose of study treatment +42 days (see Description - time per arm)
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Hide Analysis Population Description
Safety Population: All participants who received at least one dose of any study medication.
Arm/Group Title Placebo + Trastuzumab + Docetaxel Pertuzumab + Trastuzumab + Docetaxel Crossover From Placebo to Pertuzumab
Hide Arm/Group Description:
This is the placebo safety population, which includes participants who received study treatment with placebo at every cycle. Participants received placebo IV q3w and trastuzumab 6 mg/kg IV q3This is the placebo safety population, which includes participants who received study treatment with placebo at every cycle. Participants received placebo IV q3w and trastuzumab 6 mg/kg IV q3w, plus docetaxel 75 mg/m^2 IV q3w (for at least 6 cycles; 1 cycle was 21 days). After Cycle 6, continuation of docetaxel treatment was at the discretion of the participant and treating physician. Participants remained in the treatment phase of the study until investigator-assessed radiographic or clinical evidence of disease progression, unmanageable toxicity, or study termination and were followed for survival until death, loss to follow-up, withdrawal of consent, or study termination.
This is the pertuzumab safety population, which includes participants who received at least one dose of study treatment with pertuzumab. Participants received pertuzumab 420 milligrams (mg) intravenously (IV) once every 3 weeks (q3w) and trastuzumab 6 milligrams per kilogram (mg/kg) IV q3w, plus docetaxel 75 milligrams per square metre of body surface (mg/m^2) IV q3w (for at least 6 cycles; 1 cycle was 21 days). After Cycle 6, continuation of docetaxel treatment was at the discretion of the participant and treating physician. Participants remained in the treatment phase of the study until investigator-assessed radiographic or clinical evidence of disease progression, unmanageable toxicity, or study termination and were followed for survival until death, loss to follow-up, withdrawal of consent, or study termination.
Fifty of 406 participants (12.3%) randomized to the placebo treatment arm whose disease had not progressed crossed over to an open-label pertuzumab treatment group between July 2012 and November 2018. Participants received pertuzumab administered as an IV loading dose of 840 mg at cycle 1 then 420 mg IV every q3w. Trastuzumab and docetaxel doses continued in accordance with the pre-crossover placebo treatment regimens and according to dosing specifications indicated in the study protocol. Participants remained in the treatment phase of the study until investigator-assessed radiographic or clinical evidence of disease progression, unmanageable toxicity, or study termination and were followed for survival until death, loss to follow-up, withdrawal of consent, or study termination.
Overall Number of Participants Analyzed 396 408 50
Measure Type: Count of Participants
Unit of Measure: Participants
217
  54.8%
265
  65.0%
16
  32.0%
13.Secondary Outcome
Title Number of Participants Who Experienced at Least One Adverse Event During the Post-Treatment Follow-Up Period
Hide Description The post-treatment period was defined as the period following the treatment discontinuation visit. Only the following new adverse events (AEs) should have been reported during the post-treatment follow-up period: 1. Cardiac events (regardless of causality or seriousness) that started up to 1 year after the last dose, except for symptomatic left ventricular systolic dysfunction (regardless of causality) that started up to 3 years after the last dose; and 2. Treatment-related serious AEs, regardless of start date. AEs are listed by Medical Dictionary for Regulatory Activities, Version 21.1 (MedDRA v21.1) System Organ Class (SOC) and Preferred Term (PT); PTs fall under the SOC that is listed immediately above it in the table. Multiple occurrences of the same AE in one participant was counted only once. AEs reported prior to first crossover treatment were included in the Placebo arm, and after that date in the Crossover arm, for participants who crossed over from placebo to pertuzumab.
Time Frame From Day 43 after discontinuation of all study medication to end of post-treatment follow-up period (up to 3 years)
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Hide Analysis Population Description
Safety Population: All participants who received at least one dose of any study medication.
Arm/Group Title Placebo + Trastuzumab + Docetaxel Pertuzumab + Trastuzumab + Docetaxel Crossover From Placebo to Pertuzumab
Hide Arm/Group Description:
This is the placebo safety population, which includes participants who received study treatment with placebo at every cycle. Participants received placebo IV q3w and trastuzumab 6 mg/kg IV q3This is the placebo safety population, which includes participants who received study treatment with placebo at every cycle. Participants received placebo IV q3w and trastuzumab 6 mg/kg IV q3w, plus docetaxel 75 mg/m^2 IV q3w (for at least 6 cycles; 1 cycle was 21 days). After Cycle 6, continuation of docetaxel treatment was at the discretion of the participant and treating physician. Participants remained in the treatment phase of the study until investigator-assessed radiographic or clinical evidence of disease progression, unmanageable toxicity, or study termination and were followed for survival until death, loss to follow-up, withdrawal of consent, or study termination.
This is the pertuzumab safety population, which includes participants who received at least one dose of study treatment with pertuzumab. Participants received pertuzumab 420 milligrams (mg) intravenously (IV) once every 3 weeks (q3w) and trastuzumab 6 milligrams per kilogram (mg/kg) IV q3w, plus docetaxel 75 milligrams per square metre of body surface (mg/m^2) IV q3w (for at least 6 cycles; 1 cycle was 21 days). After Cycle 6, continuation of docetaxel treatment was at the discretion of the participant and treating physician. Participants remained in the treatment phase of the study until investigator-assessed radiographic or clinical evidence of disease progression, unmanageable toxicity, or study termination and were followed for survival until death, loss to follow-up, withdrawal of consent, or study termination.
Fifty of 406 participants (12.3%) randomized to the placebo treatment arm whose disease had not progressed crossed over to an open-label pertuzumab treatment group between July 2012 and November 2018. Participants received pertuzumab administered as an IV loading dose of 840 mg at cycle 1 then 420 mg IV every q3w. Trastuzumab and docetaxel doses continued in accordance with the pre-crossover placebo treatment regimens and according to dosing specifications indicated in the study protocol. Participants remained in the treatment phase of the study until investigator-assessed radiographic or clinical evidence of disease progression, unmanageable toxicity, or study termination and were followed for survival until death, loss to follow-up, withdrawal of consent, or study termination.
Overall Number of Participants Analyzed 396 408 50
Measure Type: Count of Participants
Unit of Measure: Participants
Total with at Least One AE During Post-Treatment
18
   4.5%
17
   4.2%
3
   6.0%
Cardiac Disorders (SOC)
8
   2.0%
9
   2.2%
1
   2.0%
Left Ventricular Dysfunction (PT)
6
   1.5%
5
   1.2%
1
   2.0%
Cardiac Failure (PT)
0
   0.0%
2
   0.5%
0
   0.0%
Bundle Branch Block Left (PT)
0
   0.0%
1
   0.2%
0
   0.0%
Cardiopulmonary Failure (PT)
1
   0.3%
0
   0.0%
0
   0.0%
Myocardial Ischaemia (PT)
1
   0.3%
0
   0.0%
0
   0.0%
Pericardial Effusion (PT)
0
   0.0%
1
   0.2%
0
   0.0%
Prinzmetal Angina (PT)
1
   0.3%
0
   0.0%
0
   0.0%
General Disorders & Admin. Site Conditions (SOC)
3
   0.8%
2
   0.5%
0
   0.0%
Oedema Peripheral (PT)
2
   0.5%
1
   0.2%
0
   0.0%
Asthenia (PT)
1
   0.3%
0
   0.0%
0
   0.0%
Influenza Like Illness (PT)
0
   0.0%
1
   0.2%
0
   0.0%
Infections & Infestations (SOC)
0
   0.0%
0
   0.0%
2
   4.0%
Influenza (PT)
0
   0.0%
0
   0.0%
1
   2.0%
Viral Infection (PT)
0
   0.0%
0
   0.0%
1
   2.0%
Abscess Limb (PT)
0
   0.0%
1
   0.2%
0
   0.0%
Nasopharyngitis (PT)
1
   0.3%
0
   0.0%
0
   0.0%
Subcutaneous Abscess (PT)
0
   0.0%
1
   0.2%
0
   0.0%
Musculoskeletal & Connective Tissue Disorders(SOC)
0
   0.0%
0
   0.0%
1
   2.0%
Back Pain (PT)
0
   0.0%
0
   0.0%
1
   2.0%
Pain in Extremity (PT)
1
   0.3%
0
   0.0%
0
   0.0%
Nervous System Disorders (SOC)
2
   0.5%
2
   0.5%
0
   0.0%
Neuropathy Peripheral (PT)
1
   0.3%
1
   0.2%
0
   0.0%
Cognitive Disorder (PT)
1
   0.3%
0
   0.0%
0
   0.0%
Dizziness (PT)
0
   0.0%
1
   0.2%
0
   0.0%
Headache (PT)
0
   0.0%
1
   0.2%
0
   0.0%
Respiratory, Thoracic & Mediastinal Disorders(SOC)
2
   0.5%
1
   0.2%
0
   0.0%
Cough (PT)
1
   0.3%
0
   0.0%
0
   0.0%
Dyspnoea (PT)
1
   0.3%
0
   0.0%
0
   0.0%
Rhinitis Allergic (PT)
0
   0.0%
1
   0.2%
0
   0.0%
Skin & Subcutaneous Tissue Disorders (SOC)
1
   0.3%
2
   0.5%
0
   0.0%
Erythema (PT)
0
   0.0%
1
   0.2%
0
   0.0%
Nail Disorder (PT)
1
   0.3%
0
   0.0%
0
   0.0%
Rash Macular (PT)
0
   0.0%
1
   0.2%
0
   0.0%
Blood & Lymphatic System Disorders (SOC)
1
   0.3%
1
   0.2%
0
