Flag of the European Union EU Clinical Trials Register Help

Clinical trials

The European Union Clinical Trials Register   allows you to search for protocol and results information on:
  • interventional clinical trials that were approved in the European Union (EU)/European Economic Area (EEA) under the Clinical Trials Directive 2001/20/EC
  • clinical trials conducted outside the EU/EEA that are linked to European paediatric-medicine development

    • EU/EEA interventional clinical trials approved under or transitioned to the Clinical Trial Regulation 536/2014 are publicly accessible through the
    Clinical Trials Information System (CTIS).

    The EU Clinical Trials Register currently displays   43861   clinical trials with a EudraCT protocol, of which   7284   are clinical trials conducted with subjects less than 18 years old.   The register also displays information on   18700   older paediatric trials (in scope of Article 45 of the Paediatric Regulation (EC) No 1901/2006).

    Phase 1 trials conducted solely on adults and that are not part of an agreed paediatric investigation plan (PIP) are not publicly available (see Frequently Asked Questions ).  
     
    Examples: Cancer AND drug name. Pneumonia AND sponsor name.
    How to search [pdf]
    Search Tips: Under advanced search you can use filters for Country, Age Group, Gender, Trial Phase, Trial Status, Date Range, Rare Diseases and Orphan Designation. For these items you should use the filters and not add them to your search terms in the text field.
    Advanced Search: Search tools
     

    < Back to search results

    Download PDF

    Clinical Trial Results:
    A Phase III Randomized, Multicenter, Two Arm, Open-Label Trial to Evaluate the Efficacy of Trastuzumab Emtansine Compared with Treatment of Physician's Choice in Patients with HER2-positive Metastatic Breast Cancer who have Received at Least Two Prior Regimens of HER2 Directed Therapy.

    Summary
    EudraCT number
    		 2011-000509-29
    Trial protocol
    		 GB   SE   DE   SK   BE   CZ   HU   NO   IT   ES  
    Global end of trial date
    31 Aug 2015

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

    Trial information

    		 Close Top of page
    Trial identification
    Sponsor protocol code
    BO25734/TDM4997g
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 -
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    F. Hoffmann-La Roche AG
    Sponsor organisation address
    Grenzacherstrasse 124, Basel, Switzerland, CH-4070
    Public contact
    F. Hoffmann-La Roche AG, F. Hoffmann-La Roche AG, +41 616878333, global.trial_information@roche.com
    Scientific contact
    F. Hoffmann-La Roche AG, F. Hoffmann-La Roche AG, +41 616878333, global.trial_information@roche.com
    Paediatric regulatory details
    Is trial part of an agreed paediatric investigation plan (PIP)
    No
    Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Results analysis stage
    Analysis stage
    Final
    Date of interim/final analysis
    31 Aug 2015
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    31 Aug 2015
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    This randomized, multicenter, 2-arm, open-label study (TH3RESA) evaluated the efficacy and safety of trastuzumab emtansine (T-DM1) in comparison with treatment of the physician’s choice in subjects with metastatic or unresectable locally advanced/recurrent human epidermal growth factor receptor 2 (HER2)-positive breast cancer. Eligible subjects were randomized to receive either trastuzumab emtansine 3.6 mg/kg intravenously every 21 days or treatment of the physician’s choice. Subjects continued to receive study treatment until disease progression or occurrence of unacceptable toxicity. This study is also known under Roche study protocol number BO25734.
    Protection of trial subjects
    All study subjects were required to read and sign an Informed Consent Form.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    14 Sep 2011
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Norway: 2
    Country: Number of subjects enrolled
    Poland: 10
    Country: Number of subjects enrolled
    Slovakia: 4
    Country: Number of subjects enrolled
    Spain: 37
    Country: Number of subjects enrolled
    Sweden: 4
    Country: Number of subjects enrolled
    United Kingdom: 29
    Country: Number of subjects enrolled
    Belgium: 20
    Country: Number of subjects enrolled
    Czech Republic: 13
    Country: Number of subjects enrolled
    France: 80
    Country: Number of subjects enrolled
    Germany: 22
    Country: Number of subjects enrolled
    Hungary: 20
    Country: Number of subjects enrolled
    Italy: 56
    Country: Number of subjects enrolled
    United States: 147
    Country: Number of subjects enrolled
    Switzerland: 6
    Country: Number of subjects enrolled
    Australia: 19
    Country: Number of subjects enrolled
    Brazil: 14
    Country: Number of subjects enrolled
    Canada: 16
    Country: Number of subjects enrolled
    India: 5
    Country: Number of subjects enrolled
    Israel: 26
    Country: Number of subjects enrolled
    Korea, Republic of: 52
    Country: Number of subjects enrolled
    Russian Federation: 5
    Country: Number of subjects enrolled
    Thailand: 15
    Worldwide total number of subjects
    602
    EEA total number of subjects
    297
    Number of subjects enrolled per age group
    In utero
    0
    Preterm newborn - gestational age < 37 wk
    0
    Newborns (0-27 days)
    0
    Infants and toddlers (28 days-23 months)
    0
    Children (2-11 years)
    0
    Adolescents (12-17 years)
    0
    Adults (18-64 years)
    509
    From 65 to 84 years
    91
    85 years and over
    2

    Subject disposition

    		 Close Top of page
    Recruitment
    Recruitment details
    		 -

    Pre-assignment
    Screening details
    		 A total of 602 patients were randomized to the study (404 to receive Trastuzumab Emtansine and 198 to receive Treatment of Physician’s Choice).

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

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Trastuzumab Emtansine
    Arm description
    		 Trastuzumab emtansine 3.6 mg/kg intravenously every 3 weeks until disease progression (as assessed by the investigator) or unmanageable toxicity.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Trastuzumab emtansine
    Investigational medicinal product code
    Other name
    Kadcyla, T-DM1
    Pharmaceutical forms
    Powder for solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    The dose was calculated based on the subject’s Baseline weight on Day 1 of each 3-week treatment cycle. The same dose was administered in subsequent cycles if the subject’s weight stayed within 10% of the Baseline weight. If there was a weight change > 10%, the dose was adjusted accordingly and the recorded weight became the new Baseline weight. Trastuzumab emtansine was provided as a single-use lyophilized formulation.

    Arm title
    		 Treatment of Physician’s Choice
    Arm description
    		 Treatment of physician's choice until disease progression (as assessed by the investigator) or unmanageable toxicity. The treatments included single-agent chemotherapy, single-agent or dual-agent hormonal therapy for hormone receptor positive-disease, and human epidermal growth factor receptor 2 (HER2)-directed therapy.
    Arm type
    		 Active comparator

    Investigational medicinal product name
    Treatment of physician’s choice
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule, Solution for infusion, Tablet
    Routes of administration
    Intravenous use, Oral use
    Dosage and administration details
    The treatment of physician’s choice (TPC) was a protocol-specified approved or standard of care therapy or combination of therapies, based on frequently used regimens for late-line HER2-positive metastatic breast cancer treatment after receipt of both trastuzumab- and lapatinib-containing regimens. The therapies included single-agent chemotherapy, single-agent (eg, tamoxifen or aromatase inhibitor) or dual-agent (e.g., aromatase inhibitor with luteinizing hormone releasing hormone [LHRH] agonist) hormonal therapy for hormone receptor positive-disease, and HER2-directed therapy. Subjects who had documented progressive disease (PD) were eligible to switch treatment to receive trastuzumab emtansine 3.6 mg/kg. Subjects who switched treatment remained on trastuzumab emtansine treatment until another PD event or unmanageable toxicity. The formulation, storage, and preparation of all TPC were as per the appropriate package insert or national prescribing information.

    Number of subjects in period 1
    		Trastuzumab Emtansine Treatment of Physician’s Choice
    Started
    404
    198
    Switched to Trastuzumab Emtansine
    0
    94
    Completed
    0
    0
    Not completed
    404
    198
         Study completed by Sponsor
    103
    34
         Physician decision
    4
    4
         Death
    247
    122
         Non-compliance
    3
    1
         Lost to follow-up
    14
    4
         Reason not specified
    -
    1
         Withdrawal by subject
    33
    32

    Baseline characteristics

    		 Close Top of page
    Baseline characteristics reporting groups
    Reporting group title
    Trastuzumab Emtansine
    Reporting group description
    		 Trastuzumab emtansine 3.6 mg/kg intravenously every 3 weeks until disease progression (as assessed by the investigator) or unmanageable toxicity.

