臨床試験Nctページ

Clinical Trial Results:
Multicenter Phase III Randomized Trial Comparing Doxorubicin and Cyclophosphamide Followed by Docetaxel (AC-T) With Doxorubicin and Cyclophosphamide Followed by Docetaxel and Trastuzumab (Herceptin®) (AC-TH) and With Docetaxel, Carboplatin and Trastuzumab (TCH) in the Adjuvant Treatment of Node Positive and High Risk Node Negative Patients With Operable Breast Cancer Containing the HER2 Alteration

Summary
EudraCT number
 2008-005127-29
Trial protocol
 HU   SK  
Global end of trial date
30 Dec 2014

Results information
Results version number
 v1(current)
This version publication date
02 Jul 2016
First version publication date
02 Jul 2016
Other versions

Trial information

 Close Top of page
Trial identification
Sponsor protocol code
TAX_GMA_302
Additional study identifiers
ISRCTN number
 -
US NCT number
 NCT00021255
WHO universal trial number (UTN)
 -
Sponsors
Sponsor organisation name
Sanofi aventis recherche & développement
Sponsor organisation address
1 avenue Pierre Brossolette, Chilly-Mazarin, France, 91380
Public contact
Trial Transparency Team, Sanofi aventis recherche & développement, Contact-US@sanofi.com
Scientific contact
Trial Transparency Team, Sanofi aventis recherche & développement, Contact-US@sanofi.com
Paediatric regulatory details
Is trial part of an agreed paediatric investigation plan (PIP)
No
Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?
No
Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?
No
Results analysis stage
Analysis stage
Final
Date of interim/final analysis
17 Feb 2015
Is this the analysis of the primary completion data?
No
Global end of trial reached?
Yes
Global end of trial date
30 Dec 2014
Was the trial ended prematurely?
No
General information about the trial
Main objective of the trial
To compare disease-free survival after treatment with doxorubicin and cyclophosphamide followed by docetaxel (Taxotere®) (AC-T) with doxorubicin and cyclophosphamide followed by docetaxel and trastuzumab (Herceptin®) (AC-TH) and with docetaxel in combination with carboplatin and Herceptin® (TCH) in the adjuvant treatment of node positive and high risk node negative subjects with operable breast cancer containing the human epidermal growth factor receptor 2 (HER2) alteration.
Protection of trial subjects
Subjects were fully informed of all pertinent aspects of the clinical trial as well as the possibility to discontinue at any time in language and terms appropriate for the subject and considering the local culture. During the course of the trial, subjects were provided with individual subject cards indicating the nature of the trial the subject is participating, contact details and any information needed in the event of a medical emergency. Collected personal data and human biological samples were processed in compliance with the Sanofi-Aventis Group Personal Data Protection Charter ensuring that the Group abides by the laws governing personal data protection in force in all countries in which it operates.
Background therapy
 -
Evidence for comparator
 -
Actual start date of recruitment
05 Apr 2001
Long term follow-up planned
No
Independent data monitoring committee (IDMC) involvement?
No
Population of trial subjects
Number of subjects enrolled per country
Country: Number of subjects enrolled
Slovakia: 20
Country: Number of subjects enrolled
Slovenia: 22
Country: Number of subjects enrolled
South Africa: 49
Country: Number of subjects enrolled
Spain: 90
Country: Number of subjects enrolled
Sweden: 29
Country: Number of subjects enrolled
Switzerland: 2
Country: Number of subjects enrolled
Taiwan: 57
Country: Number of subjects enrolled
Tunisia: 4
Country: Number of subjects enrolled
Turkey: 14
Country: Number of subjects enrolled
United Kingdom: 25
Country: Number of subjects enrolled
United States: 990
Country: Number of subjects enrolled
Uruguay: 7
Country: Number of subjects enrolled
Venezuela, Bolivarian Republic of: 4
Country: Number of subjects enrolled
Argentina: 23
Country: Number of subjects enrolled
Australia: 293
Country: Number of subjects enrolled
Austria: 14
Country: Number of subjects enrolled
Belgium: 68
Country: Number of subjects enrolled
Bosnia and Herzegovina: 3
Country: Number of subjects enrolled
Brazil: 25
Country: Number of subjects enrolled
Bulgaria: 15
Country: Number of subjects enrolled
Canada: 143
Country: Number of subjects enrolled
Colombia: 6
Country: Number of subjects enrolled
Croatia: 41
Country: Number of subjects enrolled
Cyprus: 3
Country: Number of subjects enrolled
Czech Republic: 23
Country: Number of subjects enrolled
Egypt: 17
Country: Number of subjects enrolled
Estonia: 11
Country: Number of subjects enrolled
France: 129
Country: Number of subjects enrolled
Germany: 313
Country: Number of subjects enrolled
Greece: 2
Country: Number of subjects enrolled
Hong Kong: 18
Country: Number of subjects enrolled
Hungary: 60
Country: Number of subjects enrolled
India: 18
Country: Number of subjects enrolled
Ireland: 129
Country: Number of subjects enrolled
Israel: 61
Country: Number of subjects enrolled
Italy: 26
Country: Number of subjects enrolled
Korea, Republic of: 64
Country: Number of subjects enrolled
Lebanon: 42
Country: Number of subjects enrolled
Mexico: 5
Country: Number of subjects enrolled
New Zealand: 32
Country: Number of subjects enrolled
Poland: 260
Country: Number of subjects enrolled
Romania: 35
Country: Number of subjects enrolled
Russian Federation: 30
Worldwide total number of subjects
3222
EEA total number of subjects
1315
Number of subjects enrolled per age group
In utero
0
Preterm newborn - gestational age
0
Newborns (0-27 days)
0
Infants and toddlers (28 days-23 months)
0
Children (2-11 years)
0
Adolescents (12-17 years)
0
Adults (18-64 years)
3028
From 65 to 84 years
194
85 years and over
0

Subject disposition

 Close Top of page
Recruitment
Recruitment details
 The study was conducted at 433 centers in 43 countries. A total of 3222 subjects were randomized between 05 April 2001 and 30 March 2004.

Pre-assignment
Screening details
 Subjects were stratified according to institution, nodal status (negative, positive 1-3 nodes, positive 4 or more nodes), hormonal receptor status (estrogen and/or progesterone receptor positive versus negative) and randomized in 1:1:1 ratio to receive adjuvant therapy with either AC→ T, AC→ TH or TCH.

Period 1
Period 1 title
Overall Study (overall period)
Is this the baseline period?
 Yes
Allocation method
Randomised - controlled
Blinding used
 Not blinded

Arms
Are arms mutually exclusive
Yes

Arm title
 Doxorubicin+Cyclophosphamide (AC) Followed by Docetaxel (AC→T)
Arm description
 Doxorubicin in combination with cyclophosphamide on Day 1 of every 3 weeks for 4 cycles followed by docetaxel every 3 weeks for another 4 cycles.
Arm type
 Experimental

Investigational medicinal product name
Doxorubicin
Investigational medicinal product code
Other name
Pharmaceutical forms
Concentrate for solution for injection/infusion
Routes of administration
Intravenous use
Dosage and administration details
Doxorubicin 60 mg/m² over 5-15 minutes by intravenous (IV) bolus injection every 3 weeks.

Investigational medicinal product name
Cyclophosphamide
Investigational medicinal product code
Other name
Pharmaceutical forms
Concentrate for solution for injection/infusion
Routes of administration
Intravenous use
Dosage and administration details
Cyclophosphamide 600 mg/m² over 5-60 minutes by IV bolus injection every 3 weeks.

Investigational medicinal product name
Docetaxel
Investigational medicinal product code
Other name
Taxotere®
Pharmaceutical forms
Concentrate for solution for injection/infusion
Routes of administration
Intravenous use
Dosage and administration details
Docetaxel 100 mg/m² over 1 hour by IV infusion every 3 weeks.

Arm title
 AC Followed by Docetaxel + Herceptin (AC→TH)
Arm description
 Doxorubicin in combination with cyclophosphamide on Day 1 of every 3 weeks for 4 cycles. Herceptin on Day 1 of Cycle 5, followed by Herceptin weekly starting from Day 8; and docetaxel on Day 2 of Cycle 5, then on Day 1 of every 3 weeks for all subsequent cycles (total 4 cycles). After completion of the last cycle of chemotherapy, Herceptin infusion was administered every 3 weeks until 1 year from date of initial Herceptin dose.
Arm type
 Experimental

Investigational medicinal product name
Doxorubicin
Investigational medicinal product code
Other name
Pharmaceutical forms
Concentrate for solution for injection/infusion
Routes of administration
Intravenous use
Dosage and administration details
Doxorubicin 60 mg/m²over 5-15 minutes by IV bolus injection every 3 weeks.

Investigational medicinal product name
Cyclophosphamide
Investigational medicinal product code
Other name
Pharmaceutical forms
Concentrate for solution for injection/infusion
Routes of administration
Intravenous use
Dosage and administration details
Cyclophosphamide 600 mg/m² over 5-60 minutes by IV bolus injection every 3 weeks.

Investigational medicinal product name
Docetaxel
Investigational medicinal product code
Other name
Taxotere®
Pharmaceutical forms
Concentrate for solution for injection/infusion
Routes of administration
Intravenous use
Dosage and administration details
Docetaxel 100 mg/m² over 1 hour by IV infusion on day 2 for the first cycle and on day 1 for all subsequent cycles.

Investigational medicinal product name
Herceptin®
Investigational medicinal product code
Other name
Trastuzumab
Pharmaceutical forms
Concentrate for solution for injection/infusion
Routes of administration
Intravenous use
Dosage and administration details
Herceptin 4 mg/kg by IV infusion over 90 minutes on Day 1 followed by Herceptin 2 mg/kg by IV infusion over 30 minutes on Day 8 and 15 respectively. After completion of the last cycle, subjects received Herceptin 6 mg/kg over 30 minutes by IV infusion every 3 weeks until 1 year from date of initial Herceptin dose.