   0.0%
Febrile Neutropenia (PT)
1
   0.3%
0
   0.0%
0
   0.0%
Leukopenia (PT)
0
   0.0%
1
   0.2%
0
   0.0%
Gastrointestinal Disorders (SOC)
0
   0.0%
2
   0.5%
0
   0.0%
Diarrhoea (PT)
0
   0.0%
1
   0.2%
0
   0.0%
Stomatitis (PT)
0
   0.0%
1
   0.2%
0
   0.0%
Endocrine Disorders (SOC)
1
   0.3%
0
   0.0%
0
   0.0%
Thyroid Mass (PT)
1
   0.3%
0
   0.0%
0
   0.0%
Eye Disorders (SOC)
1
   0.3%
0
   0.0%
0
   0.0%
Retinal Detachment (PT)
1
   0.3%
0
   0.0%
0
   0.0%
Immune System Disorders (SOC)
0
   0.0%
1
   0.2%
0
   0.0%
Iodine Allergy (PT)
0
   0.0%
1
   0.2%
0
   0.0%
Investigations (SOC)
1
   0.3%
0
   0.0%
0
   0.0%
Aspartate Aminotransferase Increased (PT)
1
   0.3%
0
   0.0%
0
   0.0%
Renal & Urinary Disorders (SOC)
0
   0.0%
1
   0.2%
0
   0.0%
Dysuria (PT)
0
   0.0%
1
   0.2%
0
   0.0%
Reproductive System & Breast Disorders (SOC)
0
   0.0%
1
   0.2%
0
   0.0%
Breast Induration (PT)
0
   0.0%
1
   0.2%
0
   0.0%
Vascular Disorders (SOC)
0
   0.0%
1
   0.2%
0
   0.0%
Venous Thrombosis (PT)
0
   0.0%
1
   0.2%
0
   0.0%
14.Secondary Outcome
Title Number of Participants by Categories for the Maximum Absolute Decrease From Baseline in LVEF Value During the Treatment Period
Hide Description All participants were required to have an left ventricular ejection fraction (LVEF) ≥50% at baseline, as measured by echocardiogram (preferred) or multiple-gated acquisition (MUGA) scan. The same method of LVEF assessment and the same institution/facility used at baseline was used throughout the study, to the extent possible. The baseline value was defined as the last valid value recorded during the pre-treatment period before or on study Day 1. The maximum absolute decrease in LVEF value was defined as the lowest post-baseline value up to the end of the overall study treatment period. Data reported prior to first crossover treatment were included in the Placebo arm, and after that date in the Crossover arm, for participants who crossed over from placebo to pertuzumab. Median [range] time on study treatment per arm: Placebo: 49.3 [0.3-514.7] weeks; Pertuzumab: 75.7 [0.6-519.6] weeks; Crossover: 129.9 [0.3-322.3] weeks.
Time Frame Every 9 weeks from the date of randomization until Treatment Discontinuation Visit (see Description for time on study treatment per arm)
Hide Outcome Measure Data
Hide Analysis Population Description
Safety Population: All participants who received at least one dose of any study medication. Only participants with evaluable LVEF assessments during the overall study treatment period were included in the analysis.
Arm/Group Title Placebo + Trastuzumab + Docetaxel Pertuzumab + Trastuzumab + Docetaxel Crossover From Placebo to Pertuzumab
Hide Arm/Group Description:
This is the placebo safety population, which includes participants who received study treatment with placebo at every cycle. Participants received placebo IV q3w and trastuzumab 6 mg/kg IV q3This is the placebo safety population, which includes participants who received study treatment with placebo at every cycle. Participants received placebo IV q3w and trastuzumab 6 mg/kg IV q3w, plus docetaxel 75 mg/m^2 IV q3w (for at least 6 cycles; 1 cycle was 21 days). After Cycle 6, continuation of docetaxel treatment was at the discretion of the participant and treating physician. Participants remained in the treatment phase of the study until investigator-assessed radiographic or clinical evidence of disease progression, unmanageable toxicity, or study termination and were followed for survival until death, loss to follow-up, withdrawal of consent, or study termination.
This is the pertuzumab safety population, which includes participants who received at least one dose of study treatment with pertuzumab. Participants received pertuzumab 420 milligrams (mg) intravenously (IV) once every 3 weeks (q3w) and trastuzumab 6 milligrams per kilogram (mg/kg) IV q3w, plus docetaxel 75 milligrams per square metre of body surface (mg/m^2) IV q3w (for at least 6 cycles; 1 cycle was 21 days). After Cycle 6, continuation of docetaxel treatment was at the discretion of the participant and treating physician. Participants remained in the treatment phase of the study until investigator-assessed radiographic or clinical evidence of disease progression, unmanageable toxicity, or study termination and were followed for survival until death, loss to follow-up, withdrawal of consent, or study termination.
Fifty of 406 participants (12.3%) randomized to the placebo treatment arm whose disease had not progressed crossed over to an open-label pertuzumab treatment group between July 2012 and November 2018. Participants received pertuzumab administered as an IV loading dose of 840 mg at cycle 1 then 420 mg IV every q3w. Trastuzumab and docetaxel doses continued in accordance with the pre-crossover placebo treatment regimens and according to dosing specifications indicated in the study protocol. Participants remained in the treatment phase of the study until investigator-assessed radiographic or clinical evidence of disease progression, unmanageable toxicity, or study termination and were followed for survival until death, loss to follow-up, withdrawal of consent, or study termination.
Overall Number of Participants Analyzed 396 408 50
Measure Type: Count of Participants
Unit of Measure: Participants
LVEF Increase/No Change/Decrease FromBL <10%Points Number Analyzed 378 participants 394 participants 49 participants
252
  66.7%
249
  63.2%
30
  61.2%
LVEF <50% and Decrease From BL ≥10% to <15% Points Number Analyzed 378 participants 394 participants 49 participants
9
   2.4%
7
   1.8%
0
   0.0%
LVEF <50% and Decrease From BL ≥15% Points Number Analyzed 378 participants 394 participants 49 participants
19
   5.0%
21
   5.3%
3
   6.1%
LVEF ≥50% and Decrease From BL ≥10% Points Number Analyzed 378 participants 394 participants 49 participants
95
  25.1%
115
  29.2%
15
  30.6%
No Baseline (BL) LVEF Value Number Analyzed 378 participants 394 participants 49 participants
3
   0.8%
2
   0.5%
1
   2.0%
15.Secondary Outcome
Title Baseline LVEF Value and Change in LVEF From Baseline at Maximum Absolute Decrease Value During the Treatment Period
Hide Description All participants were required to have a left ventricular ejection fraction (LVEF) ≥50% at baseline, as measured by echocardiogram (preferred) or multiple-gated acquisition (MUGA) scan. The same method of LVEF assessment and the same institution/facility used at baseline was used throughout the study, to the extent possible. The baseline value was defined as the last valid value recorded during the pre-treatment period before or on study Day 1. The maximum absolute decrease in LVEF value was defined as the lowest post-baseline value up to the end of the overall study treatment period. Only data reported prior to the date of first crossover treatment were included for participants who crossed over from placebo to pertuzumab.
Time Frame Every 9 weeks from the date of randomization until Treatment Discontinuation Visit (median [range] time on study treatment per arm: Placebo: 49.3 [0.3-514.7] weeks; Pertuzumab: 75.7 [0.6-519.6] weeks)
Hide Outcome Measure Data
Hide Analysis Population Description
Safety Population: All participants who received at least one dose of any study medication. Only participants with evaluable LVEF assessments at baseline (BL) or at BL and post-BL (for change in LVEF from BL at max. decrease) were included in the analyses.
Arm/Group Title Placebo + Trastuzumab + Docetaxel Pertuzumab + Trastuzumab + Docetaxel
Hide Arm/Group Description:
This is the placebo safety population, which includes participants who received study treatment with placebo at every cycle. Participants received placebo IV q3w and trastuzumab 6 mg/kg IV q3This is the placebo safety population, which includes participants who received study treatment with placebo at every cycle. Participants received placebo IV q3w and trastuzumab 6 mg/kg IV q3w, plus docetaxel 75 mg/m^2 IV q3w (for at least 6 cycles; 1 cycle was 21 days). After Cycle 6, continuation of docetaxel treatment was at the discretion of the participant and treating physician. Participants remained in the treatment phase of the study until investigator-assessed radiographic or clinical evidence of disease progression, unmanageable toxicity, or study termination and were followed for survival until death, loss to follow-up, withdrawal of consent, or study termination.
This is the pertuzumab safety population, which includes participants who received at least one dose of study treatment with pertuzumab. Participants received pertuzumab 420 milligrams (mg) intravenously (IV) once every 3 weeks (q3w) and trastuzumab 6 milligrams per kilogram (mg/kg) IV q3w, plus docetaxel 75 milligrams per square metre of body surface (mg/m^2) IV q3w (for at least 6 cycles; 1 cycle was 21 days). After Cycle 6, continuation of docetaxel treatment was at the discretion of the participant and treating physician. Participants remained in the treatment phase of the study until investigator-assessed radiographic or clinical evidence of disease progression, unmanageable toxicity, or study termination and were followed for survival until death, loss to follow-up, withdrawal of consent, or study termination.
