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    Clinical Trial Results:
    A Randomized, Multicenter, Adaptive Phase II/III Study to Evaluate The Efficacy And Safety of Trastuzumab Emtansine (T-DM1) Versus Taxane (Docetaxel or Paclitaxel) In Patients With Previously Treated Locally Advanced or Metastatic Her2-Positive Gastric Cancer, Including Adenocarcinoma of the Gastroesophageal Junction

    Summary
    EudraCT number
    		 2012-000660-22
    Trial protocol
    		 BE   CZ   DE   HU   GB   ES   FI   PL   IT  
    Global end of trial date
    30 Apr 2016

    Results information
    Results version number
    		 v2(current)
    This version publication date
    14 Apr 2017
    First version publication date
    16 Jul 2016
    Other versions
    		 v1
    Version creation reason

    Trial information

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    Trial identification
    Sponsor protocol code
    BO27952
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT01641939
    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
    Roche Trial Information Hotline, F. Hoffmann-La Roche AG, 41 616878333, global.trial_information@roche.com
    Scientific contact
    Roche Trial Information Hotline, 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
    30 Apr 2016
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    30 Apr 2016
    Was the trial ended prematurely?
    Yes
    General information about the trial
    Main objective of the trial
    The primary objective for this study was to compare the Overall Survival (OS) of subjects treated with the selected trastuzumab emtansine arm to the OS of subjects treated with physician’s choice of taxane (docetaxel or paclitaxel) in subjects with human epidermal growth factor receptor 2 (HER2)-positive advanced gastric cancer (AGC), defined as unresectable and locally advanced or metastatic gastric cancer, including adenocarcinoma of the gastroesophageal junction (GEJ).
    Protection of trial subjects
    This study was conducted in full conformance with the International Conference of Harmonization (ICH) E6 guideline for Good Clinical Practice and the principles of the Declaration of Helsinki or the laws and regulations of the country in which the research is conducted, whichever affords the greater protection to the individual. The study will comply with the requirements of the ICH E2A guideline (Clinical Safety Data Management: Definitions and Standards for Expedited Reporting).
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    03 Sep 2012
    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
    Poland: 4
    Country: Number of subjects enrolled
    Hungary: 12
    Country: Number of subjects enrolled
    China: 11
    Country: Number of subjects enrolled
    Japan: 82
    Country: Number of subjects enrolled
    Korea, Democratic People's Republic of: 83
    Country: Number of subjects enrolled
    Malaysia: 3
    Country: Number of subjects enrolled
    Philippines: 1
    Country: Number of subjects enrolled
    Singapore: 4
    Country: Number of subjects enrolled
    Taiwan: 7
    Country: Number of subjects enrolled
    Argentina: 1
    Country: Number of subjects enrolled
    Brazil: 3
    Country: Number of subjects enrolled
    Czech Republic: 7
    Country: Number of subjects enrolled
    Guatemala: 4
    Country: Number of subjects enrolled
    Mexico: 3
    Country: Number of subjects enrolled
    Panama: 1
    Country: Number of subjects enrolled
    Peru: 1
    Country: Number of subjects enrolled
    Romania: 9
    Country: Number of subjects enrolled
    Russian Federation: 7
    Country: Number of subjects enrolled
    Turkey: 9
    Country: Number of subjects enrolled
    Belgium: 4
    Country: Number of subjects enrolled
    Canada: 9
    Country: Number of subjects enrolled
    Germany: 26
    Country: Number of subjects enrolled
    Spain: 35
    Country: Number of subjects enrolled
    Finland: 3
    Country: Number of subjects enrolled
    France: 6
    Country: Number of subjects enrolled
    United Kingdom: 34
    Country: Number of subjects enrolled
    Italy: 22
    Country: Number of subjects enrolled
    United States: 24
    Worldwide total number of subjects
    415
    EEA total number of subjects
    162
    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)
    246
    From 65 to 84 years
    169
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 -

    Pre-assignment
    Screening details
    		 A total of 415 subjects were randomized, of these 117 subjects in taxane arm, 228 subjects in 2.4 milligram per kilogram (mg/kg) trastuzumab emtansine arm (across both phase 2 and 3), and 70 subjects (phase-dose selection portion of the study) in 3.6 mg/kg trastuzumab emtansine arm received at least one dose of the treatment.

    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
    		 Standard Taxane Therapy
    Arm description
    		 Docetaxel was administered at 75 milligram per meter square (mg/m^2) intravenously (IV) on Day 1 of a 21-day cycle, or paclitaxel was administered at 80 mg/m^2 IV weekly (Days 1, 8, and 15 of a 21 day cycle) as per investigator's choice, until progression of disease, intolerable toxicity, initiation of another anticancer therapy, or subjects and/or physician decision to discontinue.
    Arm type
    		 Active comparator

    Investigational medicinal product name
    Docetaxel
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Concentrate and solvent for solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Docetaxel 75 mg/m^2 IV every 3 weeks.

    Investigational medicinal product name
    Paclitaxel
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Concentrate for solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Paclitaxel 80 mg/m^2 weekly IV.

    Arm title
    		 Trastuzumab Emtansine 2.4 mg
    Arm description
    		 Trastuzumab emtansine was administered on Days 1, 8, and 15 of a 21-day cycle at 2.4 milligram per kilogram (mg/kg) IV infusion until progression of disease, intolerable toxicity, initiation of another anticancer therapy, or subjects and/or physician decision to discontinue.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Trastuzumab emtansine
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Injection
    Routes of administration
    Intravenous use
    Dosage and administration details
    Trastuzumab emtansine 2.4 mg/kg IV once a week.

    Arm title
    		 Trastuzumab Emtansine 3.6 mg
    Arm description
    		 Trastuzumab emtansine was administered on Days 1 of a 21-day cycle at 3.6 mg/kg IV infusion until progression of disease, intolerable toxicity, initiation of another anticancer therapy, or subjects and/or physician decision to discontinue.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Trastuzumab emtansine
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Injection
    Routes of administration
    Intravenous use
    Dosage and administration details
    Trastuzumab emtansine 3.6 mg/kg IV every 3 weeks.

    Number of subjects in period 1
    		Standard Taxane Therapy Trastuzumab Emtansine 2.4 mg Trastuzumab Emtansine 3.6 mg
    Started
    117
    228
    70
    Stage 1
    37
    75
    70
    Stage 2
    80
    153
    0
    Completed
    0
    0
    0
    Not completed
    117
    228
    70
         Consent withdrawn by subject
    14
    11
    5
         Study terminated by Sponsor
    10
    28
    3
         Death
    90
    187
    61
         Lost to follow-up
    3
    2
    1

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Standard Taxane Therapy
    Reporting group description
    		 Docetaxel was administered at 75 milligram per meter square (mg/m^2) intravenously (IV) on Day 1 of a 21-day cycle, or paclitaxel was administered at 80 mg/m^2 IV weekly (Days 1, 8, and 15 of a 21 day cycle) as per investigator's choice, until progression of disease, intolerable toxicity, initiation of another anticancer therapy, or subjects and/or physician decision to discontinue.

    Reporting group title
    Trastuzumab Emtansine 2.4 mg
    Reporting group description
    		 Trastuzumab emtansine was administered on Days 1, 8, and 15 of a 21-day cycle at 2.4 milligram per kilogram (mg/kg) IV infusion until progression of disease, intolerable toxicity, initiation of another anticancer therapy, or subjects and/or physician decision to discontinue.

    Reporting group title
    Trastuzumab Emtansine 3.6 mg
    Reporting group description
    		 Trastuzumab emtansine was administered on Days 1 of a 21-day cycle at 3.6 mg/kg IV infusion until progression of disease, intolerable toxicity, initiation of another anticancer therapy, or subjects and/or physician decision to discontinue.

    Reporting group values
    		 Standard Taxane Therapy Trastuzumab Emtansine 2.4 mg Trastuzumab Emtansine 3.6 mg Total
    Number of subjects
    		 117 228 70 415
    Age categorical
    Units: Subjects
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    		 62.1 ± 10.3 60.5 ± 10.9 61.2 ± 11.4 -
    Gender categorical
    Units: Subjects
        Female
    		 22 51 17 90
        Male
    		 95 177 53 325

    End points

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    End points reporting groups
    Reporting group title
    Standard Taxane Therapy
    Reporting group description
    		 Docetaxel was administered at 75 milligram per meter square (mg/m^2) intravenously (IV) on Day 1 of a 21-day cycle, or paclitaxel was administered at 80 mg/m^2 IV weekly (Days 1, 8, and 15 of a 21 day cycle) as per investigator's choice, until progression of disease, intolerable toxicity, initiation of another anticancer therapy, or subjects and/or physician decision to discontinue.