Arm title
 Docetaxel + Carboplatin + Herceptin (TCH)
Arm description
 Herceptin on Day 1 of Cycle 1 only, followed by Herceptin weekly starting from Day 8 until three weeks after the last cycle of chemotherapy. Docetaxel on Day 2 of Cycle 1, then on Day 1 of all subsequent cycles followed by carboplatin repeated every 3 weeks for a total of 6 cycles. After completion of the last cycle of chemotherapy, Herceptin was administered every 3 weeks until 1 year from date of initial Herceptin dose.
Arm type
 Experimental

Investigational medicinal product name
Herceptin®
Investigational medicinal product code
Other name
Trastuzumab
Pharmaceutical forms
Concentrate for solution for injection/infusion
Routes of administration
Intravenous use
Dosage and administration details
Herceptin 4 mg/kg by IV infusion over 90 minutes on Day 1 and 2 mg/kg by IV infusion over 30 minutes on Day 8 and 15 respectively for first cycle. Herceptin 2 mg/kg by IV infusion over 30 minutes on Day1, 8 and 15 for all subsequent cycles. After completion of the last cycle, Herceptin 6 mg/kg by IV infusion over 30 minutes was given every 3 weeks until 1 year from date of initial Herceptin dose.

Investigational medicinal product name
Docetaxel
Investigational medicinal product code
Other name
Taxotere®
Pharmaceutical forms
Concentrate for solution for injection/infusion
Routes of administration
Intravenous use
Dosage and administration details
Docetaxel 75 mg/m² by IV infusion over 1 hour on Day 2 for the first cycle and on Day 1 for all subsequent cycles.

Investigational medicinal product name
Carboplatin
Investigational medicinal product code
Other name
Pharmaceutical forms
Concentrate for solution for injection/infusion
Routes of administration
Intravenous use
Dosage and administration details
Carboplatin at target AUC = 6 mg/mL/min by IV infusion over 30-60 minutes on Day 2 for the first cycle and on Day 1 for all subsequent cycles.

Number of subjects in period 1
Doxorubicin+Cyclophosphamide (AC) Followed by Docetaxel (AC→T) AC Followed by Docetaxel + Herceptin (AC→TH) Docetaxel + Carboplatin + Herceptin (TCH)
Started
1073
1074
1075
Treated
1045
1072
1057
Completed
952
804
926
Not completed
121
270
149
     Randomized but not treated
28
2
18
     Death
1
-
2
     Missing
-
27
13
     Second primary malignancy
-
4
1
     Withdrawal by Subject
41
64
26
     Herceptin toxicity
-
22
6
     Protocol Violation
-
2
-
     Cardiac toxicity
-
61
32
     Other than specified above
-
38
19
     Adverse Event
46
30
18
     Lost to Follow-up
-
2
3
     Breast cancer relapse
5
18
11

Baseline characteristics

 Close Top of page
Baseline characteristics reporting groups
Reporting group title
Doxorubicin+Cyclophosphamide (AC) Followed by Docetaxel (AC→T)
Reporting group description
 Doxorubicin in combination with cyclophosphamide on Day 1 of every 3 weeks for 4 cycles followed by docetaxel every 3 weeks for another 4 cycles.

Reporting group title
AC Followed by Docetaxel + Herceptin (AC→TH)
Reporting group description
 Doxorubicin in combination with cyclophosphamide on Day 1 of every 3 weeks for 4 cycles. Herceptin on Day 1 of Cycle 5, followed by Herceptin weekly starting from Day 8; and docetaxel on Day 2 of Cycle 5, then on Day 1 of every 3 weeks for all subsequent cycles (total 4 cycles). After completion of the last cycle of chemotherapy, Herceptin infusion was administered every 3 weeks until 1 year from date of initial Herceptin dose.

Reporting group title
Docetaxel + Carboplatin + Herceptin (TCH)
Reporting group description
 Herceptin on Day 1 of Cycle 1 only, followed by Herceptin weekly starting from Day 8 until three weeks after the last cycle of chemotherapy. Docetaxel on Day 2 of Cycle 1, then on Day 1 of all subsequent cycles followed by carboplatin repeated every 3 weeks for a total of 6 cycles. After completion of the last cycle of chemotherapy, Herceptin was administered every 3 weeks until 1 year from date of initial Herceptin dose.

Reporting group values
 Doxorubicin+Cyclophosphamide (AC) Followed by Docetaxel (AC→T) AC Followed by Docetaxel + Herceptin (AC→TH) Docetaxel + Carboplatin + Herceptin (TCH) Total
Number of subjects
 1073 1074 1075 3222
Age categorical
Units: Subjects
Age continuous
Units: years
    arithmetic mean (standard deviation)
 48.8 ± 9.7 48.7 ± 9.7 48.6 ± 9.9 -
Gender categorical
Units: Subjects
    Female
 1073 1074 1075 3222
    Male
 0 0 0 0

End points

 Close Top of page
End points reporting groups
Reporting group title
Doxorubicin+Cyclophosphamide (AC) Followed by Docetaxel (AC→T)
Reporting group description
 Doxorubicin in combination with cyclophosphamide on Day 1 of every 3 weeks for 4 cycles followed by docetaxel every 3 weeks for another 4 cycles.

Reporting group title
AC Followed by Docetaxel + Herceptin (AC→TH)
Reporting group description
 Doxorubicin in combination with cyclophosphamide on Day 1 of every 3 weeks for 4 cycles. Herceptin on Day 1 of Cycle 5, followed by Herceptin weekly starting from Day 8; and docetaxel on Day 2 of Cycle 5, then on Day 1 of every 3 weeks for all subsequent cycles (total 4 cycles). After completion of the last cycle of chemotherapy, Herceptin infusion was administered every 3 weeks until 1 year from date of initial Herceptin dose.

Reporting group title
Docetaxel + Carboplatin + Herceptin (TCH)
Reporting group description
 Herceptin on Day 1 of Cycle 1 only, followed by Herceptin weekly starting from Day 8 until three weeks after the last cycle of chemotherapy. Docetaxel on Day 2 of Cycle 1, then on Day 1 of all subsequent cycles followed by carboplatin repeated every 3 weeks for a total of 6 cycles. After completion of the last cycle of chemotherapy, Herceptin was administered every 3 weeks until 1 year from date of initial Herceptin dose.

Primary: Percentage of Subjects With Disease Free Survival at 5 Years

 Close Top of page
End point title
 Percentage of Subjects With Disease Free Survival at 5 Years [1]
End point description
Disease Free Survival was defined as the interval from the date of randomization to the date of local, regional or metastatic relapse or the date of second primary cancer (with the exception of curatively treated non-melanoma skin cancer or in situ carcinoma of the cervix) or death from any cause whichever occured first. Disease free survival was estimated using the Kaplan-Meier method. Analysis was performed on Intent-To-Treat (ITT) population that included all randomized subjects.
End point type
Primary
End point timeframe
From randomization until relapse or death or up to 5 years.
Notes
[1] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
Justification: Only descriptive statistical analyses were performed: “Kaplan-Meier analysis, including landmark estimates of 1- to 10-year survival probabilities, median times and graph was performed”.
End point values
 Doxorubicin+Cyclophosphamide (AC) Followed by Docetaxel (AC→T) AC Followed by Docetaxel + Herceptin (AC→TH) Docetaxel + Carboplatin + Herceptin (TCH)
Number of subjects analysed
1073
1074
1074
Units: Percentage of Subjects
    number (confidence interval 95%)
75.5 (72.8 to 78.2)
83.2 (80.9 to 85.4)
81 (78.6 to 83.4)
No statistical analyses for this end point

Secondary: Percentage of Subjects With Disease Free Survival at 10 Years

 Close Top of page
End point title
 Percentage of Subjects With Disease Free Survival at 10 Years
End point description
Disease free survival was defined as the interval from the date of randomization to the date of local, regional or metastatic relapse or the date of second primary cancer (with the exception of curatively treated non-melanoma skin cancer or in situ carcinoma of the cervix) or death from any cause whichever occured first. Disease free survival was estimated using the Kaplan-Meier method. Analysis was performed on ITT population.
End point type
Secondary
End point timeframe
From randomization until relapse or death or up to 10 years.
End point values
 Doxorubicin+Cyclophosphamide (AC) Followed by Docetaxel (AC→T) AC Followed by Docetaxel + Herceptin (AC→TH) Docetaxel + Carboplatin + Herceptin (TCH)
Number of subjects analysed
1073
1074
1075
Units: Percentage of Subjects
    number (confidence interval 95%)
67.2 (64.2 to 70.2)
73.4 (70.6 to 76.2)
72.3 (69.4 to 75.1)
No statistical analyses for this end point

Secondary: Overall Survival- Percentage of Subjects who Survived at 10 Years

 Close Top of page
End point title
 Overall Survival- Percentage of Subjects who Survived at 10 Years
End point description
Overall survival of the subjects was measured from the date of randomization up to the date of death due to any cause. Overall survival was estimated using the Kaplan-Meier method. Analysis was performed on ITT population.
End point type
Secondary
End point timeframe
From randomization until death or up to 10 years
End point values
 Doxorubicin+Cyclophosphamide (AC) Followed by Docetaxel (AC→T) AC Followed by Docetaxel + Herceptin (AC→TH) Docetaxel + Carboplatin + Herceptin (TCH)
Number of subjects analysed
1073
1074
1075
Units: Percentage of Subjects
    number (confidence interval 95%)
78.9 (76.2 to 81.5)
86 (83.8 to 88.2)
83.4 (81 to 85.8)
No statistical analyses for this end point

Adverse events

 Close Top of page
Adverse events information
Timeframe for reporting adverse events
All Adverse Events (AE) were collected from the time the subject started treatment with study drug until 30 days after the last infusion of study treatment (chemotherapy or Herceptin)
Adverse event reporting additional description
Reported AEs & deaths are treatment-emergent that is AEs that developed/worsened & deaths that occurred during 'on treatment period' (from first infusion of study drug until 30 days after last infusion of study drug). Safety population included all treated subjects. Source vocabulary used to define AE term: Pooled NCI-CTC v 2.0 and COSTART v 5.0
Assessment type
 Systematic
Dictionary used for adverse event reporting
Dictionary name
 NCI V2/COSTART V5
Dictionary version
2/5
Reporting groups
Reporting group title
Doxorubicin+Cyclophosphamide (AC) Followed by Docetaxel (AC→T)
Reporting group description
 Doxorubicin in combination with cyclophosphamide on Day 1 of every 3 weeks for 4 cycles followed by docetaxel every 3 weeks for another 4 cycles.