Overall Number of Participants Analyzed 396 408
Mean (Standard Deviation)
Unit of Measure: Percentage points of LVEF
Baseline (BL) LVEF Value Number Analyzed 393 participants 406 participants
65.6  (6.51) 64.8  (6.71)
Change in LVEF From BL at Maximum Decrease Value Number Analyzed 375 participants 392 participants
-7.3  (7.15) -7.5  (7.75)
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Placebo + Trastuzumab + Docetaxel, Pertuzumab + Trastuzumab + Docetaxel
Comments Wilcoxon Test of Maximum Decrease in LVEF From BL
Type of Statistical Test Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.7174
Comments [Not Specified]
Method Wilcoxon Rank Sum Test
Comments [Not Specified]
16.Secondary Outcome
Title Number of Participants With Laboratory Abnormalities in Blood Biochemistry Tests by Highest Grade According to NCI-CTCAE v3.0 During the Treatment Period
Hide Description Clinical laboratory tests for blood biochemistry parameters were performed at local laboratories; any abnormal values (High or Low) were based on local laboratory normal ranges. Laboratory abnormalities are presented by the highest grade according to NCI-CTCAE v3.0. Not every abnormal laboratory value qualified as an adverse event, only if it met any of the following criteria: clinically significant (per investigator); accompanied by clinical symptoms; resulted in a change in study treatment; or required a change in concomitant therapy. Median [range] time on study treatment per arm: Placebo: 49.3 [0.3-514.7] weeks; Pertuzumab: 75.7 [0.6-519.6] weeks; Crossover: 129.9 [0.3-322.3] weeks. ALP = alkaline phosphatase; GGT = gamma-glutamyl transferase; SGOT = serum glutamic-oxaloacetic transaminase; SGPT = serum glutamic-pyruvic transaminase
Time Frame On Day 1 of every treatment cycle (1 cycle is 21 days) until Treatment Discontinuation Visit (see Description for time on study treatment per arm)
Hide Outcome Measure Data
Hide Analysis Population Description
Safety Population: All participants who received at least one dose of any study medication. Only participants with at least one valid laboratory value for any given parameter during the overall study treatment period were included in the analysis.
Arm/Group Title Placebo + Trastuzumab + Docetaxel Pertuzumab + Trastuzumab + Docetaxel Crossover From Placebo to Pertuzumab
Hide Arm/Group Description:
This is the placebo safety population, which includes participants who received study treatment with placebo at every cycle. Participants received placebo IV q3w and trastuzumab 6 mg/kg IV q3This is the placebo safety population, which includes participants who received study treatment with placebo at every cycle. Participants received placebo IV q3w and trastuzumab 6 mg/kg IV q3w, plus docetaxel 75 mg/m^2 IV q3w (for at least 6 cycles; 1 cycle was 21 days). After Cycle 6, continuation of docetaxel treatment was at the discretion of the participant and treating physician. Participants remained in the treatment phase of the study until investigator-assessed radiographic or clinical evidence of disease progression, unmanageable toxicity, or study termination and were followed for survival until death, loss to follow-up, withdrawal of consent, or study termination.
This is the pertuzumab safety population, which includes participants who received at least one dose of study treatment with pertuzumab. Participants received pertuzumab 420 milligrams (mg) intravenously (IV) once every 3 weeks (q3w) and trastuzumab 6 milligrams per kilogram (mg/kg) IV q3w, plus docetaxel 75 milligrams per square metre of body surface (mg/m^2) IV q3w (for at least 6 cycles; 1 cycle was 21 days). After Cycle 6, continuation of docetaxel treatment was at the discretion of the participant and treating physician. Participants remained in the treatment phase of the study until investigator-assessed radiographic or clinical evidence of disease progression, unmanageable toxicity, or study termination and were followed for survival until death, loss to follow-up, withdrawal of consent, or study termination.
Fifty of 406 participants (12.3%) randomized to the placebo treatment arm whose disease had not progressed crossed over to an open-label pertuzumab treatment group between July 2012 and November 2018. Participants received pertuzumab administered as an IV loading dose of 840 mg at cycle 1 then 420 mg IV every q3w. Trastuzumab and docetaxel doses continued in accordance with the pre-crossover placebo treatment regimens and according to dosing specifications indicated in the study protocol. Participants remained in the treatment phase of the study until investigator-assessed radiographic or clinical evidence of disease progression, unmanageable toxicity, or study termination and were followed for survival until death, loss to follow-up, withdrawal of consent, or study termination.
Overall Number of Participants Analyzed 396 408 50
Measure Type: Count of Participants
Unit of Measure: Participants
Albumin (g/L) - Low, Any Grade (Gr.) Number Analyzed 385 participants 396 participants 49 participants
163
  42.3%
196
  49.5%
15
  30.6%
Albumin (g/L) - Low, Gr. 1 Number Analyzed 385 participants 396 participants 49 participants
113
  29.4%
132
  33.3%
10
  20.4%
Albumin (g/L) - Low, Gr. 2 Number Analyzed 385 participants 396 participants 49 participants
46
  11.9%
58
  14.6%
4
   8.2%
Albumin (g/L) - Low, Gr. 3 Number Analyzed 385 participants 396 participants 49 participants
4
   1.0%
6
   1.5%
1
   2.0%
Albumin (g/L) - Low, Gr. 4 Number Analyzed 385 participants 396 participants 49 participants
0
   0.0%
0
   0.0%
0
   0.0%
ALP (U/L) - High, Any Gr. Number Analyzed 388 participants 400 participants 49 participants
184
  47.4%
210
  52.5%
17
  34.7%
ALP (U/L) - High, Gr. 1 Number Analyzed 388 participants 400 participants 49 participants
158
  40.7%
177
  44.3%
17
  34.7%
ALP (U/L) - High, Gr. 2 Number Analyzed 388 participants 400 participants 49 participants
19
   4.9%
24
   6.0%
0
   0.0%
ALP (U/L) - High, Gr. 3 Number Analyzed 388 participants 400 participants 49 participants
7
   1.8%
9
   2.3%
0
   0.0%
ALP (U/L) - High, Gr. 4 Number Analyzed 388 participants 400 participants 49 participants
0
   0.0%
0
   0.0%
0
   0.0%
Calcium (mmol/L) - Low, Any Gr. Number Analyzed 387 participants 399 participants 49 participants
156
  40.3%
203
  50.9%
14
  28.6%
Calcium (mmol/L) - Low, Gr. 1 Number Analyzed 387 participants 399 participants 49 participants
107
  27.6%
139
  34.8%
11
  22.4%
Calcium (mmol/L) - Low, Gr. 2 Number Analyzed 387 participants 399 participants 49 participants
45
  11.6%
49
  12.3%
0
   0.0%
Calcium (mmol/L) - Low, Gr. 3 Number Analyzed 387 participants 399 participants 49 participants
3
   0.8%
7
   1.8%
1
   2.0%
Calcium (mmol/L) - Low, Gr. 4 Number Analyzed 387 participants 399 participants 49 participants
1
   0.3%
8
   2.0%
2
   4.1%
Calcium (mmol/L) - High, Any Gr. Number Analyzed 387 participants 399 participants 49 participants
54
  14.0%
79
  19.8%
12
  24.5%
Calcium (mmol/L) - High, Gr. 1 Number Analyzed 387 participants 399 participants 49 participants
50
  12.9%
65
  16.3%
7
  14.3%
Calcium (mmol/L) - High, Gr. 2 Number Analyzed 387 participants 399 participants 49 participants
0
   0.0%
2
   0.5%
1
   2.0%
Calcium (mmol/L) - High, Gr. 3 Number Analyzed 387 participants 399 participants 49 participants
3
   0.8%
2
   0.5%
0
   0.0%
Calcium (mmol/L) - High, Gr. 4 Number Analyzed 387 participants 399 participants 49 participants
1
   0.3%
10
   2.5%
4
   8.2%
Creatinine (umol/L) - High, Any Gr. Number Analyzed 390 participants 402 participants 49 participants