    Reporting group title
    Trastuzumab Emtansine 2.4 mg
    Reporting group description
    		 Trastuzumab emtansine was administered on Days 1, 8, and 15 of a 21-day cycle at 2.4 milligram per kilogram (mg/kg) IV infusion until progression of disease, intolerable toxicity, initiation of another anticancer therapy, or subjects and/or physician decision to discontinue.

    Reporting group title
    Trastuzumab Emtansine 3.6 mg
    Reporting group description
    		 Trastuzumab emtansine was administered on Days 1 of a 21-day cycle at 3.6 mg/kg IV infusion until progression of disease, intolerable toxicity, initiation of another anticancer therapy, or subjects and/or physician decision to discontinue.

    Primary: Overall Survival (OS) - Phase 3

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    End point title
    		 Overall Survival (OS) - Phase 3 [1]
    End point description
    Overall survival was defined as the time between the date of randomisation and date of death due to any cause. Kaplan-Meier estimates were used for analysis. Subjects for whom no death was reported prior to an analysis cutoff (30 June 2015) was censored at the latest date before the cutoff in which they were known to be alive. All data from the standard taxane therapy and trastuzumab emtansine 2.4 mg (selected treatment arm) from phase 2 and phase 3 (Stage 2) are combined into phase 3 data, and thus cumulative data are provided within the results presented for phase 3. The confirmatory analyses are restricted to comparisons between the taxane arm and the selected trastuzumab emtansine arm (2.4 mg). ITT population.
    End point type
    Primary
    End point timeframe
    Date of randomisation until death (up to 2 years 3 months)
    Notes
    [1] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: The data for reporting groups "Standard Taxane Therapy and Trastuzumab Emtansine 2.4 mg" were planned to be reported for the endpoint.
    End point values
    		 Standard Taxane Therapy Trastuzumab Emtansine 2.4 mg
    Number of subjects analysed
    117
    228
    Units: months
        median (confidence interval 95%)
    8.6 (7.1 to 11.2)
    7.9 (6.7 to 9.5)
    Statistical analysis title
    		 Statistical Analysis 1
    Statistical analysis description
    The unstratified Cox proportional hazards model was used to estimate the hazard ratio. The 95% Confidence Interval (CI) for median was computed using the method of Brookmeyer and Crowley. Reference group: Standard Taxane Therapy.
    Comparison groups
    Standard Taxane Therapy v Trastuzumab Emtansine 2.4 mg
    Number of subjects included in analysis
    345
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.8589 [2]
    Method
    		 Logrank
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    1.15
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.87
         upper limit
    		 1.6
    Notes
    [2] - One sided p-value with correction for interim treatment selection due to adaptive seamless phase design.

    Primary: Overall Survival (OS) - Phase 2

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    End point title
    		 Overall Survival (OS) - Phase 2
    End point description
    Overall survival was defined as the time between the date of randomisation and date of death due to any cause. Kaplan-Meier estimates were used for analysis. Subjects for whom no death was reported prior to an analysis cutoff (10 August 2013) was censored at the latest date before the cutoff in which they were known to be alive. Analysis population included all subjects that had been enrolled in phase 2 (stage 1) up to a clinical cut-off date of 10 August 2013; subjects grouped according to the therapy they were randomized to receive. Here, N (number of subjects analyzed)=number of evaluable subjects during phase 2 up to 10 August 2013. The value "99999" represents non evaluable (NE) data, the upper limit of the 95% CI could not be calculated due to the large number of censored events.
    End point type
    Primary
    End point timeframe
    Date of randomisation until death (up to 1 year)
    End point values
    		 Standard Taxane Therapy Trastuzumab Emtansine 2.4 mg Trastuzumab Emtansine 3.6 mg
    Number of subjects analysed
    30
    64
    58
    Units: months
        median (confidence interval 95%)
    28 (24 to 99999)
    36.3 (23 to 99999)
    23 (18 to 99999)
    Statistical analysis title
    		 Statistical Analysis 1
    Statistical analysis description
    The unstratified Cox proportional hazards model was used to estimate the hazard ratio. The 95% CI for median was computed using the method of Brookmeyer and Crowley. Reference group: Trastuzumab Emtansine 3.6 mg
    Comparison groups
    Standard Taxane Therapy v Trastuzumab Emtansine 2.4 mg
    Number of subjects included in analysis
    94
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    Method
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.81
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.32
         upper limit
    		 2.03
    Statistical analysis title
    		 Statistical Analysis 3
    Statistical analysis description
    The unstratified Cox proportional hazards model was used to estimate the hazard ratio. The 95% CI for median was computed using the method of Brookmeyer and Crowley. Reference group: Standard Taxane Therapy.
    Comparison groups
    Trastuzumab Emtansine 3.6 mg v Trastuzumab Emtansine 2.4 mg
    Number of subjects included in analysis
    122
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    Method
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.47
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.23
         upper limit
    		 0.96
    Statistical analysis title
    		 Statistical Analysis 2
    Statistical analysis description
    The unstratified Cox proportional hazards model was used to estimate the hazard ratio. The 95% CI for median was computed using the method of Brookmeyer and Crowley. Reference group: Standard Taxane Therapy.
    Comparison groups
    Standard Taxane Therapy v Trastuzumab Emtansine 3.6 mg
    Number of subjects included in analysis
    88
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    Method
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    2.01
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.82
         upper limit
    		 4.92

    Secondary: Percentage of Subjects with Disease Progression According to Modified Response Evaluation Criteria in Solid Tumors (mRECIST v1.1) - Phase 3

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    End point title
    		 Percentage of Subjects with Disease Progression According to Modified Response Evaluation Criteria in Solid Tumors (mRECIST v1.1) - Phase 3 [3]
    End point description
    Progressive disease could base on symptom deterioration or was defined as at least a 20 percent (%) increase in the sum of the longest diameter of target lesions, taking as reference the smallest sum longest diameter recorded since treatment started or the appearance of one or more new lesions and/or the unequivocal progression of existing non-target lesions. Tumor assessment was performed using modified RECIST v1.1. Cumulative data (up to primary analysis cut-off date of 30-June-2015) are provided for both phase 2 and phase 3 within the results of this measure. ITT population.
    End point type
    Secondary
    End point timeframe
    Date of randomisation until disease progression or death, whichever occurred first (assessed at baseline, every 6 weeks up to 2 years 3 months)
    Notes
    [3] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: The data for reporting groups "Standard Taxane Therapy and Trastuzumab Emtansine 2.4 mg" were planned to be reported for the endpoint.
    End point values
    		 Standard Taxane Therapy Trastuzumab Emtansine 2.4 mg
    Number of subjects analysed
    117
    228
    Units: percentage of subjects
        number (not applicable)
    88.9
    93
    No statistical analyses for this end point

    Secondary: Progression Free Survival (PFS) According to Modified Response Evaluation Criteria in Solid Tumors (mRECIST v1.1) - Phase 3

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    End point title
    		 Progression Free Survival (PFS) According to Modified Response Evaluation Criteria in Solid Tumors (mRECIST v1.1) - Phase 3 [4]
    End point description
    Progression-free survival was defined as the time between the date of randomisation and the first date of documented progression or date of death due to any cause, whichever occurred first. Tumor assessment was performed using modified RECIST v1.1. Progressive disease could base on symptom deterioration or was defined as at least a 20% increase in the sum of the longest diameter of target lesions, taking as reference the smallest sum longest diameter recorded since treatment started or the appearance of one or more new lesions and/or the unequivocal progression of existing non-target lesions. Kaplan-Meier estimates were used for analysis. Cumulative data (up to primary analysis cut-off date of 30-June-2015) are provided for both phase 2 and phase 3 within the results of this measure. The confirmatory analyses are restricted to comparisons between the taxane arm and the selected trastuzumab emtansine arm (2.4 mg). ITT population.
    End point type
    Secondary
    End point timeframe
    Date of randomisation until disease progression or death, whichever occurred first (assessed at baseline, every 6 weeks up to 2 years 3 months)
    Notes
    [4] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: The data for reporting groups "Standard Taxane Therapy and Trastuzumab Emtansine 2.4 mg" were planned to be reported for the endpoint.
    End point values
    		 Standard Taxane Therapy Trastuzumab Emtansine 2.4 mg
    Number of subjects analysed
    117
    228
    Units: months
        median (confidence interval 95%)
    2.89 (2.76 to 4.01)
    2.66 (1.61 to 2.79)
    Statistical analysis title
    		 Statistical Analysis 1
    Statistical analysis description
    The unstratified Cox proportional hazards model was used to estimate the hazard ratio. The 95% CI for median was computed using the method of Brookmeyer and Crowley. Reference group: Standard Taxane Therapy.
    Comparison groups
    Standard Taxane Therapy v Trastuzumab Emtansine 2.4 mg
    Number of subjects included in analysis
    345
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.308
    Method
    		 Logrank
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    1.13
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.89
         upper limit
    		 1.43

