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    Clinical Trial Results:
    National Phase IIIb Prospective Two-Cohort Non-Randomized, Multi-centre, Open Label Study to Assess the Safety of Subcutaneous Trastuzumab and Molecular Biomarkers in Patients with Early and Locally Advanced HER2-Positive Breast Cancer

    Summary
    EudraCT number
    		 2013-001161-16
    Trial protocol
    		 IT  
    Global end of trial date

    Results information
    Results version number
    		 v1
    This version publication date
    28 May 2017
    First version publication date
    28 May 2017
    Other versions
    		 v2 , v3 , v4

    Trial information

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    Trial identification
    Sponsor protocol code
    ML28879
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT01940497
    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, +4161 6878333, global.trial_information@roche.com
    Scientific contact
    Roche Trial Information Hotline, F. Hoffmann-La Roche AG, +4161 6878333, 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
    Interim
    Date of interim/final analysis
    05 Apr 2016
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    05 Apr 2016
    Global end of trial reached?
    No
    General information about the trial
    Main objective of the trial
    The primary objective of the study was to assess the safety and tolerability of trastuzumab solution injected subcutaneously (vial or single-use injection device [SID]) in participants with human epidermal growth factor receptor 2 (HER2)-positive early or locally-advanced breast cancer.
    Protection of trial subjects
    The study was conducted in accordance with the principles of the “Declaration of Helsinki” and Good Clinical Practice (GCP) according to the regulations and procedures.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    07 Nov 2013
    Long term follow-up planned
    Yes
    Long term follow-up rationale
    		 Safety
    Long term follow-up duration
    		 24 Months
    Independent data monitoring committee (IDMC) involvement?
    No
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Italy: 240
    Worldwide total number of subjects
    240
    EEA total number of subjects
    240
    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)
    197
    From 65 to 84 years
    43
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 -

    Pre-assignment
    Screening details
    		 Out of 263 screened participants, 240 participants were enrolled in the study.

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

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Trastuzumab (Vial)
    Arm description
    		 Participants received trastuzumab 600 milligrams (mg) subcutaneously using a vial every 3 weeks (1 cycle) for 1 year (4 cycles in combination with adjuvant or neoadjuvant chemotherapy [consisting of doxorubicin, paclitaxel or docetaxel] and 14 cycles administered alone).
    Arm type
    		 Experimental

    Investigational medicinal product name
    Trastuzumab
    Investigational medicinal product code
    Other name
    Herceptin
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    Participants received trastuzumab 600 mg subcutaneously every 3 weeks (1 cycle) for 18 cycles.

    Arm title
    		 Trastuzumab (SID)
    Arm description
    		 Participants received trastuzumab 600 mg subcutaneously using SID every 3 weeks (1 cycle) for 1 year (4 cycles in combination with adjuvant or neoadjuvant chemotherapy [consisting of doxorubicin, paclitaxel or docetaxel] and 14 cycles administered alone).
    Arm type
    		 Experimental

    Investigational medicinal product name
    Trastuzumab
    Investigational medicinal product code
    Other name
    Herceptin
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    Participants received trastuzumab 600 mg subcutaneously every 3 weeks (1 cycle) for 18 cycles.

    Number of subjects in period 1
    		Trastuzumab (Vial) Trastuzumab (SID)
    Started
    121
    119
    Treated
    115
    113
    Completed
    1
    1
    Not completed
    120
    118
         Adverse event/Intercurrent illness
    1
    -
         Consent withdrawn by subject
    2
    -
         Failure to return
    -
    1
         Ongoing at data cut-off
    116
    117
         Protocol deviation
    1
    -

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Trastuzumab (Vial)
    Reporting group description
    		 Participants received trastuzumab 600 milligrams (mg) subcutaneously using a vial every 3 weeks (1 cycle) for 1 year (4 cycles in combination with adjuvant or neoadjuvant chemotherapy [consisting of doxorubicin, paclitaxel or docetaxel] and 14 cycles administered alone).

    Reporting group title
    Trastuzumab (SID)
    Reporting group description
    		 Participants received trastuzumab 600 mg subcutaneously using SID every 3 weeks (1 cycle) for 1 year (4 cycles in combination with adjuvant or neoadjuvant chemotherapy [consisting of doxorubicin, paclitaxel or docetaxel] and 14 cycles administered alone).