    Reporting group title
    Treatment of Physician’s Choice
    Reporting group description
    		 Treatment of physician's choice until disease progression (as assessed by the investigator) or unmanageable toxicity. The treatments included single-agent chemotherapy, single-agent or dual-agent hormonal therapy for hormone receptor positive-disease, and human epidermal growth factor receptor 2 (HER2)-directed therapy.

    Reporting group values
    		 Trastuzumab Emtansine Treatment of Physician’s Choice Total
    Number of subjects
    		 404 198 602
    Age categorical
    Units: Subjects
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    		 53.3 ± 10.4 54.3 ± 10.8 -
    Gender categorical
    Units: Subjects
        Female
    		 401 197 598
        Male
    		 3 1 4

    End points

    		 Close Top of page
    End points reporting groups
    Reporting group title
    Trastuzumab Emtansine
    Reporting group description
    		 Trastuzumab emtansine 3.6 mg/kg intravenously every 3 weeks until disease progression (as assessed by the investigator) or unmanageable toxicity.

    Reporting group title
    Treatment of Physician’s Choice
    Reporting group description
    		 Treatment of physician's choice until disease progression (as assessed by the investigator) or unmanageable toxicity. The treatments included single-agent chemotherapy, single-agent or dual-agent hormonal therapy for hormone receptor positive-disease, and human epidermal growth factor receptor 2 (HER2)-directed therapy.

    Primary: Progression-free Survival

    		 Close Top of page
    End point title
    		 Progression-free Survival
    End point description
    Progression-free survival was defined as the time from randomization to the first documented disease progression by investigator assessment using Response Evaluation Criteria In Solid Tumors (RECIST) v1.1 or death from any cause, whichever occurred first. Progression-free survival was a co-primary endpoint. Randomized population: All subjects who were randomized to the study. Subjects were included in the treatment group to which they were randomized.
    End point type
    Primary
    End point timeframe
    Baseline to the clinical cut-off date of 11 Feb 2013 (up to 2 years)
    End point values
    		 Trastuzumab Emtansine Treatment of Physician’s Choice
    Number of subjects analysed
    404
    198
    Units: Months
        median (confidence interval 95%)
    6.2 (5.59 to 6.87)
    3.3 (2.89 to 4.14)
    Statistical analysis title
    		 Stratified analysis
    Statistical analysis description
    The analysis was stratified for 1) World region (United States, Western Europe, or Other); 2) Number of prior regimens, excluding single-agent hormones, for treatment of metastatic or unresectable locally advanced/recurrent disease (≤ 3 or > 3); and 3) Presence of visceral disease (any visceral disease vs no visceral disease). The hazard ratio was estimated by Cox regression.
    Comparison groups
    Trastuzumab Emtansine v Treatment of Physician’s Choice
    Number of subjects included in analysis
    602
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 < 0.0001 [1]
    Method
    		 Logrank
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.528
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.422
         upper limit
    		 0.661
    Notes
    [1] - The two-sided stratified log-rank test was used to compare progression-free survival between the two treatment arms at the overall two-sided significance level of 0.5%.

    Primary: Overall Survival

    		 Close Top of page
    End point title
    		 Overall Survival
    End point description
    Overall survival was defined as the time from randomization to death from any cause. Overall survival was a co-primary endpoint. Randomized population: All subjects who were randomized to the study. Subjects were included in the treatment group to which they were randomized. 999 = The median and/or the upper limit of the confidence interval could not be estimated due to too few events.
    End point type
    Primary
    End point timeframe
    Baseline to the clinical cut-off date of 11 Feb 2013 (up to 2 years)
    End point values
    		 Trastuzumab Emtansine Treatment of Physician’s Choice
    Number of subjects analysed
    404
    198
    Units: Months
        median (confidence interval 95%)
    999 (13.14 to 999)
    14.9 (11.27 to 999)
    Statistical analysis title
    		 Stratified analysis
    Statistical analysis description
    The analysis was stratified for 1) World region (United States, Western Europe, or Other); 2) Number of prior regimens, excluding single-agent hormones, for treatment of metastatic or unresectable locally advanced/recurrent disease (≤ 3 or > 3); and 3) Presence of visceral disease (any visceral disease vs no visceral disease). The hazard ratio was estimated by Cox regression.
    Comparison groups
    Trastuzumab Emtansine v Treatment of Physician’s Choice
    Number of subjects included in analysis
    602
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.0034 [2]
    Method
    		 Logrank
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.552
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.369
         upper limit
    		 0.826
    Notes
    [2] - The 2-sided stratified log-rank test was used at the overall two-sided significance level of 4.5%. The pre-specified O’Brien-Fleming stopping boundary for this first OS interim analysis was HR<0.363 (p-value < 0.0000013).

    Secondary: Percentage of Subjects With an Objective Response

    		 Close Top of page
    End point title
    		 Percentage of Subjects With an Objective Response
    End point description
    An objective response was defined as a complete or partial response determined on 2 consecutive occasions ≥ 4 weeks apart using Response Evaluation Criteria in Solid Tumors (RECIST) v1.1. Complete response was defined as the disappearance of all target and non-target lesions. Any pathological lymph nodes (whether target or non-target) must be < 10 mm on the short axis. Partial response was defined as at least a 30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum. Participants who had no post-baseline tumor assessment were counted as non-responders. Randomized population: All subjects who were randomized to the study. Only subjects with measurable disease at Baseline were included in the analysis. Subjects were included in the treatment group to which they were randomized.
    End point type
    Secondary
    End point timeframe
    Baseline to the clinical cut-off date of 11 Feb 2013 (up to 2 years)
    End point values
    		 Trastuzumab Emtansine Treatment of Physician’s Choice
    Number of subjects analysed
    345
    163
    Units: Percentage of Subjects
        number (confidence interval 95%)
    31.3 (26.5 to 36.5)
    8.6 (5.1 to 13.8)
    Statistical analysis title
    		 Stratified analysis
    Statistical analysis description
    The analysis was stratified for 1) World region (United States, Western Europe, or Other); 2) Number of prior regimens, excluding single-agent hormones, for treatment of metastatic or unresectable locally advanced/recurrent disease (≤ 3 or > 3); and 3) Presence of visceral disease (any visceral disease vs no visceral disease).
    Comparison groups
    Treatment of Physician’s Choice v Trastuzumab Emtansine
    Number of subjects included in analysis
    508
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 < 0.0001
    Method
    		 Mantel-Haenszel
    Parameter type
    		 Difference in Response Percentage
    Point estimate
    22.7
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 16.2
         upper limit
    		 29.2

    Secondary: Duration of the Objective Response

    		 Close Top of page
    End point title
    		 Duration of the Objective Response
    End point description
    Duration of the objective response was defined as the time from the first tumor assessment that was judged to indicate that the subject had an objective response to the time of first documented disease progression using RECIST v1.1 per investigator assessment or death from any cause, whichever occurred first. Randomized population: All subjects who were randomized to the study. Only subjects with an objective response were included in the analysis. Subjects were included in the treatment group to which they were randomized. 999 = The median and the upper confidence interval value could not be estimated due to too few events.
    End point type
    Secondary
    End point timeframe
    Baseline to the clinical cut-off date of 11 Feb 2013 (up to 2 years)
    End point values
    		 Trastuzumab Emtansine Treatment of Physician’s Choice
    Number of subjects analysed
    108
    14
    Units: Months
        median (confidence interval 95%)
    9.7 (6.6 to 10.51)
    999 (2.4 to 999)
    No statistical analyses for this end point

    Secondary: 6-month and 1-year Survival

    		 Close Top of page
    End point title
    		 6-month and 1-year Survival
    End point description
    6-month and 1-year survival were defined as the percentage of subjects who were alive at 6 months and 1 year, respectively, as estimated using Kaplan-Meier method. Randomized population: All subjects who were randomized to the study. Subjects were included in the treatment group to which they were randomized.
    End point type
    Secondary
    End point timeframe
    Baseline to the clinical cut-off date of 11 Feb 2013 (up to 2 years)
    End point values
    		 Trastuzumab Emtansine Treatment of Physician’s Choice
    Number of subjects analysed
    404
    198
    Units: Percentage of Subjects
    number (confidence interval 95%)
        6-Month Survival
    90.9 (87.79 to 94.01)
    78.3 (71.49 to 85.19)
        1-Year Survival
    68.6 (59.91 to 77.28)
    56.9 (42.22 to 71.63)
    Statistical analysis title
    		 Difference in Survival Percentage (6 month)
    Comparison groups
    Trastuzumab Emtansine v Treatment of Physician’s Choice
    Number of subjects included in analysis
    602
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.0011 [3]
    Method
    		 z-test
    Parameter type
    		 Difference in Survival Percentage
    Point estimate
    12.6
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 5.03
         upper limit
    		 20.09
    Notes
    [3] - The p-value for the difference in survival rate was derived from the z-test using the standard errors computed using Greenwood`s method.
    Statistical analysis title
    		 Difference in Survival Percentage (1 year)
    Comparison groups
    Trastuzumab Emtansine v Treatment of Physician’s Choice
    Number of subjects included in analysis
    602
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.1805 [4]
    Method
    		 z-test
    Parameter type
    		 Difference in Survival Percentage
    Point estimate
    11.7
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -5.41
         upper limit
    		 28.75
    Notes
    [4] - The p-value for the difference in survival rates was derived from the z-test using the standard errors computed using Greenwood`s method.