    Secondary: Percentage of Subjects With Objective Response According to mRECIST v1.1 - Phase 3

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    End point title
    		 Percentage of Subjects With Objective Response According to mRECIST v1.1 - Phase 3 [5]
    End point description
    Objective response referred to subjects with complete response (CR) or partial response (PR). CR: disappearance of all target lesions, non-target lesions, and normalization of tumor marker level. PR: greater than or equal to (>=) 30% decrease in sum of the longest diameter (LD) of all target lesions taking as reference the screening sum LD. To be assigned a status of PR or CR, changes in tumor measurements had to be confirmed by repeat assessments that should have been performed no less than 4 weeks after the criteria for response were first met. Longer intervals as determined by the study protocol were also appropriate. Cumulative data (up to primary analysis cut-off date of 30-June-2015) are provided for both phase 2 and phase 3 within the results of this measure. ITT population. Here, N=number of subjects with measurable disease were included in analysis of this outcome measure.
    End point type
    Secondary
    End point timeframe
    Date of randomisation until disease progression or death, whichever occurred first (assessed at baseline, every 6 weeks up to 2 years 3 months)
    Notes
    [5] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: The data for reporting groups "Standard Taxane Therapy and Trastuzumab Emtansine 2.4 mg" were planned to be reported for the endpoint.
    End point values
    		 Standard Taxane Therapy Trastuzumab Emtansine 2.4 mg
    Number of subjects analysed
    102
    204
    Units: percentage of subjects
        number (confidence interval 95%)
    19.6 (12.56 to 28.07)
    20.6 (15.26 to 26.45)
    No statistical analyses for this end point

    Secondary: Duration of Objective Response - Phase 3

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    End point title
    		 Duration of Objective Response - Phase 3 [6]
    End point description
    DOR: time from the date when a clinical response [CR or PR] was first documented to the date of first documented progressive disease (PD) or death. CR:disappearance of all target lesions, non-target lesions, normalization of tumor marker level. PR: >= 30% decrease in sum of the LD of all target lesions taking as reference the screening sum LD. PD: could base on symptom deterioration or at least a 20% increase in the sum of diameters of target or non-target lesions and new lesions, taking as reference the smallest sum on study (nadir), including baseline. To be assigned a status of PR or CR, changes in tumor measurements had to be confirmed by repeat assessments that should have been performed no less than 4 weeks after the criteria for response were first met. Cumulative data (up to primary analysis cut-off date of 30-June-2015) are provided for both phase 2 and phase 3 within the results of this measure. ITT population. N=number of subjects evaluable for this outcome measure.
    End point type
    Secondary
    End point timeframe
    Date of randomisation until disease progression or death, whichever occurred first (assessed at baseline, every 6 weeks up to 2 years 3 months)
    Notes
    [6] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: The data for reporting groups "Standard Taxane Therapy and Trastuzumab Emtansine 2.4 mg" were planned to be reported for the endpoint.
    End point values
    		 Standard Taxane Therapy Trastuzumab Emtansine 2.4 mg
    Number of subjects analysed
    102
    204
    Units: months
        median (confidence interval 95%)
    3.65 (2.76 to 5.55)
    4.27 (3.02 to 6.83)
    No statistical analyses for this end point

    Secondary: Percentage of Subjects With European Organisation for Research and Treatment of Cancer Quality of Life Core Module 30 (EORTC QLQ-C30) Score - Phase 3

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    End point title
    		 Percentage of Subjects With European Organisation for Research and Treatment of Cancer Quality of Life Core Module 30 (EORTC QLQ-C30) Score - Phase 3 [7]
    End point description
    EORTC QLQ-C30: a validated, cancer-specific 30-item patient-reported measure, contains 14 domains to assess the impact of cancer treatment on 5 aspects of subjects functioning (physical,role,cognitive,emotional,social), 9 aspects of disease/treatment-related symptoms (fatigue,nausea and vomiting,pain,dyspnea,insomnia,loss of appetite,constipation,diarrhea) and a global QoL/overall health status scale. Questions used 4 point scale (1 'Not at all' - 4 'Very much'; with exception of QoL/health status scale which uses 7-point scale (1 'very poor' - 7 'Excellent'). Each scale is transformed on a scale of 0-100; higher score=better level of functioning or greater degree of symptoms. Change of >= 10-points has been found to be clinically significant. Cumulative data (up to primary analysis cut-off date of 30-June-2015) are provided for both phase 2 and phase 3 within the results of this measure. ITT population. N=number of subject with baseline at least 1 post-baseline valid score.
    End point type
    Secondary
    End point timeframe
    Day 1 of each treatment cycle and at the study drug completion visit, and thereafter at survival follow-up (up to 2 years 3 months)
    Notes
    [7] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: The data for reporting groups "Standard Taxane Therapy and Trastuzumab Emtansine 2.4 mg" were planned to be reported for the endpoint.
    End point values
    		 Standard Taxane Therapy Trastuzumab Emtansine 2.4 mg
    Number of subjects analysed
    91
    189
    Units: percentage of subjects
    number (confidence interval 95%)
        Appetite loss
    39.6 (29.57 to 50)
    30.2 (23.97 to 37.23)
        Cognitive Functioning
    31.9 (22.49 to 42)
    28 (21.76 to 34.68)
        Constipation
    40.7 (30.48 to 51.47)
    25.9 (19.84 to 32.66)
        Diarrhoea
    23.1 (14.89 to 32.53)
    21.7 (16.23 to 28.15)
        Dyspnea
    19.8 (12.16 to 29.19)
    21.7 (16.23 to 28.15)
        Emotional Functioning
    24.2 (15.98 to 33.56)
    29.1 (22.74 to 35.78)
        Fatigue
    46.2 (36.17 to 56.92)
    40.7 (33.67 to 47.81)
        Nausea/Vomiting
    33 (24.04 to 43.08)
    28 (21.76 to 34.68)
        Pain
    49.5 (38.8 to 60.14)
    33.9 (27.36 to 40.84)
        Physical Functioning
    17.6 (10.4 to 26.44)
    25.9 (19.84 to 32.66)
        Role Functioning
    29.7 (20.55 to 39.86)
    30.7 (24.2 to 37.75)
        Social Functioning
    34.1 (24.45 to 44.16)
    37.6 (30.8 to 44.48)
        Insomnia
    33 (24.04 to 43.08)
    33.3 (26.83 to 40.32)
        Global Health Status/QoL
    44 (33.56 to 54.75)
    34.4 (27.65 to 41.36)
    No statistical analyses for this end point

    Secondary: Percentage of Subjects With Quality of Life Questionnaire Stomach Cancer Module 22 (QLQ-STO22) Score - Phase 3