Reporting group title
Docetaxel + Carboplatin + Herceptin (TCH)
Reporting group description
 Herceptin on Day 1 of Cycle 1 only, followed by Herceptin weekly starting from Day 8 until three weeks after the last cycle of chemotherapy. Docetaxel on Day 2 of Cycle 1, then on Day 1 of all subsequent cycles followed by carboplatin repeated every 3 weeks for a total of 6 cycles. After completion of the last cycle of chemotherapy, Herceptin was administered every 3 weeks until 1 year from date of initial Herceptin dose.

Reporting group title
AC Followed by Docetaxel + Herceptin (AC→TH)
Reporting group description
 Doxorubicin in combination with cyclophosphamide on Day 1 of every 3 weeks for 4 cycles. Herceptin on Day 1 of Cycle 5, followed by Herceptin weekly starting from Day 8; and docetaxel on Day 2 of Cycle 5, then on Day 1 of every 3 weeks for all subsequent cycles (total 4 cycles). After completion of the last cycle of chemotherapy, Herceptin infusion was administered every 3 weeks until 1 year from date of initial Herceptin dose.

Serious adverse events
 Doxorubicin+Cyclophosphamide (AC) Followed by Docetaxel (AC→T) Docetaxel + Carboplatin + Herceptin (TCH) AC Followed by Docetaxel + Herceptin (AC→TH)
Total subjects affected by serious adverse events
     subjects affected / exposed
218 / 1018 (21.41%)
283 / 1056 (26.80%)
298 / 1100 (27.09%)
     number of deaths (all causes)
194
163
148
     number of deaths resulting from adverse events
Cardiac disorders
Angina Pectoris
     subjects affected / exposed
0 / 1018 (0.00%)
1 / 1056 (0.09%)
1 / 1100 (0.09%)
     occurrences causally related to treatment / all
0 / 0
0 / 1
0 / 1
     deaths causally related to treatment / all
0 / 0
0 / 0
0 / 0
Aortic Stenosis
     subjects affected / exposed
0 / 1018 (0.00%)
1 / 1056 (0.09%)
0 / 1100 (0.00%)
     occurrences causally related to treatment / all
0 / 0
0 / 1
0 / 0
     deaths causally related to treatment / all
0 / 0
0 / 0
0 / 0
Arrhythmia
     subjects affected / exposed
2 / 1018 (0.20%)
3 / 1056 (0.28%)
3 / 1100 (0.27%)
     occurrences causally related to treatment / all
1 / 3
2 / 4
3 / 6
     deaths causally related to treatment / all
0 / 0
0 / 0
0 / 0
Arterial Anomaly
     subjects affected / exposed
0 / 1018 (0.00%)
1 / 1056 (0.09%)
0 / 1100 (0.00%)
     occurrences causally related to treatment / all
0 / 0
0 / 1
0 / 0
     deaths causally related to treatment / all
0 / 0
0 / 0
0 / 0
Av Block
     subjects affected / exposed
0 / 1018 (0.00%)
1 / 1056 (0.09%)
0 / 1100 (0.00%)
     occurrences causally related to treatment / all
0 / 0
0 / 1
0 / 0
     deaths causally related to treatment / all
0 / 0
0 / 0
0 / 0
Cardiomyopathy
     subjects affected / exposed
0 / 1018 (0.00%)
1 / 1056 (0.09%)
2 / 1100 (0.18%)
     occurrences causally related to treatment / all
0 / 0
1 / 1
0 / 3
     deaths causally related to treatment / all
0 / 0
0 / 0
0 / 0
Cardiovascular Disorder
     subjects affected / exposed
2 / 1018 (0.20%)
0 / 1056 (0.00%)
0 / 1100 (0.00%)
     occurrences causally related to treatment / all
2 / 2
0 / 0
0 / 0
     deaths causally related to treatment / all
0 / 0
0 / 0
0 / 0
Carotid Occlusion
     subjects affected / exposed
0 / 1018 (0.00%)
0 / 1056 (0.00%)
1 / 1100 (0.09%)
     occurrences causally related to treatment / all
0 / 0
0 / 0
0 / 3
     deaths causally related to treatment / all
0 / 0
0 / 0
0 / 0
Cerebrovascular Accident
     subjects affected / exposed
0 / 1018 (0.00%)
3 / 1056 (0.28%)
1 / 1100 (0.09%)
     occurrences causally related to treatment / all
0 / 0
0 / 3
1 / 1
     deaths causally related to treatment / all
0 / 0
0 / 0
0 / 0
Deep Thrombophlebitis
     subjects affected / exposed
6 / 1018 (0.59%)
15 / 1056 (1.42%)
13 / 1100 (1.18%)
     occurrences causally related to treatment / all
4 / 9
5 / 19
2 / 13
     deaths causally related to treatment / all
0 / 0
0 / 0
0 / 0
Electrocardiogram Abnormal
     subjects affected / exposed
0 / 1018 (0.00%)
1 / 1056 (0.09%)
0 / 1100 (0.00%)
     occurrences causally related to treatment / all
0 / 0
1 / 1
0 / 0
     deaths causally related to treatment / all
0 / 0
0 / 0
0 / 0
Heart Arrest
     subjects affected / exposed
0 / 1018 (0.00%)
1 / 1056 (0.09%)
2 / 1100 (0.18%)
     occurrences causally related to treatment / all
0 / 0
1 / 1
0 / 2
     deaths causally related to treatment / all
0 / 0
1 / 1
0 / 1
Heart Failure
     subjects affected / exposed
0 / 1018 (0.00%)
0 / 1056 (0.00%)
1 / 1100 (0.09%)
     occurrences causally related to treatment / all
0 / 0
0 / 0
0 / 1
     deaths causally related to treatment / all
0 / 0
0 / 0
0 / 0
Hemorrhage
     subjects affected / exposed
0 / 1018 (0.00%)
2 / 1056 (0.19%)
2 / 1100 (0.18%)
     occurrences causally related to treatment / all
0 / 0
0 / 4
0 / 3
     deaths causally related to treatment / all
0 / 0
0 / 0
0 / 0
Hypertension
     subjects affected / exposed
0 / 1018 (0.00%)
1 / 1056 (0.09%)
0 / 1100 (0.00%)
     occurrences causally related to treatment / all
0 / 0
1 / 1
0 / 0
     deaths causally related to treatment / all
0 / 0
0 / 0
0 / 0
Hypotension
     subjects affected / exposed
0 / 1018 (0.00%)
0 / 1056 (0.00%)
1 / 1100 (0.09%)
     occurrences causally related to treatment / all
0 / 0
0 / 0
2 / 2
     deaths causally related to treatment / all
0 / 0
0 / 0
0 / 0
Left Heart Failure
     subjects affected / exposed
8 / 1018 (0.79%)
2 / 1056 (0.19%)
25 / 1100 (2.27%)
     occurrences causally related to treatment / all
1 / 10
2 / 3
6 / 39
     deaths causally related to treatment / all
0 / 1
0 / 0
0 / 0
Myocardial Ischemia
     subjects affected / exposed
0 / 1018 (0.00%)
4 / 1056 (0.38%)
5 / 1100 (0.45%)
     occurrences causally related to treatment / all
0 / 0
1 / 4
0 / 6
     deaths causally related to treatment / all
0 / 0
0 / 0
0 / 0
Myocarditis
     subjects affected / exposed
1 / 1018 (0.10%)
0 / 1056 (0.00%)
0 / 1100 (0.00%)
     occurrences causally related to treatment / all
0 / 1
0 / 0
0 / 0
     deaths causally related to treatment / all
0 / 0
0 / 0
0 / 0
Palpitation
     subjects affected / exposed
0 / 1018 (0.00%)
1 / 1056 (0.09%)
3 / 1100 (0.27%)
     occurrences causally related to treatment / all
0 / 0
0 / 1
0 / 3
     deaths causally related to treatment / all
0 / 0
0 / 0
0 / 0
Pericardial Effusion
     subjects affected / exposed
1 / 1018 (0.10%)
0 / 1056 (0.00%)
0 / 1100 (0.00%)
     occurrences causally related to treatment / all
1 / 1
0 / 0
0 / 0
     deaths causally related to treatment / all
0 / 0
0 / 0
0 / 0
Phlebitis
     subjects affected / exposed
0 / 1018 (0.00%)
0 / 1056 (0.00%)
1 / 1100 (0.09%)
     occurrences causally related to treatment / all
0 / 0
0 / 0
0 / 1
     deaths causally related to treatment / all
0 / 0
0 / 0
0 / 0
Postural Hypotension
     subjects affected / exposed
0 / 1018 (0.00%)
0 / 1056 (0.00%)
1 / 1100 (0.09%)
     occurrences causally related to treatment / all
0 / 0
0 / 0
0 / 1
     deaths causally related to treatment / all
0 / 0
0 / 0
0 / 0
Syncope
     subjects affected / exposed
1 / 1018 (0.10%)
1 / 1056 (0.09%)
4 / 1100 (0.36%)
     occurrences causally related to treatment / all
0 / 1
1 / 1
1 / 4
     deaths causally related to treatment / all
0 / 0
0 / 0
0 / 1
Tachycardia
     subjects affected / exposed
2 / 1018 (0.20%)
2 / 1056 (0.19%)
0 / 1100 (0.00%)
     occurrences causally related to treatment / all
2 / 2
2 / 2
0 / 0
     deaths causally related to treatment / all
0 / 0
0 / 0
0 / 0
Vasculitis
     subjects affected / exposed
0 / 1018 (0.00%)
0 / 1056 (0.00%)
1 / 1100 (0.09%)
     occurrences causally related to treatment / all
0 / 0
0 / 0
1 / 1
     deaths causally related to treatment / all
0 / 0
0 / 0
0 / 0
Ventricular Arrhythmia
     subjects affected / exposed
0 / 1018 (0.00%)
0 / 1056 (0.00%)
1 / 1100 (0.09%)
     occurrences causally related to treatment / all
0 / 0
0 / 0
0 / 1
     deaths causally related to treatment / all
0 / 0
0 / 0
0 / 0
Respiratory, thoracic and mediastinal disorders
Apnea
     subjects affected / exposed
0 / 1018 (0.00%)
1 / 1056 (0.09%)
0 / 1100 (0.00%)
     occurrences causally related to treatment / all
0 / 0
0 / 1
0 / 0
     deaths causally related to treatment / all
0 / 0
0 / 0
0 / 0
Asthma
     subjects affected / exposed
0 / 1018 (0.00%)
2 / 1056 (0.19%)
1 / 1100 (0.09%)
     occurrences causally related to treatment / all
0 / 0
0 / 3
0 / 1
     deaths causally related to treatment / all
0 / 0
0 / 0
0 / 1
Bronchiectasis
     subjects affected / exposed
0 / 1018 (0.00%)
0 / 1056 (0.00%)
1 / 1100 (0.09%)
     occurrences causally related to treatment / all
0 / 0
0 / 0
0 / 1
     deaths causally related to treatment / all
0 / 0
0 / 0
0 / 0
Dyspnea
     subjects affected / exposed
0 / 1018 (0.00%)
3 / 1056 (0.28%)
1 / 1100 (0.09%)
     occurrences causally related to treatment / all
0 / 0
1 / 5
1 / 1
     deaths causally related to treatment / all
0 / 0
0 / 0
0 / 0
Lung Disorder
     subjects affected / exposed
0 / 1018 (0.00%)
0 / 1056 (0.00%)
2 / 1100 (0.18%)
     occurrences causally related to treatment / all
0 / 0
0 / 0
1 / 2
     deaths causally related to treatment / all