    Reporting group values
    		 Trastuzumab (Vial) Trastuzumab (SID) Total
    Number of subjects
    		 121 119 240
    Age Categorical
    Units: Subjects
        In utero
    		 0 0 0
        Preterm newborn infants (gestational age < 37 wks)
    		 0 0 0
        Newborns (0-27 days)
    		 0 0 0
        Infants and toddlers (28 days-23 months)
    		 0 0 0
        Children (2-11 years)
    		 0 0 0
        Adolescents (12-17 years)
    		 0 0 0
        Adults (18-64 years)
    		 94 103 197
        From 65-84 years
    		 27 16 43
        85 years and over
    		 0 0 0
    Age Continuous
    Units: years
        arithmetic mean (standard deviation)
    		 55.1 ( 10.51 ) 53.2 ( 10.37 ) -
    Gender Categorical
    Units: Subjects
        Female
    		 120 119 239
        Male
    		 1 0 1

    End points

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    End points reporting groups
    Reporting group title
    Trastuzumab (Vial)
    Reporting group description
    		 Participants received trastuzumab 600 milligrams (mg) subcutaneously using a vial every 3 weeks (1 cycle) for 1 year (4 cycles in combination with adjuvant or neoadjuvant chemotherapy [consisting of doxorubicin, paclitaxel or docetaxel] and 14 cycles administered alone).

    Reporting group title
    Trastuzumab (SID)
    Reporting group description
    		 Participants received trastuzumab 600 mg subcutaneously using SID every 3 weeks (1 cycle) for 1 year (4 cycles in combination with adjuvant or neoadjuvant chemotherapy [consisting of doxorubicin, paclitaxel or docetaxel] and 14 cycles administered alone).

    Subject analysis set title
    Trastuzumab (Vial): Adjuvant
    Subject analysis set type
    		 Safety analysis
    Subject analysis set description
    Participants received trastuzumab 600 mg subcutaneously using a vial every 3 weeks (1 cycle) for 1 year (4 cycles in combination with adjuvant chemotherapy [consisting of doxorubicin, paclitaxel or docetaxel] and 14 cycles administered alone).

    Subject analysis set title
    Trastuzumab (Vial): Neoadjuvant
    Subject analysis set type
    		 Safety analysis
    Subject analysis set description
    Participants received trastuzumab 600 mg subcutaneously using a vial every 3 weeks (1 cycle) for 1 year (4 cycles in combination with neoadjuvant chemotherapy [consisting of doxorubicin, paclitaxel or docetaxel] and 14 cycles administered alone).

    Subject analysis set title
    Trastuzumab (SID): Adjuvant
    Subject analysis set type
    		 Safety analysis
    Subject analysis set description
    Participants received trastuzumab 600 mg subcutaneously using SID every 3 weeks (1 cycle) for 1 year (4 cycles in combination with adjuvant chemotherapy [consisting of doxorubicin, paclitaxel or docetaxel] and 14 cycles administered alone).

    Subject analysis set title
    Trastuzumab (SID): Neoadjuvant
    Subject analysis set type
    		 Safety analysis
    Subject analysis set description
    Participants received trastuzumab 600 mg subcutaneously using SID every 3 weeks (1 cycle) for 1 year (4 cycles in combination with neoadjuvant chemotherapy [consisting of doxorubicin, paclitaxel or docetaxel] and 14 cycles administered alone).

    Subject analysis set title
    Trastuzumab (Vial): Adjuvant
    Subject analysis set type
    		 Modified intention-to-treat
    Subject analysis set description
    Participants received trastuzumab 600 mg subcutaneously using a vial every 3 weeks (1 cycle) for 1 year (4 cycles in combination with adjuvant chemotherapy [consisting of doxorubicin, paclitaxel or docetaxel] and 14 cycles administered alone).

    Subject analysis set title
    Trastuzumab (Vial): Neoadjuvant
    Subject analysis set type
    		 Modified intention-to-treat
    Subject analysis set description
    Participants received trastuzumab 600 mg subcutaneously using a vial every 3 weeks (1 cycle) for 1 year (4 cycles in combination with neoadjuvant chemotherapy [consisting of doxorubicin, paclitaxel or docetaxel] and 14 cycles administered alone).

    Subject analysis set title
    Trastuzumab (SID): Adjuvant
    Subject analysis set type
    		 Modified intention-to-treat
    Subject analysis set description
    Participants received trastuzumab 600 mg subcutaneously using SID every 3 weeks (1 cycle) for 1 year (4 cycles in combination with adjuvant chemotherapy [consisting of doxorubicin, paclitaxel or docetaxel] and 14 cycles administered alone).