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    End point title
    		 Percentage of Subjects With Quality of Life Questionnaire Stomach Cancer Module 22 (QLQ-STO22) Score - Phase 3 [8]
    End point description
    The Quality of Life Questionnaire Stomach Cancer Module 22 (QLQ-STO22) supplements the EORTC QLQ-C30 to assess symptoms and treatment-related side effects commonly reported in subjects. There are 22 questions which comprise 5 scales (dysphagia, pain, reflux symptom, dietary restrictions, and anxiety) and 4 single items (dry mouth, hair loss, taste, body image). Most questions use 4-point scale (1 'Not at all' to 4 'Very much'; 1 question was a yes or no answer). A linear transformation was used to standardize all scores and single-items to a scale of 0 to 100; higher score=better level of functioning or greater degree of symptoms. Change of >=10 points has been found to be clinically significant. Cumulative data (up to primary analysis cut-off date of 30-June-2015) are provided for both phase 2 and phase 3 within the results of this measure. ITT population. Here, N=number of subjects with baseline and at least one post-baseline valid score.
    End point type
    Secondary
    End point timeframe
    Day 1 of each treatment cycle, at the study drug completion visit, and thereafter at survival follow-up (up to 2 years 3 months)
    Notes
    [8] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: The data for reporting groups "Standard Taxane Therapy and Trastuzumab Emtansine 2.4 mg" were planned to be reported for the endpoint.
    End point values
    		 Standard Taxane Therapy Trastuzumab Emtansine 2.4 mg
    Number of subjects analysed
    90
    185
    Units: percentage of subjects
    median (confidence interval 95%)
        Overall
    88.9 (81.15 to 94.54)
    88.1 (82.64 to 92.4)
        Body image
    20 (12.31 to 29.33)
    29.7 (23.25 to 36.52)
        Dry Mouth
    30 (20.79 to 40.35)
    21.1 (15.44 to 27.28)
        Dietary Restrictions
    41.1 (30.84 to 51.98)
    32.4 (25.75 to 39.66)
        Dysphagia
    35.6 (25.74 to 45.8)
    23.8 (17.84 to 30.31)
        Hair Loss
    11.1 (5.46 to 18.85)
    22.7 (17.07 to 29.29)
        Pain/discomfort
    52.2 (41.43 to 62.45)
    45.4 (38.28 to 52.87)
        Specific Emotional Problems
    63.3 (53.09 to 73.25)
    57.8 (50.71 to 65.05)
        Upper Gastrointestinal Symptoms
    46.7 (36.52 to 57.49)
    42.7 (35.47 to 50)
    No statistical analyses for this end point

    Secondary: Percentage of Subjects With Advanced Gastric Cancer (AGC) Symptom Progression - Phase 3

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    End point title
    		 Percentage of Subjects With Advanced Gastric Cancer (AGC) Symptom Progression - Phase 3 [9]
    End point description
    AGC symptomatic progression: a worsening of >=10-points in any 1 of the abdominal discomfort, loss of appetite, weakness and fatigue, upper abdominal pain, change in bowel movement, and/or weight loss scales of the EORTC QLQ-C30 and QLQ-STO22 (supplements EORTC QLQ-C30 to assess symptoms and commonly reported treatment-related side effects). There are 22 questions comprise 5 scales (dysphagia, pain, reflux symptom, diet restrictions, anxiety), 4 single items (dry mouth, hair loss, taste, body image), which are related to the symptoms of the disease. Most questions used 4-point scale (1 'Not at all' - 4 'Very much'). All scores and single-items transformed to a scale of 0-100; higher score=better level of functioning or greater degree of symptoms. Cumulative data (up to primary analysis cut-off date of 30-June-2015) are provided for both phase 2 and phase 3 within the results of this measure. ITT population. Here, N=number of subjects evaluable for this measure.
    End point type
    Secondary
    End point timeframe
    Day 1 of each treatment cycle, at the study drug completion visit, and thereafter at survival follow-up (up to 2 years 3 months)
    Notes
    [9] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: The data for reporting groups "Standard Taxane Therapy and Trastuzumab Emtansine 2.4 mg" were planned to be reported for the endpoint.
    End point values
    		 Standard Taxane Therapy Trastuzumab Emtansine 2.4 mg
    Number of subjects analysed
    117
    228
    Units: percentage of subjects
        number (not applicable)
    90.6
    93
    No statistical analyses for this end point

    Secondary: Time to Advanced Gastric Cancer (AGC) Symptom Progression - Phase 3

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    End point title
    		 Time to Advanced Gastric Cancer (AGC) Symptom Progression - Phase 3 [10]
    End point description
    Time to AGC symptom were defined as the time from randomization to the first documentation of an increase in at least one of the pre-specified abdominal discomfort, loss of appetite, weakness and fatigue, upper abdominal pain, change in bowel movement, and weight loss subscales of the QLQ STO22 and EORTC QLQ-C30. Cumulative data (up to primary analysis cut-off date of 30-June-2015) are provided for both phase 2 and phase 3 within the results of this measure. ITT population. Here, N=number of subjects evaluable for this measure.
    End point type
    Secondary
    End point timeframe
    Day 1 of each treatment cycle, at the study drug completion visit, and thereafter at survival follow-up (up to 2 years 3 months)
    Notes
    [10] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: The data for reporting groups "Standard Taxane Therapy and Trastuzumab Emtansine 2.4 mg" were planned to be reported for the endpoint.
    End point values
    		 Standard Taxane Therapy Trastuzumab Emtansine 2.4 mg
    Number of subjects analysed
    117
    228
    Units: months
        median (confidence interval 95%)
    1.61 (1.41 to 2.17)
    1.51 (1.41 to 1.64)
    No statistical analyses for this end point

    Secondary: Maximum Observed Plasma Concentration (Cmax) of Trastuzumab Emtansine (T-DM1) and Total Trastuzumab - Stage 1

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    End point title
    		 Maximum Observed Plasma Concentration (Cmax) of Trastuzumab Emtansine (T-DM1) and Total Trastuzumab - Stage 1 [11]
    End point description
    Maximum observed plasma concentration of Trastuzumab Emtansine (T-DM1) and total trastuzumab were reported. Stage 1 consists of all subjects recruited before the regimen selection decision, which was carried out after 12 weeks of randomization. Subjects who had at least one PK parameter estimated were included for analysis. Here, n=number of subjects evaluable at specified timepoint.
    End point type
    Secondary
    End point timeframe
    Day 1 (D1) of Cycle 1 (C1) and C4, C1D2, C1D3, C1D4/C1D5, C1D8, C1D15, C2D1 (up to 12 weeks)
    Notes
    [11] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: The data for reporting groups "Trastuzumab Emtansine 2.4 mg and Trastuzumab Emtansine 3.6 mg" were planned to be reported for the endpoint.
    End point values
    		 Trastuzumab Emtansine 2.4 mg Trastuzumab Emtansine 3.6 mg
    Number of subjects analysed
    41
    37
    Units: microgram per milliliter (mcg/mL)
    arithmetic mean (standard deviation)
        T-DM1 Cycle 1 First Dose (n=41, 37)
    43 ± 11.8
    58.6 ± 12.9
        T-DM1 Cycle 4 First Dose (n=25, 10)
    52.6 ± 19.4
    61.6 ± 14.5
        Total trastuzumab Cycle 1 First Dose (n=41, 37)
    46.8 ± 12.3
    61.2 ± 14.6
        Total trastuzumab Cycle 4 First Dose (n=25, 10)
    71.2 ± 23.2
    66.3 ± 14.7
    No statistical analyses for this end point

    Secondary: Maximum Observed Plasma Concentration (Cmax) of Trastuzumab Emtansine (T-DM1) and Total Trastuzumab - Stage 2

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    End point title
    		 Maximum Observed Plasma Concentration (Cmax) of Trastuzumab Emtansine (T-DM1) and Total Trastuzumab - Stage 2 [12]
    End point description
    Stage 2 consists of all subjects recruited after the regimen selection decision. Subjects who had at least one PK parameter estimated were included for analysis. Here, n=number of subjects evaluable at specified timepoint.
    End point type
    Secondary
    End point timeframe
    C1D1; C4D1
    Notes
    [12] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: The data for reporting group "Trastuzumab Emtansine 2.4 mg" was planned to be reported for the endpoint.
    End point values
    		 Trastuzumab Emtansine 2.4 mg
    Number of subjects analysed
    57
    Units: mcg/mL
    arithmetic mean (standard deviation)
        T-DM1 Cycle 1 First Dose
    34.1 ± 15.2
        T-DM1 Cycle 4 First Dose
    38 ± 13.4
        Total trastuzumab Cycle 1 First Dose
    44.5 ± 15.4
        Total trastuzumab Cycle 4 First Dose
    69.7 ± 21.3
    No statistical analyses for this end point

    Secondary: Area Under the Curve From Time Zero to Extrapolated Infinite Time [AUCinf] - Stage 1