    Secondary: Time to Pain Symptom Progression

    		 Close Top of page
    End point title
    		 Time to Pain Symptom Progression
    End point description
    Time to pain symptom progression was defined as the time from randomization to the first documentation of an increase in narcotic use and/or a 10 point increase from Baseline in the pain score as measured by the European Organisation for Research and Treatment of Cancer, Quality of Life Questionnaire for patients with bone metastases (EORTC QLQ-BM22). The EORTC QLQ-BM22 assesses the symptoms of bone metastases using 22 items: 5 items for sites of pain, 3 pain characteristics, 8 functional interference aspects, and 6 psychosocial aspects. The pain score was derived from the 3 pain characteristic items. Each item was rated on a 4-point scale, where 1=Not at all to 4=Very much. The pain score was the sum of the 3 pain characteristic scores and was normalized to a scale of 0 to 100. A higher score indicates greater pain. Subjects with Baseline pain score and ≥1 post-baseline pain score were included. Subjects were included in the treatment group to which they were randomized.
    End point type
    Secondary
    End point timeframe
    Baseline to the clinical cut-off date of 11 Feb 2013 (up to 2 years)
    End point values
    		 Trastuzumab Emtansine Treatment of Physician’s Choice
    Number of subjects analysed
    297
    117
    Units: Months
        median (confidence interval 95%)
    2.9 (2.2 to 3.7)
    3.6 (2.7 to 4.5)
    Statistical analysis title
    		 Stratified analysis
    Statistical analysis description
    The analysis was stratified for 1) World region (United States, Western Europe, or Other); 2) Number of prior regimens, excluding single-agent hormones, for treatment of metastatic or unresectable locally advanced/recurrent disease (≤ 3 or > 3); and 3) Presence of visceral disease (any visceral disease vs no visceral disease).
    Comparison groups
    Treatment of Physician’s Choice v Trastuzumab Emtansine
    Number of subjects included in analysis
    414
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.4952
    Method
    		 Logrank
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    1.115
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.819
         upper limit
    		 1.517

    Secondary: Change From Baseline in the EORTC QLQ-BM22 Pain Score on Day 1 of Each Cycle

    		 Close Top of page
    End point title
    		 Change From Baseline in the EORTC QLQ-BM22 Pain Score on Day 1 of Each Cycle
    End point description
    The EORTC QLQ-BM22 assesses the symptoms of bone metastases using 22 items: 5 items for sites of pain, 3 pain characteristics, 8 functional interference aspects, and 6 psychosocial aspects. The pain score was derived from the 3 pain characteristic items. Each item was rated on a 4-point scale, where 1=Not at all to 4=Very much. The pain score was the sum of the 3 pain characteristic scores and was normalized to a scale of 0 to 100. A higher score indicates greater pain. A negative change score indicates improvement. Randomized population: All subjects who were randomized to the study. Only subjects with a Baseline pain score and at least 1 post-baseline pain score were included in the analysis. Subjects were included in the treatment group to which they were randomized. Here, 999 signifies that there were no participants with available data.
    End point type
    Secondary
    End point timeframe
    Baseline to the clinical cut-off date of 11 Feb 2013 (up to 2 years)
    End point values
    		 Trastuzumab Emtansine Treatment of Physician’s Choice
    Number of subjects analysed
    297
    117
    Units: Units on a scale
    arithmetic mean (standard deviation)
        Cycle 2 (n=282,98)
    -3.4 ± 21.1
    -9.4 ± 22.1
        Cycle 3 (n=257,86)
    -4.6 ± 21.1
    -6.1 ± 21.4
        Cycle 4 (n=236,74)
    -4.8 ± 19.6
    -3.8 ± 24.1
        Cycle 5 (n=224,54)
    -6.6 ± 22.8
    -2.7 ± 18.9
        Cycle 6 (n=195,42)
    -4.8 ± 23.5
    2.4 ± 17.1
        Cycle 7 (n=163,30)
    -4.2 ± 23.8
    -1.5 ± 15.6
        Cycle 8 (n=130,20)
    -7 ± 21
    2.2 ± 18.6
        Cycle 9 (n=97,15)
    -5.8 ± 22.2
    6.7 ± 20.1
        Cycle 10 (n=80,7)
    -8.9 ± 21.2
    1.6 ± 11.9
        Cycle 11 (n=56,8)
    -10.5 ± 23.1
    0 ± 8.4
        Cycle 12 (n=48,7)
    -11.3 ± 25.8
    1.6 ± 7.7
        Cycle 13 (n=40,5)
    -10 ± 23.3
    2.2 ± 12.2
        Cycle 14 (n=33,5)
    -10.1 ± 21.8
    0 ± 7.9
        Cycle 15 (n=27,3)
    -13.2 ± 22
    0 ± 0
        Cycle 16 (n=19,3)
    -12.3 ± 19.6
    -3.7 ± 6.4
        Cycle 17 (n=15,2)
    -7.4 ± 22.9
    -5.6 ± 7.9
        Cycle 18 (n=11,0)
    -9.1 ± 12
    999 ± 999
        Cycle 19 (n=8,0)
    1.4 ± 9.3
    999 ± 999
        Cycle 20 (n=4,0)
    -5.6 ± 23.1
    999 ± 999
        Cycle 21 (n=3,0)
    -3.7 ± 6.4
    999 ± 999
        Termination Visit (n=84,37)
    -1.6 ± 21.8
    -9 ± 23.3
    No statistical analyses for this end point

    Secondary: Overall Survival (Final Analysis)

    		 Close Top of page
    End point title
    		 Overall Survival (Final Analysis)
    End point description
    Overall survival was defined as the time from randomization to death from any cause. Randomized population: All subjects who were randomized to the study. Subjects were included in the treatment group to which they were randomized.
    End point type
    Secondary
    End point timeframe
    Baseline to the clinical cut-off date of 13 Feb 2015 (up to 4 years)
    End point values
    		 Trastuzumab Emtansine Treatment of Physician’s Choice
    Number of subjects analysed
    404
    198
    Units: Months
        median (confidence interval 95%)
    22.7 (19.35 to 27.47)
    15.8 (13.5 to 18.66)
    Statistical analysis title
    		 Stratified analysis
    Statistical analysis description
    The analysis was stratified for 1) World region (United States, Western Europe, or Other); 2) Number of prior regimens, excluding single-agent hormones, for treatment of metastatic or unresectable locally advanced/recurrent disease (≤ 3 or > 3); and 3) Presence of visceral disease (any visceral disease vs no visceral disease). The hazard ratio was estimated by Cox regression.
    Comparison groups
    Trastuzumab Emtansine v Treatment of Physician’s Choice
    Number of subjects included in analysis
    602
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.0007 [5]
    Method
    		 Logrank
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.677
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.539
         upper limit
    		 0.85
    Notes
    [5] - The two-sided stratified log-rank test was used at the overall two-sided significance level of 4.5%. The pre-specified O’Brien-Fleming stopping boundary for this second and final interim analysis was HR<0.748 (p value < 0.012).

