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ALTTO (Adjuvant Lapatinib And/Or Trastuzumab Treatment Optimisation) Study; BIG 2-06/N063D (ALTTO)

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: NCT00490139
Recruitment Status : Active, not recruiting
First Posted : June 22, 2007
Results First Posted : August 18, 2014
Last Update Posted : September 10, 2020
Sponsor:
Collaborators:
North Central Cancer Treatment Group
National Cancer Institute (NCI)
Breast International Group
Canadian Cancer Trials Group
Information provided by (Responsible Party):
Novartis ( Novartis Pharmaceuticals )

Study Type Interventional
Study Design Allocation: Randomized;   Masking: None (Open Label);   Primary Purpose: Treatment
Condition Neoplasms, Breast
Interventions Drug: Lapatinib
Biological: Trastuzumab
Enrollment 8382
Recruitment Details  
Pre-assignment Details Treatments administered differed per timing/type of adjuvant chemotherapy. Design (D) 1: (neo) adjuvant anthracycline-based chemotherapy (AABC) prior to targeted therapy (TT); Design 2: TT concurrently with paclitaxel or docetaxel, after completion of a (neo) AABC; Design 2B: TT concurrently with chemotherapy with docetaxel and carboplatin.
Arm/Group Title Lapatinib plusTrastuzumab Trastuzumab Followed by Lapatinib Lapatinib Trastuzumab
Hide Arm/Group Description Participants (par.) received treatment per one of three designs. D1: oral lapatinib (OL) 1000 milligrams (mg) daily with trastuzumab (tras) (8 milligrams per kilogram [mg/kg] intravenous [IV] loading dose [LD], followed by 6 mg/kg IV every 3 weeks [E3W]) for 52 weeks (wks). D2: OL 750 mg daily plus wkly tras (4 mg/kg LD, followed by 2 mg/kg IV) concomitantly (conc.) with wkly paclitaxel (pac) 80 mg per squared meter (mg/m^2) IV or docetaxel (doc) 75 mg/m^2 IV E3W for 12 wks. After completion of pac or doc, par. received OL at an increased dose of 1000 mg daily in combination with tras (6 mg/kg without a LD) E3W for 40 wks. D2B: OL 750 mg plus wkly tras (4 mg/kg IV LD, followed by 2 mg/kg IV wkly) conc. with doc 75 mg/m^2 E3W and carboplatin (carb) AUC6 IV for 18 wks. After completion of doc and carb, par. received tras E3W (6 mg/kg without a LD) plus OL 1000 mg daily for 34 wks. Par. also received adjuvant radiotherapy and adjuvant anti-estrogen therapy when clinically indicated. Participants received treatment per one of the following three designs. Design 1: weekly tras for 12 weeks (4 mg/kg IV loading dose, followed by 2 mg/kg IV weekly), followed by a 6-week washout period, followed by oral lap 1500 mg daily for 34 weeks. Design 2: weekly tras (4 mg/kg IV loading dose, followed by 2 mg/kg IV) concomitantly with weekly paclitaxel 80 mg/m^2 IV or docetaxel 75 mg/m^2 IV every 3 weeks for 12 weeks, followed by a 6-week washout period, followed by oral lap 1500 mg daily for 34 weeks. Design 2B: weekly tras (4 mg/kg IV loading dose, followed by 2 mg/kg IV weekly) concomitantly with docetaxel 75 mg/m^2 every 3 weeks and carboplatin AUC6 IV for 18 weeks, followed by a 6-week washout period, followed by oral lap 1500 mg daily for 28 weeks. Participants also received adjuvant radiotherapy and adjuvant anti-estrogen therapy when clinically indicated. Participants received treatment per one of the following three designs. Design 1: oral lap 1500 mg daily for 52 weeks. Design 2: oral lap 750 mg daily concomitantly with weekly paclitaxel 80 mg/m^2 IV or docetaxel 75 mg/m^2 IV every 3 weeks, for 12 weeks. After completion of paclitaxel or docetaxel, participants received oral lap at an increased dose of 1500 mg daily for 40 weeks. Design 2B: oral lap 750 mg daily concomitantly with docetaxel 75 mg/m^2 every 3 weeks and carboplatin AUC6 IV, for 18 weeks. After completion of docetaxel and carboplatin, oral lap was given at an increased dose of 1500 mg for 34 weeks. Participants also received adjuvant radiotherapy and adjuvant anti-estrogen therapy when clinically indicated. Participants received treatment per one of the following three designs. Design 1: tras 8 mg/kg IV LD, followed by 6 mg/kg IV every 3 weeks for 52 weeks. Design 2: weekly tras (4 mg/kg IV LD, followed by 2 mg/kg IV weekly) concomitantly with weekly paclitaxel 80 mg/m^2 IV or docetaxel 75 mg/m^2 IV every 3 weeks, for 12 weeks. After completion of paclitaxel or docetaxel, participants received tras (6 mg/kg without a LD every 3 weeks for 40 weeks. Design 2B: weekly tras (4 mg/kg IV LD, followed by 2 mg/kg IV weekly) concomitantly with docetaxel 75 mg/m^2 every 3 weeks and carboplatin AUC6 IV, for 18 weeks. After completion of docetaxel and carboplatin, participants received tras every 3 weeks (6 mg/kg without a LD) for 34 weeks. Participants also received adjuvant radiotherapy and adjuvant anti-estrogen therapy when clinically indicated.
Period Title: Overall Study
Started 2093 2091 2100 2097
Completed 1785 1816 1666 1790
Not Completed 308 275 434 307
Reason Not Completed
Death             106             119             168             135
Lost to Follow-up             56             46             58             56
Participant Withdrew Consent             146             110             208             116
Arm/Group Title Lapatinib plusTrastuzumab Trastuzumab Followed by Lapatinib Lapatinib Trastuzumab Total
Hide Arm/Group Description Participants (par.) received treatment per one of three designs. D1: oral lapatinib (OL) 1000 milligrams (mg) daily with trastuzumab (tras) (8 milligrams per kilogram [mg/kg] intravenous [IV] loading dose [LD], followed by 6 mg/kg IV every 3 weeks [E3W]) for 52 weeks (wks). D2: OL 750 mg daily plus wkly tras (4 mg/kg LD, followed by 2 mg/kg IV) concomitantly (conc.) with wkly paclitaxel (pac) 80 mg per squared meter (mg/m^2) IV or docetaxel (doc) 75 mg/m^2 IV E3W for 12 wks. After completion of pac or doc, par. received OL at an increased dose of 1000 mg daily in combination with tras (6 mg/kg without a LD) E3W for 40 wks. D2B: OL 750 mg plus wkly tras (4 mg/kg IV LD, followed by 2 mg/kg IV wkly) conc. with doc 75 mg/m^2 E3W and carboplatin (carb) AUC6 IV for 18 wks. After completion of doc and carb, par. received tras E3W (6 mg/kg without a LD) plus OL 1000 mg daily for 34 wks. Par. also received adjuvant radiotherapy and adjuvant anti-estrogen therapy when clinically indicated. Participants received treatment per one of the following three designs. Design 1: weekly tras for 12 weeks (4 mg/kg IV loading dose, followed by 2 mg/kg IV weekly), followed by a 6-week washout period, followed by oral lap 1500 mg daily for 34 weeks. Design 2: weekly tras (4 mg/kg IV loading dose, followed by 2 mg/kg IV) concomitantly with weekly paclitaxel 80 mg/m^2 IV or docetaxel 75 mg/m^2 IV every 3 weeks for 12 weeks, followed by a 6-week washout period, followed by oral lap 1500 mg daily for 34 weeks. Design 2B: weekly tras (4 mg/kg IV loading dose, followed by 2 mg/kg IV weekly) concomitantly with docetaxel 75 mg/m^2 every 3 weeks and carboplatin AUC6 IV for 18 weeks, followed by a 6-week washout period, followed by oral lap 1500 mg daily for 28 weeks. Participants also received adjuvant radiotherapy and adjuvant anti-estrogen therapy when clinically indicated. Participants received treatment per one of the following three designs. Design 1: oral lap 1500 mg daily for 52 weeks. Design 2: oral lap 750 mg daily concomitantly with weekly paclitaxel 80 mg/m^2 IV or docetaxel 75 mg/m^2 IV every 3 weeks, for 12 weeks. After completion of paclitaxel or docetaxel, participants received oral lap at an increased dose of 1500 mg daily for 40 weeks. Design 2B: oral lap 750 mg daily concomitantly with docetaxel 75 mg/m^2 every 3 weeks and carboplatin AUC6 IV, for 18 weeks. After completion of docetaxel and carboplatin, oral lap was given at an increased dose of 1500 mg for 34 weeks. Participants also received adjuvant radiotherapy and adjuvant anti-estrogen therapy when clinically indicated. Participants received treatment per one of the following three designs. Design 1: tras 8 mg/kg IV LD, followed by 6 mg/kg IV every 3 weeks for 52 weeks. Design 2: weekly tras (4 mg/kg IV LD, followed by 2 mg/kg IV weekly) concomitantly with weekly paclitaxel 80 mg/m^2 IV or docetaxel 75 mg/m^2 IV every 3 weeks, for 12 weeks. After completion of paclitaxel or docetaxel, participants received tras (6 mg/kg without a LD every 3 weeks for 40 weeks. Design 2B: weekly tras (4 mg/kg IV LD, followed by 2 mg/kg IV weekly) concomitantly with docetaxel 75 mg/m^2 every 3 weeks and carboplatin AUC6 IV, for 18 weeks. After completion of docetaxel and carboplatin, participants received tras every 3 weeks (6 mg/kg without a LD) for 34 weeks. Participants also received adjuvant radiotherapy and adjuvant anti-estrogen therapy when clinically indicated. Total of all reporting groups
Overall Number of Baseline Participants 2093 2091 2100 2097 8381
Hide Baseline Analysis Population Description
[Not Specified]
Age, Continuous  
Mean (Standard Deviation)
Unit of measure:  Years
Number Analyzed 2093 participants 2091 participants 2100 participants 2097 participants 8381 participants
50.9  (10.23) 50.8  (10.32) 51.2  (10.18) 51.0  (10.25) 51.0  (10.24)
Sex: Female, Male  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 2093 participants 2091 participants 2100 participants 2097 participants 8381 participants
Female
2091
  99.9%
2086
  99.8%
2098
  99.9%
2097
 100.0%
8372
  99.9%
Male
2
   0.1%
5
   0.2%
2
   0.1%
0
   0.0%
9
   0.1%
Race/Ethnicity, Customized  
Measure Type: Number
Unit of measure:  Participants
 Number Analyzed 2093 participants 2091 participants 2100 participants 2097 participants 8381 participants
American Indian or Alaska Native 48 45 47 47 187
Asian: Central/South 107 103 110 109 429
Asian: East 311 312 299 314 1236
Asian: Japanese 33 36 33 43 145
Asian: South East 95 92 107 89 383
Black or African American 38 30 43 25 136
Native Hawaiian (NH) or Other Pacific 2 4 4 5 15
White: Arabic 53 52 62 69 236
White: Caucasian 1392 1402 1372 1382 5548
Mixed Race/Ancestry 5 7 10 3 25
Hispanic 2 1 1 3 7
Mestizo 1 1 3 0 5
Mauritius Islander 0 0 0 1 1
Coloured 1 0 1 0 2
NH and White (Arabic/North African Heritage [HER]) 0 0 1 0 1
European Heritage and South American 1 0 0 0 1
South American, African HER and European HER 0 1 0 0 1
Afrikaans-South Africa 1 0 0 0 1
White South African 0 0 0 1 1
White South American 1 0 2 0 3
Southeast and Northeast of South America 0 0 1 0 1
Mulatto 0 1 0 0 1
South American Latin American and European HER 0 1 0 0 1
Black from South America 1 0 0 0 1
Northeast of South America and European HER 0 0 1 0 1
Asian (East), NH or Other Pacific Islander 0 0 0 1 1
Peruvian 0 0 0 1 1
Mexican 0 0 0 1 1
American Indian or Alaska Native and White 0 0 1 0 1
Caucasian and Guamanian (Chamorro) 0 0 1 0 1
Unknown/Missing 1 3 1 3 8
1.Primary Outcome
Title Disease-free Survival (DFS)
Hide Description Disease-free survival is defined as the interval between randomization and the date of the first occurence of disease recurrence (local, regional or distant), a contralateral invasive breast cancer, a second primary cancer (SPC), or death from any cause. DFS was estimated using the Kaplan Meier method.The percentile data values presented here indicate the percentage (95, 90, 85, 80 and 75 percent) of participants who had disease free survival for the indicated years.
Time Frame From randomization until the date of the first occurrence of disease recurrence, a contralateral invasive breast cancer, a second primary cancer, or death from any cause (median follow-up of 4.5 years)
Hide Outcome Measure Data
Hide Analysis Population Description
Intent-to-Treat (ITT) Population: all randomized par., except for those who withdrew their consent to use any of their data prior to receiving any study medication. Par. with no recurrence of the initial disease or SPC, or who did not die, were lost to follow-up, or were withdrawn from the study were censored at the date of last clinical contact.
Arm/Group Title Lapatinib plusTrastuzumab Trastuzumab Followed by Lapatinib Lapatinib Trastuzumab
Hide Arm/Group Description:
Participants (par.) received treatment per one of three designs. D1: oral lapatinib (OL) 1000 milligrams (mg) daily with trastuzumab (tras) (8 milligrams per kilogram [mg/kg] intravenous [IV] loading dose [LD], followed by 6 mg/kg IV every 3 weeks [E3W]) for 52 weeks (wks). D2: OL 750 mg daily plus wkly tras (4 mg/kg LD, followed by 2 mg/kg IV) concomitantly (conc.) with wkly paclitaxel (pac) 80 mg per squared meter (mg/m^2) IV or docetaxel (doc) 75 mg/m^2 IV E3W for 12 wks. After completion of pac or doc, par. received OL at an increased dose of 1000 mg daily in combination with tras (6 mg/kg without a LD) E3W for 40 wks. D2B: OL 750 mg plus wkly tras (4 mg/kg IV LD, followed by 2 mg/kg IV wkly) conc. with doc 75 mg/m^2 E3W and carboplatin (carb) AUC6 IV for 18 wks. After completion of doc and carb, par. received tras E3W (6 mg/kg without a LD) plus OL 1000 mg daily for 34 wks. Par. also received adjuvant radiotherapy and adjuvant anti-estrogen therapy when clinically indicated.
Participants received treatment per one of the following three designs. Design 1: weekly tras for 12 weeks (4 mg/kg IV loading dose, followed by 2 mg/kg IV weekly), followed by a 6-week washout period, followed by oral lap 1500 mg daily for 34 weeks. Design 2: weekly tras (4 mg/kg IV loading dose, followed by 2 mg/kg IV) concomitantly with weekly paclitaxel 80 mg/m^2 IV or docetaxel 75 mg/m^2 IV every 3 weeks for 12 weeks, followed by a 6-week washout period, followed by oral lap 1500 mg daily for 34 weeks. Design 2B: weekly tras (4 mg/kg IV loading dose, followed by 2 mg/kg IV weekly) concomitantly with docetaxel 75 mg/m^2 every 3 weeks and carboplatin AUC6 IV for 18 weeks, followed by a 6-week washout period, followed by oral lap 1500 mg daily for 28 weeks. Participants also received adjuvant radiotherapy and adjuvant anti-estrogen therapy when clinically indicated.
Participants received treatment per one of the following three designs. Design 1: oral lap 1500 mg daily for 52 weeks. Design 2: oral lap 750 mg daily concomitantly with weekly paclitaxel 80 mg/m^2 IV or docetaxel 75 mg/m^2 IV every 3 weeks, for 12 weeks. After completion of paclitaxel or docetaxel, participants received oral lap at an increased dose of 1500 mg daily for 40 weeks. Design 2B: oral lap 750 mg daily concomitantly with docetaxel 75 mg/m^2 every 3 weeks and carboplatin AUC6 IV, for 18 weeks. After completion of docetaxel and carboplatin, oral lap was given at an increased dose of 1500 mg for 34 weeks. Participants also received adjuvant radiotherapy and adjuvant anti-estrogen therapy when clinically indicated.
Participants received treatment per one of the following three designs. Design 1: tras 8 mg/kg IV LD, followed by 6 mg/kg IV every 3 weeks for 52 weeks. Design 2: weekly tras (4 mg/kg IV LD, followed by 2 mg/kg IV weekly) concomitantly with weekly paclitaxel 80 mg/m^2 IV or docetaxel 75 mg/m^2 IV every 3 weeks, for 12 weeks. After completion of paclitaxel or docetaxel, participants received tras (6 mg/kg without a LD every 3 weeks for 40 weeks. Design 2B: weekly tras (4 mg/kg IV LD, followed by 2 mg/kg IV weekly) concomitantly with docetaxel 75 mg/m^2 every 3 weeks and carboplatin AUC6 IV, for 18 weeks. After completion of docetaxel and carboplatin, participants received tras every 3 weeks (6 mg/kg without a LD) for 34 weeks. Participants also received adjuvant radiotherapy and adjuvant anti-estrogen therapy when clinically indicated.
Overall Number of Participants Analyzed 2093 2091 2100 2097
Measure Type: Number
Unit of Measure: years
95th Percentile 1.9 1.3 1.0 1.5
90th Percentile 3.2 2.8 1.8 2.6
85th Percentile 5.1 4.8 2.8 4.2
80th Percentile 6.1 NA [1]  4.9 5.6
75th Percentile 6.1 NA [1]  5.5 NA [1] 
[1]
There were not enough data (insufficient follow-up) to be able to compute this data point.
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Lapatinib plusTrastuzumab, Trastuzumab
Comments [Not Specified]
Type of Statistical Test Superiority or Other (legacy)
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.048
Comments [Not Specified]
Method Stratified log-rank test
Comments Stratification was by chemotherapy timing, hormone receptor status, and axillary lymph node status.