317
  81.3%
346
  86.1%
38
  77.6%
Creatinine (umol/L) - High, Gr. 1 Number Analyzed 390 participants 402 participants 49 participants
271
  69.5%
279
  69.4%
27
  55.1%
Creatinine (umol/L) - High, Gr. 2 Number Analyzed 390 participants 402 participants 49 participants
44
  11.3%
54
  13.4%
9
  18.4%
Creatinine (umol/L) - High, Gr. 3 Number Analyzed 390 participants 402 participants 49 participants
2
   0.5%
6
   1.5%
0
   0.0%
Creatinine (umol/L) - High, Gr. 4 Number Analyzed 390 participants 402 participants 49 participants
0
   0.0%
7
   1.7%
2
   4.1%
Fasting Glucose (mmol/L) - Low, Any Gr. Number Analyzed 387 participants 400 participants 49 participants
42
  10.9%
75
  18.8%
6
  12.2%
Fasting Glucose (mmol/L) - Low, Gr. 1 Number Analyzed 387 participants 400 participants 49 participants
32
   8.3%
61
  15.3%
4
   8.2%
Fasting Glucose (mmol/L) - Low, Gr. 2 Number Analyzed 387 participants 400 participants 49 participants
9
   2.3%
9
   2.3%
0
   0.0%
Fasting Glucose (mmol/L) - Low, Gr. 3 Number Analyzed 387 participants 400 participants 49 participants
1
   0.3%
2
   0.5%
0
   0.0%
Fasting Glucose (mmol/L) - Low, Gr. 4 Number Analyzed 387 participants 400 participants 49 participants
0
   0.0%
3
   0.8%
2
   4.1%
Fasting Glucose (mmol/L) - High, Any Gr. Number Analyzed 387 participants 400 participants 49 participants
271
  70.0%
299
  74.8%
34
  69.4%
Fasting Glucose (mmol/L) - High, Gr. 1 Number Analyzed 387 participants 400 participants 49 participants
168
  43.4%
192
  48.0%
26
  53.1%
Fasting Glucose (mmol/L) - High, Gr. 2 Number Analyzed 387 participants 400 participants 49 participants
83
  21.4%
78
  19.5%
8
  16.3%
Fasting Glucose (mmol/L) - High, Gr. 3 Number Analyzed 387 participants 400 participants 49 participants
20
   5.2%
26
   6.5%
0
   0.0%
Fasting Glucose (mmol/L) - High, Gr. 4 Number Analyzed 387 participants 400 participants 49 participants
0
   0.0%
3
   0.8%
0
   0.0%
GGT (U/L) - High, Any Gr. Number Analyzed 375 participants 394 participants 48 participants
209
  55.7%
225
  57.1%
14
  29.2%
GGT (U/L) - High, Gr. 1 Number Analyzed 375 participants 394 participants 48 participants
133
  35.5%
144
  36.5%
9
  18.8%
GGT (U/L) - High, Gr. 2 Number Analyzed 375 participants 394 participants 48 participants
41
  10.9%
52
  13.2%
4
   8.3%
GGT (U/L) - High, Gr. 3 Number Analyzed 375 participants 394 participants 48 participants
30
   8.0%
27
   6.9%
1
   2.1%
GGT (U/L) - High, Gr. 4 Number Analyzed 375 participants 394 participants 48 participants
5
   1.3%
2
   0.5%
0
   0.0%
Magnesium (mmol/L) - Low, Any Gr. Number Analyzed 371 participants 398 participants 49 participants
79
  21.3%
117
  29.4%
8
  16.3%
Magnesium (mmol/L) - Low, Gr. 1 Number Analyzed 371 participants 398 participants 49 participants
71
  19.1%
98
  24.6%
6
  12.2%
Magnesium (mmol/L) - Low, Gr. 2 Number Analyzed 371 participants 398 participants 49 participants
7
   1.9%
13
   3.3%
0
   0.0%
Magnesium (mmol/L) - Low, Gr. 3 Number Analyzed 371 participants 398 participants 49 participants
1
   0.3%
3
   0.8%
0
   0.0%
Magnesium (mmol/L) - Low, Gr. 4 Number Analyzed 371 participants 398 participants 49 participants
0
   0.0%
3
   0.8%
2
   4.1%
Magnesium (mmol/L) - High, Any Gr. Number Analyzed 371 participants 398 participants 49 participants
76
  20.5%
105
  26.4%
16
  32.7%
Magnesium (mmol/L) - High, Gr. 1 Number Analyzed 371 participants 398 participants 49 participants
58
  15.6%
80
  20.1%
11
  22.4%
Magnesium (mmol/L) - High, Gr. 2 Number Analyzed 371 participants 398 participants 49 participants
0
   0.0%
0
   0.0%
0
   0.0%
Magnesium (mmol/L) - High, Gr. 3 Number Analyzed 371 participants 398 participants 49 participants
18
   4.9%
22
   5.5%
4
   8.2%
Magnesium (mmol/L) - High, Gr. 4 Number Analyzed 371 participants 398 participants 49 participants
0
   0.0%
3
   0.8%
1
   2.0%
Potassium (mmol/L) - Low, Any Gr. Number Analyzed 389 participants 401 participants 49 participants
80
  20.6%
144
  35.9%
11
  22.4%
Potassium (mmol/L) - Low, Gr. 1 Number Analyzed 389 participants 401 participants 49 participants
0
   0.0%
0
   0.0%
0
   0.0%
Potassium (mmol/L) - Low, Gr. 2 Number Analyzed 389 participants 401 participants 49 participants
68
  17.5%
118
  29.4%
8
  16.3%
Potassium (mmol/L) - Low, Gr. 3 Number Analyzed 389 participants 401 participants 49 participants
10
   2.6%
18
   4.5%
2
   4.1%
Potassium (mmol/L) - Low, Gr. 4 Number Analyzed 389 participants 401 participants 49 participants
2
   0.5%
8
   2.0%
1
   2.0%
Potassium (mmol/L) - High, Any Gr. Number Analyzed 389 participants 401 participants 49 participants
67
  17.2%
78
  19.5%
13
  26.5%
Potassium (mmol/L) - High, Gr. 1 Number Analyzed 389 participants 401 participants 49 participants
49
  12.6%
55
  13.7%
11
  22.4%
Potassium (mmol/L) - High, Gr. 2 Number Analyzed 389 participants 401 participants 49 participants
15
   3.9%
17
   4.2%
2
   4.1%
Potassium (mmol/L) - High, Gr. 3 Number Analyzed 389 participants 401 participants 49 participants
3
   0.8%
6
   1.5%
0
   0.0%
Potassium (mmol/L) - High, Gr. 4 Number Analyzed 389 participants 401 participants 49 participants
0
   0.0%
0
   0.0%
0
   0.0%
SGOT (U/L) - High, Any Gr. Number Analyzed 389 participants 400 participants 49 participants
184
  47.3%
193
  48.3%
17
  34.7%
SGOT (U/L) - High, Gr. 1 Number Analyzed 389 participants 400 participants 49 participants
169
  43.4%
170
  42.5%
15
  30.6%
SGOT (U/L) - High, Gr. 2 Number Analyzed 389 participants 400 participants 49 participants
11
   2.8%
12
   3.0%
2
   4.1%
SGOT (U/L) - High, Gr. 3 Number Analyzed 389 participants 400 participants 49 participants
4
   1.0%
10
   2.5%
0
   0.0%
SGOT (U/L) - High, Gr. 4 Number Analyzed 389 participants 400 participants 49 participants
0
   0.0%
1
   0.3%
0
   0.0%
SGPT (U/L) - High, Any Gr. Number Analyzed 390 participants 400 participants 49 participants
195
  50.0%
209
  52.3%
19
  38.8%
SGPT (U/L) - High, Gr. 1 Number Analyzed 390 participants 400 participants 49 participants
172
  44.1%
175
  43.8%
17
  34.7%
SGPT (U/L) - High, Gr. 2 Number Analyzed 390 participants 400 participants 49 participants
18
   4.6%
19
   4.8%
2
   4.1%
SGPT (U/L) - High, Gr. 3 Number Analyzed 390 participants 400 participants 49 participants
5
   1.3%
14
   3.5%
0
   0.0%
SGPT (U/L) - High, Gr. 4 Number Analyzed 390 participants 400 participants 49 participants
0
   0.0%
1
   0.3%
0
   0.0%
Sodium (mmol/L) - Low, Any Gr. Number Analyzed 389 participants 402 participants 49 participants
109
  28.0%
135
  33.6%
25
  51.0%
Sodium (mmol/L) - Low, Gr. 1 Number Analyzed 389 participants 402 participants 49 participants
87
  22.4%
121
  30.1%
22
  44.9%
Sodium (mmol/L) - Low, Gr. 2 Number Analyzed 389 participants 402 participants 49 participants
0
   0.0%
0
   0.0%
0
   0.0%
Sodium (mmol/L) - Low, Gr. 3 Number Analyzed 389 participants 402 participants 49 participants
21
   5.4%
12
   3.0%
1
   2.0%
Sodium (mmol/L) - Low, Gr. 4 Number Analyzed 389 participants 402 participants 49 participants
1
   0.3%
2
   0.5%
2
   4.1%
Sodium (mmol/L) - High, Any Gr. Number Analyzed 389 participants 402 participants 49 participants
76
  19.5%
103
  25.6%
9
  18.4%
Sodium (mmol/L) - High, Gr. 1 Number Analyzed 389 participants 402 participants 49 participants
71
  18.3%
91
  22.6%
7
  14.3%
Sodium (mmol/L) - High, Gr. 2 Number Analyzed 389 participants 402 participants 49 participants
4
   1.0%
9
   2.2%
2
   4.1%
Sodium (mmol/L) - High, Gr. 3 Number Analyzed 389 participants 402 participants 49 participants
1
   0.3%
2
   0.5%