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    End point title
    		 Area Under the Curve From Time Zero to Extrapolated Infinite Time [AUCinf] - Stage 1 [13]
    End point description
    AUCinf= Area under the plasma concentration versus time curve (AUC) from time zero (pre-dose) to extrapolated infinite time (0 - inf). It is obtained from AUC (0 - t) plus AUC (t - inf). Stage 1 consists of all subjects recruited before the regimen selection decision. Regimen selection analysis was carried out after 12 weeks of randomisation. Subjects who had at least one PK parameter estimated were included for analysis.
    End point type
    Secondary
    End point timeframe
    D1C1 and D1C4, C1D2, C1D3, C1D4/C1D5, C1D8, C1D15, C2D1 (up to 12 weeks)
    Notes
    [13] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: The data for reporting groups "Trastuzumab Emtansine 2.4 mg and Trastuzumab Emtansine 3.6 mg" were planned to be reported for the endpoint.
    End point values
    		 Trastuzumab Emtansine 2.4 mg Trastuzumab Emtansine 3.6 mg
    Number of subjects analysed
    41
    37
    Units: day*μg/mL
    arithmetic mean (standard deviation)
        T-DM1
    179 ± 51
    262 ± 90.3
        Total trastuzumab
    289 ± 129
    403 ± 237
    No statistical analyses for this end point

    Secondary: Plasma Decay Half-Life (t1/2) - Stage 1

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    End point title
    		 Plasma Decay Half-Life (t1/2) - Stage 1 [14]
    End point description
    Plasma decay half-life is the time measured for the plasma concentration to decrease by one half. Stage 1 consists of all subjects recruited before the regimen selection decision. Regimen selection analysis was carried out after 12 weeks of randomisation. Subjects who had at least one PK parameter estimated were included for analysis.
    End point type
    Secondary
    End point timeframe
    D1C1 and D1C4, C1D2, C1D3, C1D4/C1D5, C1D8, C1D15, C2D1 (up to 12 weeks)
    Notes
    [14] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: The data for reporting groups "Trastuzumab Emtansine 2.4 mg and Trastuzumab Emtansine 3.6 mg" were planned to be reported for the endpoint.
    End point values
    		 Trastuzumab Emtansine 2.4 mg Trastuzumab Emtansine 3.6 mg
    Number of subjects analysed
    41
    37
    Units: days
    arithmetic mean (standard deviation)
        T-DM1
    3.48 ± 0.747
    3.33 ± 1.21
        Total trastuzumab
    5.22 ± 1.53
    5.4 ± 2.15
    No statistical analyses for this end point

    Secondary: Volume of Distribution at Steady State (Vss) - Stage 1

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    End point title
    		 Volume of Distribution at Steady State (Vss) - Stage 1 [15]
    End point description
    Volume of distribution is defined as the theoretical volume in which the total amount of drug would need to be uniformly distributed to produce the desired blood concentration of a drug. Steady state volume of distribution (Vss) is the apparent volume of distribution at steady-state. Stage 1 consists of all subjects recruited before the regimen selection decision. Regimen selection analysis was carried out after 12 weeks of randomisation. Subjects who had at least one PK parameter estimated were included for analysis.
    End point type
    Secondary
    End point timeframe
    D1C1 and D1C4, C1D2, C1D3, C1D4/C1D5, C1D8, C1D15, C2D1 (up to 12 weeks)
    Notes
    [15] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: The data for reporting groups "Trastuzumab Emtansine 2.4 mg and Trastuzumab Emtansine 3.6 mg" were planned to be reported for the endpoint.
    End point values
    		 Trastuzumab Emtansine 2.4 mg Trastuzumab Emtansine 3.6 mg
    Number of subjects analysed
    41
    37
    Units: millilitre per kilogram (mL/kg)
    arithmetic mean (standard deviation)
        T-DM1
    66.2 ± 19.2
    67.7 ± 14
        Total trastuzumab
    65.9 ± 21.9
    72.1 ± 16.1
    No statistical analyses for this end point

    Secondary: Systemic Clearance (CL) - Stage 1

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    End point title
    		 Systemic Clearance (CL) - Stage 1 [16]
    End point description
    CL is a quantitative measure of the rate at which a drug substance is removed from the body. Stage 1 consists of all subjects recruited before the regimen selection decision. Regimen selection analysis was carried out after 12 weeks of randomisation. Subjects who had at least one PK parameter estimated were included for analysis.
    End point type
    Secondary
    End point timeframe
    D1C1 and D1C4, C1D2, C1D3, C1D4/C1D5, C1D8, C1D15, C2D1 (up to 12 weeks)
    Notes
    [16] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: The data for reporting groups "Trastuzumab Emtansine 2.4 mg and Trastuzumab Emtansine 3.6 mg" were planned to be reported for the endpoint.
    End point values
    		 Trastuzumab Emtansine 2.4 mg Trastuzumab Emtansine 3.6 mg
    Number of subjects analysed
    41
    37
    Units: mL/day/kg
    arithmetic mean (standard deviation)
        T-DM1
    14.6 ± 4.64
    15.4 ± 5.61
        Total trastuzumab
    10.2 ± 4.87
    11.3 ± 5.46
    No statistical analyses for this end point

    Secondary: Maximum Observed Plasma Concentration (Cmax) of N2'-Deacetyl-N2'-(3-mercapto-1-oxopropyl)-Maytansine (DM1) - Stage 1

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    End point title
    		 Maximum Observed Plasma Concentration (Cmax) of N2'-Deacetyl-N2'-(3-mercapto-1-oxopropyl)-Maytansine (DM1) - Stage 1 [17]
    End point description
    Maximum observed plasma concentration of DM1 were reported. Stage 1 consists of all subjects recruited before the regimen selection decision. Regimen selection analysis was carried out after 12 weeks of randomisation. Subjects who had at least one PK parameter estimated were included for analysis. Here, n=number of subjects evaluable at specified timepoint.
    End point type
    Secondary
    End point timeframe
    C1D1 and C1C4, C1D2, C1D3, C1D4/C1D5, C1D8, C1D15, C2D1 (up to 12 weeks)
    Notes
    [17] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: The data for reporting groups "Trastuzumab Emtansine 2.4 mg and Trastuzumab Emtansine 3.6 mg" were planned to be reported for the endpoint.
    End point values
    		 Trastuzumab Emtansine 2.4 mg Trastuzumab Emtansine 3.6 mg
    Number of subjects analysed
    40
    35
    Units: nanogram per milliliter (mcg/mL)
    arithmetic mean (standard deviation)
        DM1 Cycle 1 First Dose (n=40, 35)
    2.47 ± 1.05
    4.61 ± 6.26
        DM1 Cycle 4 First Dose (n=22, 9)
    3.41 ± 1.61
    3.86 ± 0.83
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Baseline up to data cut-off date 30-April-2016 (up to 3 years 8 months)
    Adverse event reporting additional description
    Safety Analysis Population included all subjects who received at least one dose of study medication. The safety parameters were analyzed and presented according to the therapy subjects received. Cumulative data (up to primary analysis cut-off date of 30-April-2016) are provided for both phase 2 and phase 3.
    Assessment type
    		 Non-systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    19.0
    Reporting groups
    Reporting group title
    Standard Taxane Therapy
    Reporting group description
    		 Docetaxel was administered at 75 milligram per meter square (mg/m^2) intravenously (IV) on Day 1 of a 21-day cycle, or paclitaxel was administered at 80 mg/m^2 IV weekly (Days 1, 8, and 15 of a 21 day cycle).

    Reporting group title
    Trastuzumab Emtansine 2.4 mg
    Reporting group description
    		 Trastuzumab emtansine was administered on Days 1, 8, and 15 of a 21-day cycle at 2.4 milligram per kilogram (mg/kg) IV infusion until progression of disease, intolerable toxicity, initiation of another anticancer therapy, or subject and/or physician decision to discontinue.

    Reporting group title
    Trastuzumab Emtansine 3.6 mg
    Reporting group description
    		 Trastuzumab emtansine was administered on Days 1 of a 21-day cycle at 3.6 mg/kg IV infursion until progression of disease, intolerable toxicity, initiation of another anticancer therapy, or subject and/or physician decision to discontinue.