    Secondary: 6-month and 1-year Survival (Final Analysis)

    		 Close Top of page
    End point title
    		 6-month and 1-year Survival (Final Analysis)
    End point description
    6-month and 1-year survival were defined as the percentage of subjects who were alive at 6 months and 1 year, respectively, as estimated using Kaplan-Meier method. Randomized population: All subjects who were randomized to the study. Subjects were included in the treatment group to which they were randomized.
    End point type
    Secondary
    End point timeframe
    Baseline to the clinical cut-off date of 13 Feb 2015 (up to 4 years)
    End point values
    		 Trastuzumab Emtansine Treatment of Physician’s Choice
    Number of subjects analysed
    404
    198
    Units: Percentage of subjects
    number (confidence interval 95%)
        6-Month Survival
    91.3 (88.52 to 94.11)
    78.9 (72.78 to 85.04)
        1-Year Survival
    76.5 (72.23 to 80.79)
    65.6 (58.36 to 72.76)
    Statistical analysis title
    		 Difference in Survival Percentage (6 month)
    Comparison groups
    Treatment of Physician’s Choice v Trastuzumab Emtansine
    Number of subjects included in analysis
    602
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.0003 [6]
    Method
    		 z-test
    Parameter type
    		 Difference in Survival Percentage
    Point estimate
    12.4
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 5.67
         upper limit
    		 19.14
    Notes
    [6] - The p-value for the difference in survival rate was derived from the z-test using the standard errors computed using Greenwood`s method.
    Statistical analysis title
    		 Difference in Survival Percentage (1 year)
    Comparison groups
    Trastuzumab Emtansine v Treatment of Physician’s Choice
    Number of subjects included in analysis
    602
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.0104 [7]
    Method
    		 z-test
    Parameter type
    		 Difference in Survival Percentage
    Point estimate
    11
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 2.58
         upper limit
    		 19.33
    Notes
    [7] - The p-value for the difference in survival rate was derived from the z-test using the standard errors computed using Greenwood`s method.

    Adverse events

    		 Close Top of page
    Adverse events information
    Timeframe for reporting adverse events
    Adverse events were collected from treatment initiation until 30 days following the last administration of study treatment or study discontinuation on 31 August 2015 (up to approximately 4 years).
    Adverse event reporting additional description
    Safety population: All subjects who received any amount of planned study treatment, according to treatment actually received. Data for subjects in the Treatment of Physician's Choice (TPC) arm who switched treatment to receive trastuzumab emtansine following disease progression on TPC are presented separately.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    18.0
    Reporting groups
    Reporting group title
    Trastuzumab Emtansine
    Reporting group description
    		 Trastuzumab emtansine 3.6 mg/kg intravenously every 3 weeks until disease progression (as assessed by the investigator) or unmanageable toxicity.

    Reporting group title
    Treatment of Physician’s Choice (TPC)
    Reporting group description
    		 Treatment of physician's choice (TPC) until disease progression (as assessed by the investigator) or unmanageable toxicity. The treatments included single-agent chemotherapy, single-agent or dual-agent hormonal therapy for hormone receptor positive-disease, and HER2-directed therapy.

    Reporting group title
    Trastuzumab Emtansine - Post TPC Treatment Switch
    Reporting group description
    		 Subjects, who switched treatment in the Treatment of Physician’s Choice arm to trastuzumab emtansine, were administered trastuzumab emtansine 3.6 mg/kg intravenously every 3 weeks until disease progression (as assessed by the investigator) or unmanageable toxicity.