Method of Estimation Estimation Parameter Hazard Ratio (HR)
Estimated Value 0.84
Confidence Interval 97.5%
0.70 to 1.02
Estimation Comments The estimate of the treatment hazard ratio (lap plus tras versus tras) is based on the Cox's proportional hazards model adjusting for the stratification factors of chemotherapy timing, hormone receptor status, and auxillary lymph node status.
Hide Statistical Analysis 2
Statistical Analysis Overview Comparison Group Selection Trastuzumab Followed by Lapatinib, Trastuzumab
Comments [Not Specified]
Type of Statistical Test Superiority or Other (legacy)
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.610
Comments [Not Specified]
Method Stratified log-rank test
Comments Stratification is by chemotherapy timing, hormone receptor status, and axillary lymph node status.
Method of Estimation Estimation Parameter Hazard Ratio (HR)
Estimated Value 0.96
Confidence Interval 97.5%
0.80 to 1.15
Estimation Comments The estimate of the treatment hazard ratio (tras followed by lap versus tras) is based on the Cox's proportional hazards model adjusting for the stratification factors of chemotherapy timing, hormone receptor status, and auxillary lymph node status.
Hide Statistical Analysis 3
Statistical Analysis Overview Comparison Group Selection Lapatinib, Trastuzumab
Comments [Not Specified]
Type of Statistical Test Superiority or Other (legacy)
Comments [Not Specified]
Statistical Test of Hypothesis P-Value <0.0005
Comments [Not Specified]
Method Stratified log-rank test
Comments Stratification is by chemotherapy timing, hormone receptor status, and axillary lymph node status.
Method of Estimation Estimation Parameter Hazard Ratio (HR)
Estimated Value 1.34
Confidence Interval 97.5%
1.13 to 1.60
Estimation Comments The estimate of the treatment hazard ratio (lap versus tras) is based on the Cox's proportional hazards model adjusting for the stratification factors of chemotherapy timing, hormone receptor status, and auxillary lymph node status.
2.Secondary Outcome
Title Overall Survival (OS)
Hide Description Overall survival is defined as the time from randomization until death due to any cause. Overall survival was calculated in years as (date of death minus the date of randomization +1) divided by 365.25. The percentile data values presented here indicate the percentage (99, 98, 97, 96, 95 and 90 percent) of participants who survived for the indicated years.
Time Frame From randomization until death due to any cause (median follow-up of 4.5 years)
Hide Outcome Measure Data
Hide Analysis Population Description
ITT Population. Participants who did not die were censored at the date of last survival contact. Zero participants were analyzed in the lapatinib arm, as the Independent Data Monitoring Committee discontinued the lapatinib-alone arm due to futility at the time of the first interim analysis (lapatinib participants were then offered trastuzumab).
Arm/Group Title Lapatinib plusTrastuzumab Trastuzumab Followed by Lapatinib Trastuzumab Lapatinib
Hide Arm/Group Description:
Participants (par.) received treatment per one of three designs. D1: oral lapatinib (OL) 1000 milligrams (mg) daily with trastuzumab (tras) (8 milligrams per kilogram [mg/kg] intravenous [IV] loading dose [LD], followed by 6 mg/kg IV every 3 weeks [E3W]) for 52 weeks (wks). D2: OL 750 mg daily plus wkly tras (4 mg/kg LD, followed by 2 mg/kg IV) concomitantly (conc.) with wkly paclitaxel (pac) 80 mg per squared meter (mg/m^2) IV or docetaxel (doc) 75 mg/m^2 IV E3W for 12 wks. After completion of pac or doc, par. received OL at an increased dose of 1000 mg daily in combination with tras (6 mg/kg without a LD) E3W for 40 wks. D2B: OL 750 mg plus wkly tras (4 mg/kg IV LD, followed by 2 mg/kg IV wkly) conc. with doc 75 mg/m^2 E3W and carboplatin (carb) AUC6 IV for 18 wks. After completion of doc and carb, par. received tras E3W (6 mg/kg without a LD) plus OL 1000 mg daily for 34 wks. Par. also received adjuvant radiotherapy and adjuvant anti-estrogen therapy when clinically indicated.
Participants received treatment per one of the following three designs. Design 1: weekly tras for 12 weeks (4 mg/kg IV loading dose, followed by 2 mg/kg IV weekly), followed by a 6-week washout period, followed by oral lap 1500 mg daily for 34 weeks. Design 2: weekly tras (4 mg/kg IV loading dose, followed by 2 mg/kg IV) concomitantly with weekly paclitaxel 80 mg/m^2 IV or docetaxel 75 mg/m^2 IV every 3 weeks for 12 weeks, followed by a 6-week washout period, followed by oral lap 1500 mg daily for 34 weeks. Design 2B: weekly tras (4 mg/kg IV loading dose, followed by 2 mg/kg IV weekly) concomitantly with docetaxel 75 mg/m^2 every 3 weeks and carboplatin AUC6 IV for 18 weeks, followed by a 6-week washout period, followed by oral lap 1500 mg daily for 28 weeks. Participants also received adjuvant radiotherapy and adjuvant anti-estrogen therapy when clinically indicated.
Participants received treatment per one of the following three designs. Design 1: tras 8 mg/kg IV LD, followed by 6 mg/kg IV every 3 weeks for 52 weeks. Design 2: weekly tras (4 mg/kg IV LD, followed by 2 mg/kg IV weekly) concomitantly with weekly paclitaxel 80 mg/m^2 IV or docetaxel 75 mg/m^2 IV every 3 weeks, for 12 weeks. After completion of paclitaxel or docetaxel, participants received tras (6 mg/kg without a LD every 3 weeks for 40 weeks. Design 2B: weekly tras (4 mg/kg IV LD, followed by 2 mg/kg IV weekly) concomitantly with docetaxel 75 mg/m^2 every 3 weeks and carboplatin AUC6 IV, for 18 weeks. After completion of docetaxel and carboplatin, participants received tras every 3 weeks (6 mg/kg without a LD) for 34 weeks. Participants also received adjuvant radiotherapy and adjuvant anti-estrogen therapy when clinically indicated.
Participants received treatment per one of the following three designs. Design 1: oral lap 1500 mg daily for 52 weeks. Design 2: oral lap 750 mg daily concomitantly with weekly paclitaxel 80 mg/m^2 IV or docetaxel 75 mg/m^2 IV every 3 weeks, for 12 weeks. After completion of paclitaxel or docetaxel, participants received oral lap at an increased dose of 1500 mg daily for 40 weeks. Design 2B: oral lap 750 mg daily concomitantly with docetaxel 75 mg/m^2 every 3 weeks and carboplatin AUC6 IV, for 18 weeks. After completion of docetaxel and carboplatin, oral lap was given at an increased dose of 1500 mg for 34 weeks. Participants also received adjuvant radiotherapy and adjuvant anti-estrogen therapy when clinically indicated.
Overall Number of Participants Analyzed 2093 2091 2097 0
Measure Type: Number
Unit of Measure: years
99th Percentile 1.7 1.2 1.7
98th Percentile 2.2 1.6 2.1
97th Percentile 2.8 2.2 2.6
96th Percentile 3.4 2.9 3.0
95th Percentile 3.9 3.7 3.6
90th Percentile NA [1]  NA [1]  5.9
[1]
There were not enough data (insufficient follow-up) to be able to compute this data point.
3.Secondary Outcome
Title Time to Recurrence
Hide Description Time to recurrence is defined as the interval between the date of randomization and the date of the first occurrence of a disease recurrence (local, regional or distant). The percentile data values presented here indicate the percentage (95, 90, 85, and 80 percent) of participants who did not have disease recurrence for the indicated years. IDMC=Independent Data Monitoring Committee.
Time Frame From randomization until the date of the first occurrence of a disease recurrence (median follow-up of 4.5 years)
Hide Outcome Measure Data
Hide Analysis Population Description
ITT Population. Participants who did not have a recurrence of the initial disease were censored at the date of the last recorded physical or radiological examination. Death was treated as a competing risk. Zero participants were analyzed in the lapatinib arm, as the IDMC discontinued the lapatinib-alone arm due to futility at the interim analysis.
Arm/Group Title Lapatinib plusTrastuzumab Trastuzumab Followed by Lapatinib Trastuzumab Lapatinib
Hide Arm/Group Description:
Participants (par.) received treatment per one of three designs. D1: oral lapatinib (OL) 1000 milligrams (mg) daily with trastuzumab (tras) (8 milligrams per kilogram [mg/kg] intravenous [IV] loading dose [LD], followed by 6 mg/kg IV every 3 weeks [E3W]) for 52 weeks (wks). D2: OL 750 mg daily plus wkly tras (4 mg/kg LD, followed by 2 mg/kg IV) concomitantly (conc.) with wkly paclitaxel (pac) 80 mg per squared meter (mg/m^2) IV or docetaxel (doc) 75 mg/m^2 IV E3W for 12 wks. After completion of pac or doc, par. received OL at an increased dose of 1000 mg daily in combination with tras (6 mg/kg without a LD) E3W for 40 wks. D2B: OL 750 mg plus wkly tras (4 mg/kg IV LD, followed by 2 mg/kg IV wkly) conc. with doc 75 mg/m^2 E3W and carboplatin (carb) AUC6 IV for 18 wks. After completion of doc and carb, par. received tras E3W (6 mg/kg without a LD) plus OL 1000 mg daily for 34 wks. Par. also received adjuvant radiotherapy and adjuvant anti-estrogen therapy when clinically indicated.
Participants received treatment per one of the following three designs. Design 1: weekly tras for 12 weeks (4 mg/kg IV loading dose, followed by 2 mg/kg IV weekly), followed by a 6-week washout period, followed by oral lap 1500 mg daily for 34 weeks. Design 2: weekly tras (4 mg/kg IV loading dose, followed by 2 mg/kg IV) concomitantly with weekly paclitaxel 80 mg/m^2 IV or docetaxel 75 mg/m^2 IV every 3 weeks for 12 weeks, followed by a 6-week washout period, followed by oral lap 1500 mg daily for 34 weeks. Design 2B: weekly tras (4 mg/kg IV loading dose, followed by 2 mg/kg IV weekly) concomitantly with docetaxel 75 mg/m^2 every 3 weeks and carboplatin AUC6 IV for 18 weeks, followed by a 6-week washout period, followed by oral lap 1500 mg daily for 28 weeks. Participants also received adjuvant radiotherapy and adjuvant anti-estrogen therapy when clinically indicated.
Participants received treatment per one of the following three designs. Design 1: tras 8 mg/kg IV LD, followed by 6 mg/kg IV every 3 weeks for 52 weeks. Design 2: weekly tras (4 mg/kg IV LD, followed by 2 mg/kg IV weekly) concomitantly with weekly paclitaxel 80 mg/m^2 IV or docetaxel 75 mg/m^2 IV every 3 weeks, for 12 weeks. After completion of paclitaxel or docetaxel, participants received tras (6 mg/kg without a LD every 3 weeks for 40 weeks. Design 2B: weekly tras (4 mg/kg IV LD, followed by 2 mg/kg IV weekly) concomitantly with docetaxel 75 mg/m^2 every 3 weeks and carboplatin AUC6 IV, for 18 weeks. After completion of docetaxel and carboplatin, participants received tras every 3 weeks (6 mg/kg without a LD) for 34 weeks. Participants also received adjuvant radiotherapy and adjuvant anti-estrogen therapy when clinically indicated.
Participants received treatment per one of the following three designs. Design 1: oral lap 1500 mg daily for 52 weeks. Design 2: oral lap 750 mg daily concomitantly with weekly paclitaxel 80 mg/m^2 IV or docetaxel 75 mg/m^2 IV every 3 weeks, for 12 weeks. After completion of paclitaxel or docetaxel, participants received oral lap at an increased dose of 1500 mg daily for 40 weeks. Design 2B: oral lap 750 mg daily concomitantly with docetaxel 75 mg/m^2 every 3 weeks and carboplatin AUC6 IV, for 18 weeks. After completion of docetaxel and carboplatin, oral lap was given at an increased dose of 1500 mg for 34 weeks. Participants also received adjuvant radiotherapy and adjuvant anti-estrogen therapy when clinically indicated.
Overall Number of Participants Analyzed 2093 2091 2097 0
Measure Type: Number
Unit of Measure: years
95th Percentile 2.2 1.5 1.7
90th Percentile 4.5 3.7 3.2
85th Percentile 6.1 NA [1]  NA [1] 
80th Percentile 6.1 NA [1]  NA [1] 
[1]
There were not enough data (insufficient follow-up) to be able to compute this data point.
4.Secondary Outcome
Title Time to Distant Recurrence
Hide Description Time to distant recurrence is defined as the interval between the date of randomization and the date of the first occurrence of distant recurrence (including central nervous system recurrence). The percentile data values presented here indicate the percentage (95, 90, 85 and 80 percent) of participants who did not have distant recurrence for the indicated years.
Time Frame From randomization until the date of the first occurrence of distant recurrence (median follow-up of 4.5 years)
Hide Outcome Measure Data
Hide Analysis Population Description
ITT Population. Participants who did not have a distant recurrence of the initial disease were censored at the date of the last recorded physical or radiological examination. Death was treated as a competing risk. Zero participants were analyzed in the lapatinib arm, as the IDMC discontinued the lapatinib-alone arm due to futility.
Arm/Group Title Lapatinib plusTrastuzumab Trastuzumab Followed by Lapatinib Trastuzumab Lapatinib
Hide Arm/Group Description:
Participants (par.) received treatment per one of three designs. D1: oral lapatinib (OL) 1000 milligrams (mg) daily with trastuzumab (tras) (8 milligrams per kilogram [mg/kg] intravenous [IV] loading dose [LD], followed by 6 mg/kg IV every 3 weeks [E3W]) for 52 weeks (wks). D2: OL 750 mg daily plus wkly tras (4 mg/kg LD, followed by 2 mg/kg IV) concomitantly (conc.) with wkly paclitaxel (pac) 80 mg per squared meter (mg/m^2) IV or docetaxel (doc) 75 mg/m^2 IV E3W for 12 wks. After completion of pac or doc, par. received OL at an increased dose of 1000 mg daily in combination with tras (6 mg/kg without a LD) E3W for 40 wks. D2B: OL 750 mg plus wkly tras (4 mg/kg IV LD, followed by 2 mg/kg IV wkly) conc. with doc 75 mg/m^2 E3W and carboplatin (carb) AUC6 IV for 18 wks. After completion of doc and carb, par. received tras E3W (6 mg/kg without a LD) plus OL 1000 mg daily for 34 wks. Par. also received adjuvant radiotherapy and adjuvant anti-estrogen therapy when clinically indicated.
Participants received treatment per one of the following three designs. Design 1: weekly tras for 12 weeks (4 mg/kg IV loading dose, followed by 2 mg/kg IV weekly), followed by a 6-week washout period, followed by oral lap 1500 mg daily for 34 weeks. Design 2: weekly tras (4 mg/kg IV loading dose, followed by 2 mg/kg IV) concomitantly with weekly paclitaxel 80 mg/m^2 IV or docetaxel 75 mg/m^2 IV every 3 weeks for 12 weeks, followed by a 6-week washout period, followed by oral lap 1500 mg daily for 34 weeks. Design 2B: weekly tras (4 mg/kg IV loading dose, followed by 2 mg/kg IV weekly) concomitantly with docetaxel 75 mg/m^2 every 3 weeks and carboplatin AUC6 IV for 18 weeks, followed by a 6-week washout period, followed by oral lap 1500 mg daily for 28 weeks. Participants also received adjuvant radiotherapy and adjuvant anti-estrogen therapy when clinically indicated.
Participants received treatment per one of the following three designs. Design 1: tras 8 mg/kg IV LD, followed by 6 mg/kg IV every 3 weeks for 52 weeks. Design 2: weekly tras (4 mg/kg IV LD, followed by 2 mg/kg IV weekly) concomitantly with weekly paclitaxel 80 mg/m^2 IV or docetaxel 75 mg/m^2 IV every 3 weeks, for 12 weeks. After completion of paclitaxel or docetaxel, participants received tras (6 mg/kg without a LD every 3 weeks for 40 weeks. Design 2B: weekly tras (4 mg/kg IV LD, followed by 2 mg/kg IV weekly) concomitantly with docetaxel 75 mg/m^2 every 3 weeks and carboplatin AUC6 IV, for 18 weeks. After completion of docetaxel and carboplatin, participants received tras every 3 weeks (6 mg/kg without a LD) for 34 weeks. Participants also received adjuvant radiotherapy and adjuvant anti-estrogen therapy when clinically indicated.
Participants received treatment per one of the following three designs. Design 1: oral lap 1500 mg daily for 52 weeks. Design 2: oral lap 750 mg daily concomitantly with weekly paclitaxel 80 mg/m^2 IV or docetaxel 75 mg/m^2 IV every 3 weeks, for 12 weeks. After completion of paclitaxel or docetaxel, participants received oral lap at an increased dose of 1500 mg daily for 40 weeks. Design 2B: oral lap 750 mg daily concomitantly with docetaxel 75 mg/m^2 every 3 weeks and carboplatin AUC6 IV, for 18 weeks. After completion of docetaxel and carboplatin, oral lap was given at an increased dose of 1500 mg for 34 weeks. Participants also received adjuvant radiotherapy and adjuvant anti-estrogen therapy when clinically indicated.
Overall Number of Participants Analyzed 2093 2091 2097 0
Measure Type: Number
Unit of Measure: years
95th Percentile 2.4 1.8 1.9
90th Percentile 5.5 4.2 4.1
85th Percentile 6.1 NA [1]  NA [1] 
80th Percentile 6.1 NA [1]  NA [1] 
[1]
There were not enough data (insufficient follow-up) to be able to compute this data point.