    Serious adverse events
    		 Standard Taxane Therapy Trastuzumab Emtansine 2.4 mg Trastuzumab Emtansine 3.6 mg
    Total subjects affected by serious adverse events
         subjects affected / exposed
    31 / 111 (27.93%)
    65 / 224 (29.02%)
    23 / 69 (33.33%)
         number of deaths (all causes)
    87
    185
    61
         number of deaths resulting from adverse events
    4
    8
    5
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Bladder transitional cell carcinoma
         subjects affected / exposed
    0 / 111 (0.00%)
    1 / 224 (0.45%)
    0 / 69 (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
    Myelodysplastic syndrome
         subjects affected / exposed
    0 / 111 (0.00%)
    0 / 224 (0.00%)
    1 / 69 (1.45%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    Tumour haemorrhage
         subjects affected / exposed
    0 / 111 (0.00%)
    1 / 224 (0.45%)
    0 / 69 (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
    General disorders and administration site conditions
    Death
         subjects affected / exposed
    1 / 111 (0.90%)
    0 / 224 (0.00%)
    0 / 69 (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
    Fatigue
         subjects affected / exposed
    2 / 111 (1.80%)
    0 / 224 (0.00%)
    0 / 69 (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
    General physical health deterioration
         subjects affected / exposed
    0 / 111 (0.00%)
    0 / 224 (0.00%)
    1 / 69 (1.45%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pyrexia
         subjects affected / exposed
    1 / 111 (0.90%)
    2 / 224 (0.89%)
    3 / 69 (4.35%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 2
    1 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Immune system disorders
    Anaphylactic reaction
         subjects affected / exposed
    2 / 111 (1.80%)
    0 / 224 (0.00%)
    0 / 69 (0.00%)
         occurrences causally related to treatment / all
    2 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hypersensitivity
         subjects affected / exposed
    1 / 111 (0.90%)
    0 / 224 (0.00%)
    0 / 69 (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
    Respiratory, thoracic and mediastinal disorders
    Interstitial lung disease
         subjects affected / exposed
    1 / 111 (0.90%)
    1 / 224 (0.45%)
    0 / 69 (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
    Pleural effusion
         subjects affected / exposed
    0 / 111 (0.00%)
    1 / 224 (0.45%)
    0 / 69 (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 aspiration
         subjects affected / exposed
    0 / 111 (0.00%)
    1 / 224 (0.45%)
    0 / 69 (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
    Pneumonitis
         subjects affected / exposed
    1 / 111 (0.90%)
    2 / 224 (0.89%)
    0 / 69 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    2 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pulmonary alveolar haemorrhage
         subjects affected / exposed
    0 / 111 (0.00%)
    1 / 224 (0.45%)
    0 / 69 (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
    Pulmonary embolism
         subjects affected / exposed
    1 / 111 (0.90%)
    0 / 224 (0.00%)
    0 / 69 (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 oedema
         subjects affected / exposed
    0 / 111 (0.00%)
    1 / 224 (0.45%)
    0 / 69 (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
    Respiratory failure
         subjects affected / exposed
    1 / 111 (0.90%)
    0 / 224 (0.00%)
    0 / 69 (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
    Aspiration
         subjects affected / exposed
    0 / 111 (0.00%)
    1 / 224 (0.45%)
    0 / 69 (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
    Psychiatric disorders
    Confusional state
         subjects affected / exposed
    0 / 111 (0.00%)
    1 / 224 (0.45%)
    0 / 69 (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
    Investigations
    Blood bilirubin increased
         subjects affected / exposed
    0 / 111 (0.00%)
    4 / 224 (1.79%)
    0 / 69 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 4
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Blood creatinine increased
         subjects affected / exposed
    0 / 111 (0.00%)
    2 / 224 (0.89%)
    0 / 69 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    2 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hepatic enzyme increased
         subjects affected / exposed
    0 / 111 (0.00%)
    1 / 224 (0.45%)
    0 / 69 (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
    Liver function test abnormal
         subjects affected / exposed
    0 / 111 (0.00%)
    1 / 224 (0.45%)
    0 / 69 (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
    Facial bones fracture
         subjects affected / exposed
    1 / 111 (0.90%)
    0 / 224 (0.00%)
    0 / 69 (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
    Fall
         subjects affected / exposed
    0 / 111 (0.00%)
    0 / 224 (0.00%)
    1 / 69 (1.45%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Overdose
         subjects affected / exposed
    0 / 111 (0.00%)
    1 / 224 (0.45%)
    0 / 69 (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
    Cardiac disorders
    Atrial fibrillation
         subjects affected / exposed
    0 / 111 (0.00%)
    1 / 224 (0.45%)
    0 / 69 (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
    Cardiac failure
         subjects affected / exposed
    0 / 111 (0.00%)
    0 / 224 (0.00%)
    1 / 69 (1.45%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    Supraventricular tachycardia
         subjects affected / exposed
    1 / 111 (0.90%)
    0 / 224 (0.00%)
    0 / 69 (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
    Encephalopathy
         subjects affected / exposed
    0 / 111 (0.00%)
    1 / 224 (0.45%)
    0 / 69 (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
    Hepatic encephalopathy
         subjects affected / exposed
    0 / 111 (0.00%)
    2 / 224 (0.89%)
    0 / 69 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    2 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Metabolic encephalopathy
         subjects affected / exposed
    0 / 111 (0.00%)
    1 / 224 (0.45%)
    0 / 69 (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
    Subarachnoid haemorrhage
         subjects affected / exposed
    0 / 111 (0.00%)
    0 / 224 (0.00%)
    1 / 69 (1.45%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    Syncope
         subjects affected / exposed
    0 / 111 (0.00%)
    1 / 224 (0.45%)
    0 / 69 (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
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    3 / 111 (2.70%)
    8 / 224 (3.57%)
    2 / 69 (2.90%)
         occurrences causally related to treatment / all
    2 / 3
    3 / 9
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Coagulopathy
         subjects affected / exposed
    0 / 111 (0.00%)
    1 / 224 (0.45%)
    0 / 69 (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
    Disseminated intravascular coagulation
         subjects affected / exposed
    0 / 111 (0.00%)
    1 / 224 (0.45%)
    0 / 69 (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
    Febrile neutropenia
         subjects affected / exposed
    4 / 111 (3.60%)
    1 / 224 (0.45%)
    0 / 69 (0.00%)
         occurrences causally related to treatment / all
    4 / 4
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Neutropenia
         subjects affected / exposed
    3 / 111 (2.70%)
    0 / 224 (0.00%)
    0 / 69 (0.00%)
         occurrences causally related to treatment / all
    4 / 4
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Thrombocytopenia
         subjects affected / exposed
    0 / 111 (0.00%)
    3 / 224 (1.34%)
    0 / 69 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    3 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Abdominal pain
         subjects affected / exposed
    1 / 111 (0.90%)
    0 / 224 (0.00%)
    1 / 69 (1.45%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Diarrhoea
         subjects affected / exposed
    0 / 111 (0.00%)
    1 / 224 (0.45%)
    0 / 69 (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
    Dysphagia
         subjects affected / exposed
    1 / 111 (0.90%)
    2 / 224 (0.89%)
    1 / 69 (1.45%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Gastric haemorrhage
         subjects affected / exposed
    2 / 111 (1.80%)
    6 / 224 (2.68%)
    4 / 69 (5.80%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 8
    2 / 5
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    1 / 1
    Gastric ulcer haemorrhage
         subjects affected / exposed
    0 / 111 (0.00%)
    0 / 224 (0.00%)
    1 / 69 (1.45%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal haemorrhage
         subjects affected / exposed
    1 / 111 (0.90%)
    5 / 224 (2.23%)
    0 / 69 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    1 / 10
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal ulcer