    Serious adverse events
    		 Trastuzumab Emtansine Treatment of Physician’s Choice (TPC) Trastuzumab Emtansine - Post TPC Treatment Switch
    Total subjects affected by serious adverse events
         subjects affected / exposed
    102 / 403 (25.31%)
    41 / 184 (22.28%)
    19 / 94 (20.21%)
         number of deaths (all causes)
    247
    67
    55
         number of deaths resulting from adverse events
    3
    1
    1
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Rectal adenocarcinoma
         subjects affected / exposed
    1 / 403 (0.25%)
    0 / 184 (0.00%)
    0 / 94 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Tumour haemorrhage
         subjects affected / exposed
    2 / 403 (0.50%)
    0 / 184 (0.00%)
    0 / 94 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Tumour pain
         subjects affected / exposed
    0 / 403 (0.00%)
    1 / 184 (0.54%)
    0 / 94 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Tumour necrosis
         subjects affected / exposed
    0 / 403 (0.00%)
    0 / 184 (0.00%)
    1 / 94 (1.06%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Vascular disorders
    Deep vein thrombosis
         subjects affected / exposed
    2 / 403 (0.50%)
    0 / 184 (0.00%)
    0 / 94 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Embolism
         subjects affected / exposed
    1 / 403 (0.25%)
    0 / 184 (0.00%)
    0 / 94 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Embolism venous
         subjects affected / exposed
    0 / 403 (0.00%)
    1 / 184 (0.54%)
    0 / 94 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hypertensive crisis
         subjects affected / exposed
    1 / 403 (0.25%)
    0 / 184 (0.00%)
    0 / 94 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hypotension
         subjects affected / exposed
    1 / 403 (0.25%)
    0 / 184 (0.00%)
    0 / 94 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Lymphoedema
         subjects affected / exposed
    0 / 403 (0.00%)
    1 / 184 (0.54%)
    1 / 94 (1.06%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Superior vena cava syndrome
         subjects affected / exposed
    1 / 403 (0.25%)
    0 / 184 (0.00%)
    0 / 94 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Adverse drug reaction
         subjects affected / exposed
    1 / 403 (0.25%)
    0 / 184 (0.00%)
    0 / 94 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Asthenia
         subjects affected / exposed
    3 / 403 (0.74%)
    0 / 184 (0.00%)
    0 / 94 (0.00%)
         occurrences causally related to treatment / all
    1 / 3
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Death
         subjects affected / exposed
    1 / 403 (0.25%)
    0 / 184 (0.00%)
    0 / 94 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    Device occlusion
         subjects affected / exposed
    1 / 403 (0.25%)
    0 / 184 (0.00%)
    0 / 94 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Fatigue
         subjects affected / exposed
    1 / 403 (0.25%)
    1 / 184 (0.54%)
    0 / 94 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    General physical health deterioration
         subjects affected / exposed
    1 / 403 (0.25%)
    0 / 184 (0.00%)
    0 / 94 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Malaise
         subjects affected / exposed
    2 / 403 (0.50%)
    0 / 184 (0.00%)
    0 / 94 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Non-cardiac chest pain
         subjects affected / exposed
    0 / 403 (0.00%)
    1 / 184 (0.54%)
    0 / 94 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Oedema peripheral
         subjects affected / exposed
    2 / 403 (0.50%)
    2 / 184 (1.09%)
    0 / 94 (0.00%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pain
         subjects affected / exposed
    0 / 403 (0.00%)
    1 / 184 (0.54%)
    0 / 94 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pyrexia
         subjects affected / exposed
    7 / 403 (1.74%)
    2 / 184 (1.09%)
    1 / 94 (1.06%)
         occurrences causally related to treatment / all
    3 / 7
    1 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Vessel puncture site haemorrhage
         subjects affected / exposed
    1 / 403 (0.25%)
    0 / 184 (0.00%)
    0 / 94 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Immune system disorders
    Drug hypersensitivity
         subjects affected / exposed
    0 / 403 (0.00%)
    1 / 184 (0.54%)
    0 / 94 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hypersensitivity
         subjects affected / exposed
    1 / 403 (0.25%)
    0 / 184 (0.00%)
    1 / 94 (1.06%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Reproductive system and breast disorders
    Vaginal haemorrhage
         subjects affected / exposed
    2 / 403 (0.50%)
    0 / 184 (0.00%)
    0 / 94 (0.00%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Dyspnoea
         subjects affected / exposed
    6 / 403 (1.49%)
    5 / 184 (2.72%)
    2 / 94 (2.13%)
         occurrences causally related to treatment / all
    2 / 7
    0 / 7
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Epistaxis
         subjects affected / exposed
    1 / 403 (0.25%)
    0 / 184 (0.00%)
    0 / 94 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Haemoptysis
         subjects affected / exposed
    1 / 403 (0.25%)
    0 / 184 (0.00%)
    0 / 94 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Non-cardiogenic pulmonary oedema
         subjects affected / exposed
    0 / 403 (0.00%)
    1 / 184 (0.54%)
    0 / 94 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    Obliterative bronchiolitis
         subjects affected / exposed
    1 / 403 (0.25%)
    0 / 184 (0.00%)
    0 / 94 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pleural effusion
         subjects affected / exposed
    3 / 403 (0.74%)
    2 / 184 (1.09%)
    0 / 94 (0.00%)
         occurrences causally related to treatment / all
    0 / 3
    1 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pleuritic pain
         subjects affected / exposed
    1 / 403 (0.25%)
    0 / 184 (0.00%)
    0 / 94 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pneumonia aspiration
         subjects affected / exposed
    1 / 403 (0.25%)
    0 / 184 (0.00%)
    0 / 94 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pneumonitis
         subjects affected / exposed
    2 / 403 (0.50%)
    1 / 184 (0.54%)
    0 / 94 (0.00%)
         occurrences causally related to treatment / all
    1 / 2
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    Pneumothorax
         subjects affected / exposed
    1 / 403 (0.25%)
    1 / 184 (0.54%)
    0 / 94 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pulmonary embolism
         subjects affected / exposed
    1 / 403 (0.25%)
    2 / 184 (1.09%)
    1 / 94 (1.06%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    Respiratory failure
         subjects affected / exposed
    1 / 403 (0.25%)
    0 / 184 (0.00%)
    0 / 94 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pulmonary fibrosis
         subjects affected / exposed
    0 / 403 (0.00%)
    0 / 184 (0.00%)
    1 / 94 (1.06%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Psychiatric disorders
    Confusional state
         subjects affected / exposed
    1 / 403 (0.25%)
    0 / 184 (0.00%)
    0 / 94 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Investigations
    Transaminases increased
         subjects affected / exposed
    1 / 403 (0.25%)
    0 / 184 (0.00%)
    0 / 94 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    White blood cell count decreased
         subjects affected / exposed
    0 / 403 (0.00%)
    1 / 184 (0.54%)
    0 / 94 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Fall
         subjects affected / exposed
    2 / 403 (0.50%)
    0 / 184 (0.00%)
    0 / 94 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Femoral neck fracture
         subjects affected / exposed
    2 / 403 (0.50%)
    0 / 184 (0.00%)
    0 / 94 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Femur fracture
         subjects affected / exposed
    1 / 403 (0.25%)
    0 / 184 (0.00%)
    0 / 94 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Infusion related reaction
         subjects affected / exposed
    1 / 403 (0.25%)
    1 / 184 (0.54%)
    0 / 94 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Sternal fracture
         subjects affected / exposed
    1 / 403 (0.25%)
    0 / 184 (0.00%)
    0 / 94 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Subdural haematoma
         subjects affected / exposed
    2 / 403 (0.50%)
    0 / 184 (0.00%)
    0 / 94 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Subdural haemorrhage
         subjects affected / exposed
    1 / 403 (0.25%)
    0 / 184 (0.00%)
    0 / 94 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Thoracic vertebral fracture
         subjects affected / exposed
    1 / 403 (0.25%)
    0 / 184 (0.00%)
    0 / 94 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Traumatic intracranial haemorrhage
         subjects affected / exposed
    1 / 403 (0.25%)
    0 / 184 (0.00%)
    0 / 94 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Wound decomposition
         subjects affected / exposed
    0 / 403 (0.00%)
    1 / 184 (0.54%)
    0 / 94 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Wound haemorrhage
         subjects affected / exposed
    1 / 403 (0.25%)
    1 / 184 (0.54%)
    0 / 94 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Toxicity to various agents
         subjects affected / exposed
    0 / 403 (0.00%)
    0 / 184 (0.00%)
    1 / 94 (1.06%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Upper limb fracture
         subjects affected / exposed
    0 / 403 (0.00%)
    0 / 184 (0.00%)
    1 / 94 (1.06%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cardiac disorders
    Cardiac failure
         subjects affected / exposed
    1 / 403 (0.25%)
    0 / 184 (0.00%)
    0 / 94 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Nervous system disorders
    Ataxia
         subjects affected / exposed
    1 / 403 (0.25%)
    1 / 184 (0.54%)
    0 / 94 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Brain oedema
         subjects affected / exposed
    1 / 403 (0.25%)
    0 / 184 (0.00%)
    0 / 94 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cerebral haematoma
         subjects affected / exposed
    1 / 403 (0.25%)
    0 / 184 (0.00%)
    0 / 94 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cerebral haemorrhage
         subjects affected / exposed
    2 / 403 (0.50%)
    0 / 184 (0.00%)
    0 / 94 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cognitive disorder
         subjects affected / exposed
    0 / 403 (0.00%)
    1 / 184 (0.54%)
    0 / 94 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Depressed level of consciousness
         subjects affected / exposed
    1 / 403 (0.25%)
    0 / 184 (0.00%)
    0 / 94 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Dizziness
         subjects affected / exposed
    1 / 403 (0.25%)
    0 / 184 (0.00%)
    0 / 94 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Haemorrhage intracranial
         subjects affected / exposed
    1 / 403 (0.25%)
    0 / 184 (0.00%)
    0 / 94 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hepatic encephalopathy
         subjects affected / exposed
    1 / 403 (0.25%)
    0 / 184 (0.00%)
    0 / 94 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    Loss of consciousness
         subjects affected / exposed
    1 / 403 (0.25%)
    0 / 184 (0.00%)
    0 / 94 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Paraesthesia