0
   0.0%
Sodium (mmol/L) - High, Gr. 4 Number Analyzed 389 participants 402 participants 49 participants
0
   0.0%
1
   0.2%
0
   0.0%
Total Bilirubin (umol/L) - High, Any Gr. Number Analyzed 390 participants 401 participants 49 participants
35
   9.0%
57
  14.2%
7
  14.3%
Total Bilirubin (umol/L) - High, Gr. 1 Number Analyzed 390 participants 401 participants 49 participants
26
   6.7%
44
  11.0%
6
  12.2%
Total Bilirubin (umol/L) - High, Gr. 2 Number Analyzed 390 participants 401 participants 49 participants
7
   1.8%
9
   2.2%
0
   0.0%
Total Bilirubin (umol/L) - High, Gr. 3 Number Analyzed 390 participants 401 participants 49 participants
2
   0.5%
2
   0.5%
0
   0.0%
Total Bilirubin (umol/L) - High, Gr. 4 Number Analyzed 390 participants 401 participants 49 participants
0
   0.0%
2
   0.5%
1
   2.0%
Uric Acid (umol/L) - High, Any Gr. Number Analyzed 370 participants 397 participants 49 participants
118
  31.9%
113
  28.5%
15
  30.6%
Uric Acid (umol/L) - High, Gr. 1 Number Analyzed 370 participants 397 participants 49 participants
0
   0.0%
0
   0.0%
0
   0.0%
Uric Acid (umol/L) - High, Gr. 2 Number Analyzed 370 participants 397 participants 49 participants
0
   0.0%
0
   0.0%
0
   0.0%
Uric Acid (umol/L) - High, Gr. 3 Number Analyzed 370 participants 397 participants 49 participants
116
  31.4%
98
  24.7%
10
  20.4%
Uric Acid (umol/L) - High, Gr. 4 Number Analyzed 370 participants 397 participants 49 participants
2
   0.5%
15
   3.8%
5
  10.2%
17.Secondary Outcome
Title Number of Participants With Laboratory Abnormalities in Hematology Tests by Highest Grade According to NCI-CTCAE v3.0 During the Treatment Period
Hide Description Clinical laboratory tests for hematology parameters were performed at local laboratories; any abnormal values (High or Low) were based on local laboratory normal ranges. Laboratory abnormalities are presented by the highest grade according to NCI-CTCAE v3.0. Not every abnormal laboratory value qualified as an adverse event, only if it met any of the following criteria: clinically significant (per investigator); accompanied by clinical symptoms; resulted in a change in study treatment; or required a change in concomitant therapy. Median [range] time on study treatment per arm: Placebo: 49.3 [0.3-514.7] weeks; Pertuzumab: 75.7 [0.6-519.6] weeks; Crossover: 129.9 [0.3-322.3] weeks. INR = International Normalized Ratio; PTT = partial thromboplastin time; WBC = white blood cell
Time Frame On Day 1 (and Day 8 for some measures) of every treatment cycle (1 cycle is 21 days) until Treatment Discontinuation Visit (see Description for time on study treatment per arm)
Hide Outcome Measure Data
Hide Analysis Population Description
Safety Population: All participants who received at least one dose of any study medication. Only participants with at least one valid laboratory value for any given parameter during the overall study treatment period were included in the analysis.
Arm/Group Title Placebo + Trastuzumab + Docetaxel Pertuzumab + Trastuzumab + Docetaxel Crossover From Placebo to Pertuzumab
Hide Arm/Group Description:
This is the placebo safety population, which includes participants who received study treatment with placebo at every cycle. Participants received placebo IV q3w and trastuzumab 6 mg/kg IV q3This is the placebo safety population, which includes participants who received study treatment with placebo at every cycle. Participants received placebo IV q3w and trastuzumab 6 mg/kg IV q3w, plus docetaxel 75 mg/m^2 IV q3w (for at least 6 cycles; 1 cycle was 21 days). After Cycle 6, continuation of docetaxel treatment was at the discretion of the participant and treating physician. Participants remained in the treatment phase of the study until investigator-assessed radiographic or clinical evidence of disease progression, unmanageable toxicity, or study termination and were followed for survival until death, loss to follow-up, withdrawal of consent, or study termination.
This is the pertuzumab safety population, which includes participants who received at least one dose of study treatment with pertuzumab. Participants received pertuzumab 420 milligrams (mg) intravenously (IV) once every 3 weeks (q3w) and trastuzumab 6 milligrams per kilogram (mg/kg) IV q3w, plus docetaxel 75 milligrams per square metre of body surface (mg/m^2) IV q3w (for at least 6 cycles; 1 cycle was 21 days). After Cycle 6, continuation of docetaxel treatment was at the discretion of the participant and treating physician. Participants remained in the treatment phase of the study until investigator-assessed radiographic or clinical evidence of disease progression, unmanageable toxicity, or study termination and were followed for survival until death, loss to follow-up, withdrawal of consent, or study termination.
Fifty of 406 participants (12.3%) randomized to the placebo treatment arm whose disease had not progressed crossed over to an open-label pertuzumab treatment group between July 2012 and November 2018. Participants received pertuzumab administered as an IV loading dose of 840 mg at cycle 1 then 420 mg IV every q3w. Trastuzumab and docetaxel doses continued in accordance with the pre-crossover placebo treatment regimens and according to dosing specifications indicated in the study protocol. Participants remained in the treatment phase of the study until investigator-assessed radiographic or clinical evidence of disease progression, unmanageable toxicity, or study termination and were followed for survival until death, loss to follow-up, withdrawal of consent, or study termination.
Overall Number of Participants Analyzed 396 408 50
Measure Type: Count of Participants
Unit of Measure: Participants
Hemoglobin (g/L) - Low, Any Grade (Gr.) Number Analyzed 392 participants 404 participants 49 participants
350
  89.3%
372
  92.1%
20
  40.8%
Hemoglobin (g/L) - Low, Gr. 1 Number Analyzed 392 participants 404 participants 49 participants
202
  51.5%
186
  46.0%
9
  18.4%
Hemoglobin (g/L) - Low, Gr. 2 Number Analyzed 392 participants 404 participants 49 participants
127
  32.4%
161
  39.9%
6
  12.2%
Hemoglobin (g/L) - Low, Gr. 3 Number Analyzed 392 participants 404 participants 49 participants
21
   5.4%
25
   6.2%
5
  10.2%
Hemoglobin (g/L) - Low, Gr. 4 Number Analyzed 392 participants 404 participants 49 participants
0
   0.0%
0
   0.0%
0
   0.0%
Hemoglobin (g/L) - High, Any Gr. Number Analyzed 392 participants 404 participants 49 participants
10
   2.6%
23
   5.7%
4
   8.2%
Hemoglobin (g/L) - High, Gr. 1 Number Analyzed 392 participants 404 participants 49 participants
9
   2.3%
20
   5.0%
2
   4.1%
Hemoglobin (g/L) - High, Gr. 2 Number Analyzed 392 participants 404 participants 49 participants
1
   0.3%
2
   0.5%
0
   0.0%
Hemoglobin (g/L) - High, Gr. 3 Number Analyzed 392 participants 404 participants 49 participants
0
   0.0%
1
   0.2%
2
   4.1%
Hemoglobin (g/L) - High, Gr. 4 Number Analyzed 392 participants 404 participants 49 participants
0
   0.0%
0
   0.0%
0
   0.0%
Lymphocytes (10^9/L) - Low, Any Gr. Number Analyzed 391 participants 404 participants 49 participants
259
  66.2%
276
  68.3%
8
  16.3%
Lymphocytes (10^9/L) - Low, Gr. 1 Number Analyzed 391 participants 404 participants 49 participants
36
   9.2%
39
   9.7%
0
   0.0%
Lymphocytes (10^9/L) - Low, Gr. 2 Number Analyzed 391 participants 404 participants 49 participants
128
  32.7%
136
  33.7%
4
   8.2%
Lymphocytes (10^9/L) - Low, Gr. 3 Number Analyzed 391 participants 404 participants 49 participants
64
  16.4%
69
  17.1%
3
   6.1%