0 / 0
0 / 0
0 / 0
Lung Edema
     subjects affected / exposed
0 / 1018 (0.00%)
0 / 1056 (0.00%)
1 / 1100 (0.09%)
     occurrences causally related to treatment / all
0 / 0
0 / 0
1 / 2
     deaths causally related to treatment / all
0 / 0
0 / 0
0 / 0
Lung Fibrosis
     subjects affected / exposed
0 / 1018 (0.00%)
0 / 1056 (0.00%)
1 / 1100 (0.09%)
     occurrences causally related to treatment / all
0 / 0
0 / 0
0 / 1
     deaths causally related to treatment / all
0 / 0
0 / 0
0 / 0
Pharyngitis
     subjects affected / exposed
1 / 1018 (0.10%)
2 / 1056 (0.19%)
0 / 1100 (0.00%)
     occurrences causally related to treatment / all
1 / 1
2 / 2
0 / 0
     deaths causally related to treatment / all
0 / 0
0 / 0
0 / 0
Pleural Effusion
     subjects affected / exposed
0 / 1018 (0.00%)
1 / 1056 (0.09%)
0 / 1100 (0.00%)
     occurrences causally related to treatment / all
0 / 0
1 / 1
0 / 0
     deaths causally related to treatment / all
0 / 0
0 / 0
0 / 0
Pneumonia
     subjects affected / exposed
4 / 1018 (0.39%)
3 / 1056 (0.28%)
4 / 1100 (0.36%)
     occurrences causally related to treatment / all
4 / 5
1 / 3
1 / 5
     deaths causally related to treatment / all
1 / 1
0 / 0
0 / 0
Pneumothorax
     subjects affected / exposed
0 / 1018 (0.00%)
0 / 1056 (0.00%)
3 / 1100 (0.27%)
     occurrences causally related to treatment / all
0 / 0
0 / 0
0 / 3
     deaths causally related to treatment / all
0 / 0
0 / 0
0 / 0
Rhinitis
     subjects affected / exposed
1 / 1018 (0.10%)
0 / 1056 (0.00%)
2 / 1100 (0.18%)
     occurrences causally related to treatment / all
1 / 1
0 / 0
2 / 2
     deaths causally related to treatment / all
0 / 0
0 / 0
0 / 0
Sinusitis
     subjects affected / exposed
0 / 1018 (0.00%)
1 / 1056 (0.09%)
1 / 1100 (0.09%)
     occurrences causally related to treatment / all
0 / 0
2 / 2
0 / 1
     deaths causally related to treatment / all
0 / 0
0 / 0
0 / 0
Blood and lymphatic system disorders
Anemia
     subjects affected / exposed
1 / 1018 (0.10%)
9 / 1056 (0.85%)
8 / 1100 (0.73%)
     occurrences causally related to treatment / all
1 / 1
9 / 11
9 / 9
     deaths causally related to treatment / all
0 / 0
0 / 0
0 / 0
Leukopenia
     subjects affected / exposed
21 / 1018 (2.06%)
20 / 1056 (1.89%)
23 / 1100 (2.09%)
     occurrences causally related to treatment / all
24 / 24
19 / 22
27 / 28
     deaths causally related to treatment / all
0 / 0
0 / 0
0 / 0
Lymphedema
     subjects affected / exposed
0 / 1018 (0.00%)
0 / 1056 (0.00%)
1 / 1100 (0.09%)
     occurrences causally related to treatment / all
0 / 0
0 / 0
0 / 1
     deaths causally related to treatment / all
0 / 0
0 / 0
0 / 0
Pancytopenia
     subjects affected / exposed
1 / 1018 (0.10%)
2 / 1056 (0.19%)
1 / 1100 (0.09%)
     occurrences causally related to treatment / all
1 / 1
2 / 2
1 / 1
     deaths causally related to treatment / all
0 / 0
0 / 0
0 / 0
Thrombocytopenia
     subjects affected / exposed
0 / 1018 (0.00%)
3 / 1056 (0.28%)
1 / 1100 (0.09%)
     occurrences causally related to treatment / all
0 / 0
3 / 3
1 / 1
     deaths causally related to treatment / all
0 / 0
0 / 0
0 / 0
Nervous system disorders
Anxiety
     subjects affected / exposed
1 / 1018 (0.10%)
0 / 1056 (0.00%)
1 / 1100 (0.09%)
     occurrences causally related to treatment / all
0 / 1
0 / 0
0 / 2
     deaths causally related to treatment / all
0 / 0
0 / 0
0 / 0
Cerebral Infarct
     subjects affected / exposed
0 / 1018 (0.00%)
0 / 1056 (0.00%)
1 / 1100 (0.09%)
     occurrences causally related to treatment / all
0 / 0
0 / 0
0 / 1
     deaths causally related to treatment / all
0 / 0
0 / 0
0 / 0
Coma
     subjects affected / exposed
0 / 1018 (0.00%)
1 / 1056 (0.09%)
0 / 1100 (0.00%)
     occurrences causally related to treatment / all
0 / 0
0 / 1
0 / 0
     deaths causally related to treatment / all
0 / 0
0 / 1
0 / 0
Confusion
     subjects affected / exposed
0 / 1018 (0.00%)
0 / 1056 (0.00%)
1 / 1100 (0.09%)
     occurrences causally related to treatment / all
0 / 0
0 / 0
1 / 1
     deaths causally related to treatment / all
0 / 0
0 / 0
0 / 0
Convulsion
     subjects affected / exposed
0 / 1018 (0.00%)
1 / 1056 (0.09%)
0 / 1100 (0.00%)
     occurrences causally related to treatment / all
0 / 0
0 / 2
0 / 0
     deaths causally related to treatment / all
0 / 0
0 / 0
0 / 0
Depression
     subjects affected / exposed
0 / 1018 (0.00%)
3 / 1056 (0.28%)
5 / 1100 (0.45%)
     occurrences causally related to treatment / all
0 / 0
0 / 3
0 / 6
     deaths causally related to treatment / all
0 / 0
0 / 0
0 / 0
Dizziness
     subjects affected / exposed
0 / 1018 (0.00%)
0 / 1056 (0.00%)
1 / 1100 (0.09%)
     occurrences causally related to treatment / all
0 / 0
0 / 0
0 / 1
     deaths causally related to treatment / all
0 / 0
0 / 0
0 / 0
Emotional Lability
     subjects affected / exposed
0 / 1018 (0.00%)
0 / 1056 (0.00%)
2 / 1100 (0.18%)
     occurrences causally related to treatment / all
0 / 0
0 / 0
0 / 2
     deaths causally related to treatment / all
0 / 0
0 / 0
0 / 0
Grand Mal Convulsion
     subjects affected / exposed
0 / 1018 (0.00%)
0 / 1056 (0.00%)
1 / 1100 (0.09%)
     occurrences causally related to treatment / all
0 / 0
0 / 0
0 / 1
     deaths causally related to treatment / all
0 / 0
0 / 0
0 / 0
Meningitis
     subjects affected / exposed
1 / 1018 (0.10%)
0 / 1056 (0.00%)
0 / 1100 (0.00%)
     occurrences causally related to treatment / all
0 / 1
0 / 0
0 / 0
     deaths causally related to treatment / all
0 / 0
0 / 0
0 / 0
Neuropathy
     subjects affected / exposed
3 / 1018 (0.29%)
4 / 1056 (0.38%)
3 / 1100 (0.27%)
     occurrences causally related to treatment / all
3 / 4
4 / 7
2 / 3
     deaths causally related to treatment / all
0 / 0
0 / 0
0 / 0
Trismus
     subjects affected / exposed
0 / 1018 (0.00%)
1 / 1056 (0.09%)
0 / 1100 (0.00%)
     occurrences causally related to treatment / all
0 / 0
0 / 1
0 / 0
     deaths causally related to treatment / all
0 / 0
0 / 0
0 / 0
Vertigo
     subjects affected / exposed
0 / 1018 (0.00%)
2 / 1056 (0.19%)
0 / 1100 (0.00%)
     occurrences causally related to treatment / all
0 / 0
1 / 2
0 / 0
     deaths causally related to treatment / all
0 / 0
0 / 0
0 / 0
General disorders and administration site conditions
Abdominal Pain
     subjects affected / exposed
2 / 1018 (0.20%)
2 / 1056 (0.19%)
3 / 1100 (0.27%)
     occurrences causally related to treatment / all
1 / 2
2 / 2
3 / 3
     deaths causally related to treatment / all
0 / 0
0 / 0
0 / 0
Abscess
     subjects affected / exposed
0 / 1018 (0.00%)
1 / 1056 (0.09%)
0 / 1100 (0.00%)
     occurrences causally related to treatment / all
0 / 0
0 / 1
0 / 0
     deaths causally related to treatment / all
0 / 0
0 / 0
0 / 0
Accidental Injury
     subjects affected / exposed
0 / 1018 (0.00%)
3 / 1056 (0.28%)
3 / 1100 (0.27%)
     occurrences causally related to treatment / all
0 / 0
0 / 3
0 / 3
     deaths causally related to treatment / all
0 / 0
0 / 1
0 / 0
Aggravation Reaction
     subjects affected / exposed
0 / 1018 (0.00%)
1 / 1056 (0.09%)
0 / 1100 (0.00%)
     occurrences causally related to treatment / all
0 / 0
0 / 2
0 / 0
     deaths causally related to treatment / all
0 / 0
0 / 0
0 / 0
Allergic Reaction
     subjects affected / exposed
2 / 1018 (0.20%)
5 / 1056 (0.47%)
7 / 1100 (0.64%)
     occurrences causally related to treatment / all
1 / 2
4 / 5
5 / 7
     deaths causally related to treatment / all
0 / 0
0 / 0
0 / 0
Asthenia
     subjects affected / exposed
4 / 1018 (0.39%)
6 / 1056 (0.57%)
3 / 1100 (0.27%)
     occurrences causally related to treatment / all
4 / 4
7 / 7
2 / 4
     deaths causally related to treatment / all
0 / 0
0 / 0
0 / 0
Back Pain
     subjects affected / exposed
1 / 1018 (0.10%)
0 / 1056 (0.00%)
3 / 1100 (0.27%)
     occurrences causally related to treatment / all
0 / 1
0 / 0
1 / 4
     deaths causally related to treatment / all
0 / 0
0 / 0
0 / 0
Cellulitis
     subjects affected / exposed
7 / 1018 (0.69%)
11 / 1056 (1.04%)
7 / 1100 (0.64%)
     occurrences causally related to treatment / all
5 / 9
4 / 13
4 / 9
     deaths causally related to treatment / all
0 / 0
0 / 0
0 / 0
Chest Pain
     subjects affected / exposed
5 / 1018 (0.49%)
6 / 1056 (0.57%)
7 / 1100 (0.64%)
     occurrences causally related to treatment / all
3 / 5
1 / 7
2 / 8
     deaths causally related to treatment / all
0 / 0
0 / 0
0 / 0
Chills
     subjects affected / exposed
1 / 1018 (0.10%)
0 / 1056 (0.00%)
0 / 1100 (0.00%)
     occurrences causally related to treatment / all
1 / 1
0 / 0
0 / 0
     deaths causally related to treatment / all
0 / 0
0 / 0
0 / 0
Cyst
     subjects affected / exposed
0 / 1018 (0.00%)
4 / 1056 (0.38%)
0 / 1100 (0.00%)
     occurrences causally related to treatment / all
0 / 0
0 / 4
0 / 0
     deaths causally related to treatment / all
0 / 0
0 / 0
0 / 0
Fever
     subjects affected / exposed
85 / 1018 (8.35%)
86 / 1056 (8.14%)
109 / 1100 (9.91%)
     occurrences causally related to treatment / all
93 / 94
88 / 93
120 / 124
     deaths causally related to treatment / all
0 / 0
0 / 0
0 / 0
Headache
     subjects affected / exposed