         subjects affected / exposed
    0 / 403 (0.00%)
    1 / 184 (0.54%)
    0 / 94 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Paraparesis
         subjects affected / exposed
    0 / 403 (0.00%)
    1 / 184 (0.54%)
    0 / 94 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Seizure
         subjects affected / exposed
    5 / 403 (1.24%)
    0 / 184 (0.00%)
    1 / 94 (1.06%)
         occurrences causally related to treatment / all
    0 / 10
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Somnolence
         subjects affected / exposed
    1 / 403 (0.25%)
    0 / 184 (0.00%)
    0 / 94 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Subarachnoid haemorrhage
         subjects affected / exposed
    1 / 403 (0.25%)
    0 / 184 (0.00%)
    0 / 94 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    Transient ischaemic attack
         subjects affected / exposed
    1 / 403 (0.25%)
    0 / 184 (0.00%)
    0 / 94 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Visual field defect
         subjects affected / exposed
    1 / 403 (0.25%)
    0 / 184 (0.00%)
    0 / 94 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Epilepsy
         subjects affected / exposed
    0 / 403 (0.00%)
    0 / 184 (0.00%)
    1 / 94 (1.06%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hemiplegia
         subjects affected / exposed
    0 / 403 (0.00%)
    0 / 184 (0.00%)
    1 / 94 (1.06%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    1 / 403 (0.25%)
    2 / 184 (1.09%)
    1 / 94 (1.06%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Febrile neutropenia
         subjects affected / exposed
    1 / 403 (0.25%)
    7 / 184 (3.80%)
    0 / 94 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    6 / 7
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Granulocytopenia
         subjects affected / exposed
    0 / 403 (0.00%)
    1 / 184 (0.54%)
    0 / 94 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Neutropenia
         subjects affected / exposed
    1 / 403 (0.25%)
    2 / 184 (1.09%)
    0 / 94 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    2 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Thrombocytopenia
         subjects affected / exposed
    1 / 403 (0.25%)
    1 / 184 (0.54%)
    0 / 94 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Ear and labyrinth disorders
    Vertigo
         subjects affected / exposed
    1 / 403 (0.25%)
    0 / 184 (0.00%)
    0 / 94 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Eye disorders
    Vision blurred
         subjects affected / exposed
    1 / 403 (0.25%)
    0 / 184 (0.00%)
    0 / 94 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Abdominal discomfort
         subjects affected / exposed
    0 / 403 (0.00%)
    1 / 184 (0.54%)
    0 / 94 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Abdominal pain
         subjects affected / exposed
    4 / 403 (0.99%)
    3 / 184 (1.63%)
    1 / 94 (1.06%)
         occurrences causally related to treatment / all
    0 / 6
    0 / 4
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Abdominal pain upper
         subjects affected / exposed
    0 / 403 (0.00%)
    1 / 184 (0.54%)
    0 / 94 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Abdominal wall haematoma
         subjects affected / exposed
    1 / 403 (0.25%)
    0 / 184 (0.00%)
    0 / 94 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Colitis
         subjects affected / exposed
    2 / 403 (0.50%)
    0 / 184 (0.00%)
    0 / 94 (0.00%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Diarrhoea
         subjects affected / exposed
    2 / 403 (0.50%)
    1 / 184 (0.54%)
    0 / 94 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Gastric haemorrhage
         subjects affected / exposed
    1 / 403 (0.25%)
    0 / 184 (0.00%)
    0 / 94 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Ileus
         subjects affected / exposed
    1 / 403 (0.25%)
    0 / 184 (0.00%)
    0 / 94 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Nausea
         subjects affected / exposed
    0 / 403 (0.00%)
    2 / 184 (1.09%)
    0 / 94 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Obstruction gastric
         subjects affected / exposed
    1 / 403 (0.25%)
    0 / 184 (0.00%)
    0 / 94 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pancreatitis
         subjects affected / exposed
    1 / 403 (0.25%)
    0 / 184 (0.00%)
    0 / 94 (0.00%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Proctitis haemorrhagic
         subjects affected / exposed
    1 / 403 (0.25%)
    0 / 184 (0.00%)
    0 / 94 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Small intestinal obstruction
         subjects affected / exposed
    1 / 403 (0.25%)
    0 / 184 (0.00%)
    0 / 94 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Upper gastrointestinal haemorrhage
         subjects affected / exposed
    0 / 403 (0.00%)
    1 / 184 (0.54%)
    1 / 94 (1.06%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    Vomiting
         subjects affected / exposed
    2 / 403 (0.50%)
    2 / 184 (1.09%)
    0 / 94 (0.00%)
         occurrences causally related to treatment / all
    1 / 2
    2 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hepatobiliary disorders
    Bile duct obstruction
         subjects affected / exposed
    1 / 403 (0.25%)
    1 / 184 (0.54%)
    0 / 94 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cholangitis
         subjects affected / exposed
    1 / 403 (0.25%)
    0 / 184 (0.00%)
    0 / 94 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cholecystitis
         subjects affected / exposed
    1 / 403 (0.25%)
    0 / 184 (0.00%)
    0 / 94 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Nodular regenerative hyperplasia
         subjects affected / exposed
    3 / 403 (0.74%)
    0 / 184 (0.00%)
    0 / 94 (0.00%)
         occurrences causally related to treatment / all
    3 / 3
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hepatotoxicity
         subjects affected / exposed
    0 / 403 (0.00%)
    0 / 184 (0.00%)
    1 / 94 (1.06%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Renal and urinary disorders
    Haematuria
         subjects affected / exposed
    1 / 403 (0.25%)
    1 / 184 (0.54%)
    0 / 94 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Endocrine disorders
    Hypercalcaemia of malignancy
         subjects affected / exposed
    0 / 403 (0.00%)
    1 / 184 (0.54%)
    0 / 94 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    1 / 403 (0.25%)
    0 / 184 (0.00%)
    0 / 94 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Back pain
         subjects affected / exposed
    2 / 403 (0.50%)
    0 / 184 (0.00%)
    0 / 94 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Bone pain
         subjects affected / exposed
    0 / 403 (0.00%)
    1 / 184 (0.54%)
    0 / 94 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Muscle haemorrhage
         subjects affected / exposed
    1 / 403 (0.25%)
    0 / 184 (0.00%)
    0 / 94 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Musculoskeletal chest pain
         subjects affected / exposed
    1 / 403 (0.25%)
    1 / 184 (0.54%)
    0 / 94 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Myalgia
         subjects affected / exposed
    0 / 403 (0.00%)
    1 / 184 (0.54%)
    0 / 94 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Spinal pain
         subjects affected / exposed
    1 / 403 (0.25%)
    0 / 184 (0.00%)
    0 / 94 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Muscular weakness
         subjects affected / exposed
    0 / 403 (0.00%)
    0 / 184 (0.00%)
    1 / 94 (1.06%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Infections and infestations
    Appendicitis
         subjects affected / exposed
    1 / 403 (0.25%)
    0 / 184 (0.00%)
    0 / 94 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Bronchopneumonia
         subjects affected / exposed
    1 / 403 (0.25%)
    0 / 184 (0.00%)
    0 / 94 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    Cellulitis
         subjects affected / exposed
    2 / 403 (0.50%)
    4 / 184 (2.17%)
    1 / 94 (1.06%)
         occurrences causally related to treatment / all
    2 / 4
    0 / 4
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Clostridium bacteraemia
         subjects affected / exposed
    0 / 403 (0.00%)
    1 / 184 (0.54%)
    0 / 94 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    Device related infection
         subjects affected / exposed
    1 / 403 (0.25%)
    1 / 184 (0.54%)
    0 / 94 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Device related sepsis
         subjects affected / exposed
    1 / 403 (0.25%)
    0 / 184 (0.00%)
    0 / 94 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Gastroenteritis
         subjects affected / exposed
    2 / 403 (0.50%)
    0 / 184 (0.00%)
    0 / 94 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Infected fistula
         subjects affected / exposed
    1 / 403 (0.25%)
    0 / 184 (0.00%)
    0 / 94 (0.00%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Infection
         subjects affected / exposed
    2 / 403 (0.50%)
    0 / 184 (0.00%)
    0 / 94 (0.00%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Infectious colitis
         subjects affected / exposed
    0 / 403 (0.00%)
    1 / 184 (0.54%)
    0 / 94 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Lung infection
         subjects affected / exposed
    1 / 403 (0.25%)
    0 / 184 (0.00%)
    1 / 94 (1.06%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    Lymphangitis
         subjects affected / exposed
    1 / 403 (0.25%)
    0 / 184 (0.00%)
    0 / 94 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Mastitis
         subjects affected / exposed
    0 / 403 (0.00%)
    1 / 184 (0.54%)
    0 / 94 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Neutropenic sepsis
         subjects affected / exposed
    0 / 403 (0.00%)
    1 / 184 (0.54%)
    0 / 94 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pharyngotonsillitis
         subjects affected / exposed
    0 / 403 (0.00%)
    1 / 184 (0.54%)
    0 / 94 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pneumonia
         subjects affected / exposed
    5 / 403 (1.24%)
    0 / 184 (0.00%)
    1 / 94 (1.06%)
         occurrences causally related to treatment / all
    0 / 6
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    Postoperative wound infection
         subjects affected / exposed
    1 / 403 (0.25%)
    0 / 184 (0.00%)
    0 / 94 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Sepsis
         subjects affected / exposed
    3 / 403 (0.74%)
    0 / 184 (0.00%)
    0 / 94 (0.00%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 2
    0 / 0
    0 / 0
    Sinusitis
         subjects affected / exposed
    1 / 403 (0.25%)
    1 / 184 (0.54%)
    0 / 94 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Tracheitis
         subjects affected / exposed
    1 / 403 (0.25%)
    0 / 184 (0.00%)
    0 / 94 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Upper respiratory tract infection
         subjects affected / exposed
    2 / 403 (0.50%)
    0 / 184 (0.00%)
    0 / 94 (0.00%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Urinary tract infection
         subjects affected / exposed
    4 / 403 (0.99%)
    0 / 184 (0.00%)
    0 / 94 (0.00%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Urosepsis
         subjects affected / exposed
    1 / 403 (0.25%)
    0 / 184 (0.00%)
    0 / 94 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Viral upper respiratory tract infection