    Subject analysis set title
    Trastuzumab (SID): Neoadjuvant
    Subject analysis set type
    		 Modified intention-to-treat
    Subject analysis set description
    Participants received trastuzumab 600 mg subcutaneously using SID every 3 weeks (1 cycle) for 1 year (4 cycles in combination with neoadjuvant chemotherapy [consisting of doxorubicin, paclitaxel or docetaxel] and 14 cycles administered alone).

    Subject analysis set title
    HCPs: Trastuzumab (Vial)
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Participants received trastuzumab 600 mg subcutaneously using a vial every 3 weeks (1 cycle) for 1 year (4 cycles in combination with adjuvant or neoadjuvant chemotherapy [consisting of doxorubicin, paclitaxel or docetaxel] and 14 cycles administered alone). Trastuzumab using vial had to be administered by an HCP. Such HCPs were included in this group.

    Subject analysis set title
    HCPs: Trastuzumab (SID)
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Participants received trastuzumab 600 mg subcutaneously using SID every 3 weeks (1 cycle) for 1 year (4 cycles in combination with adjuvant or neoadjuvant chemotherapy [consisting of doxorubicin, paclitaxel or docetaxel] and 14 cycles administered alone). Trastuzumab using SID had to be administered by an HCP or by the participant after appropriate training and under HCP supervision. Such HCPs were included in this group.

    Primary: Percentage of Participants With Treatment-Emergent Adverse Events (TEAEs)

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    End point title
    		 Percentage of Participants With Treatment-Emergent Adverse Events (TEAEs) [1]
    End point description
    An AE was any untoward medical occurrence in a participant who received study drug without regard to possibility of causal relationship. TEAEs were the AEs occurring from starting on the day of or after first administration of trastuzumab and within 28 days after last dose of trastuzumab. Data for this outcome measure were analyzed and reported by adjuvant versus neo-adjuvant chemotherapy groups within each treatment arm. Safety population included all enrolled participants who received at least one dose of study medication. Data for this outcome measure were analyzed and reported by adjuvant versus neoadjuvant chemotherapy groups within each treatment arm.
    End point type
    Primary
    End point timeframe
    Day 1 up to 28 days after last dose of trastuzumab (assessed up to cut off date 05 April 2016; up to approximately 1 year)
    Notes
    [1] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: No statistical analysis was planned for this endpoint.
    End point values
    		 Trastuzumab (Vial): Adjuvant Trastuzumab (Vial): Neoadjuvant Trastuzumab (SID): Adjuvant Trastuzumab (SID): Neoadjuvant
    Number of subjects analysed
    95
    20
    92
    21
    Units: percentage of participants
        number (not applicable)
    98.9
    100
    89.1
    95.2
    No statistical analyses for this end point

    Secondary: Actual Dose of Trastuzumab Administered

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    End point title
    		 Actual Dose of Trastuzumab Administered
    End point description
    Actual dose (mg) administered = (sum over all cycles of actual dose received [mg] divided by number of cycles). Safety population. Data for this outcome measure were analyzed and reported by adjuvant versus neoadjuvant chemotherapy groups within each treatment arm.
    End point type
    Secondary
    End point timeframe
    Day 1 up last dose of trastuzumab (assessed up to cut off date 05 April 2016; up to approximately 1 year)
    End point values
    		 Trastuzumab (Vial): Adjuvant Trastuzumab (Vial): Neoadjuvant Trastuzumab (SID): Adjuvant Trastuzumab (SID): Neoadjuvant
    Number of subjects analysed
    95
    20
    92
    21
    Units: mg
        arithmetic mean (standard deviation)
    599.68 ( 3.078 )
    600 ( 0 )
    593.34 ( 16.551 )
    595.86 ( 10.413 )
    No statistical analyses for this end point

    Secondary: Duration of Treatment with Trastuzumab

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    End point title
    		 Duration of Treatment with Trastuzumab
    End point description
    Safety population. Data for this outcome measure were analyzed and reported by adjuvant versus neoadjuvant chemotherapy groups within each treatment arm.
    End point type
    Secondary
    End point timeframe
    Day 1 up last dose of trastuzumab (assessed up to cut off date 05 April 2016; up to approximately 1 year)
    End point values
    		 Trastuzumab (Vial): Adjuvant Trastuzumab (Vial): Neoadjuvant Trastuzumab (SID): Adjuvant Trastuzumab (SID): Neoadjuvant
    Number of subjects analysed
    95
    20
    92
    21
    Units: days
        arithmetic mean (standard deviation)
    344.99 ( 72.128 )
    351.2 ( 55.821 )
    339.11 ( 85.467 )
    350.86 ( 90.017 )
    No statistical analyses for this end point