5.Secondary Outcome
Title Time to Central Nervous System Recurrence
Hide Description Time to central nervous system recurrence is defined as the time from randomization until the first central nervous system recurrence. Both brain metastasis and meningitis carcinomatosa were considered.The percentile data values presented here indicate that 95 percent of participants did not have central nervous system recurrence for the indicated years.
Time Frame From randomization until the first central nervous system recurrence (median follow-up of 4.5 years)
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ITT Population. Participants who did not have a central nervous system recurrence were censored at the date of the last recorded physical or radiological examination. Death was treated as a competing risk. Zero participants were analyzed in the lapatinib arm, as the IDMC discontinued the lapatinib-alone arm due to futility at the interim analysis.
Arm/Group Title Lapatinib plusTrastuzumab Trastuzumab Followed by Lapatinib Trastuzumab Lapatinib
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Participants (par.) received treatment per one of three designs. D1: oral lapatinib (OL) 1000 milligrams (mg) daily with trastuzumab (tras) (8 milligrams per kilogram [mg/kg] intravenous [IV] loading dose [LD], followed by 6 mg/kg IV every 3 weeks [E3W]) for 52 weeks (wks). D2: OL 750 mg daily plus wkly tras (4 mg/kg LD, followed by 2 mg/kg IV) concomitantly (conc.) with wkly paclitaxel (pac) 80 mg per squared meter (mg/m^2) IV or docetaxel (doc) 75 mg/m^2 IV E3W for 12 wks. After completion of pac or doc, par. received OL at an increased dose of 1000 mg daily in combination with tras (6 mg/kg without a LD) E3W for 40 wks. D2B: OL 750 mg plus wkly tras (4 mg/kg IV LD, followed by 2 mg/kg IV wkly) conc. with doc 75 mg/m^2 E3W and carboplatin (carb) AUC6 IV for 18 wks. After completion of doc and carb, par. received tras E3W (6 mg/kg without a LD) plus OL 1000 mg daily for 34 wks. Par. also received adjuvant radiotherapy and adjuvant anti-estrogen therapy when clinically indicated.
Participants received treatment per one of the following three designs. Design 1: weekly tras for 12 weeks (4 mg/kg IV loading dose, followed by 2 mg/kg IV weekly), followed by a 6-week washout period, followed by oral lap 1500 mg daily for 34 weeks. Design 2: weekly tras (4 mg/kg IV loading dose, followed by 2 mg/kg IV) concomitantly with weekly paclitaxel 80 mg/m^2 IV or docetaxel 75 mg/m^2 IV every 3 weeks for 12 weeks, followed by a 6-week washout period, followed by oral lap 1500 mg daily for 34 weeks. Design 2B: weekly tras (4 mg/kg IV loading dose, followed by 2 mg/kg IV weekly) concomitantly with docetaxel 75 mg/m^2 every 3 weeks and carboplatin AUC6 IV for 18 weeks, followed by a 6-week washout period, followed by oral lap 1500 mg daily for 28 weeks. Participants also received adjuvant radiotherapy and adjuvant anti-estrogen therapy when clinically indicated.
Participants received treatment per one of the following three designs. Design 1: tras 8 mg/kg IV LD, followed by 6 mg/kg IV every 3 weeks for 52 weeks. Design 2: weekly tras (4 mg/kg IV LD, followed by 2 mg/kg IV weekly) concomitantly with weekly paclitaxel 80 mg/m^2 IV or docetaxel 75 mg/m^2 IV every 3 weeks, for 12 weeks. After completion of paclitaxel or docetaxel, participants received tras (6 mg/kg without a LD every 3 weeks for 40 weeks. Design 2B: weekly tras (4 mg/kg IV LD, followed by 2 mg/kg IV weekly) concomitantly with docetaxel 75 mg/m^2 every 3 weeks and carboplatin AUC6 IV, for 18 weeks. After completion of docetaxel and carboplatin, participants received tras every 3 weeks (6 mg/kg without a LD) for 34 weeks. Participants also received adjuvant radiotherapy and adjuvant anti-estrogen therapy when clinically indicated.
Participants received treatment per one of the following three designs. Design 1: oral lap 1500 mg daily for 52 weeks. Design 2: oral lap 750 mg daily concomitantly with weekly paclitaxel 80 mg/m^2 IV or docetaxel 75 mg/m^2 IV every 3 weeks, for 12 weeks. After completion of paclitaxel or docetaxel, participants received oral lap at an increased dose of 1500 mg daily for 40 weeks. Design 2B: oral lap 750 mg daily concomitantly with docetaxel 75 mg/m^2 every 3 weeks and carboplatin AUC6 IV, for 18 weeks. After completion of docetaxel and carboplatin, oral lap was given at an increased dose of 1500 mg for 34 weeks. Participants also received adjuvant radiotherapy and adjuvant anti-estrogen therapy when clinically indicated.
Overall Number of Participants Analyzed 2093 2091 2097 0
Measure Type: Number
Unit of Measure: years
5.8 NA [1]  NA [1] 
[1]
There were not enough data (insufficient follow-up) to be able to compute this data point.
6.Secondary Outcome
Title DFS Ignoring Non-breast Second Primary Malignancies
Hide Description Disease-free survival is defined as the interval between randomization and the date of the first occurence of disease recurrence (local, regional or distant), a contralateral invasive breast cancer, a second primary cancer, or death from any cause. DFS was estimated using the Kaplan Meier method. The non-breast second primary malignancies were not considered events.The percentile data values presented here indicate the percentage (95, 90, 85, 80 and 75 percent) of participants who did not have DFS ignoring non-breast second primary malignancies for the indicated years. Zero participants were analyzed in the lapatinib arm, as the IDMC discontinued the lapatinib-alone arm due to futility at the time of the first interim analysis (lapatinib participants were then offered trastuzumab).
Time Frame From randomization until the date of the first occurrence of disease recurrence, a contralateral invasive breast cancer, a second primary cancer, or death from any cause (median follow-up of 4.5 years)
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ITT Population. Participants who did not have a recurrence of the initial disease, or did not die, were lost to follow-up, or were withdrawn from the study were censored at the date of last clinical contact. Non-breast second primary cancers were ignored.
Arm/Group Title Lapatinib plusTrastuzumab Trastuzumab Followed by Lapatinib Trastuzumab Lapatinib
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Participants (par.) received treatment per one of three designs. D1: oral lapatinib (OL) 1000 milligrams (mg) daily with trastuzumab (tras) (8 milligrams per kilogram [mg/kg] intravenous [IV] loading dose [LD], followed by 6 mg/kg IV every 3 weeks [E3W]) for 52 weeks (wks). D2: OL 750 mg daily plus wkly tras (4 mg/kg LD, followed by 2 mg/kg IV) concomitantly (conc.) with wkly paclitaxel (pac) 80 mg per squared meter (mg/m^2) IV or docetaxel (doc) 75 mg/m^2 IV E3W for 12 wks. After completion of pac or doc, par. received OL at an increased dose of 1000 mg daily in combination with tras (6 mg/kg without a LD) E3W for 40 wks. D2B: OL 750 mg plus wkly tras (4 mg/kg IV LD, followed by 2 mg/kg IV wkly) conc. with doc 75 mg/m^2 E3W and carboplatin (carb) AUC6 IV for 18 wks. After completion of doc and carb, par. received tras E3W (6 mg/kg without a LD) plus OL 1000 mg daily for 34 wks. Par. also received adjuvant radiotherapy and adjuvant anti-estrogen therapy when clinically indicated.
Participants received treatment per one of the following three designs. Design 1: weekly tras for 12 weeks (4 mg/kg IV loading dose, followed by 2 mg/kg IV weekly), followed by a 6-week washout period, followed by oral lap 1500 mg daily for 34 weeks. Design 2: weekly tras (4 mg/kg IV loading dose, followed by 2 mg/kg IV) concomitantly with weekly paclitaxel 80 mg/m^2 IV or docetaxel 75 mg/m^2 IV every 3 weeks for 12 weeks, followed by a 6-week washout period, followed by oral lap 1500 mg daily for 34 weeks. Design 2B: weekly tras (4 mg/kg IV loading dose, followed by 2 mg/kg IV weekly) concomitantly with docetaxel 75 mg/m^2 every 3 weeks and carboplatin AUC6 IV for 18 weeks, followed by a 6-week washout period, followed by oral lap 1500 mg daily for 28 weeks. Participants also received adjuvant radiotherapy and adjuvant anti-estrogen therapy when clinically indicated.
Participants received treatment per one of the following three designs. Design 1: tras 8 mg/kg IV LD, followed by 6 mg/kg IV every 3 weeks for 52 weeks. Design 2: weekly tras (4 mg/kg IV LD, followed by 2 mg/kg IV weekly) concomitantly with weekly paclitaxel 80 mg/m^2 IV or docetaxel 75 mg/m^2 IV every 3 weeks, for 12 weeks. After completion of paclitaxel or docetaxel, participants received tras (6 mg/kg without a LD every 3 weeks for 40 weeks. Design 2B: weekly tras (4 mg/kg IV LD, followed by 2 mg/kg IV weekly) concomitantly with docetaxel 75 mg/m^2 every 3 weeks and carboplatin AUC6 IV, for 18 weeks. After completion of docetaxel and carboplatin, participants received tras every 3 weeks (6 mg/kg without a LD) for 34 weeks. Participants also received adjuvant radiotherapy and adjuvant anti-estrogen therapy when clinically indicated.
Participants received treatment per one of the following three designs. Design 1: oral lap 1500 mg daily for 52 weeks. Design 2: oral lap 750 mg daily concomitantly with weekly paclitaxel 80 mg/m^2 IV or docetaxel 75 mg/m^2 IV every 3 weeks, for 12 weeks. After completion of paclitaxel or docetaxel, participants received oral lap at an increased dose of 1500 mg daily for 40 weeks. Design 2B: oral lap 750 mg daily concomitantly with docetaxel 75 mg/m^2 every 3 weeks and carboplatin AUC6 IV, for 18 weeks. After completion of docetaxel and carboplatin, oral lap was given at an increased dose of 1500 mg for 34 weeks. Participants also received adjuvant radiotherapy and adjuvant anti-estrogen therapy when clinically indicated.
Overall Number of Participants Analyzed 1155 1143 1147 0
Measure Type: Number
Unit of Measure: years
95th Percentile 1.9 1.2 1.4
90th Percentile 3.0 2.3 2.3
85th Percentile 5.6 4.7 3.5
80th Percentile 6.1 NA [1]  NA [1] 
75th Percentile 6.1 NA [1]  NA [1] 
[1]
There were not enough data (insufficient follow-up) to be able to compute this data point.
Time Frame Serious adverse events (SAEs) and non-serious AEs were collected from randomization until 10 years post-study entry.
Adverse Event Reporting Description SAEs and non-serious AEs are reported for the Safety Population, comprised of all randomized participants who were administered at least one dose of investigational targeted treatment, as recorded on the "administration of study drug" Case Report Form pages, but excluding any post-event treatments and not considering compliance.
 
Arm/Group Title Lapatinib plusTrastuzumab Trastuzumab Followed by Lapatinib Lapatinib Trastuzumab
Hide Arm/Group Description Participants (par.) received treatment per one of three designs. D1: oral lapatinib (OL) 1000 milligrams (mg) daily with trastuzumab (tras) (8 milligrams per kilogram [mg/kg] intravenous [IV] loading dose [LD], followed by 6 mg/kg IV every 3 weeks [E3W]) for 52 weeks (wks). D2: OL 750 mg daily plus wkly tras (4 mg/kg LD, followed by 2 mg/kg IV) concomitantly (conc.) with wkly paclitaxel (pac) 80 mg per squared meter (mg/m^2) IV or docetaxel (doc) 75 mg/m^2 IV E3W for 12 wks. After completion of pac or doc, par. received OL at an increased dose of 1000 mg daily in combination with tras (6 mg/kg without a LD) E3W for 40 wks. D2B: OL 750 mg plus wkly tras (4 mg/kg IV LD, followed by 2 mg/kg IV wkly) conc. with doc 75 mg/m^2 E3W and carboplatin (carb) AUC6 IV for 18 wks. After completion of doc and carb, par. received tras E3W (6 mg/kg without a LD) plus OL 1000 mg daily for 34 wks. Par. also received adjuvant radiotherapy and adjuvant anti-estrogen therapy when clinically indicated. Participants received treatment per one of the following three designs. Design 1: weekly tras for 12 weeks (4 mg/kg IV loading dose, followed by 2 mg/kg IV weekly), followed by a 6-week washout period, followed by oral lap 1500 mg daily for 34 weeks. Design 2: weekly tras (4 mg/kg IV loading dose, followed by 2 mg/kg IV) concomitantly with weekly paclitaxel 80 mg/m^2 IV or docetaxel 75 mg/m^2 IV every 3 weeks for 12 weeks, followed by a 6-week washout period, followed by oral lap 1500 mg daily for 34 weeks. Design 2B: weekly tras (4 mg/kg IV loading dose, followed by 2 mg/kg IV weekly) concomitantly with docetaxel 75 mg/m^2 every 3 weeks and carboplatin AUC6 IV for 18 weeks, followed by a 6-week washout period, followed by oral lap 1500 mg daily for 28 weeks. Participants also received adjuvant radiotherapy and adjuvant anti-estrogen therapy when clinically indicated. Participants received treatment per one of the following three designs. Design 1: oral lap 1500 mg daily for 52 weeks. Design 2: oral lap 750 mg daily concomitantly with weekly paclitaxel 80 mg/m^2 IV or docetaxel 75 mg/m^2 IV every 3 weeks, for 12 weeks. After completion of paclitaxel or docetaxel, participants received oral lap at an increased dose of 1500 mg daily for 40 weeks. Design 2B: oral lap 750 mg daily concomitantly with docetaxel 75 mg/m^2 every 3 weeks and carboplatin AUC6 IV, for 18 weeks. After completion of docetaxel and carboplatin, oral lap was given at an increased dose of 1500 mg for 34 weeks. Participants also received adjuvant radiotherapy and adjuvant anti-estrogen therapy when clinically indicated. Participants received treatment per one of the following three designs. Design 1: tras 8 mg/kg IV LD, followed by 6 mg/kg IV every 3 weeks for 52 weeks. Design 2: weekly tras (4 mg/kg IV LD, followed by 2 mg/kg IV weekly) concomitantly with weekly paclitaxel 80 mg/m^2 IV or docetaxel 75 mg/m^2 IV every 3 weeks, for 12 weeks. After completion of paclitaxel or docetaxel, participants received tras (6 mg/kg without a LD every 3 weeks for 40 weeks. Design 2B: weekly tras (4 mg/kg IV LD, followed by 2 mg/kg IV weekly) concomitantly with docetaxel 75 mg/m^2 every 3 weeks and carboplatin AUC6 IV, for 18 weeks. After completion of docetaxel and carboplatin, participants received tras every 3 weeks (6 mg/kg without a LD) for 34 weeks. Participants also received adjuvant radiotherapy and adjuvant anti-estrogen therapy when clinically indicated.