         subjects affected / exposed
    1 / 403 (0.25%)
    0 / 184 (0.00%)
    0 / 94 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Wound infection
         subjects affected / exposed
    1 / 403 (0.25%)
    0 / 184 (0.00%)
    0 / 94 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Abdominal infection
         subjects affected / exposed
    0 / 403 (0.00%)
    0 / 184 (0.00%)
    1 / 94 (1.06%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Abscess
         subjects affected / exposed
    0 / 403 (0.00%)
    0 / 184 (0.00%)
    1 / 94 (1.06%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Biliary tract infection
         subjects affected / exposed
    0 / 403 (0.00%)
    0 / 184 (0.00%)
    1 / 94 (1.06%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Decreased appetite
         subjects affected / exposed
    1 / 403 (0.25%)
    0 / 184 (0.00%)
    1 / 94 (1.06%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Dehydration
         subjects affected / exposed
    1 / 403 (0.25%)
    0 / 184 (0.00%)
    0 / 94 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hypercalcaemia
         subjects affected / exposed
    1 / 403 (0.25%)
    0 / 184 (0.00%)
    0 / 94 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hyperglycaemia
         subjects affected / exposed
    1 / 403 (0.25%)
    0 / 184 (0.00%)
    0 / 94 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hypokalaemia
         subjects affected / exposed
    1 / 403 (0.25%)
    0 / 184 (0.00%)
    0 / 94 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hyponatraemia
         subjects affected / exposed
    4 / 403 (0.99%)
    0 / 184 (0.00%)
    0 / 94 (0.00%)
         occurrences causally related to treatment / all
    1 / 4
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hypophagia
         subjects affected / exposed
    1 / 403 (0.25%)
    0 / 184 (0.00%)
    0 / 94 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Malnutrition
         subjects affected / exposed
    0 / 403 (0.00%)
    1 / 184 (0.54%)
    0 / 94 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Trastuzumab Emtansine Treatment of Physician’s Choice (TPC) Trastuzumab Emtansine - Post TPC Treatment Switch
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    371 / 403 (92.06%)
    148 / 184 (80.43%)
    74 / 94 (78.72%)
    Investigations
    Alanine aminotransferase increased
         subjects affected / exposed
    38 / 403 (9.43%)
    10 / 184 (5.43%)
    7 / 94 (7.45%)
         occurrences all number
    50
    11
    9
    Aspartate aminotransferase increased
         subjects affected / exposed
    51 / 403 (12.66%)
    13 / 184 (7.07%)
    13 / 94 (13.83%)
         occurrences all number
    64
    13
    15
    Blood alkaline phosphatase increased
         subjects affected / exposed
    21 / 403 (5.21%)
    5 / 184 (2.72%)
    7 / 94 (7.45%)
         occurrences all number
    24
    5
    7
    Blood bilirubin increased
         subjects affected / exposed
    38 / 403 (9.43%)
    2 / 184 (1.09%)
    5 / 94 (5.32%)
         occurrences all number
    50
    2
    8
    Ejection fraction decreased
         subjects affected / exposed
    11 / 403 (2.73%)
    12 / 184 (6.52%)
    0 / 94 (0.00%)
         occurrences all number
    13
    13
    0
    Nervous system disorders
    Dizziness
         subjects affected / exposed
    31 / 403 (7.69%)
    6 / 184 (3.26%)
    6 / 94 (6.38%)
         occurrences all number
    39
    7
    7
    Headache
         subjects affected / exposed
    100 / 403 (24.81%)
    22 / 184 (11.96%)
    16 / 94 (17.02%)
         occurrences all number
    182
    34
    22
    Neuropathy peripheral
         subjects affected / exposed
    20 / 403 (4.96%)
    10 / 184 (5.43%)
    7 / 94 (7.45%)
         occurrences all number
    22
    12
    7
    Paraesthesia
         subjects affected / exposed
    28 / 403 (6.95%)
    11 / 184 (5.98%)
    9 / 94 (9.57%)
         occurrences all number
    31
    12
    10
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    45 / 403 (11.17%)
    19 / 184 (10.33%)
    7 / 94 (7.45%)
         occurrences all number
    60
    22
    10
    Leukopenia
         subjects affected / exposed
    9 / 403 (2.23%)
    11 / 184 (5.98%)
    0 / 94 (0.00%)
         occurrences all number
    20
    11
    0
    Neutropenia
         subjects affected / exposed
    30 / 403 (7.44%)
    39 / 184 (21.20%)
    5 / 94 (5.32%)
         occurrences all number
    81
    84
    8
    Thrombocytopenia
         subjects affected / exposed
    81 / 403 (20.10%)
    6 / 184 (3.26%)
    17 / 94 (18.09%)
         occurrences all number
    167
    17
    25
    General disorders and administration site conditions
    Asthenia
         subjects affected / exposed
    76 / 403 (18.86%)
    33 / 184 (17.93%)
    15 / 94 (15.96%)
         occurrences all number
    136
    44
    23
    Chills
         subjects affected / exposed
    21 / 403 (5.21%)
    4 / 184 (2.17%)
    0 / 94 (0.00%)
         occurrences all number
    26
    4
    0
    Fatigue
         subjects affected / exposed
    123 / 403 (30.52%)
    48 / 184 (26.09%)
    10 / 94 (10.64%)
         occurrences all number
    194
    55
    18
    Influenza like illness
         subjects affected / exposed
    21 / 403 (5.21%)
    2 / 184 (1.09%)
    0 / 94 (0.00%)
         occurrences all number
    27
    2
    0
    Mucosal inflammation
         subjects affected / exposed
    17 / 403 (4.22%)
    10 / 184 (5.43%)
    7 / 94 (7.45%)
         occurrences all number
    19
    16
    9
    Oedema peripheral
         subjects affected / exposed
    26 / 403 (6.45%)
    11 / 184 (5.98%)
    0 / 94 (0.00%)
         occurrences all number
    30
    11
    0
    Pyrexia
         subjects affected / exposed
    77 / 403 (19.11%)
    22 / 184 (11.96%)
    14 / 94 (14.89%)
         occurrences all number
    118
    49
    20
    Pain
         subjects affected / exposed
    0 / 403 (0.00%)
    0 / 184 (0.00%)
    5 / 94 (5.32%)
         occurrences all number
    0
    0
    6
    Eye disorders
    Lacrimation increased
         subjects affected / exposed
    0 / 403 (0.00%)
    0 / 184 (0.00%)
    5 / 94 (5.32%)
         occurrences all number
    0
    0
    6
    Gastrointestinal disorders
    Abdominal pain
         subjects affected / exposed
    27 / 403 (6.70%)
    20 / 184 (10.87%)
    9 / 94 (9.57%)
         occurrences all number
    40
    21
    12
    Constipation
         subjects affected / exposed
    90 / 403 (22.33%)
    32 / 184 (17.39%)
    7 / 94 (7.45%)
         occurrences all number
    129
    35
    11
    Abdominal pain upper
         subjects affected / exposed
    0 / 403 (0.00%)
    0 / 184 (0.00%)
    7 / 94 (7.45%)
         occurrences all number
    0
    0
    8
    Diarrhoea
         subjects affected / exposed
    52 / 403 (12.90%)
    40 / 184 (21.74%)
    10 / 94 (10.64%)
         occurrences all number
    67
    84
    12
    Dry mouth
         subjects affected / exposed
    51 / 403 (12.66%)
    2 / 184 (1.09%)
    9 / 94 (9.57%)
         occurrences all number
    55
    2
    13
    Dyspepsia
         subjects affected / exposed
    21 / 403 (5.21%)
    12 / 184 (6.52%)
    0 / 94 (0.00%)
         occurrences all number
    29
    13
    0
    Gingival bleeding
         subjects affected / exposed
    21 / 403 (5.21%)
    0 / 184 (0.00%)
    0 / 94 (0.00%)
         occurrences all number
    30
    0
    0
    Nausea
         subjects affected / exposed
    144 / 403 (35.73%)
    40 / 184 (21.74%)
    16 / 94 (17.02%)
         occurrences all number
    268
    54
    17
    Stomatitis
         subjects affected / exposed
    13 / 403 (3.23%)
    11 / 184 (5.98%)
    0 / 94 (0.00%)
         occurrences all number
    14
    11
    0
    Vomiting
         subjects affected / exposed
    77 / 403 (19.11%)
    16 / 184 (8.70%)
    10 / 94 (10.64%)
         occurrences all number
    104
    31
    11
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    76 / 403 (18.86%)
    24 / 184 (13.04%)
    12 / 94 (12.77%)
         occurrences all number
    97
    27
    14
    Dyspnoea
         subjects affected / exposed
    42 / 403 (10.42%)
    21 / 184 (11.41%)
    6 / 94 (6.38%)
         occurrences all number
    53
    25
    8
    Epistaxis
         subjects affected / exposed
    67 / 403 (16.63%)
    7 / 184 (3.80%)
    12 / 94 (12.77%)
         occurrences all number
    135
    9
    20
    Skin and subcutaneous tissue disorders
    Alopecia
         subjects affected / exposed
    9 / 403 (2.23%)
    20 / 184 (10.87%)
    0 / 94 (0.00%)
         occurrences all number
    9
    20
    0
    Pruritus
         subjects affected / exposed
    23 / 403 (5.71%)
    17 / 184 (9.24%)
    0 / 94 (0.00%)
         occurrences all number
    29
    18
    0
    Rash
         subjects affected / exposed
    27 / 403 (6.70%)
    19 / 184 (10.33%)
    0 / 94 (0.00%)
         occurrences all number
    30
    20
    0
    Psychiatric disorders
    Insomnia
         subjects affected / exposed
    35 / 403 (8.68%)
    6 / 184 (3.26%)
    8 / 94 (8.51%)
         occurrences all number
    35
    6
    8
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    60 / 403 (14.89%)
    8 / 184 (4.35%)
    7 / 94 (7.45%)
         occurrences all number
    75
    9
    8
    Back pain
         subjects affected / exposed
    35 / 403 (8.68%)
    13 / 184 (7.07%)
    6 / 94 (6.38%)
         occurrences all number
    40
    15
    6
    Bone pain
         subjects affected / exposed
    22 / 403 (5.46%)
    7 / 184 (3.80%)
    0 / 94 (0.00%)
         occurrences all number
    32
    7
    0
    Muscle spasms
         subjects affected / exposed
    26 / 403 (6.45%)
    9 / 184 (4.89%)
    0 / 94 (0.00%)
         occurrences all number
    39
    9
    0
    Musculoskeletal pain
         subjects affected / exposed
    18 / 403 (4.47%)
    10 / 184 (5.43%)
    7 / 94 (7.45%)
         occurrences all number
    22
    11
    9
    Myalgia
         subjects affected / exposed
    47 / 403 (11.66%)
    14 / 184 (7.61%)
    6 / 94 (6.38%)
         occurrences all number
    83
    17
    6
    Pain in extremity
         subjects affected / exposed
    44 / 403 (10.92%)
    9 / 184 (4.89%)
    0 / 94 (0.00%)
         occurrences all number
    54
    10
    0
    Infections and infestations
    Nasopharyngitis
         subjects affected / exposed
    35 / 403 (8.68%)
    12 / 184 (6.52%)
    6 / 94 (6.38%)
         occurrences all number
    45
    12
    7
    Upper respiratory tract infection
         subjects affected / exposed
    35 / 403 (8.68%)
    8 / 184 (4.35%)
    8 / 94 (8.51%)
         occurrences all number
    51
    11
    9
    Urinary tract infection
         subjects affected / exposed
    26 / 403 (6.45%)
    7 / 184 (3.80%)
    9 / 94 (9.57%)
         occurrences all number
    37
    15
    12
    Sinusitis
         subjects affected / exposed
    0 / 403 (0.00%)
    0 / 184 (0.00%)
    5 / 94 (5.32%)
         occurrences all number
    0
    0
    5
    Metabolism and nutrition disorders
    Decreased appetite
         subjects affected / exposed
    66 / 403 (16.38%)
    25 / 184 (13.59%)
    15 / 94 (15.96%)
         occurrences all number
    85
    30
    19
    Hypokalaemia
         subjects affected / exposed
    30 / 403 (7.44%)
    4 / 184 (2.17%)
    6 / 94 (6.38%)
         occurrences all number
    39
    4
    6
    Hyperglycaemia
         subjects affected / exposed
    0 / 403 (0.00%)
    0 / 184 (0.00%)
    5 / 94 (5.32%)
         occurrences all number
    0
    0
    7