    Secondary: Percentage of Participants Who Received Concomitant Medications

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    End point title
    		 Percentage of Participants Who Received Concomitant Medications
    End point description
    Safety population.
    End point type
    Secondary
    End point timeframe
    Screening (Day -28 to -1) up to 2.5 years (assessed up to cut off date 05 April 2016)
    End point values
    		 Trastuzumab (Vial) Trastuzumab (SID)
    Number of subjects analysed
    115
    113
    Units: percentage of participants
        number (not applicable)
    100
    100
    No statistical analyses for this end point

    Secondary: Percentage of Participants with Pathological Complete Response (pCR) (Neoadjuvant Groups Only) Using Mammography

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    End point title
    		 Percentage of Participants with Pathological Complete Response (pCR) (Neoadjuvant Groups Only) Using Mammography
    End point description
    In the neoadjuvant setting, the activity of two sequential drug regimens, doxorubicin-containing chemotherapy followed by paclitaxel or docetaxel chemotherapy in combination with trastuzumab, was assessed as the percentage of participants with pCR in breast and nodes using mammography. pCR was defined as the absence of histological evidence of invasive breast cancer cells in the tissue specimen removed from the breast after preoperative treatment. Modified intent-to-treat (mITT) population included all enrolled participants satisfying criteria for eligibility. Data for this outcome measure were analyzed and reported only for neoadjuvant groups within each treatment arm.
    End point type
    Secondary
    End point timeframe
    Day 1 up to 24 weeks
    End point values
    		 Trastuzumab (Vial): Neoadjuvant Trastuzumab (SID): Neoadjuvant
    Number of subjects analysed
    22
    19
    Units: percentage of participants
        number (confidence interval 95%)
    47.4 (31 to 51)
    16.7 (8 to 24)
    No statistical analyses for this end point

    Secondary: Percentage of Participants with Event (Local, Regional or Distant Recurrence, Contralateral Breast Cancer or Death) Using Mammography

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    End point title
    		 Percentage of Participants with Event (Local, Regional or Distant Recurrence, Contralateral Breast Cancer or Death) Using Mammography
    End point description
    A participant was considered as disease free if the participant was free from local, regional or distant recurrence, contralateral breast cancer or death due to any cause (whichever occurred first). Percentage of participants with event at the cut off date were reported. m-ITT population. Here, ‘Number of Subjects Analysed’ = participants who were evaluable for this outcome measure. Data for this outcome measure were analyzed and reported by adjuvant versus neoadjuvant chemotherapy groups within each treatment arm.
    End point type
    Secondary
    End point timeframe
    Day 1 up to local, regional or distant recurrence, contralateral breast cancer or death due to any cause (whichever occurred first) (assessed up to cut off date 05 April 2016; up to approximately 2.5 years)
    End point values
    		 Trastuzumab (Vial): Adjuvant Trastuzumab (Vial): Neoadjuvant Trastuzumab (SID): Adjuvant Trastuzumab (SID): Neoadjuvant
    Number of subjects analysed
    92
    18
    91
    18
    Units: percentage of participants
        number (not applicable)
    12
    5.6
    2.2
    5.6
    No statistical analyses for this end point

    Secondary: Disease-Free Survival (DFS) Using Mammography

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    End point title
    		 Disease-Free Survival (DFS) Using Mammography
    End point description
    DFS was defined as the time from the first treatment to local, regional or distant recurrence, contralateral breast cancer or death due to any cause (whichever occurred first). Kaplan-Meier estimates were used for analysis. Participants who were disease-free were censored at the data cut off date. m-ITT population. Here, ‘Number of Subjects Analysed’ = participants who were evaluable for this outcome measure. Data for this outcome measure were analyzed and reported by adjuvant versus neoadjuvant chemotherapy groups within each treatment arm. Here, '99999' indicates that median and corresponding 95% confidence interval (CI) could not be estimated because majority of participants were censored at data cut off date.
    End point type
    Secondary
    End point timeframe
    Day 1 up to local, regional or distant recurrence, contralateral breast cancer or death due to any cause (whichever occurred first) (assessed up to cut off date 05 April 2016; up to approximately 2.5 years)
    End point values
    		 Trastuzumab (Vial): Adjuvant Trastuzumab (Vial): Neoadjuvant Trastuzumab (SID): Adjuvant Trastuzumab (SID): Neoadjuvant
    Number of subjects analysed
    92
    18
    91
    18
    Units: months
        median (confidence interval 95%)
    99999 (99999 to 99999)
    99999 (99999 to 99999)
    99999 (99999 to 99999)
    99999 (99999 to 99999)
    No statistical analyses for this end point