1 / 1018 (0.10%)
1 / 1056 (0.09%)
0 / 1100 (0.00%)
     occurrences causally related to treatment / all
0 / 1
1 / 1
0 / 0
     deaths causally related to treatment / all
0 / 0
0 / 0
0 / 0
Hypothermia
     subjects affected / exposed
0 / 1018 (0.00%)
0 / 1056 (0.00%)
1 / 1100 (0.09%)
     occurrences causally related to treatment / all
0 / 0
0 / 0
1 / 1
     deaths causally related to treatment / all
0 / 0
0 / 0
0 / 0
Immune System Disorder
     subjects affected / exposed
0 / 1018 (0.00%)
0 / 1056 (0.00%)
1 / 1100 (0.09%)
     occurrences causally related to treatment / all
0 / 0
0 / 0
0 / 2
     deaths causally related to treatment / all
0 / 0
0 / 0
0 / 0
Infection
     subjects affected / exposed
68 / 1018 (6.68%)
85 / 1056 (8.05%)
85 / 1100 (7.73%)
     occurrences causally related to treatment / all
57 / 82
64 / 99
73 / 107
     deaths causally related to treatment / all
0 / 0
2 / 2
0 / 0
Injection Site Pain
     subjects affected / exposed
0 / 1018 (0.00%)
1 / 1056 (0.09%)
0 / 1100 (0.00%)
     occurrences causally related to treatment / all
0 / 0
0 / 1
0 / 0
     deaths causally related to treatment / all
0 / 0
0 / 0
0 / 0
Mucous Membrane Disorder
     subjects affected / exposed
0 / 1018 (0.00%)
1 / 1056 (0.09%)
0 / 1100 (0.00%)
     occurrences causally related to treatment / all
0 / 0
1 / 1
0 / 0
     deaths causally related to treatment / all
0 / 0
0 / 0
0 / 0
Pain
     subjects affected / exposed
1 / 1018 (0.10%)
0 / 1056 (0.00%)
1 / 1100 (0.09%)
     occurrences causally related to treatment / all
0 / 1
0 / 0
1 / 1
     deaths causally related to treatment / all
0 / 0
0 / 0
0 / 0
Peritonitis
     subjects affected / exposed
0 / 1018 (0.00%)
1 / 1056 (0.09%)
0 / 1100 (0.00%)
     occurrences causally related to treatment / all
0 / 0
0 / 1
0 / 0
     deaths causally related to treatment / all
0 / 0
0 / 0
0 / 0
Photosensitivity Reaction
     subjects affected / exposed
0 / 1018 (0.00%)
0 / 1056 (0.00%)
1 / 1100 (0.09%)
     occurrences causally related to treatment / all
0 / 0
0 / 0
0 / 1
     deaths causally related to treatment / all
0 / 0
0 / 0
0 / 0
Radiation Injury
     subjects affected / exposed
0 / 1018 (0.00%)
0 / 1056 (0.00%)
1 / 1100 (0.09%)
     occurrences causally related to treatment / all
0 / 0
0 / 0
0 / 1
     deaths causally related to treatment / all
0 / 0
0 / 0
0 / 0
Reaction Unevaluable
     subjects affected / exposed
0 / 1018 (0.00%)
1 / 1056 (0.09%)
0 / 1100 (0.00%)
     occurrences causally related to treatment / all
0 / 0
0 / 1
0 / 0
     deaths causally related to treatment / all
0 / 0
0 / 0
0 / 0
Sepsis
     subjects affected / exposed
0 / 1018 (0.00%)
1 / 1056 (0.09%)
0 / 1100 (0.00%)
     occurrences causally related to treatment / all
0 / 0
0 / 1
0 / 0
     deaths causally related to treatment / all
0 / 0
0 / 0
0 / 0
Deafness
     subjects affected / exposed
0 / 1018 (0.00%)
0 / 1056 (0.00%)
1 / 1100 (0.09%)
     occurrences causally related to treatment / all
0 / 0
0 / 0
0 / 1
     deaths causally related to treatment / all
0 / 0
0 / 0
0 / 0
Ear Pain
     subjects affected / exposed
1 / 1018 (0.10%)
0 / 1056 (0.00%)
0 / 1100 (0.00%)
     occurrences causally related to treatment / all
1 / 1
0 / 0
0 / 0
     deaths causally related to treatment / all
0 / 0
0 / 0
0 / 0
Otitis Media
     subjects affected / exposed
0 / 1018 (0.00%)
0 / 1056 (0.00%)
1 / 1100 (0.09%)
     occurrences causally related to treatment / all
0 / 0
0 / 0
0 / 1
     deaths causally related to treatment / all
0 / 0
0 / 0
0 / 0
Vestibular Disorder
     subjects affected / exposed
0 / 1018 (0.00%)
0 / 1056 (0.00%)
1 / 1100 (0.09%)
     occurrences causally related to treatment / all
0 / 0
0 / 0
0 / 1
     deaths causally related to treatment / all
0 / 0
0 / 0
0 / 0
Gastrointestinal disorders
Anorexia
     subjects affected / exposed
0 / 1018 (0.00%)
1 / 1056 (0.09%)
0 / 1100 (0.00%)
     occurrences causally related to treatment / all
0 / 0
1 / 1
0 / 0
     deaths causally related to treatment / all
0 / 0
0 / 0
0 / 0
Cholecystitis
     subjects affected / exposed
2 / 1018 (0.20%)
1 / 1056 (0.09%)
0 / 1100 (0.00%)
     occurrences causally related to treatment / all
1 / 2
0 / 1
0 / 0
     deaths causally related to treatment / all
0 / 0
0 / 0
0 / 0
Cholelithiasis
     subjects affected / exposed
0 / 1018 (0.00%)
1 / 1056 (0.09%)
2 / 1100 (0.18%)
     occurrences causally related to treatment / all
0 / 0
0 / 1
1 / 2
     deaths causally related to treatment / all
0 / 0
0 / 0
0 / 0
Colitis
     subjects affected / exposed
0 / 1018 (0.00%)
4 / 1056 (0.38%)
1 / 1100 (0.09%)
     occurrences causally related to treatment / all
0 / 0
1 / 4
0 / 1
     deaths causally related to treatment / all
0 / 0
0 / 0
0 / 0
Constipation
     subjects affected / exposed
1 / 1018 (0.10%)
1 / 1056 (0.09%)
0 / 1100 (0.00%)
     occurrences causally related to treatment / all
1 / 1
1 / 1
0 / 0
     deaths causally related to treatment / all
0 / 0
0 / 0
0 / 0
Diarrhea
     subjects affected / exposed
2 / 1018 (0.20%)
11 / 1056 (1.04%)
10 / 1100 (0.91%)
     occurrences causally related to treatment / all
2 / 2
13 / 13
12 / 13
     deaths causally related to treatment / all
0 / 0
1 / 1
0 / 0
Dysphagia
     subjects affected / exposed
0 / 1018 (0.00%)
1 / 1056 (0.09%)
0 / 1100 (0.00%)
     occurrences causally related to treatment / all
0 / 0
0 / 1
0 / 0
     deaths causally related to treatment / all
0 / 0
0 / 0
0 / 0
Esophagitis
     subjects affected / exposed
1 / 1018 (0.10%)
0 / 1056 (0.00%)
0 / 1100 (0.00%)
     occurrences causally related to treatment / all
0 / 1
0 / 0
0 / 0
     deaths causally related to treatment / all
0 / 0
0 / 0
0 / 0
Gastritis
     subjects affected / exposed
1 / 1018 (0.10%)
0 / 1056 (0.00%)
1 / 1100 (0.09%)
     occurrences causally related to treatment / all
1 / 1
0 / 0
1 / 1
     deaths causally related to treatment / all
0 / 0
0 / 0
0 / 0
Gastroenteritis
     subjects affected / exposed
1 / 1018 (0.10%)
3 / 1056 (0.28%)
2 / 1100 (0.18%)
     occurrences causally related to treatment / all
0 / 1
1 / 3
0 / 2
     deaths causally related to treatment / all
0 / 0
0 / 0
0 / 0
Gastrointestinal Hemorrhage
     subjects affected / exposed
0 / 1018 (0.00%)
1 / 1056 (0.09%)
0 / 1100 (0.00%)
     occurrences causally related to treatment / all
0 / 0
0 / 1
0 / 0
     deaths causally related to treatment / all
0 / 0
0 / 0
0 / 0
Hematemesis
     subjects affected / exposed
0 / 1018 (0.00%)
1 / 1056 (0.09%)
1 / 1100 (0.09%)
     occurrences causally related to treatment / all
0 / 0
0 / 1
1 / 1
     deaths causally related to treatment / all
0 / 0
0 / 0
0 / 0
Intestinal Perforation
     subjects affected / exposed
0 / 1018 (0.00%)
1 / 1056 (0.09%)
0 / 1100 (0.00%)
     occurrences causally related to treatment / all
0 / 0
1 / 1
0 / 0
     deaths causally related to treatment / all
0 / 0
0 / 0
0 / 0
Melena
     subjects affected / exposed
1 / 1018 (0.10%)
0 / 1056 (0.00%)
1 / 1100 (0.09%)
     occurrences causally related to treatment / all
1 / 1
0 / 0
1 / 1
     deaths causally related to treatment / all
0 / 0
0 / 0
0 / 0
Nausea
     subjects affected / exposed
3 / 1018 (0.29%)
3 / 1056 (0.28%)
7 / 1100 (0.64%)
     occurrences causally related to treatment / all
5 / 5
4 / 5
8 / 8
     deaths causally related to treatment / all
0 / 0
0 / 0
0 / 0
Perforated Stomach Ulcer
     subjects affected / exposed
0 / 1018 (0.00%)
0 / 1056 (0.00%)
1 / 1100 (0.09%)
     occurrences causally related to treatment / all
0 / 0
0 / 0
1 / 2
     deaths causally related to treatment / all
0 / 0
0 / 0
0 / 0
Proctitis
     subjects affected / exposed
0 / 1018 (0.00%)
1 / 1056 (0.09%)
0 / 1100 (0.00%)
     occurrences causally related to treatment / all
0 / 0
0 / 1
0 / 0
     deaths causally related to treatment / all
0 / 0
0 / 0
0 / 0
Rectal Hemorrhage
     subjects affected / exposed
0 / 1018 (0.00%)
1 / 1056 (0.09%)
0 / 1100 (0.00%)
     occurrences causally related to treatment / all
0 / 0
0 / 1
0 / 0
     deaths causally related to treatment / all
0 / 0
0 / 0
0 / 0
Stomach Ulcer
     subjects affected / exposed
0 / 1018 (0.00%)
2 / 1056 (0.19%)
0 / 1100 (0.00%)
     occurrences causally related to treatment / all
0 / 0
1 / 2
0 / 0
     deaths causally related to treatment / all
0 / 0
0 / 0
0 / 0
Stomatitis
     subjects affected / exposed
7 / 1018 (0.69%)
1 / 1056 (0.09%)
4 / 1100 (0.36%)
     occurrences causally related to treatment / all
7 / 8
1 / 1
4 / 4
     deaths causally related to treatment / all
0 / 0
0 / 0
0 / 0
Vomiting
     subjects affected / exposed
12 / 1018 (1.18%)
11 / 1056 (1.04%)
16 / 1100 (1.45%)
     occurrences causally related to treatment / all
15 / 17
13 / 15
16 / 16
     deaths causally related to treatment / all
0 / 0
1 / 1
0 / 0
Renal and urinary disorders
Breast Neoplasm
     subjects affected / exposed
0 / 1018 (0.00%)
1 / 1056 (0.09%)
1 / 1100 (0.09%)
     occurrences causally related to treatment / all
0 / 0
0 / 1
0 / 1
     deaths causally related to treatment / all
0 / 0
0 / 0
0 / 0
Cystitis
     subjects affected / exposed
0 / 1018 (0.00%)
0 / 1056 (0.00%)