    More information

    		 Close Top of page

    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    16 Dec 2011
    The inclusion criteria were modified as follows: 1) screening requirements were added for subjects with a history of bilateral breast cancer, 2) the maximum total bilirubin was changed to a direct bilirubin upper limit of normal for subjects with documented Gilbert’s syndrome, 3) to ensure that subjects, who had a history of or newly diagnosed brain metastases, were not enrolled after only receiving prior systemic therapy without localised treatment. To conduct screening tumor assessments (computed tomography [CT]/magnetic resonance imaging and bone scans) within 28 days prior to randomization to align with the Response Evaluation Criteria in Solid Tumors guidelines Version 1.1. This amendment also modified the required tumor assessment interval to every 12 weeks (±7 days) for subjects in either treatment arm who had remained on a stable dose of study treatment with a maintained clinical response of stable disease (SD) or better at least 54 weeks after randomization. To clarify that patients who develop isolated progression in the brain but have systemic control of disease would be allowed to continue study treatment after localized treatment of brain metastasis. To clarify acceptable options and provide examples for the treatment of physician's choice (TPC). The dose modification criteria for trastuzumab emtansine were adjusted for thrombocytopenia and hepatotoxicity.
    16 May 2012
    The eligibility criteria were modified as follows: 1) removed the requirements for prior anthracycline and capecitabine, 2) removed the requirements around prior hormonal therapy, 3) shortened the time from treatment of brain metastases from 2 months to 1 month, 4) removed the specification that no more than 25% of a patient’s bone marrow has received radiotherapy. Clarified that, in the control group with subjects receiving TPC, a combination of two agents maximum is allowed, except doublet chemotherapies. Clarified the doses of trastuzumab emtansine administered at cycles following the first cycle depend on the subject’s weight variability. Clarified guidance around discontinuation or dose modification of trastuzumab emtansine. Clarified that subjects may withdraw from study treatment but still consent to follow-up for overall survival.
    17 Sep 2012
    The co-primary efficacy endpoints were changed from objective response rate (ORR) and overall survival (OS) to progression-free-survival (PFS) per investigator assessment and OS. ORR became a secondary efficacy endpoint. The sample size was reduced from 795 to 600 subjects. Independent review of tumor assessments was removed. One additional OS interim analysis was added. The secondary endpoint of clinical benefit rate was removed. Additional efficacy and safety analyses were added for subjects in the TPC arm who receive trastuzumab emtansine treatment after disease progression. The independent Data Monitoring Committee (iDMC) safety data review was to continue until the primary PFS analysis. To ensure the safety of subjects who wish to switch from TPC treatment to trastuzumab emtansine, specific eligibility criteria must be met prior to administration of their first dose of trastuzumab emtansine. The safety plan for subjects receiving trastuzumab emtansine arm was modified to reflect clinical experience with trastuzumab emtansine in multiple breast cancer studies.
    03 Jul 2013
    To facilitate a PFS audit, an Independent Review Facility (IRF) were to perform a blinded review of tumor scans from a subset of 160 subjects selected at random prior to unblinding of data for the primary PFS analysis. Following completion of the primary analysis of PFS, the following were to occur: 1)The frequency, method, and evaluation criteria for tumor assessments was to be determined by the investigator per local clinical practice, 2) The quality-of-life (patient-reported outcome [PRO]) assessments were to be discontinued. Updates were made to the safety plan for trastuzumab emtansine for clarity. Additional details on potential toxicities associated with trastuzumab emtansine, as well as suggestions for managing those toxicities, were provided. Exclusion criteria were added for subjects in the TPC arm who switched to receive trastuzumab emtansine treatment: 1) History of intolerance or hypersensitivity to trastuzumab or murine proteins, 2) History of pulmonary toxicity (e.g., interstitial lung disease, pneumonitis) due to trastuzumab, 3) Current bleeding of Grade ≥ 2. The dosing and administration section on trastuzumab emtansine was updated to include instructions on monitoring the infusion site. It has been clarified that hospitalization due solely to progression of the underlying cancer should not be reported as a serious adverse event. Suspected transmission of an infectious agent by the study drug has been added as an adverse event that requires expedited reporting to the Sponsor. A new safety section has been added regarding pregnancy and breastfeeding.
    28 Apr 2014
    Severe or fatal hemorrhage was added as an identified risk. The inclusion criterion with respect to pregnancy avoidance was amended. The time period to maintain pregnancy avoidance and notification to the Sponsor was increased from 6 months to at least 7 months after last dose of study drug. The period of time required for use of contraceptive measures and abstention from breastfeeding was extended from 6 months to 7 months after the last dose of study treatment. The adverse event reporting period was clarified. New adverse events were to be collected until 30 days after the last dose of study treatment.

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

    Limitations and caveats
    Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.
    None reported
    For support, Contact us.
    The status and protocol content of GB trials is no longer updated since 1 January 2021. For the UK, as of 31 January 2021, EU Law applies only to the territory of Northern Ireland (NI) to the extent foreseen in the Protocol on Ireland/NI. Legal notice
    As of 31 January 2023, all EU/EEA initial clinical trial applications must be submitted through CTIS . Updated EudraCT trials information and information on PIP/Art 46 trials conducted exclusively in third countries continues to be submitted through EudraCT and published on this website.

    European Medicines Agency © 1995-Fri Apr 26 09:06:23 CEST 2024 | Domenico Scarlattilaan 6, 1083 HS Amsterdam, The Netherlands
    EMA HMA