All-Cause Mortality
Lapatinib plusTrastuzumab Trastuzumab Followed by Lapatinib Lapatinib Trastuzumab
Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%)
Total   --/--   --/--   --/--   --/-- 
Hide Serious Adverse Events
Lapatinib plusTrastuzumab Trastuzumab Followed by Lapatinib Lapatinib Trastuzumab
Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%)
Total   430/2061 (20.86%)   352/2076 (16.96%)   431/2057 (20.95%)   292/2076 (14.07%) 
Blood and lymphatic system disorders         
Neutropenia † 1  37/2061 (1.80%)  21/2076 (1.01%)  37/2057 (1.80%)  20/2076 (0.96%) 
Leukopenia † 1  20/2061 (0.97%)  3/2076 (0.14%)  13/2057 (0.63%)  6/2076 (0.29%) 
Anaemia † 1  7/2061 (0.34%)  6/2076 (0.29%)  13/2057 (0.63%)  7/2076 (0.34%) 
Febrile Neutropenia † 1  9/2061 (0.44%)  6/2076 (0.29%)  12/2057 (0.58%)  3/2076 (0.14%) 
Thrombocytopenia † 1  2/2061 (0.10%)  1/2076 (0.05%)  2/2057 (0.10%)  7/2076 (0.34%) 
Agranulocytosis † 1  0/2061 (0.00%)  1/2076 (0.05%)  0/2057 (0.00%)  0/2076 (0.00%) 
Eosinophilia † 1  0/2061 (0.00%)  1/2076 (0.05%)  0/2057 (0.00%)  0/2076 (0.00%) 
Iron Deficiency Anaemia † 1  0/2061 (0.00%)  0/2076 (0.00%)  0/2057 (0.00%)  1/2076 (0.05%) 
Pancytopenia † 1  1/2061 (0.05%)  0/2076 (0.00%)  0/2057 (0.00%)  0/2076 (0.00%) 
Cardiac disorders         
Cardiac Failure Congestive † 1  24/2061 (1.16%)  12/2076 (0.58%)  8/2057 (0.39%)  20/2076 (0.96%) 
Left Ventricular Dysfunction † 1  3/2061 (0.15%)  9/2076 (0.43%)  5/2057 (0.24%)  4/2076 (0.19%) 
Atrial Fibrillation † 1  6/2061 (0.29%)  7/2076 (0.34%)  0/2057 (0.00%)  3/2076 (0.14%) 
Myocardial Infarction † 1  3/2061 (0.15%)  1/2076 (0.05%)  2/2057 (0.10%)  3/2076 (0.14%) 
Cardiac Failure † 1  1/2061 (0.05%)  2/2076 (0.10%)  0/2057 (0.00%)  1/2076 (0.05%) 
Myocardial Ischaemia † 1  1/2061 (0.05%)  1/2076 (0.05%)  1/2057 (0.05%)  1/2076 (0.05%) 
Acute Coronary Syndrome † 1  0/2061 (0.00%)  1/2076 (0.05%)  1/2057 (0.05%)  1/2076 (0.05%) 
Arrhythmia † 1  1/2061 (0.05%)  1/2076 (0.05%)  1/2057 (0.05%)  0/2076 (0.00%) 
Cardiac Arrest † 1  1/2061 (0.05%)  1/2076 (0.05%)  0/2057 (0.00%)  1/2076 (0.05%) 
Pericarditis † 1  0/2061 (0.00%)  1/2076 (0.05%)  1/2057 (0.05%)  1/2076 (0.05%) 
Supraventricular Tachycardia † 1  2/2061 (0.10%)  1/2076 (0.05%)  0/2057 (0.00%)  0/2076 (0.00%) 
Angina Pectoris † 1  0/2061 (0.00%)  1/2076 (0.05%)  0/2057 (0.00%)  1/2076 (0.05%) 
Angina Unstable † 1  0/2061 (0.00%)  1/2076 (0.05%)  0/2057 (0.00%)  1/2076 (0.05%) 
Coronary Artery Disease † 1  0/2061 (0.00%)  1/2076 (0.05%)  1/2057 (0.05%)  0/2076 (0.00%) 
Palpitations † 1  0/2061 (0.00%)  1/2076 (0.05%)  0/2057 (0.00%)  1/2076 (0.05%) 
Ventricular Tachycardia † 1  1/2061 (0.05%)  0/2076 (0.00%)  1/2057 (0.05%)  0/2076 (0.00%) 
Acute Myocardial Infarction † 1  0/2061 (0.00%)  0/2076 (0.00%)  1/2057 (0.05%)  0/2076 (0.00%) 
Aortic Valve Sclerosis † 1  0/2061 (0.00%)  0/2076 (0.00%)  0/2057 (0.00%)  1/2076 (0.05%) 
Atrial Tachycardia † 1  0/2061 (0.00%)  1/2076 (0.05%)  0/2057 (0.00%)  0/2076 (0.00%) 
Atrial Thrombosis † 1  0/2061 (0.00%)  0/2076 (0.00%)  1/2057 (0.05%)  0/2076 (0.00%) 
Atrioventricular Block Complete † 1  0/2061 (0.00%)  0/2076 (0.00%)  1/2057 (0.05%)  0/2076 (0.00%) 
Cardiac Ventricular Thrombosis † 1  1/2061 (0.05%)  0/2076 (0.00%)  0/2057 (0.00%)  0/2076 (0.00%) 
Cardio-Respiratory Arrest † 1  1/2061 (0.05%)  0/2076 (0.00%)  0/2057 (0.00%)  0/2076 (0.00%) 
Cardiomyopathy † 1  0/2061 (0.00%)  0/2076 (0.00%)  1/2057 (0.05%)  0/2076 (0.00%) 
Intracardiac Thrombus † 1  0/2061 (0.00%)  0/2076 (0.00%)  0/2057 (0.00%)  1/2076 (0.05%) 
Ischaemic Cardiomyopathy † 1  1/2061 (0.05%)  0/2076 (0.00%)  0/2057 (0.00%)  0/2076 (0.00%) 
Myocarditis † 1  0/2061 (0.00%)  1/2076 (0.05%)  0/2057 (0.00%)  0/2076 (0.00%) 
Pericardial Effusion † 1  0/2061 (0.00%)  0/2076 (0.00%)  0/2057 (0.00%)  1/2076 (0.05%) 
Vascular Insufficiency † 1  1/2061 (0.05%)  0/2076 (0.00%)  0/2057 (0.00%)  0/2076 (0.00%) 
Ventricular Arrhythmia † 1  0/2061 (0.00%)  0/2076 (0.00%)  1/2057 (0.05%)  0/2076 (0.00%) 
Ventricular Extrasystoles † 1  0/2061 (0.00%)  1/2076 (0.05%)  0/2057 (0.00%)  0/2076 (0.00%) 
Congenital, familial and genetic disorders         
Gilbert's Syndrome † 1  1/2061 (0.05%)  0/2076 (0.00%)  0/2057 (0.00%)  0/2076 (0.00%) 
Trisomy 21 † 1  0/2061 (0.00%)  1/2076 (0.05%)  0/2057 (0.00%)  0/2076 (0.00%) 
Ear and labyrinth disorders         
Vertigo † 1  2/2061 (0.10%)  2/2076 (0.10%)  0/2057 (0.00%)  1/2076 (0.05%) 
Tinnitus † 1  1/2061 (0.05%)  0/2076 (0.00%)  0/2057 (0.00%)  0/2076 (0.00%) 
Vertigo Positional † 1  0/2061 (0.00%)  0/2076 (0.00%)  1/2057 (0.05%)  0/2076 (0.00%) 
Endocrine disorders         
Autoimmune Thyroiditis † 1  0/2061 (0.00%)  0/2076 (0.00%)  1/2057 (0.05%)  0/2076 (0.00%) 
Goitre † 1  0/2061 (0.00%)  0/2076 (0.00%)  0/2057 (0.00%)  1/2076 (0.05%) 
Hyperparathyroidism † 1  0/2061 (0.00%)  0/2076 (0.00%)  0/2057 (0.00%)  1/2076 (0.05%) 
Hypothyroidism † 1  1/2061 (0.05%)  0/2076 (0.00%)  0/2057 (0.00%)  0/2076 (0.00%) 
Eye disorders         
Retinal Detachment † 1  0/2061 (0.00%)  0/2076 (0.00%)  0/2057 (0.00%)  2/2076 (0.10%) 
Diplopia † 1  0/2061 (0.00%)  1/2076 (0.05%)  0/2057 (0.00%)  0/2076 (0.00%) 
Periorbital Oedema † 1  0/2061 (0.00%)  0/2076 (0.00%)  1/2057 (0.05%)  0/2076 (0.00%) 
Gastrointestinal disorders         
Diarrhoea † 1  53/2061 (2.57%)  6/2076 (0.29%)  44/2057 (2.14%)  9/2076 (0.43%) 
Vomiting † 1  9/2061 (0.44%)  3/2076 (0.14%)  9/2057 (0.44%)  8/2076 (0.39%) 
Nausea † 1  5/2061 (0.24%)  3/2076 (0.14%)  7/2057 (0.34%)  6/2076 (0.29%) 
Abdominal Pain † 1  6/2061 (0.29%)  4/2076 (0.19%)  4/2057 (0.19%)  2/2076 (0.10%) 
Colitis † 1  4/2061 (0.19%)  0/2076 (0.00%)  2/2057 (0.10%)  1/2076 (0.05%) 
Gastritis † 1  2/2061 (0.10%)  2/2076 (0.10%)  1/2057 (0.05%)  2/2076 (0.10%) 
Haemorrhoids † 1  1/2061 (0.05%)  1/2076 (0.05%)  0/2057 (0.00%)  4/2076 (0.19%) 
Constipation † 1  0/2061 (0.00%)  0/2076 (0.00%)  2/2057 (0.10%)  1/2076 (0.05%) 
Gastrointestinal Haemorrhage † 1  1/2061 (0.05%)  1/2076 (0.05%)  0/2057 (0.00%)  1/2076 (0.05%) 
Ileus † 1  1/2061 (0.05%)  1/2076 (0.05%)  1/2057 (0.05%)  0/2076 (0.00%) 
Intestinal Obstruction † 1  2/2061 (0.10%)  1/2076 (0.05%)  0/2057 (0.00%)  0/2076 (0.00%) 
Pancreatitis † 1  0/2061 (0.00%)  1/2076 (0.05%)  1/2057 (0.05%)  1/2076 (0.05%) 
Abdominal Pain Upper † 1  1/2061 (0.05%)  0/2076 (0.00%)  1/2057 (0.05%)  0/2076 (0.00%) 
Duodenal Ulcer † 1  1/2061 (0.05%)  0/2076 (0.00%)  1/2057 (0.05%)  0/2076 (0.00%) 
Enteritis † 1  1/2061 (0.05%)  0/2076 (0.00%)  0/2057 (0.00%)  1/2076 (0.05%) 
Enterocolitis † 1  1/2061 (0.05%)  0/2076 (0.00%)  0/2057 (0.00%)  1/2076 (0.05%) 
Gastrointestinal Obstruction † 1  1/2061 (0.05%)  0/2076 (0.00%)  1/2057 (0.05%)  0/2076 (0.00%) 
Gastrointestinal Toxicity † 1  1/2061 (0.05%)  0/2076 (0.00%)  1/2057 (0.05%)  0/2076 (0.00%) 
Oesophagitis † 1  0/2061 (0.00%)  0/2076 (0.00%)  1/2057 (0.05%)  1/2076 (0.05%) 
Pancreatitis Acute † 1  1/2061 (0.05%)  0/2076 (0.00%)  1/2057 (0.05%)  0/2076 (0.00%) 
Stomatitis † 1  1/2061 (0.05%)  0/2076 (0.00%)  0/2057 (0.00%)  1/2076 (0.05%) 
Abdominal Distension † 1  0/2061 (0.00%)  1/2076 (0.05%)  0/2057 (0.00%)  0/2076 (0.00%) 
Abdominal Mass † 1  0/2061 (0.00%)  0/2076 (0.00%)  1/2057 (0.05%)  0/2076 (0.00%) 
Abdominal Pain Lower † 1  0/2061 (0.00%)  0/2076 (0.00%)  0/2057 (0.00%)  1/2076 (0.05%) 
Anal Fissure † 1  0/2061 (0.00%)  0/2076 (0.00%)  1/2057 (0.05%)  0/2076 (0.00%) 
Anal Fistula † 1  1/2061 (0.05%)  0/2076 (0.00%)  0/2057 (0.00%)  0/2076 (0.00%) 
Anal Haemorrhage † 1  0/2061 (0.00%)  0/2076 (0.00%)  0/2057 (0.00%)  1/2076 (0.05%) 
Dyspepsia † 1  0/2061 (0.00%)  0/2076 (0.00%)  1/2057 (0.05%)  0/2076 (0.00%) 
Dysphagia † 1  0/2061 (0.00%)  0/2076 (0.00%)  1/2057 (0.05%)  0/2076 (0.00%) 
Epiploic Appendagitis † 1  1/2061 (0.05%)  0/2076 (0.00%)  0/2057 (0.00%)  0/2076 (0.00%) 
Gastric Haemorrhage † 1  0/2061 (0.00%)  1/2076 (0.05%)  0/2057 (0.00%)  0/2076 (0.00%) 
Gastric Ulcer † 1  0/2061 (0.00%)  0/2076 (0.00%)  0/2057 (0.00%)  1/2076 (0.05%) 
Gastritis Erosive † 1  1/2061 (0.05%)  0/2076 (0.00%)  0/2057 (0.00%)  0/2076 (0.00%) 
Gastrointestinal Perforation † 1  0/2061 (0.00%)  1/2076 (0.05%)  0/2057 (0.00%)  0/2076 (0.00%) 
Gastrointestinal Ulcer † 1  1/2061 (0.05%)  0/2076 (0.00%)  0/2057 (0.00%)  0/2076 (0.00%) 
Intestinal Haemorrhage † 1  1/2061 (0.05%)  0/2076 (0.00%)  0/2057 (0.00%)  0/2076 (0.00%) 
Large Intestine Perforation † 1  0/2061 (0.00%)  0/2076 (0.00%)  0/2057 (0.00%)  1/2076 (0.05%) 
Reflux Gastritis † 1  0/2061 (0.00%)  0/2076 (0.00%)  1/2057 (0.05%)  0/2076 (0.00%) 
Small Intestinal Obstruction † 1  1/2061 (0.05%)  0/2076 (0.00%)  0/2057 (0.00%)  0/2076 (0.00%) 
Upper Gastrointestinal Haemorrhage † 1  0/2061 (0.00%)  0/2076 (0.00%)  0/2057 (0.00%)  1/2076 (0.05%) 
Volvulus † 1  1/2061 (0.05%)  0/2076 (0.00%)  0/2057 (0.00%)  0/2076 (0.00%) 
General disorders         
Pyrexia † 1  11/2061 (0.53%)  16/2076 (0.77%)  14/2057 (0.68%)  5/2076 (0.24%) 
Fatigue † 1  5/2061 (0.24%)  2/2076 (0.10%)  7/2057 (0.34%)  2/2076 (0.10%) 
Chest Pain † 1  1/2061 (0.05%)  5/2076 (0.24%)  2/2057 (0.10%)  1/2076 (0.05%) 
Asthenia † 1  2/2061 (0.10%)  0/2076 (0.00%)  4/2057 (0.19%)  1/2076 (0.05%) 
Mucosal Inflammation † 1  2/2061 (0.10%)  0/2076 (0.00%)  3/2057 (0.15%)  0/2076 (0.00%) 
Chills † 1  1/2061 (0.05%)  1/2076 (0.05%)  0/2057 (0.00%)  2/2076 (0.10%) 
Thrombosis In Device † 1  1/2061 (0.05%)  2/2076 (0.10%)  1/2057 (0.05%)  0/2076 (0.00%) 
Oedema Peripheral † 1  0/2061 (0.00%)  2/2076 (0.10%)  0/2057 (0.00%)  1/2076 (0.05%) 
Adverse Drug Reaction † 1  2/2061 (0.10%)  0/2076 (0.00%)  0/2057 (0.00%)  0/2076 (0.00%) 
Death † 1  0/2061 (0.00%)  1/2076 (0.05%)  1/2057 (0.05%)  0/2076 (0.00%) 
Device Dislocation † 1  2/2061 (0.10%)  0/2076 (0.00%)  0/2057 (0.00%)  0/2076 (0.00%) 
Fat Necrosis † 1  1/2061 (0.05%)  0/2076 (0.00%)  0/2057 (0.00%)  1/2076 (0.05%) 
General Physical Health Deterioration † 1  0/2061 (0.00%)  0/2076 (0.00%)  2/2057 (0.10%)  0/2076 (0.00%) 
Impaired Healing † 1  0/2061 (0.00%)  0/2076 (0.00%)  1/2057 (0.05%)  1/2076 (0.05%) 
Malaise † 1  1/2061 (0.05%)  0/2076 (0.00%)  1/2057 (0.05%)  0/2076 (0.00%) 
Chronic Fatigue Syndrome † 1  0/2061 (0.00%)  0/2076 (0.00%)  1/2057 (0.05%)  0/2076 (0.00%) 
Device Expulsion † 1  0/2061 (0.00%)  1/2076 (0.05%)  0/2057 (0.00%)  0/2076 (0.00%) 
Feeling Cold † 1  1/2061 (0.05%)  0/2076 (0.00%)  0/2057 (0.00%)  0/2076 (0.00%) 
Granuloma † 1  0/2061 (0.00%)  0/2076 (0.00%)  0/2057 (0.00%)  1/2076 (0.05%) 
Inflammation † 1  0/2061 (0.00%)  0/2076 (0.00%)  0/2057 (0.00%)  1/2076 (0.05%) 
Lipogranuloma † 1  1/2061 (0.05%)  0/2076 (0.00%)  0/2057 (0.00%)  0/2076 (0.00%) 
Local Swelling † 1  0/2061 (0.00%)  0/2076 (0.00%)  0/2057 (0.00%)  1/2076 (0.05%) 
Necrosis † 1  0/2061 (0.00%)  0/2076 (0.00%)  1/2057 (0.05%)  0/2076 (0.00%) 
Non-Cardiac Chest Pain † 1  0/2061 (0.00%)  0/2076 (0.00%)  0/2057 (0.00%)  1/2076 (0.05%) 
Oedema † 1  0/2061 (0.00%)  0/2076 (0.00%)  0/2057 (0.00%)  1/2076 (0.05%) 
Sudden Death † 1  0/2061 (0.00%)  1/2076 (0.05%)  0/2057 (0.00%)  0/2076 (0.00%) 
Hepatobiliary disorders         
Hypertransaminasaemia † 1  74/2061 (3.59%)  55/2076 (2.65%)  87/2057 (4.23%)  11/2076 (0.53%) 