1 / 1100 (0.09%)
     occurrences causally related to treatment / all
0 / 0
0 / 0
0 / 1
     deaths causally related to treatment / all
0 / 0
0 / 0
0 / 0
Endometrial Carcinoma
     subjects affected / exposed
0 / 1018 (0.00%)
0 / 1056 (0.00%)
1 / 1100 (0.09%)
     occurrences causally related to treatment / all
0 / 0
0 / 0
0 / 1
     deaths causally related to treatment / all
0 / 0
0 / 0
0 / 0
Endometrial Disorder
     subjects affected / exposed
1 / 1018 (0.10%)
0 / 1056 (0.00%)
0 / 1100 (0.00%)
     occurrences causally related to treatment / all
0 / 1
0 / 0
0 / 0
     deaths causally related to treatment / all
0 / 0
0 / 0
0 / 0
Hematuria
     subjects affected / exposed
0 / 1018 (0.00%)
2 / 1056 (0.19%)
0 / 1100 (0.00%)
     occurrences causally related to treatment / all
0 / 0
2 / 2
0 / 0
     deaths causally related to treatment / all
0 / 0
0 / 0
0 / 0
Kidney Failure
     subjects affected / exposed
0 / 1018 (0.00%)
1 / 1056 (0.09%)
0 / 1100 (0.00%)
     occurrences causally related to treatment / all
0 / 0
1 / 1
0 / 0
     deaths causally related to treatment / all
0 / 0
1 / 1
0 / 0
Kidney Function Abnormal
     subjects affected / exposed
0 / 1018 (0.00%)
1 / 1056 (0.09%)
0 / 1100 (0.00%)
     occurrences causally related to treatment / all
0 / 0
1 / 1
0 / 0
     deaths causally related to treatment / all
0 / 0
0 / 0
0 / 0
Menstrual Disorder
     subjects affected / exposed
0 / 1018 (0.00%)
1 / 1056 (0.09%)
0 / 1100 (0.00%)
     occurrences causally related to treatment / all
0 / 0
0 / 1
0 / 0
     deaths causally related to treatment / all
0 / 0
0 / 0
0 / 0
Toxic Nephropathy
     subjects affected / exposed
0 / 1018 (0.00%)
0 / 1056 (0.00%)
1 / 1100 (0.09%)
     occurrences causally related to treatment / all
0 / 0
0 / 0
0 / 1
     deaths causally related to treatment / all
0 / 0
0 / 0
0 / 0
Urinary Tract Disorder
     subjects affected / exposed
0 / 1018 (0.00%)
1 / 1056 (0.09%)
0 / 1100 (0.00%)
     occurrences causally related to treatment / all
0 / 0
0 / 1
0 / 0
     deaths causally related to treatment / all
0 / 0
0 / 0
0 / 0
Urinary Tract Infection
     subjects affected / exposed
0 / 1018 (0.00%)
1 / 1056 (0.09%)
2 / 1100 (0.18%)
     occurrences causally related to treatment / all
0 / 0
1 / 1
1 / 2
     deaths causally related to treatment / all
0 / 0
0 / 0
0 / 0
Vaginitis
     subjects affected / exposed
0 / 1018 (0.00%)
1 / 1056 (0.09%)
0 / 1100 (0.00%)
     occurrences causally related to treatment / all
0 / 0
0 / 1
0 / 0
     deaths causally related to treatment / all
0 / 0
0 / 0
0 / 0
Skin and subcutaneous tissue disorders
Acne
     subjects affected / exposed
0 / 1018 (0.00%)
0 / 1056 (0.00%)
1 / 1100 (0.09%)
     occurrences causally related to treatment / all
0 / 0
0 / 0
1 / 1
     deaths causally related to treatment / all
0 / 0
0 / 0
0 / 0
Application Site Reaction
     subjects affected / exposed
1 / 1018 (0.10%)
0 / 1056 (0.00%)
1 / 1100 (0.09%)
     occurrences causally related to treatment / all
1 / 1
0 / 0
0 / 1
     deaths causally related to treatment / all
0 / 0
0 / 0
0 / 0
Exfoliative Dermatitis
     subjects affected / exposed
3 / 1018 (0.29%)
0 / 1056 (0.00%)
1 / 1100 (0.09%)
     occurrences causally related to treatment / all
3 / 3
0 / 0
1 / 1
     deaths causally related to treatment / all
0 / 0
0 / 0
0 / 0
Fungal Dermatitis
     subjects affected / exposed
0 / 1018 (0.00%)
1 / 1056 (0.09%)
0 / 1100 (0.00%)
     occurrences causally related to treatment / all
0 / 0
1 / 1
0 / 0
     deaths causally related to treatment / all
0 / 0
0 / 0
0 / 0
Maculopapular Rash
     subjects affected / exposed
4 / 1018 (0.39%)
1 / 1056 (0.09%)
1 / 1100 (0.09%)
     occurrences causally related to treatment / all
4 / 6
0 / 1
1 / 1
     deaths causally related to treatment / all
0 / 0
0 / 0
0 / 0
Nail Disorder
     subjects affected / exposed
1 / 1018 (0.10%)
0 / 1056 (0.00%)
0 / 1100 (0.00%)
     occurrences causally related to treatment / all
0 / 1
0 / 0
0 / 0
     deaths causally related to treatment / all
0 / 0
0 / 0
0 / 0
Rash
     subjects affected / exposed
0 / 1018 (0.00%)
3 / 1056 (0.28%)
0 / 1100 (0.00%)
     occurrences causally related to treatment / all
0 / 0
0 / 5
0 / 0
     deaths causally related to treatment / all
0 / 0
0 / 0
0 / 0
Skin Benign Neoplasm
     subjects affected / exposed
0 / 1018 (0.00%)
0 / 1056 (0.00%)
1 / 1100 (0.09%)
     occurrences causally related to treatment / all
0 / 0
0 / 0
0 / 1
     deaths causally related to treatment / all
0 / 0
0 / 0
0 / 0
Musculoskeletal and connective tissue disorders
Arthralgia
     subjects affected / exposed
1 / 1018 (0.10%)
1 / 1056 (0.09%)
1 / 1100 (0.09%)
     occurrences causally related to treatment / all
1 / 1
1 / 1
1 / 1
     deaths causally related to treatment / all
0 / 0
0 / 0
0 / 0
Arthritis
     subjects affected / exposed
0 / 1018 (0.00%)
0 / 1056 (0.00%)
1 / 1100 (0.09%)
     occurrences causally related to treatment / all
0 / 0
0 / 0
0 / 1
     deaths causally related to treatment / all
0 / 0
0 / 0
0 / 1
Bone Pain
     subjects affected / exposed
0 / 1018 (0.00%)
0 / 1056 (0.00%)
1 / 1100 (0.09%)
     occurrences causally related to treatment / all
0 / 0
0 / 0
1 / 1
     deaths causally related to treatment / all
0 / 0
0 / 0
0 / 0
Joint Disorder
     subjects affected / exposed
0 / 1018 (0.00%)
1 / 1056 (0.09%)
1 / 1100 (0.09%)
     occurrences causally related to treatment / all
0 / 0
0 / 1
0 / 1
     deaths causally related to treatment / all
0 / 0
0 / 0
0 / 0
Myalgia
     subjects affected / exposed
1 / 1018 (0.10%)
1 / 1056 (0.09%)
1 / 1100 (0.09%)
     occurrences causally related to treatment / all
1 / 1
1 / 1
1 / 1
     deaths causally related to treatment / all
0 / 0
0 / 0
0 / 0
Endocrine disorders
Thyroid Disorder
     subjects affected / exposed
1 / 1018 (0.10%)
0 / 1056 (0.00%)
0 / 1100 (0.00%)
     occurrences causally related to treatment / all
0 / 1
0 / 0
0 / 0
     deaths causally related to treatment / all
0 / 0
0 / 0
0 / 0
Metabolism and nutrition disorders
Acidosis
     subjects affected / exposed
0 / 1018 (0.00%)
1 / 1056 (0.09%)
0 / 1100 (0.00%)
     occurrences causally related to treatment / all
0 / 0
0 / 1
0 / 0
     deaths causally related to treatment / all
0 / 0
0 / 0
0 / 0
Dehydration
     subjects affected / exposed
1 / 1018 (0.10%)
5 / 1056 (0.47%)
5 / 1100 (0.45%)
     occurrences causally related to treatment / all
1 / 1
5 / 5
5 / 5
     deaths causally related to treatment / all
0 / 0
1 / 1
0 / 0
Edema
     subjects affected / exposed
0 / 1018 (0.00%)
1 / 1056 (0.09%)
0 / 1100 (0.00%)
     occurrences causally related to treatment / all
0 / 0
1 / 1
0 / 0
     deaths causally related to treatment / all
0 / 0
0 / 0
0 / 0
Enzymatic Abnormality
     subjects affected / exposed
0 / 1018 (0.00%)
0 / 1056 (0.00%)
1 / 1100 (0.09%)
     occurrences causally related to treatment / all
0 / 0
0 / 0
1 / 1
     deaths causally related to treatment / all
0 / 0
0 / 0
0 / 0
Generalized Edema
     subjects affected / exposed
0 / 1018 (0.00%)
0 / 1056 (0.00%)
1 / 1100 (0.09%)
     occurrences causally related to treatment / all
0 / 0
0 / 0
1 / 1
     deaths causally related to treatment / all
0 / 0
0 / 0
0 / 0
Hyperglycemia
     subjects affected / exposed
1 / 1018 (0.10%)
1 / 1056 (0.09%)
0 / 1100 (0.00%)
     occurrences causally related to treatment / all
0 / 1
0 / 1
0 / 0
     deaths causally related to treatment / all
0 / 0
0 / 0
0 / 0
Hypokalemia
     subjects affected / exposed
0 / 1018 (0.00%)
2 / 1056 (0.19%)
0 / 1100 (0.00%)
     occurrences causally related to treatment / all
0 / 0
2 / 2
0 / 0
     deaths causally related to treatment / all
0 / 0
0 / 0
0 / 0
Hypomagnesemia
     subjects affected / exposed
0 / 1018 (0.00%)
3 / 1056 (0.28%)
0 / 1100 (0.00%)
     occurrences causally related to treatment / all
0 / 0
2 / 3
0 / 0
     deaths causally related to treatment / all
0 / 0
0 / 0
0 / 0
Hyponatremia
     subjects affected / exposed
0 / 1018 (0.00%)
1 / 1056 (0.09%)
0 / 1100 (0.00%)
     occurrences causally related to treatment / all
0 / 0
1 / 1
0 / 0
     deaths causally related to treatment / all
0 / 0
0 / 0
0 / 0
Hypovolemia
     subjects affected / exposed
0 / 1018 (0.00%)
1 / 1056 (0.09%)
0 / 1100 (0.00%)
     occurrences causally related to treatment / all
0 / 0
1 / 1
0 / 0
     deaths causally related to treatment / all
0 / 0
0 / 0
0 / 0
Peripheral Edema
     subjects affected / exposed
1 / 1018 (0.10%)
1 / 1056 (0.09%)
1 / 1100 (0.09%)
     occurrences causally related to treatment / all
0 / 1
1 / 1
1 / 1
     deaths causally related to treatment / all
0 / 0
0 / 0
0 / 0
Sgot Increased
     subjects affected / exposed
0 / 1018 (0.00%)
0 / 1056 (0.00%)
1 / 1100 (0.09%)
     occurrences causally related to treatment / all
0 / 0
0 / 0
1 / 2
     deaths causally related to treatment / all
0 / 0
0 / 0
0 / 0
Frequency threshold for reporting non-serious adverse events: 5%
Non-serious adverse events
 Doxorubicin+Cyclophosphamide (AC) Followed by Docetaxel (AC→T) Docetaxel + Carboplatin + Herceptin (TCH) AC Followed by Docetaxel + Herceptin (AC→TH)