Lymphocytes (10^9/L) - Low, Gr. 4 Number Analyzed 391 participants 404 participants 49 participants
31
   7.9%
32
   7.9%
1
   2.0%
Lymphocytes (10^9/L)- High, Any Gr. Number Analyzed 391 participants 404 participants 49 participants
58
  14.8%
72
  17.8%
9
  18.4%
Lymphocytes (10^9/L)- High, Gr. 1 Number Analyzed 391 participants 404 participants 49 participants
0
   0.0%
0
   0.0%
0
   0.0%
Lymphocytes (10^9/L)- High, Gr. 2 Number Analyzed 391 participants 404 participants 49 participants
49
  12.5%
57
  14.1%
6
  12.2%
Lymphocytes (10^9/L)- High, Gr. 3 Number Analyzed 391 participants 404 participants 49 participants
9
   2.3%
15
   3.7%
3
   6.1%
Lymphocytes (10^9/L)- High, Gr. 4 Number Analyzed 391 participants 404 participants 49 participants
0
   0.0%
0
   0.0%
0
   0.0%
Neutrophils (10^9/L)- Low, Any Gr. Number Analyzed 391 participants 404 participants 49 participants
349
  89.3%
371
  91.8%
2
   4.1%
Neutrophils (10^9/L)- Low, Gr. 1 Number Analyzed 391 participants 404 participants 49 participants
7
   1.8%
4
   1.0%
0
   0.0%
Neutrophils (10^9/L)- Low, Gr. 2 Number Analyzed 391 participants 404 participants 49 participants
25
   6.4%
34
   8.4%
0
   0.0%
Neutrophils (10^9/L)- Low, Gr. 3 Number Analyzed 391 participants 404 participants 49 participants
81
  20.7%
99
  24.5%
0
   0.0%
Neutrophils (10^9/L)- Low, Gr. 4 Number Analyzed 391 participants 404 participants 49 participants
236
  60.4%
234
  57.9%
2
   4.1%
PTT (sec) - High, Any Gr. Number Analyzed 28 participants 35 participants 3 participants
6
  21.4%
9
  25.7%
1
  33.3%
PTT (sec) - High, Gr. 1 Number Analyzed 28 participants 35 participants 3 participants
5
  17.9%
2
   5.7%
1
  33.3%
PTT (sec) - High, Gr. 2 Number Analyzed 28 participants 35 participants 3 participants
0
   0.0%
4
  11.4%
0
   0.0%
PTT (sec) - High, Gr. 3 Number Analyzed 28 participants 35 participants 3 participants
1
   3.6%
3
   8.6%
0
   0.0%
PTT (sec) - High, Gr. 4 Number Analyzed 28 participants 35 participants 3 participants
0
   0.0%
0
   0.0%
0
   0.0%
Platelets (10^9/L) - Low, Any Gr. Number Analyzed 392 participants 404 participants 49 participants
82
  20.9%
92
  22.8%
13
  26.5%
Platelets (10^9/L) - Low, Gr. 1 Number Analyzed 392 participants 404 participants 49 participants
75
  19.1%
78
  19.3%
11
  22.4%
Platelets (10^9/L) - Low, Gr. 2 Number Analyzed 392 participants 404 participants 49 participants
5
   1.3%
5
   1.2%
0
   0.0%
Platelets (10^9/L) - Low, Gr. 3 Number Analyzed 392 participants 404 participants 49 participants
2
   0.5%
3
   0.7%
0
   0.0%
Platelets (10^9/L) - Low, Gr. 4 Number Analyzed 392 participants 404 participants 49 participants
0
   0.0%
6
   1.5%
2
   4.1%
Prothrombin Time (INR) - High, Any Gr. Number Analyzed 198 participants 216 participants 14 participants
135
  68.2%
157
  72.7%
11
  78.6%
Prothrombin Time (INR) - High, Gr. 1 Number Analyzed 198 participants 216 participants 14 participants
127
  64.1%
136
  63.0%
9
  64.3%
Prothrombin Time (INR) - High, Gr. 2 Number Analyzed 198 participants 216 participants 14 participants
3
   1.5%
6
   2.8%
0
   0.0%
Prothrombin Time (INR) - High, Gr. 3 Number Analyzed 198 participants 216 participants 14 participants
5
   2.5%
15
   6.9%
2
  14.3%
Prothrombin Time (INR) - High, Gr. 4 Number Analyzed 198 participants 216 participants 14 participants
0
   0.0%
0
   0.0%
0
   0.0%
WBC (10^9/L) - Low, Any Gr. Number Analyzed 392 participants 404 participants 49 participants
366
  93.4%
387
  95.8%
5
  10.2%
WBC (10^9/L) - Low, Gr. 1 Number Analyzed 392 participants 404 participants 49 participants
36
   9.2%
34
   8.4%
1
   2.0%
WBC (10^9/L) - Low, Gr. 2 Number Analyzed 392 participants 404 participants 49 participants
92
  23.5%
92
  22.8%
3
   6.1%
WBC (10^9/L) - Low, Gr. 3 Number Analyzed 392 participants 404 participants 49 participants
186
  47.4%
206
  51.0%
0
   0.0%
WBC (10^9/L) - Low, Gr. 4 Number Analyzed 392 participants 404 participants 49 participants
52
  13.3%
55
  13.6%
1
   2.0%
WBC (10^9/L) - High, Any Gr. Number Analyzed 392 participants 404 participants 49 participants
0
   0.0%
3
   0.7%
1
   2.0%
WBC (10^9/L) - High, Gr. 1 Number Analyzed 392 participants 404 participants 49 participants
0
   0.0%
0
   0.0%
0
   0.0%
WBC (10^9/L) - High, Gr. 2 Number Analyzed 392 participants 404 participants 49 participants
0
   0.0%
0
   0.0%
0
   0.0%
WBC (10^9/L) - High, Gr. 3 Number Analyzed 392 participants 404 participants 49 participants
0
   0.0%
3
   0.7%
1
   2.0%
WBC (10^9/L) - High, Gr. 4 Number Analyzed 392 participants 404 participants 49 participants
0
   0.0%
0
   0.0%
0
   0.0%
Time Frame From first treatment dose (12-Feb-2008) through to end of study (23-Nov-2018) for a total safety analysis timeframe of 10 years, 9.5 months.
Adverse Event Reporting Description Of enrolled participants (Pertuzumab [Ptz]: N=402, Placebo [Pla]: N=406), 2 in each arm received no treatment (total of 4), 9 in Pla arm received at least 1 dose of Ptz, and 1 in Ptz arm received Pla at every cycle; resulting in a Safety Population of Ptz: N=408 (402-2+9-1), Pla: N=396 (406-2-9+1), and 50 participants in Pla arm crossed over to Ptz.
 
Arm/Group Title Placebo + Trastuzumab + Docetaxel Pertuzumab + Trastuzumab + Docetaxel Crossover From Placebo to Pertuzumab
Hide Arm/Group Description This is the placebo safety population, which includes participants who received study treatment with placebo at every cycle. Participants received placebo IV q3w and trastuzumab 6 mg/kg IV q3w, plus docetaxel 75 mg/m^2 IV q3w (for at least 6 cycles; 1 cycle was 21 days). After Cycle 6, continuation of docetaxel treatment was at the discretion of the participant and treating physician. Participants remained in the treatment phase of the study until investigator-assessed radiographic or clinical evidence of disease progression, unmanageable toxicity, or study termination and were followed for survival until death, loss to follow-up, withdrawal of consent, or study termination. This is the pertuzumab safety population, which includes participants who received at least one dose of study treatment with pertuzumab. Participants received pertuzumab 420 milligrams (mg) intravenously (IV) once every 3 weeks (q3w) and trastuzumab 6 milligrams per kilogram (mg/kg) IV q3w, plus docetaxel 75 milligrams per square metre of body surface (mg/m^2) IV q3w (for at least 6 cycles; 1 cycle was 21 days). After Cycle 6, continuation of docetaxel treatment was at the discretion of the participant and treating physician. Participants remained in the treatment phase of the study until investigator-assessed radiographic or clinical evidence of disease progression, unmanageable toxicity, or study termination and were followed for survival until death, loss to follow-up, withdrawal of consent, or study termination. Fifty of 406 participants (12.3%) randomized to the placebo treatment arm whose disease had not progressed crossed over to an open-label pertuzumab treatment group between July 2012 and November 2018. Participants received pertuzumab administered as an IV loading dose of 840 mg at cycle 1 then 420 mg IV every q3w. Trastuzumab and docetaxel doses continued in accordance with the pre-crossover placebo treatment regimens and according to dosing specifications indicated in the study protocol. Participants remained in the treatment phase of the study until investigator-assessed radiographic or clinical evidence of disease progression, unmanageable toxicity, or study termination and were followed for survival until death, loss to follow-up, withdrawal of consent, or study termination.