Hyperbilirubinaemia † 1  6/2061 (0.29%)  12/2076 (0.58%)  18/2057 (0.88%)  1/2076 (0.05%) 
Hepatotoxicity † 1  3/2061 (0.15%)  3/2076 (0.14%)  4/2057 (0.19%)  0/2076 (0.00%) 
Cholecystitis † 1  3/2061 (0.15%)  0/2076 (0.00%)  2/2057 (0.10%)  3/2076 (0.14%) 
Hepatic Function Abnormal † 1  0/2061 (0.00%)  4/2076 (0.19%)  4/2057 (0.19%)  0/2076 (0.00%) 
Biliary Colic † 1  0/2061 (0.00%)  2/2076 (0.10%)  0/2057 (0.00%)  1/2076 (0.05%) 
Cholelithiasis † 1  1/2061 (0.05%)  1/2076 (0.05%)  0/2057 (0.00%)  1/2076 (0.05%) 
Drug-Induced Liver Injury † 1  2/2061 (0.10%)  0/2076 (0.00%)  0/2057 (0.00%)  1/2076 (0.05%) 
Jaundice † 1  1/2061 (0.05%)  2/2076 (0.10%)  0/2057 (0.00%)  0/2076 (0.00%) 
Cystitis † 1  0/2061 (0.00%)  1/2076 (0.05%)  0/2057 (0.00%)  1/2076 (0.05%) 
Autoimmune Hepatitis † 1  1/2061 (0.05%)  0/2076 (0.00%)  0/2057 (0.00%)  0/2076 (0.00%) 
Bile Duct Stenosis † 1  0/2061 (0.00%)  0/2076 (0.00%)  1/2057 (0.05%)  0/2076 (0.00%) 
Cholecystitis Acute † 1  0/2061 (0.00%)  0/2076 (0.00%)  1/2057 (0.05%)  0/2076 (0.00%) 
Gallbladder Obstruction † 1  0/2061 (0.00%)  1/2076 (0.05%)  0/2057 (0.00%)  0/2076 (0.00%) 
Hepatic Cirrhosis † 1  0/2061 (0.00%)  0/2076 (0.00%)  1/2057 (0.05%)  0/2076 (0.00%) 
Hepatic Failure † 1  0/2061 (0.00%)  1/2076 (0.05%)  0/2057 (0.00%)  0/2076 (0.00%) 
Hepatic Lesion † 1  0/2061 (0.00%)  0/2076 (0.00%)  1/2057 (0.05%)  0/2076 (0.00%) 
Immune system disorders         
Hypersensitivity † 1  4/2061 (0.19%)  4/2076 (0.19%)  1/2057 (0.05%)  4/2076 (0.19%) 
Anaphylactic Reaction † 1  3/2061 (0.15%)  1/2076 (0.05%)  0/2057 (0.00%)  1/2076 (0.05%) 
Drug Hypersensitivity † 1  1/2061 (0.05%)  0/2076 (0.00%)  2/2057 (0.10%)  0/2076 (0.00%) 
Anaphylactoid Reaction † 1  0/2061 (0.00%)  0/2076 (0.00%)  1/2057 (0.05%)  0/2076 (0.00%) 
Sarcoidosis † 1  0/2061 (0.00%)  0/2076 (0.00%)  1/2057 (0.05%)  0/2076 (0.00%) 
Infections and infestations         
Cellulitis † 1  16/2061 (0.78%)  14/2076 (0.67%)  7/2057 (0.34%)  5/2076 (0.24%) 
Pneumonia † 1  12/2061 (0.58%)  9/2076 (0.43%)  9/2057 (0.44%)  10/2076 (0.48%) 
Device Related Infection † 1  8/2061 (0.39%)  2/2076 (0.10%)  4/2057 (0.19%)  3/2076 (0.14%) 
Erysipelas † 1  6/2061 (0.29%)  4/2076 (0.19%)  4/2057 (0.19%)  3/2076 (0.14%) 
Urinary Tract Infection † 1  2/2061 (0.10%)  6/2076 (0.29%)  2/2057 (0.10%)  7/2076 (0.34%) 
Sepsis † 1  1/2061 (0.05%)  3/2076 (0.14%)  5/2057 (0.24%)  5/2076 (0.24%) 
Mastitis † 1  2/2061 (0.10%)  1/2076 (0.05%)  6/2057 (0.29%)  3/2076 (0.14%) 
Gastroenteritis † 1  3/2061 (0.15%)  3/2076 (0.14%)  3/2057 (0.15%)  1/2076 (0.05%) 
Lower Respiratory Tract Infection † 1  3/2061 (0.15%)  2/2076 (0.10%)  1/2057 (0.05%)  1/2076 (0.05%) 
Herpes Zoster † 1  1/2061 (0.05%)  2/2076 (0.10%)  3/2057 (0.15%)  0/2076 (0.00%) 
Bronchitis † 1  0/2061 (0.00%)  2/2076 (0.10%)  1/2057 (0.05%)  2/2076 (0.10%) 
Infection † 1  2/2061 (0.10%)  1/2076 (0.05%)  2/2057 (0.10%)  0/2076 (0.00%) 
Skin Infection † 1  2/2061 (0.10%)  0/2076 (0.00%)  2/2057 (0.10%)  1/2076 (0.05%) 
Wound Infection † 1  0/2061 (0.00%)  2/2076 (0.10%)  2/2057 (0.10%)  1/2076 (0.05%) 
Breast Cellulitis † 1  1/2061 (0.05%)  0/2076 (0.00%)  3/2057 (0.15%)  0/2076 (0.00%) 
Subcutaneous Abscess † 1  0/2061 (0.00%)  2/2076 (0.10%)  1/2057 (0.05%)  1/2076 (0.05%) 
Respiratory Tract Infection † 1  0/2061 (0.00%)  1/2076 (0.05%)  2/2057 (0.10%)  0/2076 (0.00%) 
Sinusitis † 1  1/2061 (0.05%)  0/2076 (0.00%)  0/2057 (0.00%)  2/2076 (0.10%) 
Abdominal Wall Abscess † 1  0/2061 (0.00%)  0/2076 (0.00%)  1/2057 (0.05%)  1/2076 (0.05%) 
Anal Abscess † 1  1/2061 (0.05%)  0/2076 (0.00%)  1/2057 (0.05%)  0/2076 (0.00%) 
Bacteraemia † 1  0/2061 (0.00%)  0/2076 (0.00%)  1/2057 (0.05%)  1/2076 (0.05%) 
Device Related Sepsis † 1  2/2061 (0.10%)  0/2076 (0.00%)  0/2057 (0.00%)  0/2076 (0.00%) 
Diverticulitis † 1  0/2061 (0.00%)  1/2076 (0.05%)  0/2057 (0.00%)  1/2076 (0.05%) 
Gastroenteritis Viral † 1  1/2061 (0.05%)  1/2076 (0.05%)  0/2057 (0.00%)  0/2076 (0.00%) 
Hepatitis C † 1  1/2061 (0.05%)  0/2076 (0.00%)  1/2057 (0.05%)  0/2076 (0.00%) 
Influenza † 1  1/2061 (0.05%)  0/2076 (0.00%)  0/2057 (0.00%)  1/2076 (0.05%) 
Lobar Pneumonia † 1  1/2061 (0.05%)  1/2076 (0.05%)  0/2057 (0.00%)  0/2076 (0.00%) 
Localised Infection † 1  1/2061 (0.05%)  1/2076 (0.05%)  0/2057 (0.00%)  0/2076 (0.00%) 
Lung Infection † 1  1/2061 (0.05%)  1/2076 (0.05%)  0/2057 (0.00%)  0/2076 (0.00%) 
Lymph Gland Infection † 1  1/2061 (0.05%)  0/2076 (0.00%)  1/2057 (0.05%)  0/2076 (0.00%) 
Osteomyelitis † 1  0/2061 (0.00%)  0/2076 (0.00%)  1/2057 (0.05%)  1/2076 (0.05%) 
Otitis Media † 1  0/2061 (0.00%)  0/2076 (0.00%)  0/2057 (0.00%)  2/2076 (0.10%) 
Pyelonephritis † 1  2/2061 (0.10%)  0/2076 (0.00%)  0/2057 (0.00%)  0/2076 (0.00%) 
Upper Respiratory Tract Infection † 1  1/2061 (0.05%)  1/2076 (0.05%)  0/2057 (0.00%)  0/2076 (0.00%) 
Viral Infection † 1  1/2061 (0.05%)  1/2076 (0.05%)  0/2057 (0.00%)  0/2076 (0.00%) 
Abscess † 1  0/2061 (0.00%)  0/2076 (0.00%)  1/2057 (0.05%)  0/2076 (0.00%) 
Acute Hepatitis B † 1  0/2061 (0.00%)  0/2076 (0.00%)  0/2057 (0.00%)  1/2076 (0.05%) 
Acute Sinusitis † 1  0/2061 (0.00%)  0/2076 (0.00%)  0/2057 (0.00%)  1/2076 (0.05%) 
Amoebic Dysentery † 1  0/2061 (0.00%)  0/2076 (0.00%)  1/2057 (0.05%)  0/2076 (0.00%) 
Anal Infection † 1  0/2061 (0.00%)  1/2076 (0.05%)  0/2057 (0.00%)  0/2076 (0.00%) 
Atypical Pneumonia † 1  0/2061 (0.00%)  0/2076 (0.00%)  0/2057 (0.00%)  1/2076 (0.05%) 
Bacterial Infection † 1  0/2061 (0.00%)  0/2076 (0.00%)  0/2057 (0.00%)  1/2076 (0.05%) 
Bronchitis Viral † 1  0/2061 (0.00%)  0/2076 (0.00%)  1/2057 (0.05%)  0/2076 (0.00%) 
Candida Infection † 1  1/2061 (0.05%)  0/2076 (0.00%)  0/2057 (0.00%)  0/2076 (0.00%) 
Catheter Site Cellulitis † 1  0/2061 (0.00%)  0/2076 (0.00%)  1/2057 (0.05%)  0/2076 (0.00%) 
Chest Wall Abscess † 1  0/2061 (0.00%)  1/2076 (0.05%)  0/2057 (0.00%)  0/2076 (0.00%) 
Chlamydial Infection † 1  0/2061 (0.00%)  1/2076 (0.05%)  0/2057 (0.00%)  0/2076 (0.00%) 
Clostridium Difficile Colitis † 1  0/2061 (0.00%)  0/2076 (0.00%)  1/2057 (0.05%)  0/2076 (0.00%) 
Clostridium Difficile Infection † 1  1/2061 (0.05%)  0/2076 (0.00%)  0/2057 (0.00%)  0/2076 (0.00%) 
Conjunctivitis † 1  1/2061 (0.05%)  0/2076 (0.00%)  0/2057 (0.00%)  0/2076 (0.00%) 
Diarrhoea Infectious † 1  1/2061 (0.05%)  0/2076 (0.00%)  0/2057 (0.00%)  0/2076 (0.00%) 
Gastric Infection † 1  0/2061 (0.00%)  0/2076 (0.00%)  0/2057 (0.00%)  1/2076 (0.05%) 
Gastrointestinal Infection † 1  0/2061 (0.00%)  0/2076 (0.00%)  1/2057 (0.05%)  0/2076 (0.00%) 
Hepatitis † 1  1/2061 (0.05%)  0/2076 (0.00%)  0/2057 (0.00%)  0/2076 (0.00%) 
Hepatitis B † 1  0/2061 (0.00%)  1/2076 (0.05%)  0/2057 (0.00%)  0/2076 (0.00%) 
Hepatitis Viral † 1  0/2061 (0.00%)  1/2076 (0.05%)  0/2057 (0.00%)  0/2076 (0.00%) 
Implant Site Cellulitis † 1  1/2061 (0.05%)  0/2076 (0.00%)  0/2057 (0.00%)  0/2076 (0.00%) 
Infected Cyst † 1  1/2061 (0.05%)  0/2076 (0.00%)  0/2057 (0.00%)  0/2076 (0.00%) 
Infected Lymphocele † 1  0/2061 (0.00%)  0/2076 (0.00%)  1/2057 (0.05%)  0/2076 (0.00%) 
Infectious Colitis † 1  1/2061 (0.05%)  0/2076 (0.00%)  0/2057 (0.00%)  0/2076 (0.00%) 
Infective Exacerbation Of Chronic Obstructive Airways Disease † 1  1/2061 (0.05%)  0/2076 (0.00%)  0/2057 (0.00%)  0/2076 (0.00%) 
Intervertebral Discitis † 1  0/2061 (0.00%)  0/2076 (0.00%)  0/2057 (0.00%)  1/2076 (0.05%) 
Laryngitis † 1  0/2061 (0.00%)  0/2076 (0.00%)  1/2057 (0.05%)  0/2076 (0.00%) 
Lymph Node Abscess † 1  0/2061 (0.00%)  1/2076 (0.05%)  0/2057 (0.00%)  0/2076 (0.00%) 
Lymphangitis † 1  0/2061 (0.00%)  1/2076 (0.05%)  0/2057 (0.00%)  0/2076 (0.00%) 
Malaria † 1  0/2061 (0.00%)  0/2076 (0.00%)  1/2057 (0.05%)  0/2076 (0.00%) 
Meningitis Viral † 1  0/2061 (0.00%)  0/2076 (0.00%)  1/2057 (0.05%)  0/2076 (0.00%) 
Nail Infection † 1  1/2061 (0.05%)  0/2076 (0.00%)  0/2057 (0.00%)  0/2076 (0.00%) 
Nasopharyngitis † 1  1/2061 (0.05%)  0/2076 (0.00%)  0/2057 (0.00%)  0/2076 (0.00%) 
Neuroborreliosis † 1  1/2061 (0.05%)  0/2076 (0.00%)  0/2057 (0.00%)  0/2076 (0.00%) 
Neutropenic Sepsis † 1  0/2061 (0.00%)  1/2076 (0.05%)  0/2057 (0.00%)  0/2076 (0.00%) 
Oesophageal Candidiasis † 1  0/2061 (0.00%)  0/2076 (0.00%)  1/2057 (0.05%)  0/2076 (0.00%) 
Oesophageal Infection † 1  0/2061 (0.00%)  0/2076 (0.00%)  1/2057 (0.05%)  0/2076 (0.00%) 
Ovarian Abscess † 1  0/2061 (0.00%)  0/2076 (0.00%)  0/2057 (0.00%)  1/2076 (0.05%) 
Paronychia † 1  0/2061 (0.00%)  1/2076 (0.05%)  0/2057 (0.00%)  0/2076 (0.00%) 
Peritonitis † 1  0/2061 (0.00%)  0/2076 (0.00%)  0/2057 (0.00%)  1/2076 (0.05%) 
Pharyngitis † 1  0/2061 (0.00%)  0/2076 (0.00%)  0/2057 (0.00%)  1/2076 (0.05%) 
Pneumocystis Jirovecii Infection † 1  0/2061 (0.00%)  1/2076 (0.05%)  0/2057 (0.00%)  0/2076 (0.00%) 
Pneumonia Cytomegaloviral † 1  1/2061 (0.05%)  0/2076 (0.00%)  0/2057 (0.00%)  0/2076 (0.00%) 
Post Procedural Pneumonia † 1  0/2061 (0.00%)  0/2076 (0.00%)  1/2057 (0.05%)  0/2076 (0.00%) 
Progressive Multifocal Leukoencephalopathy † 1  1/2061 (0.05%)  0/2076 (0.00%)  0/2057 (0.00%)  0/2076 (0.00%) 
Pyelonephritis Acute † 1  0/2061 (0.00%)  0/2076 (0.00%)  0/2057 (0.00%)  1/2076 (0.05%) 
Sialoadenitis † 1  0/2061 (0.00%)  1/2076 (0.05%)  0/2057 (0.00%)  0/2076 (0.00%) 
Soft Tissue Infection † 1  0/2061 (0.00%)  0/2076 (0.00%)  0/2057 (0.00%)  1/2076 (0.05%) 
Staphylococcal Bacteraemia † 1  0/2061 (0.00%)  0/2076 (0.00%)  1/2057 (0.05%)  0/2076 (0.00%) 
Staphylococcal Infection † 1  1/2061 (0.05%)  0/2076 (0.00%)  0/2057 (0.00%)  0/2076 (0.00%) 
Streptococcal Infection † 1  0/2061 (0.00%)  0/2076 (0.00%)  1/2057 (0.05%)  0/2076 (0.00%) 
Streptococcal Sepsis † 1  0/2061 (0.00%)  0/2076 (0.00%)  1/2057 (0.05%)  0/2076 (0.00%) 
Superinfection † 1  0/2061 (0.00%)  0/2076 (0.00%)  0/2057 (0.00%)  1/2076 (0.05%) 
Tooth Infection † 1  0/2061 (0.00%)  0/2076 (0.00%)  0/2057 (0.00%)  1/2076 (0.05%) 
Tuberculosis † 1  0/2061 (0.00%)  1/2076 (0.05%)  0/2057 (0.00%)  0/2076 (0.00%) 
Tuberculous Pleurisy † 1  0/2061 (0.00%)  0/2076 (0.00%)  1/2057 (0.05%)  0/2076 (0.00%) 
Upper Respiratory Tract Infection Bacterial † 1  1/2061 (0.05%)  0/2076 (0.00%)  0/2057 (0.00%)  0/2076 (0.00%) 
Urosepsis † 1  0/2061 (0.00%)  0/2076 (0.00%)  1/2057 (0.05%)  0/2076 (0.00%) 
Wound Infection Bacterial † 1  0/2061 (0.00%)  0/2076 (0.00%)  0/2057 (0.00%)  1/2076 (0.05%) 
Wound Infection Staphylococcal † 1  0/2061 (0.00%)  0/2076 (0.00%)  0/2057 (0.00%)  1/2076 (0.05%) 
Injury, poisoning and procedural complications         
Radiation Skin Injury † 1  1/2061 (0.05%)  3/2076 (0.14%)  0/2057 (0.00%)  1/2076 (0.05%) 
Seroma † 1  1/2061 (0.05%)  2/2076 (0.10%)  1/2057 (0.05%)  1/2076 (0.05%) 
Radiation Fibrosis - Lung † 1  0/2061 (0.00%)  1/2076 (0.05%)  2/2057 (0.10%)  1/2076 (0.05%) 
Radiation Pneumonitis † 1  1/2061 (0.05%)  1/2076 (0.05%)  1/2057 (0.05%)  1/2076 (0.05%) 
Ankle Fracture † 1  1/2061 (0.05%)  0/2076 (0.00%)  0/2057 (0.00%)  2/2076 (0.10%) 
Humerus Fracture † 1  1/2061 (0.05%)  0/2076 (0.00%)  1/2057 (0.05%)  1/2076 (0.05%) 
Upper Limb Fracture † 1  1/2061 (0.05%)  0/2076 (0.00%)  0/2057 (0.00%)  2/2076 (0.10%) 