Total subjects affected by non serious adverse events
     subjects affected / exposed
1017 / 1018 (99.90%)
1052 / 1056 (99.62%)
1100 / 1100 (100.00%)
Cardiac disorders
Hypertension
     subjects affected / exposed
40 / 1018 (3.93%)
78 / 1056 (7.39%)
72 / 1100 (6.55%)
     occurrences all number
59
141
124
Left Heart Failure
     subjects affected / exposed
30 / 1018 (2.95%)
31 / 1056 (2.94%)
71 / 1100 (6.45%)
     occurrences all number
42
53
132
Palpitation
     subjects affected / exposed
69 / 1018 (6.78%)
95 / 1056 (9.00%)
94 / 1100 (8.55%)
     occurrences all number
103
164
155
Tachycardia
     subjects affected / exposed
50 / 1018 (4.91%)
67 / 1056 (6.34%)
62 / 1100 (5.64%)
     occurrences all number
79
107
101
Respiratory, thoracic and mediastinal disorders
Cough Increased
     subjects affected / exposed
187 / 1018 (18.37%)
147 / 1056 (13.92%)
205 / 1100 (18.64%)
     occurrences all number
312
218
361
Dyspnea
     subjects affected / exposed
227 / 1018 (22.30%)
229 / 1056 (21.69%)
270 / 1100 (24.55%)
     occurrences all number
408
442
544
Epistaxis
     subjects affected / exposed
60 / 1018 (5.89%)
170 / 1056 (16.10%)
143 / 1100 (13.00%)
     occurrences all number
85
268
219
Pharyngitis
     subjects affected / exposed
74 / 1018 (7.27%)
60 / 1056 (5.68%)
94 / 1100 (8.55%)
     occurrences all number
98
81
135
Rhinitis
     subjects affected / exposed
175 / 1018 (17.19%)
193 / 1056 (18.28%)
277 / 1100 (25.18%)
     occurrences all number
324
347
501
Blood and lymphatic system disorders
Lymphedema
     subjects affected / exposed
81 / 1018 (7.96%)
107 / 1056 (10.13%)
94 / 1100 (8.55%)
     occurrences all number
125
176
156
Nervous system disorders
Anxiety
     subjects affected / exposed
86 / 1018 (8.45%)
70 / 1056 (6.63%)
78 / 1100 (7.09%)
     occurrences all number
134
96
136
Depression
     subjects affected / exposed
106 / 1018 (10.41%)
119 / 1056 (11.27%)
139 / 1100 (12.64%)
     occurrences all number
205
199
256
Dizziness
     subjects affected / exposed
112 / 1018 (11.00%)
130 / 1056 (12.31%)
154 / 1100 (14.00%)
     occurrences all number
179
218
226
Dry Mouth
     subjects affected / exposed
87 / 1018 (8.55%)
37 / 1056 (3.50%)
55 / 1100 (5.00%)
     occurrences all number
163
63
87
Emotional Lability
     subjects affected / exposed
56 / 1018 (5.50%)
41 / 1056 (3.88%)
65 / 1100 (5.91%)
     occurrences all number
90
61
110
Insomnia
     subjects affected / exposed
226 / 1018 (22.20%)
252 / 1056 (23.86%)
288 / 1100 (26.18%)
     occurrences all number
494
488
556
Neuropathy
     subjects affected / exposed
514 / 1018 (50.49%)
406 / 1056 (38.45%)
569 / 1100 (51.73%)
     occurrences all number
1294
940
1416
Vasodilatation
     subjects affected / exposed
364 / 1018 (35.76%)
384 / 1056 (36.36%)
416 / 1100 (37.82%)
     occurrences all number
873
958
993
General disorders and administration site conditions
Abdominal Pain
     subjects affected / exposed
179 / 1018 (17.58%)
240 / 1056 (22.73%)
220 / 1100 (20.00%)
     occurrences all number
312
390
370
Allergic Reaction
     subjects affected / exposed
100 / 1018 (9.82%)
153 / 1056 (14.49%)
137 / 1100 (12.45%)
     occurrences all number
139
225
192
Asthenia
     subjects affected / exposed
838 / 1018 (82.32%)
878 / 1056 (83.14%)
925 / 1100 (84.09%)
     occurrences all number
3138
3138
3476
Back Pain
     subjects affected / exposed
82 / 1018 (8.06%)
96 / 1056 (9.09%)
132 / 1100 (12.00%)
     occurrences all number
124
149
205
Chest Pain
     subjects affected / exposed
73 / 1018 (7.17%)
91 / 1056 (8.62%)
103 / 1100 (9.36%)
     occurrences all number
106
149
163
Chills
     subjects affected / exposed
58 / 1018 (5.70%)
78 / 1056 (7.39%)
88 / 1100 (8.00%)
     occurrences all number
81
94
113
Fever
     subjects affected / exposed
162 / 1018 (15.91%)
145 / 1056 (13.73%)
206 / 1100 (18.73%)
     occurrences all number
217
178
282
Headache
     subjects affected / exposed
301 / 1018 (29.57%)
306 / 1056 (28.98%)
323 / 1100 (29.36%)
     occurrences all number
622
566
625
Infection
     subjects affected / exposed
350 / 1018 (34.38%)
327 / 1056 (30.97%)
445 / 1100 (40.45%)
     occurrences all number
694
583
852
Injection Site Reaction
     subjects affected / exposed
66 / 1018 (6.48%)
84 / 1056 (7.95%)
70 / 1100 (6.36%)
     occurrences all number
100
125
108
Pain
     subjects affected / exposed
222 / 1018 (21.81%)
217 / 1056 (20.55%)
268 / 1100 (24.36%)
     occurrences all number
394
368
527
Amblyopia
     subjects affected / exposed
34 / 1018 (3.34%)
55 / 1056 (5.21%)
52 / 1100 (4.73%)
     occurrences all number
62
95
95
Conjunctivitis
     subjects affected / exposed
111 / 1018 (10.90%)
45 / 1056 (4.26%)
122 / 1100 (11.09%)
     occurrences all number
221
69
239
Dry Eyes
     subjects affected / exposed
41 / 1018 (4.03%)
30 / 1056 (2.84%)
56 / 1100 (5.09%)
     occurrences all number
88
54
98
Lacrimation Disorder
     subjects affected / exposed
210 / 1018 (20.63%)
124 / 1056 (11.74%)
264 / 1100 (24.00%)
     occurrences all number
384
246
534
Taste Perversion
     subjects affected / exposed
291 / 1018 (28.59%)
320 / 1056 (30.30%)
312 / 1100 (28.36%)
     occurrences all number
691
738
699
Gastrointestinal disorders
Anorexia
     subjects affected / exposed
230 / 1018 (22.59%)
252 / 1056 (23.86%)
238 / 1100 (21.64%)
     occurrences all number
486
537
527
Constipation
     subjects affected / exposed
383 / 1018 (37.62%)
351 / 1056 (33.24%)
403 / 1100 (36.64%)
     occurrences all number
874
768
913
Diarrhea
     subjects affected / exposed
439 / 1018 (43.12%)
658 / 1056 (62.31%)
555 / 1100 (50.45%)
     occurrences all number
926
1568
1268
Dyspepsia
     subjects affected / exposed
204 / 1018 (20.04%)
263 / 1056 (24.91%)
273 / 1100 (24.82%)
     occurrences all number
398
509
550
Nausea
     subjects affected / exposed
890 / 1018 (87.43%)
863 / 1056 (81.72%)
967 / 1100 (87.91%)
     occurrences all number
3242
2880
3405
Stomatitis
     subjects affected / exposed
660 / 1018 (64.83%)
564 / 1056 (53.41%)
735 / 1100 (66.82%)
     occurrences all number
1847
1252
1959
Vomiting
     subjects affected / exposed
563 / 1018 (55.30%)
428 / 1056 (40.53%)
628 / 1100 (57.09%)
     occurrences all number
1375
892
1412
Renal and urinary disorders
Breast Pain
     subjects affected / exposed
53 / 1018 (5.21%)
62 / 1056 (5.87%)
59 / 1100 (5.36%)
     occurrences all number
80
107
91
Dysuria
     subjects affected / exposed
24 / 1018 (2.36%)
58 / 1056 (5.49%)
51 / 1100 (4.64%)
     occurrences all number
32
73
76
Menstrual Disorder
     subjects affected / exposed
368 / 1018 (36.15%)
384 / 1056 (36.36%)
356 / 1100 (32.36%)
     occurrences all number
827
907
818
Skin and subcutaneous tissue disorders
Alopecia
     subjects affected / exposed
1003 / 1018 (98.53%)
1018 / 1056 (96.40%)
1083 / 1100 (98.45%)
     occurrences all number
2350
2486
2556
Dry Skin
     subjects affected / exposed
76 / 1018 (7.47%)
61 / 1056 (5.78%)
101 / 1100 (9.18%)
     occurrences all number
148
100
168
Exfoliative Dermatitis
     subjects affected / exposed
87 / 1018 (8.55%)
32 / 1056 (3.03%)
87 / 1100 (7.91%)
     occurrences all number
189
51
175
Maculopapular Rash
     subjects affected / exposed
275 / 1018 (27.01%)
330 / 1056 (31.25%)
354 / 1100 (32.18%)
     occurrences all number
540
644
680
Nail Disorder
     subjects affected / exposed
507 / 1018 (49.80%)
303 / 1056 (28.69%)
484 / 1100 (44.00%)
     occurrences all number
1075
620
1026
Pruritus
     subjects affected / exposed
38 / 1018 (3.73%)
66 / 1056 (6.25%)
50 / 1100 (4.55%)
     occurrences all number
65
103
71
Rash
     subjects affected / exposed
238 / 1018 (23.38%)
313 / 1056 (29.64%)
279 / 1100 (25.36%)
     occurrences all number
357
526
425
Skin Discoloration
     subjects affected / exposed
65 / 1018 (6.39%)
50 / 1056 (4.73%)
67 / 1100 (6.09%)
     occurrences all number
124
83
123
Sweating
     subjects affected / exposed
67 / 1018 (6.58%)
73 / 1056 (6.91%)
67 / 1100 (6.09%)
     occurrences all number
119
118
104
Musculoskeletal and connective tissue disorders
Arthralgia
     subjects affected / exposed
439 / 1018 (43.12%)
335 / 1056 (31.72%)
515 / 1100 (46.82%)
     occurrences all number
1003
739
1223
Bone Pain
     subjects affected / exposed
187 / 1018 (18.37%)
144 / 1056 (13.64%)
235 / 1100 (21.36%)
     occurrences all number
393
287
475
Myalgia
     subjects affected / exposed
541 / 1018 (53.14%)
415 / 1056 (39.30%)
614 / 1100 (55.82%)
     occurrences all number
1381
944
1493
Metabolism and nutrition disorders
Hyperglycemia
     subjects affected / exposed
77 / 1018 (7.56%)
79 / 1056 (7.48%)
85 / 1100 (7.73%)
     occurrences all number
213
218
239
Peripheral Edema
     subjects affected / exposed
339 / 1018 (33.30%)
347 / 1056 (32.86%)
405 / 1100 (36.82%)
     occurrences all number
681
708
862
Weight Gain
     subjects affected / exposed
197 / 1018 (19.35%)
254 / 1056 (24.05%)
262 / 1100 (23.82%)
     occurrences all number
425
559
574
Weight Loss
     subjects affected / exposed
81 / 1018 (7.96%)
69 / 1056 (6.53%)
100 / 1100 (9.09%)
     occurrences all number
164
143
236