         subjects affected / exposed
    0 / 111 (0.00%)
    1 / 224 (0.45%)
    0 / 69 (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
    Haematemesis
         subjects affected / exposed
    0 / 111 (0.00%)
    1 / 224 (0.45%)
    0 / 69 (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
    Ileus
         subjects affected / exposed
    0 / 111 (0.00%)
    2 / 224 (0.89%)
    1 / 69 (1.45%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 3
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Intestinal obstruction
         subjects affected / exposed
    0 / 111 (0.00%)
    1 / 224 (0.45%)
    0 / 69 (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
    Jejunal perforation
         subjects affected / exposed
    1 / 111 (0.90%)
    0 / 224 (0.00%)
    0 / 69 (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
    Lower gastrointestinal haemorrhage
         subjects affected / exposed
    1 / 111 (0.90%)
    0 / 224 (0.00%)
    0 / 69 (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
    Nausea
         subjects affected / exposed
    0 / 111 (0.00%)
    0 / 224 (0.00%)
    1 / 69 (1.45%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Oesophageal haemorrhage
         subjects affected / exposed
    0 / 111 (0.00%)
    3 / 224 (1.34%)
    0 / 69 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Oesophageal stenosis
         subjects affected / exposed
    0 / 111 (0.00%)
    1 / 224 (0.45%)
    0 / 69 (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
    Pancreatitis
         subjects affected / exposed
    0 / 111 (0.00%)
    1 / 224 (0.45%)
    0 / 69 (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
    Regurgitation
         subjects affected / exposed
    1 / 111 (0.90%)
    0 / 224 (0.00%)
    0 / 69 (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 haemorrhage
         subjects affected / exposed
    0 / 111 (0.00%)
    1 / 224 (0.45%)
    0 / 69 (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
    Upper gastrointestinal haemorrhage
         subjects affected / exposed
    0 / 111 (0.00%)
    8 / 224 (3.57%)
    1 / 69 (1.45%)
         occurrences causally related to treatment / all
    0 / 0
    4 / 10
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    Vomiting
         subjects affected / exposed
    1 / 111 (0.90%)
    1 / 224 (0.45%)
    1 / 69 (1.45%)
         occurrences causally related to treatment / all
    0 / 1
    1 / 2
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hepatobiliary disorders
    Bile duct stenosis
         subjects affected / exposed
    0 / 111 (0.00%)
    1 / 224 (0.45%)
    0 / 69 (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
    Cholangitis acute
         subjects affected / exposed
    0 / 111 (0.00%)
    0 / 224 (0.00%)
    1 / 69 (1.45%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Renal and urinary disorders
    Acute kidney injury
         subjects affected / exposed
    0 / 111 (0.00%)
    1 / 224 (0.45%)
    1 / 69 (1.45%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    Musculoskeletal and connective tissue disorders
    Back pain
         subjects affected / exposed
    1 / 111 (0.90%)
    0 / 224 (0.00%)
    0 / 69 (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
    Myalgia
         subjects affected / exposed
    0 / 111 (0.00%)
    1 / 224 (0.45%)
    0 / 69 (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
    Infections and infestations
    Atypical pneumonia
         subjects affected / exposed
    0 / 111 (0.00%)
    1 / 224 (0.45%)
    0 / 69 (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
    Cellulitis
         subjects affected / exposed
    0 / 111 (0.00%)
    0 / 224 (0.00%)
    1 / 69 (1.45%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Device related infection
         subjects affected / exposed
    0 / 111 (0.00%)
    1 / 224 (0.45%)
    0 / 69 (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
    Escherichia infection
         subjects affected / exposed
    0 / 111 (0.00%)
    1 / 224 (0.45%)
    0 / 69 (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
    Gastrointestinal infection
         subjects affected / exposed
    0 / 111 (0.00%)
    1 / 224 (0.45%)
    0 / 69 (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
    Infection
         subjects affected / exposed
    0 / 111 (0.00%)
    2 / 224 (0.89%)
    0 / 69 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Lower respiratory tract infection
         subjects affected / exposed
    0 / 111 (0.00%)
    1 / 224 (0.45%)
    0 / 69 (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 abscess
         subjects affected / exposed
    0 / 111 (0.00%)
    1 / 224 (0.45%)
    0 / 69 (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
    Lung infection
         subjects affected / exposed
    0 / 111 (0.00%)
    0 / 224 (0.00%)
    1 / 69 (1.45%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Meningitis
         subjects affected / exposed
    0 / 111 (0.00%)
    0 / 224 (0.00%)
    1 / 69 (1.45%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pneumonia
         subjects affected / exposed
    5 / 111 (4.50%)
    7 / 224 (3.13%)
    2 / 69 (2.90%)
         occurrences causally related to treatment / all
    2 / 5
    1 / 7
    0 / 2
         deaths causally related to treatment / all
    1 / 2
    0 / 2
    0 / 0
    Respiratory tract infection
         subjects affected / exposed
    1 / 111 (0.90%)
    1 / 224 (0.45%)
    0 / 69 (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
    Sepsis
         subjects affected / exposed
    0 / 111 (0.00%)
    1 / 224 (0.45%)
    0 / 69 (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
    Septic shock
         subjects affected / exposed
    0 / 111 (0.00%)
    2 / 224 (0.89%)
    0 / 69 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    Staphylococcal sepsis
         subjects affected / exposed
    1 / 111 (0.90%)
    0 / 224 (0.00%)
    0 / 69 (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
    Urinary tract infection
         subjects affected / exposed
    0 / 111 (0.00%)
    1 / 224 (0.45%)
    0 / 69 (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
    Intervertebral Discitis
         subjects affected / exposed
    0 / 111 (0.00%)
    1 / 224 (0.45%)
    0 / 69 (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
    Metabolism and nutrition disorders
    Decreased appetite
         subjects affected / exposed
    0 / 111 (0.00%)
    1 / 224 (0.45%)
    0 / 69 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Dehydration
         subjects affected / exposed
    0 / 111 (0.00%)
    1 / 224 (0.45%)
    0 / 69 (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
    Diabetes mellitus
         subjects affected / exposed
    0 / 111 (0.00%)
    0 / 224 (0.00%)
    1 / 69 (1.45%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hyperglycaemia
         subjects affected / exposed
    0 / 111 (0.00%)
    1 / 224 (0.45%)
    0 / 69 (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
    Hypophagia
         subjects affected / exposed
    0 / 111 (0.00%)
    0 / 224 (0.00%)
    1 / 69 (1.45%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
         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
    		 Standard Taxane Therapy Trastuzumab Emtansine 2.4 mg Trastuzumab Emtansine 3.6 mg
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    105 / 111 (94.59%)
    211 / 224 (94.20%)
    62 / 69 (89.86%)
    Investigations
    Alanine aminotransferase increased
         subjects affected / exposed
    4 / 111 (3.60%)
    21 / 224 (9.38%)
    5 / 69 (7.25%)
         occurrences all number
    8
    34
    8
    Aspartate aminotransferase increased
         subjects affected / exposed
    5 / 111 (4.50%)
    36 / 224 (16.07%)
    10 / 69 (14.49%)
         occurrences all number
    6
    49
    15
    Blood alkaline phosphatase increased
         subjects affected / exposed
    3 / 111 (2.70%)
    8 / 224 (3.57%)
    5 / 69 (7.25%)
         occurrences all number
    4
    12
    6
    Blood bilirubin increased
         subjects affected / exposed
    3 / 111 (2.70%)
    13 / 224 (5.80%)
    1 / 69 (1.45%)
         occurrences all number
    4
    18
    2
    Weight decereased
         subjects affected / exposed
    8 / 111 (7.21%)
    13 / 224 (5.80%)
    3 / 69 (4.35%)
         occurrences all number
    9
    13
    3
    Nervous system disorders
    Dizziness
         subjects affected / exposed
    5 / 111 (4.50%)
    14 / 224 (6.25%)
    5 / 69 (7.25%)
         occurrences all number
    5
    17
    6
    Headache
         subjects affected / exposed
    6 / 111 (5.41%)
    24 / 224 (10.71%)
    2 / 69 (2.90%)
         occurrences all number
    6
    31
    3
    Dysgeusia
         subjects affected / exposed
    11 / 111 (9.91%)
    18 / 224 (8.04%)
    5 / 69 (7.25%)
         occurrences all number
    11
    18
    5
    Neuropathy peripheral
         subjects affected / exposed
    11 / 111 (9.91%)