Hip Fracture † 1  1/2061 (0.05%)  0/2076 (0.00%)  1/2057 (0.05%)  0/2076 (0.00%) 
Rib Fracture † 1  0/2061 (0.00%)  2/2076 (0.10%)  0/2057 (0.00%)  0/2076 (0.00%) 
Tibia Fracture † 1  1/2061 (0.05%)  0/2076 (0.00%)  1/2057 (0.05%)  0/2076 (0.00%) 
Wound Complication † 1  0/2061 (0.00%)  1/2076 (0.05%)  1/2057 (0.05%)  0/2076 (0.00%) 
Wrist Fracture † 1  0/2061 (0.00%)  0/2076 (0.00%)  2/2057 (0.10%)  0/2076 (0.00%) 
Alcohol Poisoning † 1  1/2061 (0.05%)  0/2076 (0.00%)  0/2057 (0.00%)  0/2076 (0.00%) 
Carbon Monoxide Poisoning † 1  0/2061 (0.00%)  1/2076 (0.05%)  0/2057 (0.00%)  0/2076 (0.00%) 
Concussion † 1  0/2061 (0.00%)  0/2076 (0.00%)  1/2057 (0.05%)  0/2076 (0.00%) 
Contusion † 1  0/2061 (0.00%)  0/2076 (0.00%)  1/2057 (0.05%)  0/2076 (0.00%) 
Fibula Fracture † 1  1/2061 (0.05%)  0/2076 (0.00%)  0/2057 (0.00%)  0/2076 (0.00%) 
Foot Fracture † 1  0/2061 (0.00%)  0/2076 (0.00%)  0/2057 (0.00%)  1/2076 (0.05%) 
Foreign Body † 1  1/2061 (0.05%)  0/2076 (0.00%)  0/2057 (0.00%)  0/2076 (0.00%) 
Fracture † 1  0/2061 (0.00%)  0/2076 (0.00%)  0/2057 (0.00%)  1/2076 (0.05%) 
Fractured Coccyx † 1  0/2061 (0.00%)  1/2076 (0.05%)  0/2057 (0.00%)  0/2076 (0.00%) 
Infusion Related Reaction † 1  0/2061 (0.00%)  1/2076 (0.05%)  0/2057 (0.00%)  0/2076 (0.00%) 
Ligament Sprain † 1  0/2061 (0.00%)  0/2076 (0.00%)  1/2057 (0.05%)  0/2076 (0.00%) 
Lower Limb Fracture † 1  0/2061 (0.00%)  0/2076 (0.00%)  0/2057 (0.00%)  1/2076 (0.05%) 
Multiple Injuries † 1  0/2061 (0.00%)  1/2076 (0.05%)  0/2057 (0.00%)  0/2076 (0.00%) 
Pelvic Fracture † 1  0/2061 (0.00%)  0/2076 (0.00%)  0/2057 (0.00%)  1/2076 (0.05%) 
Radius Fracture † 1  0/2061 (0.00%)  0/2076 (0.00%)  1/2057 (0.05%)  0/2076 (0.00%) 
Road Traffic Accident † 1  0/2061 (0.00%)  0/2076 (0.00%)  1/2057 (0.05%)  0/2076 (0.00%) 
Spinal Compression Fracture † 1  1/2061 (0.05%)  0/2076 (0.00%)  0/2057 (0.00%)  0/2076 (0.00%) 
Spinal Fracture † 1  0/2061 (0.00%)  1/2076 (0.05%)  0/2057 (0.00%)  0/2076 (0.00%) 
Sternal Fracture † 1  0/2061 (0.00%)  0/2076 (0.00%)  0/2057 (0.00%)  1/2076 (0.05%) 
Subdural Haemorrhage † 1  0/2061 (0.00%)  0/2076 (0.00%)  0/2057 (0.00%)  1/2076 (0.05%) 
Thermal Burn † 1  0/2061 (0.00%)  1/2076 (0.05%)  0/2057 (0.00%)  0/2076 (0.00%) 
Investigations         
Gamma-Glutamyltransferase Increased † 1  2/2061 (0.10%)  3/2076 (0.14%)  3/2057 (0.15%)  0/2076 (0.00%) 
Blood Creatinine Increased † 1  1/2061 (0.05%)  1/2076 (0.05%)  0/2057 (0.00%)  1/2076 (0.05%) 
Eastern Cooperative Oncology Group Performance Status Worsened † 1  1/2061 (0.05%)  0/2076 (0.00%)  1/2057 (0.05%)  0/2076 (0.00%) 
Electrocardiogram Qt Prolonged † 1  0/2061 (0.00%)  1/2076 (0.05%)  1/2057 (0.05%)  0/2076 (0.00%) 
Lipase † 1  1/2061 (0.05%)  0/2076 (0.00%)  0/2057 (0.00%)  1/2076 (0.05%) 
Liver Function Test Abnormal † 1  1/2061 (0.05%)  0/2076 (0.00%)  1/2057 (0.05%)  0/2076 (0.00%) 
Platelet Count Decreased † 1  2/2061 (0.10%)  0/2076 (0.00%)  0/2057 (0.00%)  0/2076 (0.00%) 
Alanine Aminotransferase Increased † 1  0/2061 (0.00%)  0/2076 (0.00%)  1/2057 (0.05%)  0/2076 (0.00%) 
Amylase † 1  1/2061 (0.05%)  0/2076 (0.00%)  0/2057 (0.00%)  0/2076 (0.00%) 
Blood Alkaline Phosphatase Increased † 1  0/2061 (0.00%)  1/2076 (0.05%)  0/2057 (0.00%)  0/2076 (0.00%) 
Blood Bilirubin Increased † 1  0/2061 (0.00%)  0/2076 (0.00%)  1/2057 (0.05%)  0/2076 (0.00%) 
Blood Creatinine † 1  0/2061 (0.00%)  0/2076 (0.00%)  0/2057 (0.00%)  1/2076 (0.05%) 
Blood Magnesium Decreased † 1  0/2061 (0.00%)  0/2076 (0.00%)  0/2057 (0.00%)  1/2076 (0.05%) 
Blood Potassium Decreased † 1  0/2061 (0.00%)  0/2076 (0.00%)  0/2057 (0.00%)  1/2076 (0.05%) 
Blood Urea Increased † 1  1/2061 (0.05%)  0/2076 (0.00%)  0/2057 (0.00%)  0/2076 (0.00%) 
Blood Urine Present † 1  0/2061 (0.00%)  0/2076 (0.00%)  1/2057 (0.05%)  0/2076 (0.00%) 
Coagulation Test Abnormal † 1  0/2061 (0.00%)  0/2076 (0.00%)  0/2057 (0.00%)  1/2076 (0.05%) 
Ejection Fraction Decreased † 1  0/2061 (0.00%)  0/2076 (0.00%)  0/2057 (0.00%)  1/2076 (0.05%) 
Electrocardiogram Abnormal † 1  0/2061 (0.00%)  0/2076 (0.00%)  0/2057 (0.00%)  1/2076 (0.05%) 
Electrocardiogram St Segment Depression † 1  1/2061 (0.05%)  0/2076 (0.00%)  0/2057 (0.00%)  0/2076 (0.00%) 
Electrocardiogram T Wave Inversion † 1  0/2061 (0.00%)  1/2076 (0.05%)  0/2057 (0.00%)  0/2076 (0.00%) 
Gamma-Glutamyltransferase † 1  0/2061 (0.00%)  1/2076 (0.05%)  0/2057 (0.00%)  0/2076 (0.00%) 
International Normalised Ratio † 1  1/2061 (0.05%)  0/2076 (0.00%)  0/2057 (0.00%)  0/2076 (0.00%) 
Weight Decreased † 1  1/2061 (0.05%)  0/2076 (0.00%)  0/2057 (0.00%)  0/2076 (0.00%) 
White Blood Cell Count Decreased † 1  0/2061 (0.00%)  1/2076 (0.05%)  0/2057 (0.00%)  0/2076 (0.00%) 
Metabolism and nutrition disorders         
Dehydration † 1  11/2061 (0.53%)  3/2076 (0.14%)  12/2057 (0.58%)  4/2076 (0.19%) 
Hypokalaemia † 1  8/2061 (0.39%)  1/2076 (0.05%)  9/2057 (0.44%)  3/2076 (0.14%) 
Hyperphosphatasaemia † 1  4/2061 (0.19%)  4/2076 (0.19%)  1/2057 (0.05%)  0/2076 (0.00%) 
Decreased Appetite † 1  3/2061 (0.15%)  0/2076 (0.00%)  3/2057 (0.15%)  0/2076 (0.00%) 
Hypocalcaemia † 1  2/2061 (0.10%)  1/2076 (0.05%)  1/2057 (0.05%)  0/2076 (0.00%) 
Diabetes Mellitus † 1  0/2061 (0.00%)  0/2076 (0.00%)  0/2057 (0.00%)  3/2076 (0.14%) 
Hyperglycaemia † 1  0/2061 (0.00%)  1/2076 (0.05%)  1/2057 (0.05%)  1/2076 (0.05%) 
Hypomagnesaemia † 1  1/2061 (0.05%)  0/2076 (0.00%)  1/2057 (0.05%)  1/2076 (0.05%) 
Hypovolaemia † 1  1/2061 (0.05%)  0/2076 (0.00%)  0/2057 (0.00%)  1/2076 (0.05%) 
Hypercholesterolaemia † 1  0/2061 (0.00%)  0/2076 (0.00%)  0/2057 (0.00%)  1/2076 (0.05%) 
Hypernatraemia † 1  1/2061 (0.05%)  0/2076 (0.00%)  0/2057 (0.00%)  0/2076 (0.00%) 
Hyperuricaemia † 1  0/2061 (0.00%)  0/2076 (0.00%)  0/2057 (0.00%)  1/2076 (0.05%) 
Hyponatraemia † 1  0/2061 (0.00%)  0/2076 (0.00%)  1/2057 (0.05%)  0/2076 (0.00%) 
Hypophagia † 1  0/2061 (0.00%)  0/2076 (0.00%)  1/2057 (0.05%)  0/2076 (0.00%) 
Hypophosphataemia † 1  1/2061 (0.05%)  0/2076 (0.00%)  0/2057 (0.00%)  0/2076 (0.00%) 
Metabolic Acidosis † 1  0/2061 (0.00%)  0/2076 (0.00%)  0/2057 (0.00%)  1/2076 (0.05%) 
Musculoskeletal and connective tissue disorders         
Arthralgia † 1  1/2061 (0.05%)  2/2076 (0.10%)  1/2057 (0.05%)  0/2076 (0.00%) 
Back Pain † 1  4/2061 (0.19%)  0/2076 (0.00%)  0/2057 (0.00%)  0/2076 (0.00%) 
Costochondritis † 1  0/2061 (0.00%)  1/2076 (0.05%)  1/2057 (0.05%)  0/2076 (0.00%) 
Myalgia † 1  2/2061 (0.10%)  0/2076 (0.00%)  0/2057 (0.00%)  0/2076 (0.00%) 
Bone Pain † 1  0/2061 (0.00%)  1/2076 (0.05%)  0/2057 (0.00%)  0/2076 (0.00%) 
Ligament Disorder † 1  0/2061 (0.00%)  1/2076 (0.05%)  0/2057 (0.00%)  0/2076 (0.00%) 
Lumbar Spinal Stenosis † 1  0/2061 (0.00%)  0/2076 (0.00%)  0/2057 (0.00%)  1/2076 (0.05%) 
Musculoskeletal Chest Pain † 1  1/2061 (0.05%)  0/2076 (0.00%)  0/2057 (0.00%)  0/2076 (0.00%) 
Musculoskeletal Pain † 1  0/2061 (0.00%)  1/2076 (0.05%)  0/2057 (0.00%)  0/2076 (0.00%) 
Myositis † 1  0/2061 (0.00%)  1/2076 (0.05%)  0/2057 (0.00%)  0/2076 (0.00%) 
Osteoarthritis † 1  0/2061 (0.00%)  0/2076 (0.00%)  1/2057 (0.05%)  0/2076 (0.00%) 
Osteoporosis † 1  1/2061 (0.05%)  0/2076 (0.00%)  0/2057 (0.00%)  0/2076 (0.00%) 
Scleroderma † 1  0/2061 (0.00%)  1/2076 (0.05%)  0/2057 (0.00%)  0/2076 (0.00%) 
Spondylolisthesis † 1  1/2061 (0.05%)  0/2076 (0.00%)  0/2057 (0.00%)  0/2076 (0.00%) 
Synovial Cyst † 1  0/2061 (0.00%)  0/2076 (0.00%)  0/2057 (0.00%)  1/2076 (0.05%) 
Synovitis † 1  0/2061 (0.00%)  0/2076 (0.00%)  1/2057 (0.05%)  0/2076 (0.00%) 
Neoplasms benign, malignant and unspecified (incl cysts and polyps)         
Contralateral Breast Cancer † 1  22/2061 (1.07%)  13/2076 (0.63%)  11/2057 (0.53%)  12/2076 (0.58%) 
Colon Cancer † 1  1/2061 (0.05%)  2/2076 (0.10%)  6/2057 (0.29%)  5/2076 (0.24%) 
Breast Cancer † 1  1/2061 (0.05%)  3/2076 (0.14%)  3/2057 (0.15%)  4/2076 (0.19%) 
Intraductal Proliferative Breast Lesion † 1  4/2061 (0.19%)  2/2076 (0.10%)  1/2057 (0.05%)  4/2076 (0.19%) 
Malignant Melanoma † 1  5/2061 (0.24%)  2/2076 (0.10%)  3/2057 (0.15%)  1/2076 (0.05%) 
Gastric Cancer † 1  0/2061 (0.00%)  3/2076 (0.14%)  4/2057 (0.19%)  3/2076 (0.14%) 
Acute Myeloid Leukaemia † 1  2/2061 (0.10%)  0/2076 (0.00%)  0/2057 (0.00%)  5/2076 (0.24%) 
Ovarian Cancer † 1  2/2061 (0.10%)  2/2076 (0.10%)  0/2057 (0.00%)  2/2076 (0.10%) 
Papillary Thyroid Cancer † 1  3/2061 (0.15%)  0/2076 (0.00%)  2/2057 (0.10%)  1/2076 (0.05%) 
Thyroid Cancer † 1  0/2061 (0.00%)  1/2076 (0.05%)  1/2057 (0.05%)  4/2076 (0.19%) 
Endometrial Cancer † 1  2/2061 (0.10%)  2/2076 (0.10%)  1/2057 (0.05%)  0/2076 (0.00%) 
Lung Adenocarcinoma † 1  2/2061 (0.10%)  3/2076 (0.14%)  0/2057 (0.00%)  0/2076 (0.00%) 
Rectal Cancer † 1  2/2061 (0.10%)  2/2076 (0.10%)  1/2057 (0.05%)  0/2076 (0.00%) 
Adenocarcinoma Of Colon † 1  1/2061 (0.05%)  1/2076 (0.05%)  1/2057 (0.05%)  1/2076 (0.05%) 
Basal Cell Carcinoma † 1  2/2061 (0.10%)  0/2076 (0.00%)  1/2057 (0.05%)  1/2076 (0.05%) 
Invasive Ductal Breast Carcinoma † 1  0/2061 (0.00%)  2/2076 (0.10%)  0/2057 (0.00%)  2/2076 (0.10%) 
Acute Lymphocytic Leukaemia † 1  3/2061 (0.15%)  0/2076 (0.00%)  0/2057 (0.00%)  0/2076 (0.00%) 
Lung Neoplasm Malignant † 1  2/2061 (0.10%)  0/2076 (0.00%)  1/2057 (0.05%)  0/2076 (0.00%) 
Small Cell Lung Cancer † 1  1/2061 (0.05%)  0/2076 (0.00%)  0/2057 (0.00%)  2/2076 (0.10%) 
Uterine Leiomyoma † 1  0/2061 (0.00%)  1/2076 (0.05%)  1/2057 (0.05%)  1/2076 (0.05%) 
Acute Promyelocytic Leukaemia † 1  1/2061 (0.05%)  0/2076 (0.00%)  1/2057 (0.05%)  0/2076 (0.00%) 
Adenocarcinoma Gastric † 1  1/2061 (0.05%)  0/2076 (0.00%)  0/2057 (0.00%)  1/2076 (0.05%) 
Chronic Lymphocytic Leukaemia † 1  1/2061 (0.05%)  0/2076 (0.00%)  1/2057 (0.05%)  0/2076 (0.00%) 
Endometrial Adenocarcinoma † 1  2/2061 (0.10%)  0/2076 (0.00%)  0/2057 (0.00%)  0/2076 (0.00%) 
Leukaemia † 1  1/2061 (0.05%)  0/2076 (0.00%)  1/2057 (0.05%)  0/2076 (0.00%) 
Metastases To Central Nervous System † 1  1/2061 (0.05%)  0/2076 (0.00%)  1/2057 (0.05%)  0/2076 (0.00%) 
Myelodysplastic Syndrome † 1  2/2061 (0.10%)  0/2076 (0.00%)  0/2057 (0.00%)  0/2076 (0.00%) 
Non-Hodgkin's Lymphoma † 1  1/2061 (0.05%)  0/2076 (0.00%)  0/2057 (0.00%)  1/2076 (0.05%) 
Transitional Cell Carcinoma † 1  0/2061 (0.00%)  0/2076 (0.00%)  2/2057 (0.10%)  0/2076 (0.00%) 
Uterine Cancer † 1  0/2061 (0.00%)  1/2076 (0.05%)  1/2057 (0.05%)  0/2076 (0.00%) 
Acral Lentiginous Melanoma † 1  0/2061 (0.00%)  1/2076 (0.05%)  0/2057 (0.00%)  0/2076 (0.00%) 
Acute Leukaemia † 1  1/2061 (0.05%)  0/2076 (0.00%)  0/2057 (0.00%)  0/2076 (0.00%) 
Anaplastic Meningioma † 1  0/2061 (0.00%)  1/2076 (0.05%)  0/2057 (0.00%)  0/2076 (0.00%) 
B-Cell Lymphoma † 1  1/2061 (0.05%)  0/2076 (0.00%)  0/2057 (0.00%)  0/2076 (0.00%) 
Benign Breast Neoplasm † 1  0/2061 (0.00%)  0/2076 (0.00%)  0/2057 (0.00%)  1/2076 (0.05%) 
Benign Ovarian Tumour † 1  0/2061 (0.00%)  0/2076 (0.00%)  0/2057 (0.00%)  1/2076 (0.05%) 
Bladder Neoplasm † 1  0/2061 (0.00%)  0/2076 (0.00%)  1/2057 (0.05%)  0/2076 (0.00%) 
Bladder Transitional Cell Carcinoma † 1  0/2061 (0.00%)  0/2076 (0.00%)  0/2057 (0.00%)  1/2076 (0.05%) 
Borderline Ovarian Tumour † 1  1/2061 (0.05%)  0/2076 (0.00%)  0/2057 (0.00%)  0/2076 (0.00%) 