All-Cause Mortality
Placebo + Trastuzumab + Docetaxel Pertuzumab + Trastuzumab + Docetaxel Crossover From Placebo to Pertuzumab
Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%)
Total   261/396 (65.91%)      238/408 (58.33%)      14/50 (28.00%)    
Hide Serious Adverse Events
Placebo + Trastuzumab + Docetaxel Pertuzumab + Trastuzumab + Docetaxel Crossover From Placebo to Pertuzumab
Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events
Total   116/396 (29.29%)      160/408 (39.22%)      10/50 (20.00%)    
Blood and lymphatic system disorders       
Anaemia  1  3/396 (0.76%)  3 3/408 (0.74%)  4 1/50 (2.00%)  1
Febrile neutropenia  1  20/396 (5.05%)  23 46/408 (11.27%)  48 0/50 (0.00%)  0
Granulocytopenia  1  1/396 (0.25%)  1 0/408 (0.00%)  0 0/50 (0.00%)  0
Leukopenia  1  1/396 (0.25%)  1 0/408 (0.00%)  0 0/50 (0.00%)  0
Neutropenia  1  19/396 (4.80%)  20 18/408 (4.41%)  23 0/50 (0.00%)  0
Cardiac disorders       
Atrial fibrillation  1  3/396 (0.76%)  3 0/408 (0.00%)  0 0/50 (0.00%)  0
Cardiac failure congestive  1  0/396 (0.00%)  0 2/408 (0.49%)  2 0/50 (0.00%)  0
Coronary artery disease  1  0/396 (0.00%)  0 1/408 (0.25%)  1 0/50 (0.00%)  0
Left ventricular dysfunction  1  7/396 (1.77%)  7 6/408 (1.47%)  6 1/50 (2.00%)  1
Myocardial infarction  1  3/396 (0.76%)  3 0/408 (0.00%)  0 0/50 (0.00%)  0
Myocardial ischaemia  1  1/396 (0.25%)  1 0/408 (0.00%)  0 0/50 (0.00%)  0
Ventricular fibrillation  1  0/396 (0.00%)  0 1/408 (0.25%)  1 0/50 (0.00%)  0
Ear and labyrinth disorders       
Vertigo  1  0/396 (0.00%)  0 1/408 (0.25%)  1 0/50 (0.00%)  0
Eye disorders       
Cataract  1  0/396 (0.00%)  0 2/408 (0.49%)  2 1/50 (2.00%)  1
Gastrointestinal disorders       
Abdominal pain  1  1/396 (0.25%)  2 0/408 (0.00%)  0 0/50 (0.00%)  0
Colitis  1  0/396 (0.00%)  0 1/408 (0.25%)  1 0/50 (0.00%)  0
Constipation  1  2/396 (0.51%)  3 0/408 (0.00%)  0 0/50 (0.00%)  0
Diarrhoea  1  5/396 (1.26%)  5 13/408 (3.19%)  16 1/50 (2.00%)  1
Duodenal ulcer  1  1/396 (0.25%)  1 0/408 (0.00%)  0 0/50 (0.00%)  0
Duodenal ulcer haemorrhage  1  1/396 (0.25%)  1 0/408 (0.00%)  0 0/50 (0.00%)  0
Enteritis  1  0/396 (0.00%)  0 1/408 (0.25%)  1 0/50 (0.00%)  0
Gastrointestinal haemorrhage  1  1/396 (0.25%)  1 0/408 (0.00%)  0 0/50 (0.00%)  0
Haemorrhoidal haemorrhage  1  0/396 (0.00%)  0 1/408 (0.25%)  1 0/50 (0.00%)  0
Haemorrhoids  1  0/396 (0.00%)  0 1/408 (0.25%)  1 0/50 (0.00%)  0
Intestinal ischaemia  1  1/396 (0.25%)  1 0/408 (0.00%)  0 0/50 (0.00%)  0
Intestinal obstruction  1  0/396 (0.00%)  0 1/408 (0.25%)  1 0/50 (0.00%)  0
Intestinal perforation  1  2/396 (0.51%)  2 0/408 (0.00%)  0 0/50 (0.00%)  0
Lower gastrointestinal haemorrhage  1  1/396 (0.25%)  1 0/408 (0.00%)  0 0/50 (0.00%)  0
Nausea  1  1/396 (0.25%)  1 0/408 (0.00%)  0 0/50 (0.00%)  0
Oesophagitis  1  0/396 (0.00%)  0 2/408 (0.49%)  2 0/50 (0.00%)  0
Rectal haemorrhage  1  1/396 (0.25%)  1 1/408 (0.25%)  1 0/50 (0.00%)  0
Upper gastrointestinal haemorrhage  1  1/396 (0.25%)  1 0/408 (0.00%)  0 0/50 (0.00%)  0
Vomiting  1  1/396 (0.25%)  1 2/408 (0.49%)  2 0/50 (0.00%)  0
Volvulus  1  0/396 (0.00%)  0 1/408 (0.25%)  1 0/50 (0.00%)  0
Small intestinal obstruction  1  0/396 (0.00%)  0 1/408 (0.25%)  1 0/50 (0.00%)  0
General disorders       
Drowning  1  1/396 (0.25%)  1 0/408 (0.00%)  0 0/50 (0.00%)  0
Asthenia  1  0/396 (0.00%)  0 2/408 (0.49%)  2 0/50 (0.00%)  0
Chest pain  1  2/396 (0.51%)  2 1/408 (0.25%)  1 0/50 (0.00%)  0
Death  1  0/396 (0.00%)  0 1/408 (0.25%)  1 1/50 (2.00%)  1
Fatigue  1  1/396 (0.25%)  1 2/408 (0.49%)  2 0/50 (0.00%)  0
General physical health deterioration  1  2/396 (0.51%)  2 0/408 (0.00%)  0 0/50 (0.00%)  0
Influenza like illness  1  0/396 (0.00%)  0 2/408 (0.49%)  2 0/50 (0.00%)  0
Mucosal inflammation  1  1/396 (0.25%)  1 1/408 (0.25%)  1 0/50 (0.00%)  0
Pyrexia  1  3/396 (0.76%)  3 6/408 (1.47%)  6 2/50 (4.00%)  2
Hepatobiliary disorders       
Cholecystitis acute  1  0/396 (0.00%)  0 1/408 (0.25%)  1 0/50 (0.00%)  0
Cholelithiasis  1  1/396 (0.25%)  1 0/408 (0.00%)  0 0/50 (0.00%)  0
Hepatic failure  1  1/396 (0.25%)  1 0/408 (0.00%)  0 0/50 (0.00%)  0
Immune system disorders       
Anaphylactic reaction  1  1/396 (0.25%)  1 1/408 (0.25%)  1 0/50 (0.00%)  0
Drug hypersensitivity  1  3/396 (0.76%)  3 3/408 (0.74%)  3 0/50 (0.00%)  0
Hypersensitivity  1  0/396 (0.00%)  0 3/408 (0.74%)  3 0/50 (0.00%)  0
Infections and infestations       
Acute sinusitis  1  0/396 (0.00%)  0 1/408 (0.25%)  1 0/50 (0.00%)  0
Anal abscess  1  0/396 (0.00%)  0 1/408 (0.25%)  1 0/50 (0.00%)  0
Appendicitis  1  0/396 (0.00%)  0 2/408 (0.49%)  2 0/50 (0.00%)  0
Breast abscess  1  1/396 (0.25%)  1 0/408 (0.00%)  0 0/50 (0.00%)  0
Breast cellulitis  1  1/396 (0.25%)  1 0/408 (0.00%)  0 0/50 (0.00%)  0
Campylobacter gastroenteritis  1  0/396 (0.00%)  0 1/408 (0.25%)  1 0/50 (0.00%)  0
Catheter site infection  1  0/396 (0.00%)  0 1/408 (0.25%)  1 0/50 (0.00%)  0
Cellulitis  1  2/396 (0.51%)  2 10/408 (2.45%)  12 0/50 (0.00%)  0
Cellulitis gangrenous  1  0/396 (0.00%)  0 0/408 (0.00%)  0 1/50 (2.00%)  1
Clostridium difficile colitis  1  0/396 (0.00%)  0 1/408 (0.25%)  1 0/50 (0.00%)  0
Coccidioidomycosis  1  1/396 (0.25%)  1 0/408 (0.00%)  0 0/50 (0.00%)  0
Vascular device infection  1  1/396 (0.25%)  1 2/408 (0.49%)  2 0/50 (0.00%)  0
Diarrhoea infectious  1  0/396 (0.00%)  0 1/408 (0.25%)  1 0/50 (0.00%)  0
Erysipelas  1  0/396 (0.00%)  0 2/408 (0.49%)  2 0/50 (0.00%)  0
Gastroenteritis  1  2/396 (0.51%)  3 2/408 (0.49%)  2 0/50 (0.00%)  0
Gastrointestinal infection  1  1/396 (0.25%)  1 0/408 (0.00%)  0 0/50 (0.00%)  0
H1N1 influenza  1  0/396 (0.00%)  0 1/408 (0.25%)  1 0/50 (0.00%)  0
Herpes zoster  1  3/396 (0.76%)  3 1/408 (0.25%)  1 0/50 (0.00%)  0
Infection  1  1/396 (0.25%)  1 0/408 (0.00%)  0 0/50 (0.00%)  0
Lower respiratory tract infection  1  0/396 (0.00%)  0 4/408 (0.98%)  4 0/50 (0.00%)  0
Lymph node tuberculosis  1  0/396 (0.00%)  0 0/408 (0.00%)  0 1/50 (2.00%)  1
Neutropenic infection  1  1/396 (0.25%)  1 4/408 (0.98%)  4 0/50 (0.00%)  0
Neutropenic sepsis  1  2/396 (0.51%)  2 0/408 (0.00%)  0 0/50 (0.00%)  0
Onychomycosis  1  1/396 (0.25%)  1 0/408 (0.00%)  0 0/50 (0.00%)  0
Oral candidiasis  1  0/396 (0.00%)  0 1/408 (0.25%)  1 0/50 (0.00%)  0
Osteomyelitis  1  0/396 (0.00%)  0 1/408 (0.25%)  1 0/50 (0.00%)  0