    22 / 224 (9.82%)
    2 / 69 (2.90%)
         occurrences all number
    14
    24
    2
    Peripheral sensory neuropathy
         subjects affected / exposed
    22 / 111 (19.82%)
    21 / 224 (9.38%)
    4 / 69 (5.80%)
         occurrences all number
    22
    23
    4
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    35 / 111 (31.53%)
    75 / 224 (33.48%)
    15 / 69 (21.74%)
         occurrences all number
    47
    98
    17
    Leukopenia
         subjects affected / exposed
    10 / 111 (9.01%)
    2 / 224 (0.89%)
    1 / 69 (1.45%)
         occurrences all number
    23
    7
    2
    Febrile neutropenia
         subjects affected / exposed
    7 / 111 (6.31%)
    1 / 224 (0.45%)
    0 / 69 (0.00%)
         occurrences all number
    7
    1
    0
    Neutropenia
         subjects affected / exposed
    55 / 111 (49.55%)
    24 / 224 (10.71%)
    7 / 69 (10.14%)
         occurrences all number
    108
    55
    9
    Thrombocytopenia
         subjects affected / exposed
    3 / 111 (2.70%)
    60 / 224 (26.79%)
    18 / 69 (26.09%)
         occurrences all number
    3
    110
    26
    General disorders and administration site conditions
    Asthenia
         subjects affected / exposed
    9 / 111 (8.11%)
    39 / 224 (17.41%)
    9 / 69 (13.04%)
         occurrences all number
    18
    49
    11
    Chills
         subjects affected / exposed
    2 / 111 (1.80%)
    12 / 224 (5.36%)
    4 / 69 (5.80%)
         occurrences all number
    2
    17
    4
    Malaise
         subjects affected / exposed
    5 / 111 (4.50%)
    12 / 224 (5.36%)
    1 / 69 (1.45%)
         occurrences all number
    8
    13
    1
    Fatigue
         subjects affected / exposed
    51 / 111 (45.95%)
    68 / 224 (30.36%)
    24 / 69 (34.78%)
         occurrences all number
    71
    87
    37
    Oedema peripheral
         subjects affected / exposed
    16 / 111 (14.41%)
    14 / 224 (6.25%)
    5 / 69 (7.25%)
         occurrences all number
    19
    18
    5
    Mucosal inflammation
         subjects affected / exposed
    7 / 111 (6.31%)
    8 / 224 (3.57%)
    1 / 69 (1.45%)
         occurrences all number
    8
    8
    1
    Pain
         subjects affected / exposed
    11 / 111 (9.91%)
    6 / 224 (2.68%)
    3 / 69 (4.35%)
         occurrences all number
    14
    6
    3
    Pyrexia
         subjects affected / exposed
    17 / 111 (15.32%)
    44 / 224 (19.64%)
    11 / 69 (15.94%)
         occurrences all number
    19
    61
    14
    Gastrointestinal disorders
    Abdominal distension
         subjects affected / exposed
    4 / 111 (3.60%)
    10 / 224 (4.46%)
    6 / 69 (8.70%)
         occurrences all number
    4
    10
    6
    Abdominal pain
         subjects affected / exposed
    12 / 111 (10.81%)
    42 / 224 (18.75%)
    10 / 69 (14.49%)
         occurrences all number
    12
    46
    13
    Abdominal pain upper
         subjects affected / exposed
    8 / 111 (7.21%)
    19 / 224 (8.48%)
    6 / 69 (8.70%)
         occurrences all number
    10
    23
    6
    Constipation
         subjects affected / exposed
    22 / 111 (19.82%)
    47 / 224 (20.98%)
    10 / 69 (14.49%)
         occurrences all number
    25
    59
    11
    Diarrhoea
         subjects affected / exposed
    27 / 111 (24.32%)
    33 / 224 (14.73%)
    10 / 69 (14.49%)
         occurrences all number
    42
    47
    11
    Dry mouth
         subjects affected / exposed
    2 / 111 (1.80%)
    20 / 224 (8.93%)
    4 / 69 (5.80%)
         occurrences all number
    3
    20
    4
    Dyspepsia
         subjects affected / exposed
    11 / 111 (9.91%)
    17 / 224 (7.59%)
    6 / 69 (8.70%)
         occurrences all number
    11
    18
    6
    Dysphagia
         subjects affected / exposed
    4 / 111 (3.60%)
    9 / 224 (4.02%)
    4 / 69 (5.80%)
         occurrences all number
    4
    9
    4
    Nausea
         subjects affected / exposed
    30 / 111 (27.03%)
    57 / 224 (25.45%)
    15 / 69 (21.74%)
         occurrences all number
    42
    73
    19
    Stomatitis
         subjects affected / exposed
    21 / 111 (18.92%)
    14 / 224 (6.25%)
    3 / 69 (4.35%)
         occurrences all number
    23
    16
    5
    Vomiting
         subjects affected / exposed
    15 / 111 (13.51%)
    41 / 224 (18.30%)
    17 / 69 (24.64%)
         occurrences all number
    24
    59
    24
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    12 / 111 (10.81%)
    13 / 224 (5.80%)
    7 / 69 (10.14%)
         occurrences all number
    16
    13
    9
    Epistaxis
         subjects affected / exposed
    6 / 111 (5.41%)
    26 / 224 (11.61%)
    7 / 69 (10.14%)
         occurrences all number
    6
    37
    10
    Dyspnoea
         subjects affected / exposed
    9 / 111 (8.11%)
    21 / 224 (9.38%)
    10 / 69 (14.49%)
         occurrences all number
    9
    23
    12
    Hiccups
         subjects affected / exposed
    8 / 111 (7.21%)
    5 / 224 (2.23%)
    6 / 69 (8.70%)
         occurrences all number
    10
    5
    9
    Skin and subcutaneous tissue disorders
    Alopecia
         subjects affected / exposed
    57 / 111 (51.35%)
    7 / 224 (3.13%)
    1 / 69 (1.45%)
         occurrences all number
    60
    7
    1
    Nail disorder
         subjects affected / exposed
    7 / 111 (6.31%)
    4 / 224 (1.79%)
    0 / 69 (0.00%)
         occurrences all number
    7
    4
    0
    Palmar−plantar erythrodysaesthesia syndrome
         subjects affected / exposed
    8 / 111 (7.21%)
    8 / 224 (3.57%)
    2 / 69 (2.90%)
         occurrences all number
    10
    8
    2
    Rash
         subjects affected / exposed
    12 / 111 (10.81%)
    15 / 224 (6.70%)
    3 / 69 (4.35%)
         occurrences all number
    16
    16
    3
    Pruritus
         subjects affected / exposed
    11 / 111 (9.91%)
    7 / 224 (3.13%)
    4 / 69 (5.80%)
         occurrences all number
    13
    7
    4
    Psychiatric disorders
    Insominia
         subjects affected / exposed
    10 / 111 (9.01%)
    18 / 224 (8.04%)
    5 / 69 (7.25%)
         occurrences all number
    14
    21
    5
    Depression
         subjects affected / exposed
    0 / 111 (0.00%)
    5 / 224 (2.23%)
    4 / 69 (5.80%)
         occurrences all number
    0
    5
    4
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    13 / 111 (11.71%)
    13 / 224 (5.80%)
    6 / 69 (8.70%)
         occurrences all number
    16
    17
    6
    Back pain
         subjects affected / exposed
    6 / 111 (5.41%)
    13 / 224 (5.80%)
    6 / 69 (8.70%)
         occurrences all number
    7
    13
    6
    Myalgia
         subjects affected / exposed
    18 / 111 (16.22%)
    13 / 224 (5.80%)
    6 / 69 (8.70%)
         occurrences all number
    21
    16
    6
    Metabolism and nutrition disorders
    Deceased appetite
         subjects affected / exposed
    32 / 111 (28.83%)
    57 / 224 (25.45%)
    22 / 69 (31.88%)
         occurrences all number
    37
    60
    26
    Hypoalbuminaemia
         subjects affected / exposed
    5 / 111 (4.50%)
    13 / 224 (5.80%)
    3 / 69 (4.35%)
         occurrences all number
    5
    14
    3
    Hypokalaemia
         subjects affected / exposed
    1 / 111 (0.90%)
    22 / 224 (9.82%)
    3 / 69 (4.35%)
         occurrences all number
    1
    29
    4

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    12 Sep 2012
    The distinctions between “Stage 1” and “Stage 2” were clarified; methods for study conduct (taxane selection, concomitant therapies, cycle length, PK and pharmacodynamic sampling, and dosing instructions) were clarified; the dose modification guidance was aligned with the most current, harmonized standards across the trastuzumab emtansine clinical program; the description of the futility analysis was updated; the eligibility criteria were revised.
    13 Jan 2014
    The IDMC regimen selection recommendation from 14 October 2013, to continue with the 2.4mg/kg qw regimen was added; important safety language updates for severe bleeding events, severe hepatotoxicity, and risk of left ventricular ejection fraction (LVEF), as well as dose modification guideline updates were included; the allowed use of HER2 testing from other studies for eligibility was been clarified.
    19 Jun 2014
    Option to open an extension cohort to enroll in China after the last patient in (LPI) had been enrolled into the main study (this option has not been implemented). The study exclusion criteria were also modified to disallow prior enrollment in Study BO25114 (NCT01774786 and EudraCT 2012-003554-83).
    21 Apr 2015
    This version was released to clearly spell out the study end rules for the main study, and the China extension cohort in the event this was initiated.

    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.
    The study was terminated by the Sponsor as the primary analysis results did not meet the primary endpoint.
    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.

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