Breast Cancer In Situ † 1  1/2061 (0.05%)  0/2076 (0.00%)  0/2057 (0.00%)  0/2076 (0.00%) 
Bronchioloalveolar Carcinoma † 1  0/2061 (0.00%)  1/2076 (0.05%)  0/2057 (0.00%)  0/2076 (0.00%) 
Cervix Carcinoma † 1  1/2061 (0.05%)  0/2076 (0.00%)  0/2057 (0.00%)  0/2076 (0.00%) 
Cervix Carcinoma Stage 0 † 1  1/2061 (0.05%)  0/2076 (0.00%)  0/2057 (0.00%)  0/2076 (0.00%) 
Chronic Myeloid Leukaemia † 1  1/2061 (0.05%)  0/2076 (0.00%)  0/2057 (0.00%)  0/2076 (0.00%) 
Colon Cancer Metastatic † 1  0/2061 (0.00%)  0/2076 (0.00%)  1/2057 (0.05%)  0/2076 (0.00%) 
Colon Neoplasm † 1  1/2061 (0.05%)  0/2076 (0.00%)  0/2057 (0.00%)  0/2076 (0.00%) 
Colorectal Cancer † 1  0/2061 (0.00%)  0/2076 (0.00%)  1/2057 (0.05%)  0/2076 (0.00%) 
Fallopian Tube Cancer † 1  0/2061 (0.00%)  0/2076 (0.00%)  0/2057 (0.00%)  1/2076 (0.05%) 
Follicular Thyroid Cancer † 1  0/2061 (0.00%)  0/2076 (0.00%)  0/2057 (0.00%)  1/2076 (0.05%) 
Gallbladder Neoplasm † 1  1/2061 (0.05%)  0/2076 (0.00%)  0/2057 (0.00%)  0/2076 (0.00%) 
Gastric Cancer Stage I † 1  1/2061 (0.05%)  0/2076 (0.00%)  0/2057 (0.00%)  0/2076 (0.00%) 
Gastrointestinal Carcinoma † 1  0/2061 (0.00%)  0/2076 (0.00%)  1/2057 (0.05%)  0/2076 (0.00%) 
Gastrointestinal Stromal Tumour † 1  0/2061 (0.00%)  0/2076 (0.00%)  1/2057 (0.05%)  0/2076 (0.00%) 
Haemangioma † 1  0/2061 (0.00%)  1/2076 (0.05%)  0/2057 (0.00%)  0/2076 (0.00%) 
Hepatocellular Carcinoma † 1  0/2061 (0.00%)  1/2076 (0.05%)  0/2057 (0.00%)  0/2076 (0.00%) 
Intestinal Adenocarcinoma † 1  0/2061 (0.00%)  0/2076 (0.00%)  0/2057 (0.00%)  1/2076 (0.05%) 
Intraductal Papilloma Of Breast † 1  0/2061 (0.00%)  0/2076 (0.00%)  0/2057 (0.00%)  1/2076 (0.05%) 
Invasive Lobular Breast Carcinoma † 1  1/2061 (0.05%)  0/2076 (0.00%)  0/2057 (0.00%)  0/2076 (0.00%) 
Leiomyoma † 1  0/2061 (0.00%)  1/2076 (0.05%)  0/2057 (0.00%)  0/2076 (0.00%) 
Leiomyosarcoma † 1  0/2061 (0.00%)  0/2076 (0.00%)  0/2057 (0.00%)  1/2076 (0.05%) 
Lentigo Maligna † 1  0/2061 (0.00%)  0/2076 (0.00%)  0/2057 (0.00%)  1/2076 (0.05%) 
Lipoma † 1  0/2061 (0.00%)  0/2076 (0.00%)  0/2057 (0.00%)  1/2076 (0.05%) 
Malignant Melanoma In Situ † 1  0/2061 (0.00%)  1/2076 (0.05%)  0/2057 (0.00%)  0/2076 (0.00%) 
Malignant Neoplasm Of Unknown Primary Site † 1  0/2061 (0.00%)  1/2076 (0.05%)  0/2057 (0.00%)  0/2076 (0.00%) 
Melanocytic Naevus † 1  0/2061 (0.00%)  0/2076 (0.00%)  0/2057 (0.00%)  1/2076 (0.05%) 
Meningioma † 1  0/2061 (0.00%)  0/2076 (0.00%)  1/2057 (0.05%)  0/2076 (0.00%) 
Meningioma Benign † 1  0/2061 (0.00%)  0/2076 (0.00%)  1/2057 (0.05%)  0/2076 (0.00%) 
Metastases To Meninges † 1  0/2061 (0.00%)  0/2076 (0.00%)  1/2057 (0.05%)  0/2076 (0.00%) 
Neuroendocrine Tumour † 1  0/2061 (0.00%)  0/2076 (0.00%)  1/2057 (0.05%)  0/2076 (0.00%) 
Nodular Melanoma † 1  0/2061 (0.00%)  0/2076 (0.00%)  0/2057 (0.00%)  1/2076 (0.05%) 
Oropharyngeal Cancer † 1  1/2061 (0.05%)  0/2076 (0.00%)  0/2057 (0.00%)  0/2076 (0.00%) 
Ovarian Adenoma † 1  0/2061 (0.00%)  0/2076 (0.00%)  1/2057 (0.05%)  0/2076 (0.00%) 
Ovarian Germ Cell Teratoma Benign † 1  1/2061 (0.05%)  0/2076 (0.00%)  0/2057 (0.00%)  0/2076 (0.00%) 
Ovarian Neoplasm † 1  0/2061 (0.00%)  1/2076 (0.05%)  0/2057 (0.00%)  0/2076 (0.00%) 
Pancreatic Carcinoma † 1  0/2061 (0.00%)  0/2076 (0.00%)  1/2057 (0.05%)  0/2076 (0.00%) 
Parathyroid Tumour Benign † 1  0/2061 (0.00%)  0/2076 (0.00%)  1/2057 (0.05%)  0/2076 (0.00%) 
Plasma Cell Myeloma † 1  1/2061 (0.05%)  0/2076 (0.00%)  0/2057 (0.00%)  0/2076 (0.00%) 
Rectal Adenocarcinoma † 1  0/2061 (0.00%)  1/2076 (0.05%)  0/2057 (0.00%)  0/2076 (0.00%) 
Rectosigmoid Cancer † 1  0/2061 (0.00%)  0/2076 (0.00%)  1/2057 (0.05%)  0/2076 (0.00%) 
Renal Cancer † 1  0/2061 (0.00%)  1/2076 (0.05%)  0/2057 (0.00%)  0/2076 (0.00%) 
Second Primary Malignancy † 1  0/2061 (0.00%)  0/2076 (0.00%)  0/2057 (0.00%)  1/2076 (0.05%) 
Small Intestine Adenocarcinoma † 1  0/2061 (0.00%)  1/2076 (0.05%)  0/2057 (0.00%)  0/2076 (0.00%) 
Squamous Cell Carcinoma Of Skin † 1  0/2061 (0.00%)  1/2076 (0.05%)  0/2057 (0.00%)  0/2076 (0.00%) 
Squamous Cell Carcinoma Of The Vulva † 1  0/2061 (0.00%)  0/2076 (0.00%)  1/2057 (0.05%)  0/2076 (0.00%) 
Superficial Spreading Melanoma Stage Unspecified † 1  0/2061 (0.00%)  0/2076 (0.00%)  0/2057 (0.00%)  1/2076 (0.05%) 
Urethral Cancer † 1  1/2061 (0.05%)  0/2076 (0.00%)  0/2057 (0.00%)  0/2076 (0.00%) 
Nervous system disorders         
Syncope † 1  2/2061 (0.10%)  1/2076 (0.05%)  3/2057 (0.15%)  5/2076 (0.24%) 
Neuropathy Peripheral † 1  0/2061 (0.00%)  4/2076 (0.19%)  2/2057 (0.10%)  1/2076 (0.05%) 
Headache † 1  2/2061 (0.10%)  0/2076 (0.00%)  3/2057 (0.15%)  1/2076 (0.05%) 
Convulsion † 1  2/2061 (0.10%)  0/2076 (0.00%)  3/2057 (0.15%)  0/2076 (0.00%) 
Dizziness † 1  1/2061 (0.05%)  1/2076 (0.05%)  0/2057 (0.00%)  1/2076 (0.05%) 
Cerebrovascular Accident † 1  0/2061 (0.00%)  1/2076 (0.05%)  0/2057 (0.00%)  1/2076 (0.05%) 
Polyneuropathy † 1  0/2061 (0.00%)  0/2076 (0.00%)  2/2057 (0.10%)  0/2076 (0.00%) 
Quadriparesis † 1  0/2061 (0.00%)  0/2076 (0.00%)  1/2057 (0.05%)  1/2076 (0.05%) 
Amnesia † 1  1/2061 (0.05%)  0/2076 (0.00%)  0/2057 (0.00%)  0/2076 (0.00%) 
Amyotrophic Lateral Sclerosis † 1  0/2061 (0.00%)  0/2076 (0.00%)  0/2057 (0.00%)  1/2076 (0.05%) 
Brain Hypoxia † 1  0/2061 (0.00%)  1/2076 (0.05%)  0/2057 (0.00%)  0/2076 (0.00%) 
Cerebellar Ataxia † 1  1/2061 (0.05%)  0/2076 (0.00%)  0/2057 (0.00%)  0/2076 (0.00%) 
Epilepsy † 1  0/2061 (0.00%)  0/2076 (0.00%)  1/2057 (0.05%)  0/2076 (0.00%) 
Hypotonia † 1  0/2061 (0.00%)  0/2076 (0.00%)  0/2057 (0.00%)  1/2076 (0.05%) 
Intracranial Aneurysm † 1  1/2061 (0.05%)  0/2076 (0.00%)  0/2057 (0.00%)  0/2076 (0.00%) 
Migraine † 1  0/2061 (0.00%)  0/2076 (0.00%)  0/2057 (0.00%)  1/2076 (0.05%) 
Motor Neurone Disease † 1  0/2061 (0.00%)  0/2076 (0.00%)  0/2057 (0.00%)  1/2076 (0.05%) 
Peripheral Motor Neuropathy † 1  1/2061 (0.05%)  0/2076 (0.00%)  0/2057 (0.00%)  0/2076 (0.00%) 
Peripheral Sensory Neuropathy † 1  1/2061 (0.05%)  0/2076 (0.00%)  0/2057 (0.00%)  0/2076 (0.00%) 
Serotonin Syndrome † 1  0/2061 (0.00%)  0/2076 (0.00%)  0/2057 (0.00%)  1/2076 (0.05%) 
Somnolence † 1  0/2061 (0.00%)  0/2076 (0.00%)  0/2057 (0.00%)  1/2076 (0.05%) 
Subarachnoid Haemorrhage † 1  0/2061 (0.00%)  0/2076 (0.00%)  0/2057 (0.00%)  1/2076 (0.05%) 
Viith Nerve Paralysis † 1  1/2061 (0.05%)  0/2076 (0.00%)  0/2057 (0.00%)  0/2076 (0.00%) 
Pregnancy, puerperium and perinatal conditions         
Abortion Spontaneous † 1  0/2061 (0.00%)  1/2076 (0.05%)  0/2057 (0.00%)  0/2076 (0.00%) 
Foetal Death † 1  0/2061 (0.00%)  1/2076 (0.05%)  0/2057 (0.00%)  0/2076 (0.00%) 
Psychiatric disorders         
Depression † 1  3/2061 (0.15%)  2/2076 (0.10%)  1/2057 (0.05%)  3/2076 (0.14%) 
Suicide Attempt † 1  0/2061 (0.00%)  1/2076 (0.05%)  1/2057 (0.05%)  1/2076 (0.05%) 
Major Depression † 1  0/2061 (0.00%)  1/2076 (0.05%)  1/2057 (0.05%)  0/2076 (0.00%) 
Abnormal Behaviour † 1  0/2061 (0.00%)  0/2076 (0.00%)  1/2057 (0.05%)  0/2076 (0.00%) 
Alcohol Withdrawal Syndrome † 1  0/2061 (0.00%)  1/2076 (0.05%)  0/2057 (0.00%)  0/2076 (0.00%) 
Completed Suicide † 1  0/2061 (0.00%)  1/2076 (0.05%)  0/2057 (0.00%)  0/2076 (0.00%) 
Insomnia † 1  1/2061 (0.05%)  0/2076 (0.00%)  0/2057 (0.00%)  0/2076 (0.00%) 
Mental Disorder † 1  0/2061 (0.00%)  0/2076 (0.00%)  0/2057 (0.00%)  1/2076 (0.05%) 
Restlessness † 1  0/2061 (0.00%)  0/2076 (0.00%)  1/2057 (0.05%)  0/2076 (0.00%) 
Schizophrenia † 1  0/2061 (0.00%)  1/2076 (0.05%)  0/2057 (0.00%)  0/2076 (0.00%) 
Renal and urinary disorders         
Renal Failure † 1  1/2061 (0.05%)  0/2076 (0.00%)  2/2057 (0.10%)  1/2076 (0.05%) 
Nephrolithiasis † 1  0/2061 (0.00%)  2/2076 (0.10%)  0/2057 (0.00%)  0/2076 (0.00%) 
Calculus Urinary † 1  0/2061 (0.00%)  0/2076 (0.00%)  1/2057 (0.05%)  0/2076 (0.00%) 
Nephritic Syndrome † 1  0/2061 (0.00%)  0/2076 (0.00%)  1/2057 (0.05%)  0/2076 (0.00%) 
Renal Colic † 1  1/2061 (0.05%)  0/2076 (0.00%)  0/2057 (0.00%)  0/2076 (0.00%) 
Renal Failure Acute † 1  0/2061 (0.00%)  0/2076 (0.00%)  1/2057 (0.05%)  0/2076 (0.00%) 
Urethral Obstruction † 1  0/2061 (0.00%)  0/2076 (0.00%)  1/2057 (0.05%)  0/2076 (0.00%) 
Urinary Bladder Haemorrhage † 1  0/2061 (0.00%)  0/2076 (0.00%)  1/2057 (0.05%)  0/2076 (0.00%) 
Reproductive system and breast disorders         
Ovarian Cyst † 1  0/2061 (0.00%)  4/2076 (0.19%)  1/2057 (0.05%)  3/2076 (0.14%) 
Breast Calcifications † 1  1/2061 (0.05%)  1/2076 (0.05%)  1/2057 (0.05%)  1/2076 (0.05%) 
Uterine Polyp † 1  1/2061 (0.05%)  1/2076 (0.05%)  0/2057 (0.00%)  1/2076 (0.05%) 
Endometrial Hyperplasia † 1  0/2061 (0.00%)  0/2076 (0.00%)  1/2057 (0.05%)  1/2076 (0.05%) 
Adenomyosis † 1  0/2061 (0.00%)  1/2076 (0.05%)  0/2057 (0.00%)  0/2076 (0.00%) 
Breast Disorder † 1  0/2061 (0.00%)  0/2076 (0.00%)  1/2057 (0.05%)  0/2076 (0.00%) 
Breast Fibrosis † 1  0/2061 (0.00%)  1/2076 (0.05%)  0/2057 (0.00%)  0/2076 (0.00%) 
Breast Haematoma † 1  0/2061 (0.00%)  0/2076 (0.00%)  0/2057 (0.00%)  1/2076 (0.05%) 
Breast Inflammation † 1  1/2061 (0.05%)  0/2076 (0.00%)  0/2057 (0.00%)  0/2076 (0.00%) 
Breast Necrosis † 1  1/2061 (0.05%)  0/2076 (0.00%)  0/2057 (0.00%)  0/2076 (0.00%) 
Breast Swelling † 1  0/2061 (0.00%)  1/2076 (0.05%)  0/2057 (0.00%)  0/2076 (0.00%) 
Metrorrhagia † 1  0/2061 (0.00%)  0/2076 (0.00%)  0/2057 (0.00%)  1/2076 (0.05%) 
Ovarian Cyst Ruptured † 1  1/2061 (0.05%)  0/2076 (0.00%)  0/2057 (0.00%)  0/2076 (0.00%) 
Pelvic Pain † 1  0/2061 (0.00%)  0/2076 (0.00%)  1/2057 (0.05%)  0/2076 (0.00%) 
Postmenopausal Haemorrhage † 1  0/2061 (0.00%)  0/2076 (0.00%)  1/2057 (0.05%)  0/2076 (0.00%) 
Vaginal Haemorrhage † 1  0/2061 (0.00%)  0/2076 (0.00%)  1/2057 (0.05%)  0/2076 (0.00%) 
Respiratory, thoracic and mediastinal disorders         
Dyspnoea † 1  4/2061 (0.19%)  4/2076 (0.19%)  2/2057 (0.10%)  6/2076 (0.29%) 
Pulmonary Embolism † 1  2/2061 (0.10%)  4/2076 (0.19%)  6/2057 (0.29%)  2/2076 (0.10%) 
Pneumonitis † 1  0/2061 (0.00%)  4/2076 (0.19%)  2/2057 (0.10%)  5/2076 (0.24%) 
Interstitial Lung Disease † 1  2/2061 (0.10%)  1/2076 (0.05%)  2/2057 (0.10%)  0/2076 (0.00%) 
Lung Disorder † 1  0/2061 (0.00%)  0/2076 (0.00%)  0/2057 (0.00%)  3/2076 (0.14%) 
Lung Infiltration † 1  1/2061 (0.05%)  0/2076 (0.00%)  1/2057 (0.05%)  1/2076 (0.05%) 
Bronchiectasis † 1  1/2061 (0.05%)  0/2076 (0.00%)  1/2057 (0.05%)  0/2076 (0.00%) 
Pleural Effusion † 1  2/2061 (0.10%)  0/2076 (0.00%)  0/2057 (0.00%)  0/2076 (0.00%) 
Pleuritic Pain † 1  0/2061 (0.00%)  0/2076 (0.00%)  0/2057 (0.00%)  2/2076 (0.10%) 
Acute Respiratory Distress Syndrome † 1  0/2061 (0.00%)  1/2076 (0.05%)  0/2057 (0.00%)  0/2076 (0.00%) 
Atelectasis † 1  0/2061 (0.00%)  0/2076 (0.00%)  1/2057 (0.05%)  0/2076 (0.00%) 
Bronchospasm † 1  1/2061 (0.05%)  0/2076 (0.00%)  0/2057 (0.00%)  0/2076 (0.00%) 
Cough † 1  0/2061 (0.00%)  0/2076 (0.00%)  0/2057 (0.00%)  1/2076 (0.05%) 
Dysphonia † 1  0/2061 (0.00%)  0/2076 (0.00%)  1/2057 (0.05%)  0/2076 (0.00%) 
Dyspnoea Exertional † 1  0/2061 (0.00%)  0/2076 (0.00%)  0/2057 (0.00%)  1/2076 (0.05%) 
Epistaxis † 1  0/2061 (0.00%)  1/2076 (0.05%)  0/2057 (0.00%)  0/2076 (0.00%) 
Haemoptysis † 1  0/2061 (0.00%)  0/2076 (0.00%)  0/2057 (0.00%)  1/2076 (0.05%) 