More information

 Close Top of page

Substantial protocol amendments (globally)
Were there any global substantial amendments to the protocol? Yes
Date
Amendment
08 May 2001
This amendment contained the following substantive changes: • Echocardiography was allowed at study entry (in addition to multiple-gated acquisition [MUGA] scans) for confirmation of a subject’s left ventricular ejection fraction (LVEF) status. • Echocardiography guidelines and availability of videotapes of echocardiograms were added. • An LVEF evaluation was added at 36 months (AC→T and AC→TH) and 37.5 months (TCH) to allow for long-term assessment of cardiac function. • Clarifications regarding the dosing of carboplatin and trastuzumab, according to a subject’s weight modification, were added.
30 Jul 2001
This amendment contained the following substantive changes: • The dosing schedule for trastuzumab monotherapy after completion of chemotherapy was modified from administration once a week to administration every 3 weeks based on the results of two studies of the safety, anti-tumor activity, and pharmacokinetics of trastuzumab when administered every 3 weeks to subjects with HER2-positive (by immunohistochemistry or fluorescence in situ hybridization [FISH]) metastatic breast cancer (MBC). • Guidelines for trastuzumab initiation were modified for the AC→TH arm. • The trastuzumab post-infusion observation periods were revised. • The optional HER2 extracellular domain (ECD) and cardiac biochemical marker substudies were extended.
10 Apr 2002
This amendment contained the following substantive changes: • The TCH regimen was modified so that the platinum salt was limited to carboplatin (ie, cisplatin was no longer allowed), based on updated results from the BCIRG 101 and 102 studies. • The instructions describing the administration of trastuzumab and the dose calculation for carboplatin was clarified. • Measurement of the follicle-stimulating hormone to luteinizing hormone ratio to assess menopausal status in subjects <55 years old with a history of hysterectomy without bilateral ovariectomy was no longer required.
17 Mar 2005
This amendment contained the following substantive changes: • Statistical considerations were revised as follows: − Based on the results of BCIRG 001 study, the assumed DFS rate at 5 years in the AC→T arm was changed from 55% to 70%. − The independed data monitoring committee (IDMC) requested interim efficacy analyses when 300, 450, and 650 DFS events had been observed and a main analysis when 900 DFS events had been observed (the initial protocol called for one interim analysis at 654 events and a final analysis at 1308 events). − In order to gain power for the two comparisons of main interest, a “step-down” testing procedure was proposed (instead of three pairwise comparisons). It was also proposed to use the O’Brien-Fleming spending function instead of the Haybittle-Peto. • Following a request from the IDMC, one additional cardiac safety analysis was to be conducted when all subjects had been observed for at least 9 months. • The indication for adjuvant hormonal therapy was modified to allow the use of aromatase inhibitors for postmenopausal subjects who were estrogen receptor (ER)- or progesteron receptor (PR)-positive, as well as for subjects for whom tamoxifen was contraindicated. • In addition, the use of letrozole was allowed for subjects having completed 5 years of tamoxifen therapy. • Based on American Society of Clinical Oncology 2002 follow-up guidelines, hematologic and blood chemistry evaluations and chest X-rays were no longer required during the follow-up period.

Interruptions (globally)
Were there any global interruptions to the trial? No

Limitations and caveats
Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.
None reported

Online references
http://www.ncbi.nlm.nih.gov/pubmed/21991949
http://www.ncbi.nlm.nih.gov/pubmed/23814044
http://www.ncbi.nlm.nih.gov/pubmed/23420271
http://www.ncbi.nlm.nih.gov/pubmed/21189395
http://www.ncbi.nlm.nih.gov/pubmed/25649019

スポンサーと協力者

医学的状態

薬物療法

3
購読する