Osteomyelitis chronic  1  1/396 (0.25%)  1 0/408 (0.00%)  0 0/50 (0.00%)  0
Pharyngitis  1  0/396 (0.00%)  0 2/408 (0.49%)  2 0/50 (0.00%)  0
Pneumonia  1  11/396 (2.78%)  11 7/408 (1.72%)  7 1/50 (2.00%)  1
Pneumonia staphylococcal  1  0/396 (0.00%)  1/408 (0.25%)  0/50 (0.00%) 
Postoperative wound infection  1  0/396 (0.00%)  0 1/408 (0.25%)  1 0/50 (0.00%)  0
Pyelonephritis acute  1  1/396 (0.25%)  1 0/408 (0.00%)  0 0/50 (0.00%)  0
Rash pustular  1  0/396 (0.00%)  0 1/408 (0.25%)  1 0/50 (0.00%)  0
Respiratory tract infection  1  1/396 (0.25%)  1 1/408 (0.25%)  1 0/50 (0.00%)  0
Respiratory tract infection viral  1  0/396 (0.00%)  0 1/408 (0.25%)  1 0/50 (0.00%)  0
Sepsis  1  3/396 (0.76%)  3 1/408 (0.25%)  1 0/50 (0.00%)  0
Sepsis syndrome  1  0/396 (0.00%)  0 1/408 (0.25%)  1 0/50 (0.00%)  0
Septic shock  1  1/396 (0.25%)  1 1/408 (0.25%)  1 0/50 (0.00%)  0
Skin infection  1  0/396 (0.00%)  0 1/408 (0.25%)  1 0/50 (0.00%)  0
Soft tissue infection  1  0/396 (0.00%)  0 1/408 (0.25%)  1 0/50 (0.00%)  0
Upper respiratory tract infection  1  0/396 (0.00%)  0 2/408 (0.49%)  2 0/50 (0.00%)  0
Urinary tract infection  1  1/396 (0.25%)  1 3/408 (0.74%)  3 0/50 (0.00%)  0
Urosepsis  1  0/396 (0.00%)  0 2/408 (0.49%)  2 0/50 (0.00%)  0
Viral infection  1  2/396 (0.51%)  2 0/408 (0.00%)  0 0/50 (0.00%)  0
Wound infection  1  1/396 (0.25%)  1 0/408 (0.00%)  0 0/50 (0.00%)  0
Wound infection staphylococcal  1  1/396 (0.25%)  1 0/408 (0.00%)  0 0/50 (0.00%)  0
Acute hepatitis B  1  0/396 (0.00%)  0 0/408 (0.00%)  0 1/50 (2.00%)  1
Pyelonephritis  1  0/396 (0.00%)  0 0/408 (0.00%)  0 1/50 (2.00%)  1
Groin abscess  1  0/396 (0.00%)  0 1/408 (0.25%)  1 0/50 (0.00%)  0
Pharyngotonsillitis  1  1/396 (0.25%)  1 0/408 (0.00%)  0 0/50 (0.00%)  0
Urinary tract infection bacterial  1  0/396 (0.00%)  0 1/408 (0.25%)  1 0/50 (0.00%)  0
Injury, poisoning and procedural complications       
Compression fracture  1  0/396 (0.00%)  0 1/408 (0.25%)  1 0/50 (0.00%)  0
Contusion  1  1/396 (0.25%)  1 0/408 (0.00%)  0 0/50 (0.00%)  0
Femur fracture  1  1/396 (0.25%)  1 3/408 (0.74%)  3 0/50 (0.00%)  0
Fracture  1  0/396 (0.00%)  0 1/408 (0.25%)  1 0/50 (0.00%)  0
Post procedural discomfort  1  0/396 (0.00%)  0 1/408 (0.25%)  1 0/50 (0.00%)  0
Scapula fracture  1  0/396 (0.00%)  1/408 (0.25%)  0/50 (0.00%)  0
Tendon injury  1  0/396 (0.00%)  0 1/408 (0.25%)  1 0/50 (0.00%)  0
Thermal burn  1  1/396 (0.25%)  1 0/408 (0.00%)  0 0/50 (0.00%)  0
Tibia fracture  1  0/396 (0.00%)  0 1/408 (0.25%)  1 0/50 (0.00%)  0
Hip fracture  1  0/396 (0.00%)  0 1/408 (0.25%)  1 0/50 (0.00%)  0
Tendon rupture  1  0/396 (0.00%)  0 1/408 (0.25%)  1 0/50 (0.00%)  0
Upper limb fracture  1  0/396 (0.00%)  0 1/408 (0.25%)  1 0/50 (0.00%)  0
Investigations       
Blood electrolytes abnormal  1  0/396 (0.00%)  0 1/408 (0.25%)  1 0/50 (0.00%)  0
Blood glucose increased  1  0/396 (0.00%)  0 1/408 (0.25%)  1 0/50 (0.00%)  0
Ejection fraction decreased  1  1/396 (0.25%)  1 0/408 (0.00%)  0 0/50 (0.00%)  0
Metabolism and nutrition disorders       
Decreased appetite  1  0/396 (0.00%)  0 1/408 (0.25%)  1 0/50 (0.00%)  0
Dehydration  1  2/396 (0.51%)  2 1/408 (0.25%)  1 1/50 (2.00%)  1
Diabetes mellitus  1  1/396 (0.25%)  1 0/408 (0.00%)  0 0/50 (0.00%)  0
Fluid retention  1  0/396 (0.00%)  0 1/408 (0.25%)  1 0/50 (0.00%)  0
Hyperglycaemia  1  0/396 (0.00%)  0 1/408 (0.25%)  1 0/50 (0.00%)  0
Hypoglycaemia  1  0/396 (0.00%)  0 1/408 (0.25%)  1 0/50 (0.00%)  0
Musculoskeletal and connective tissue disorders       
Back pain  1  1/396 (0.25%)  1 2/408 (0.49%)  2 0/50 (0.00%)  0
Mobility decreased  1  0/396 (0.00%)  0 1/408 (0.25%)  1 0/50 (0.00%)  0
Muscular weakness  1  0/396 (0.00%)  0 1/408 (0.25%)  1 0/50 (0.00%)  0
Myalgia  1  1/396 (0.25%)  1 1/408 (0.25%)  1 0/50 (0.00%)  0
Neck pain  1  1/396 (0.25%)  1 0/408 (0.00%)  0 0/50 (0.00%)  0
Osteonecrosis of jaw  1  0/396 (0.00%)  0 2/408 (0.49%)  2 0/50 (0.00%)  0
Neoplasms benign, malignant and unspecified (incl cysts and polyps)       
Breast cancer  1  1/396 (0.25%)  1 0/408 (0.00%)  0 0/50 (0.00%)  0
Colon cancer  1  0/396 (0.00%)  0 1/408 (0.25%)  1 0/50 (0.00%)  0
Endometrial cancer  1  0/396 (0.00%)  0 1/408 (0.25%)  1 0/50 (0.00%)  0
Glioblastoma multiforme  1  1/396 (0.25%)  1 0/408 (0.00%)  0 0/50 (0.00%)  0
Ocular neoplasm  1  0/396 (0.00%)  0 1/408 (0.25%)  1 0/50 (0.00%)  0
Pituitary tumour benign  1  0/396 (0.00%)  0 1/408 (0.25%)  1 0/50 (0.00%)  0
Tumour haemorrhage  1  0/396 (0.00%)  0 1/408 (0.25%)  1 0/50 (0.00%)  0
Uterine leiomyoma  1  0/396 (0.00%)  0 1/408 (0.25%)  1 0/50 (0.00%)  0
Nervous system disorders       
Cerebrovascular accident  1  1/396 (0.25%)  1 1/408 (0.25%)  1 0/50 (0.00%)  0
Seizure  1  1/396 (0.25%)  1 0/408 (0.00%)  0 0/50 (0.00%)  0
Monoparesis  1  0/396 (0.00%)  0 1/408 (0.25%)  1 0/50 (0.00%)  0
Peripheral sensorimotor neuropathy  1  1/396 (0.25%)  1 0/408 (0.00%)  0 0/50 (0.00%)  0
Somnolence  1  0/396 (0.00%)  0 1/408 (0.25%)  1 0/50 (0.00%)  0
Spinal cord compression  1  1/396 (0.25%)  1 0/408 (0.00%)  0 0/50 (0.00%)  0
Syncope  1  0/396 (0.00%)  0 1/408 (0.25%)  1 0/50 (0.00%)  0
Facial paralysis  1  1/396 (0.25%)  1 0/408 (0.00%)  0 0/50 (0.00%)  0
Cerebral haematoma  1  0/396 (0.00%)  0 1/408 (0.25%)  1 0/50 (0.00%)  0
Headache  1  0/396 (0.00%)  0 1/408 (0.25%)  1 0/50 (0.00%)  0
Loss of consciousness  1  0/396 (0.00%)  0 1/408 (0.25%)  1 0/50 (0.00%)  0
Pregnancy, puerperium and perinatal conditions       
Abortion spontaneous  1  0/396 (0.00%)  0 1/408 (0.25%)  1 0/50 (0.00%)  0
Psychiatric disorders       
Suicide attempt  1  0/396 (0.00%)  0 1/408 (0.25%)  1 0/50 (0.00%)  0
Renal and urinary disorders       
Haematuria  1  0/396 (0.00%)  0 1/408 (0.25%)  1 0/50 (0.00%)  0
Nephrolithiasis  1  0/396 (0.00%)  0 1/408 (0.25%)  1 0/50 (0.00%)  0
Renal failure  1  1/396 (0.25%)  1 1/408 (0.25%)  1 0/50 (0.00%)  0
Chronic kidney disease  1  0/396 (0.00%)  0 0/408 (0.00%)  0 1/50 (2.00%)  1
Acute kidney injury  1  2/396 (0.51%)  2 2/408 (0.49%)  2 0/50 (0.00%)  0
Reproductive system and breast disorders       
Breast haemorrhage  1  1/396 (0.25%)  2 0/408 (0.00%)  0 0/50 (0.00%)  0
Metrorrhagia  1  0/396 (0.00%)  0 1/408 (0.25%)  1 0/50 (0.00%)  0
Vaginal haemorrhage  1  0/396 (0.00%)  0 1/408 (0.25%)  1 0/50 (0.00%)  0
Respiratory, thoracic and mediastinal disorders       
Asthma  1