Hypoxia † 1  0/2061 (0.00%)  1/2076 (0.05%)  0/2057 (0.00%)  0/2076 (0.00%) 
Laryngeal Oedema † 1  0/2061 (0.00%)  0/2076 (0.00%)  1/2057 (0.05%)  0/2076 (0.00%) 
Lung Consolidation † 1  0/2061 (0.00%)  1/2076 (0.05%)  0/2057 (0.00%)  0/2076 (0.00%) 
Pleurisy † 1  0/2061 (0.00%)  0/2076 (0.00%)  0/2057 (0.00%)  1/2076 (0.05%) 
Pneumonia Aspiration † 1  0/2061 (0.00%)  0/2076 (0.00%)  0/2057 (0.00%)  1/2076 (0.05%) 
Pneumothorax † 1  0/2061 (0.00%)  1/2076 (0.05%)  0/2057 (0.00%)  0/2076 (0.00%) 
Pulmonary Granuloma † 1  0/2061 (0.00%)  0/2076 (0.00%)  1/2057 (0.05%)  0/2076 (0.00%) 
Pulmonary Mass † 1  0/2061 (0.00%)  0/2076 (0.00%)  0/2057 (0.00%)  1/2076 (0.05%) 
Pulmonary Oedema † 1  1/2061 (0.05%)  0/2076 (0.00%)  0/2057 (0.00%)  0/2076 (0.00%) 
Pulmonary Thrombosis † 1  1/2061 (0.05%)  0/2076 (0.00%)  0/2057 (0.00%)  0/2076 (0.00%) 
Respiratory Failure † 1  0/2061 (0.00%)  0/2076 (0.00%)  0/2057 (0.00%)  1/2076 (0.05%) 
Skin and subcutaneous tissue disorders         
Rash † 1  4/2061 (0.19%)  4/2076 (0.19%)  7/2057 (0.34%)  0/2076 (0.00%) 
Dermatitis Acneiform † 1  0/2061 (0.00%)  1/2076 (0.05%)  2/2057 (0.10%)  0/2076 (0.00%) 
Acne † 1  2/2061 (0.10%)  0/2076 (0.00%)  0/2057 (0.00%)  0/2076 (0.00%) 
Angioedema † 1  0/2061 (0.00%)  0/2076 (0.00%)  2/2057 (0.10%)  0/2076 (0.00%) 
Erythema † 1  1/2061 (0.05%)  1/2076 (0.05%)  0/2057 (0.00%)  0/2076 (0.00%) 
Nail Disorder † 1  0/2061 (0.00%)  0/2076 (0.00%)  1/2057 (0.05%)  1/2076 (0.05%) 
Photosensitivity Reaction † 1  0/2061 (0.00%)  1/2076 (0.05%)  1/2057 (0.05%)  0/2076 (0.00%) 
Pruritus † 1  1/2061 (0.05%)  0/2076 (0.00%)  1/2057 (0.05%)  0/2076 (0.00%) 
Urticaria † 1  1/2061 (0.05%)  0/2076 (0.00%)  1/2057 (0.05%)  0/2076 (0.00%) 
Angiodermatitis † 1  0/2061 (0.00%)  0/2076 (0.00%)  0/2057 (0.00%)  1/2076 (0.05%) 
Exfoliative Rash † 1  1/2061 (0.05%)  0/2076 (0.00%)  0/2057 (0.00%)  0/2076 (0.00%) 
Hypersensitivity Vasculitis † 1  0/2061 (0.00%)  0/2076 (0.00%)  1/2057 (0.05%)  0/2076 (0.00%) 
Hypertrophic Scar † 1  1/2061 (0.05%)  0/2076 (0.00%)  0/2057 (0.00%)  0/2076 (0.00%) 
Palmar-Plantar Erythrodysaesthesia Syndrome † 1  1/2061 (0.05%)  0/2076 (0.00%)  0/2057 (0.00%)  0/2076 (0.00%) 
Rash Maculo-Papular † 1  0/2061 (0.00%)  1/2076 (0.05%)  0/2057 (0.00%)  0/2076 (0.00%) 
Skin Necrosis † 1  0/2061 (0.00%)  0/2076 (0.00%)  0/2057 (0.00%)  1/2076 (0.05%) 
Skin Swelling † 1  0/2061 (0.00%)  0/2076 (0.00%)  1/2057 (0.05%)  0/2076 (0.00%) 
Skin Ulcer † 1  0/2061 (0.00%)  1/2076 (0.05%)  0/2057 (0.00%)  0/2076 (0.00%) 
Toxic Epidermal Necrolysis † 1  1/2061 (0.05%)  0/2076 (0.00%)  0/2057 (0.00%)  0/2076 (0.00%) 
Surgical and medical procedures         
Abortion Induced † 1  0/2061 (0.00%)  0/2076 (0.00%)  1/2057 (0.05%)  0/2076 (0.00%) 
Vascular disorders         
Hypotension † 1  2/2061 (0.10%)  1/2076 (0.05%)  2/2057 (0.10%)  3/2076 (0.14%) 
Thrombosis † 1  2/2061 (0.10%)  2/2076 (0.10%)  2/2057 (0.10%)  2/2076 (0.10%) 
Deep Vein Thrombosis † 1  2/2061 (0.10%)  2/2076 (0.10%)  2/2057 (0.10%)  0/2076 (0.00%) 
Hypertension † 1  2/2061 (0.10%)  2/2076 (0.10%)  0/2057 (0.00%)  1/2076 (0.05%) 
Hypertensive Crisis † 1  0/2061 (0.00%)  1/2076 (0.05%)  0/2057 (0.00%)  1/2076 (0.05%) 
Jugular Vein Thrombosis † 1  0/2061 (0.00%)  1/2076 (0.05%)  0/2057 (0.00%)  1/2076 (0.05%) 
Venous Thrombosis Limb † 1  1/2061 (0.05%)  1/2076 (0.05%)  0/2057 (0.00%)  0/2076 (0.00%) 
Circulatory Collapse † 1  1/2061 (0.05%)  0/2076 (0.00%)  0/2057 (0.00%)  0/2076 (0.00%) 
Embolism Venous † 1  0/2061 (0.00%)  0/2076 (0.00%)  1/2057 (0.05%)  0/2076 (0.00%) 
Flushing † 1  1/2061 (0.05%)  0/2076 (0.00%)  0/2057 (0.00%)  0/2076 (0.00%) 
Orthostatic Hypotension † 1  0/2061 (0.00%)  1/2076 (0.05%)  0/2057 (0.00%)  0/2076 (0.00%) 
Rheumatoid Vasculitis † 1  0/2061 (0.00%)  0/2076 (0.00%)  0/2057 (0.00%)  1/2076 (0.05%) 
Subclavian Vein Thrombosis † 1  0/2061 (0.00%)  0/2076 (0.00%)  0/2057 (0.00%)  1/2076 (0.05%) 
Thrombophlebitis Superficial † 1  0/2061 (0.00%)  0/2076 (0.00%)  1/2057 (0.05%)  0/2076 (0.00%) 
†
Indicates events were collected by systematic assessment
1
Term from vocabulary, MedDRA
Hide Other (Not Including Serious) Adverse Events
Frequency Threshold for Reporting Other Adverse Events 5%
Lapatinib plusTrastuzumab Trastuzumab Followed by Lapatinib Lapatinib Trastuzumab
Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%)
Total   1928/2061 (93.55%)   1861/2076 (89.64%)   1887/2057 (91.74%)   1652/2076 (79.58%) 
Blood and lymphatic system disorders         
Neutropenia † 1  233/2061 (11.31%)  175/2076 (8.43%)  221/2057 (10.74%)  179/2076 (8.62%) 
Anaemia † 1  226/2061 (10.97%)  168/2076 (8.09%)  170/2057 (8.26%)  223/2076 (10.74%) 
Leukopenia † 1  172/2061 (8.35%)  136/2076 (6.55%)  153/2057 (7.44%)  164/2076 (7.90%) 
Cardiac disorders         
Left Ventricular Dysfunction † 1  69/2061 (3.35%)  56/2076 (2.70%)  54/2057 (2.63%)  116/2076 (5.59%) 
Gastrointestinal disorders         
Diarrhoea † 1  1514/2061 (73.46%)  1038/2076 (50.00%)  1278/2057 (62.13%)  401/2076 (19.32%) 
Nausea † 1  394/2061 (19.12%)  393/2076 (18.93%)  381/2057 (18.52%)  286/2076 (13.78%) 
Vomiting † 1  251/2061 (12.18%)  181/2076 (8.72%)  215/2057 (10.45%)  151/2076 (7.27%) 
Stomatitis † 1  203/2061 (9.85%)  141/2076 (6.79%)  161/2057 (7.83%)  98/2076 (4.72%) 
Constipation † 1  120/2061 (5.82%)  183/2076 (8.82%)  133/2057 (6.47%)  156/2076 (7.51%) 
Dyspepsia † 1  175/2061 (8.49%)  140/2076 (6.74%)  156/2057 (7.58%)  116/2076 (5.59%) 
Abdominal Pain † 1  146/2061 (7.08%)  108/2076 (5.20%)  149/2057 (7.24%)  79/2076 (3.81%) 
Abdominal Pain Upper † 1  137/2061 (6.65%)  111/2076 (5.35%)  110/2057 (5.35%)  77/2076 (3.71%) 
General disorders         
Fatigue † 1  511/2061 (24.79%)  517/2076 (24.90%)  443/2057 (21.54%)  438/2076 (21.10%) 
Asthenia † 1  202/2061 (9.80%)  178/2076 (8.57%)  175/2057 (8.51%)  171/2076 (8.24%) 
Pyrexia † 1  227/2061 (11.01%)  188/2076 (9.06%)  131/2057 (6.37%)  171/2076 (8.24%) 
Mucosal Inflammation † 1  227/2061 (11.01%)  149/2076 (7.18%)  164/2057 (7.97%)  114/2076 (5.49%) 
Oedema Peripheral † 1  145/2061 (7.04%)  149/2076 (7.18%)  137/2057 (6.66%)  161/2076 (7.76%) 
Hepatobiliary disorders         
Hypertransaminasaemia † 1  351/2061 (17.03%)  380/2076 (18.30%)  367/2057 (17.84%)  281/2076 (13.54%) 
Hyperbilirubinaemia † 1  97/2061 (4.71%)  103/2076 (4.96%)  121/2057 (5.88%)  32/2076 (1.54%) 
Infections and infestations         
Paronychia † 1  260/2061 (12.62%)  165/2076 (7.95%)  206/2057 (10.01%)  22/2076 (1.06%) 
Nasopharyngitis † 1  130/2061 (6.31%)  113/2076 (5.44%)  95/2057 (4.62%)  152/2076 (7.32%) 
Upper Respiratory Tract Infection † 1  117/2061 (5.68%)  96/2076 (4.62%)  92/2057 (4.47%)  118/2076 (5.68%) 
Injury, poisoning and procedural complications         
Radiation Skin Injury † 1  96/2061 (4.66%)  134/2076 (6.45%)  83/2057 (4.04%)  138/2076 (6.65%) 
Metabolism and nutrition disorders         
Decreased Appetite † 1  224/2061 (10.87%)  172/2076 (8.29%)  187/2057 (9.09%)  143/2076 (6.89%) 
Hyperphosphatasaemia † 1  82/2061 (3.98%)  110/2076 (5.30%)  120/2057 (5.83%)  77/2076 (3.71%) 
Musculoskeletal and connective tissue disorders         
Arthralgia † 1  306/2061 (14.85%)  311/2076 (14.98%)  290/2057 (14.10%)  402/2076 (19.36%) 
Myalgia † 1  213/2061 (10.33%)  215/2076 (10.36%)  174/2057 (8.46%)  253/2076 (12.19%) 
Pain In Extremity † 1  135/2061 (6.55%)  125/2076 (6.02%)  99/2057 (4.81%)  175/2076 (8.43%) 
Back Pain † 1  129/2061 (6.26%)  135/2076 (6.50%)  119/2057 (5.79%)  128/2076 (6.17%) 
Bone Pain † 1  88/2061 (4.27%)  110/2076 (5.30%)  91/2057 (4.42%)  123/2076 (5.92%) 
Musculoskeletal Pain † 1  79/2061 (3.83%)  97/2076 (4.67%)  70/2057 (3.40%)  110/2076 (5.30%) 
Nervous system disorders         
Headache † 1  193/2061 (9.36%)  240/2076 (11.56%)  161/2057 (7.83%)  262/2076 (12.62%) 
Neuropathy peripheral † 1  179/2061 (8.69%)  182/2076 (8.77%)  174/2057 (8.46%)  178/2076 (8.57%) 
Peripheral Sensory Neuropathy † 1  166/2061 (8.05%)  161/2076 (7.76%)  162/2057 (7.88%)  195/2076 (9.39%) 
Dysgeusia † 1  138/2061 (6.70%)  119/2076 (5.73%)  119/2057 (5.79%)  106/2076 (5.11%) 
Paraesthesia † 1  125/2061 (6.07%)  111/2076 (5.35%)  107/2057 (5.20%)  130/2076 (6.26%) 
Dizziness † 1  104/2061 (5.05%)  128/2076 (6.17%)  115/2057 (5.59%)  118/2076 (5.68%) 
Psychiatric disorders         
Insomnia † 1  168/2061 (8.15%)  172/2076 (8.29%)  153/2057 (7.44%)  190/2076 (9.15%) 
Respiratory, thoracic and mediastinal disorders         
Epistaxis † 1  319/2061 (15.48%)  214/2076 (10.31%)  244/2057 (11.86%)  165/2076 (7.95%) 
Cough † 1  218/2061 (10.58%)  202/2076 (9.73%)  152/2057 (7.39%)  242/2076 (11.66%) 
Dyspnoea † 1  146/2061 (7.08%)  147/2076 (7.08%)  105/2057 (5.10%)  171/2076 (8.24%) 
Skin and subcutaneous tissue disorders         
Rash † 1  757/2061 (36.73%)  673/2076 (32.42%)  753/2057 (36.61%)  221/2076 (10.65%) 
Nail Disorder † 1  359/2061 (17.42%)  280/2076 (13.49%)  295/2057 (14.34%)  221/2076 (10.65%) 
Pruritus † 1  287/2061 (13.93%)  249/2076 (11.99%)  313/2057 (15.22%)  124/2076 (5.97%) 
Dry Skin † 1  262/2061 (12.71%)  245/2076 (11.80%)  280/2057 (13.61%)  86/2076 (4.14%) 
Alopecia † 1  109/2061 (5.29%)  136/2076 (6.55%)  110/2057 (5.35%)  151/2076 (7.27%) 
Palmar-Plantar Erythrodysaesthesia Syndrome † 1  181/2061 (8.78%)  106/2076 (5.11%)  126/2057 (6.13%)  47/2076 (2.26%) 
Erythema † 1  122/2061 (5.92%)  104/2076 (5.01%)  92/2057 (4.47%)  87/2076 (4.19%) 
Acne † 1  134/2061 (6.50%)  138/2076 (6.65%)  112/2057 (5.44%)  20/2076 (0.96%) 
Skin Fissures † 1  145/2061 (7.04%)  98/2076 (4.72%)  124/2057 (6.03%)  7/2076 (0.34%) 
Dermatitis Acneiform † 1  116/2061 (5.63%)  96/2076 (4.62%)  124/2057 (6.03%)  19/2076 (0.92%) 
Vascular disorders         
Hot Flush † 1  214/2061 (10.38%)  226/2076 (10.89%)  191/2057 (9.29%)  274/2076 (13.20%) 
†
Indicates events were collected by systematic assessment
1
Term from vocabulary, MedDRA
[Not Specified]
Certain Agreements
Principal Investigators are NOT employed by the organization sponsoring the study.
There IS an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.
The terms and conditions of Novartis' agreements with its investigators may vary. However, Novartis does not prohibit any investigator from publishing. Any publications from a single-site are postponed until the publication of the pooled data (i.e., data from all sites) in the clinical trial or disclosure of trial results in their entirety.
Results Point of Contact
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Name/Title: Clinical Disclosure Office
Organization: Novartis Pharmaceuticals
Phone: 862-778-8300
Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):
Layout table for additonal information
Responsible Party: Novartis ( Novartis Pharmaceuticals )
ClinicalTrials.gov Identifier: NCT00490139    
Obsolete Identifiers: NCT00609024
Other Study ID Numbers: EGF106708
CLAP016B2301 ( Other Identifier: Novartis )
2006-000562-36 ( EudraCT Number )
First Submitted: June 20, 2007
First Posted: June 22, 2007
Results First Submitted: July 30, 2014
Results First Posted: August 18, 2014
Last Update Posted: September 10, 2020