    Secondary: Percentage of Participants Who Died

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    End point title
    		 Percentage of Participants Who Died
    End point description
    m-ITT population. Data for this outcome measure were analyzed and reported by adjuvant versus neoadjuvant chemotherapy groups within each treatment arm.
    End point type
    Secondary
    End point timeframe
    Day 1 up to death due to any cause (assessed up to cut off date 05 April 2016; up to approximately 2.5 years)
    End point values
    		 Trastuzumab (Vial): Adjuvant Trastuzumab (Vial): Neoadjuvant Trastuzumab (SID): Adjuvant Trastuzumab (SID): Neoadjuvant
    Number of subjects analysed
    96
    22
    93
    19
    Units: percentage of participants
        number (not applicable)
    3.1
    0
    0
    0
    No statistical analyses for this end point

    Secondary: Overall Survival (OS)

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    End point title
    		 Overall Survival (OS)
    End point description
    Overall survival was defined as the time from the first treatment to death from any cause. Kaplan-Meier estimates were used for analysis. Participants who did not die were censored on the date they were last known to be alive. m-ITT population. Data for this outcome measure were analyzed and reported by adjuvant versus neoadjuvant chemotherapy groups within each treatment arm. Here, '99999' indicates that median and corresponding 95% CI could not be estimated because majority of participants were censored at data cut off date.
    End point type
    Secondary
    End point timeframe
    Day 1 up to death due to any cause (assessed up to cut off date 05 April 2016; up to approximately 2.5 years)
    End point values
    		 Trastuzumab (Vial): Adjuvant Trastuzumab (Vial): Neoadjuvant Trastuzumab (SID): Adjuvant Trastuzumab (SID): Neoadjuvant
    Number of subjects analysed
    96
    22
    93
    19
    Units: months
        median (confidence interval 95%)
    99999 (99999 to 99999)
    99999 (99999 to 99999)
    99999 (99999 to 99999)
    99999 (99999 to 99999)
    No statistical analyses for this end point

    Secondary: Percentage of Participants by Response to Patient Satisfaction Questionnaire (PSQ)

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    End point title
    		 Percentage of Participants by Response to Patient Satisfaction Questionnaire (PSQ) [2]
    End point description
    Participants were asked following 5 questions:(1)“Following first injection given by physician/nurse and training on SID, I felt comfortable injecting it by myself”;(2)“ SID was convenient and easy to use”;(3)“I am confident giving myself injection in thigh with SID”;(4)“Taking all things into account, I find self-administration using SID satisfactory”;(5)“If given opportunity, I would choose to continue self-injection using SID at home”. Responses were recorded as:“Unknown”,“Strongly Disagree”,“Disagree”,“Unsure”,“Agree”,“Strongly Agree”.Percentage of participants providing responses was reported. PSQ population included all enrolled participants from SID group who were able to use SID and had completed a minimum 14 administrations subcutaneously using SID (at least 10 of which were self-administered). Here, ‘Number of Subjects Analysed’ = participants who were evaluable for this outcome measure.Data for this outcome measure were analyzed and reported only for SID arm.
    End point type
    Secondary
    End point timeframe
    After at least 14 cycles (1 cycle = 21 days; maximum up to 1 year)
    Notes
    [2] - 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: Data were not reported for vial group as this endpoint was only applicable for SID group.
    End point values
    		 Trastuzumab (SID)
    Number of subjects analysed
    19
    Units: percentage of participants
    number (not applicable)
        Comfortable: Unknown
    0
        Comfortable: Strongly Disagree
    0
        Comfortable: Disagree
    0
        Comfortable: Unsure
    5.3
        Comfortable: Agree
    57.9
        Comfortable: Strongly Agree
    36.8
        Convenient: Unknown
    0
        Convenient: Strongly Disagree
    0
        Convenient: Disagree
    0
        Convenient: Unsure
    10.5
        Convenient: Agree
    36.8
        Convenient: Strongly Agree
    52.6
        Confident: Unknown
    0
        Confident: Strongly Disagree
    0
        Confident: Disagree
    0
        Confident: Unsure
    5.3
        Confident: Agree
    52.6
        Confident: Strongly Agree
    42.1
        Satisfactory: Unknown
    5.3
        Satisfactory: Strongly Disagree
    0
        Satisfactory: Disagree
    0
        Satisfactory: Unsure
    10.5
        Satisfactory: Agree
    36.8
        Satisfactory: Strongly Agree
    47.4
        Would continue: Unknown
    0
        Would continue: Strongly Disagree
    0
        Would continue: Disagree
    15.8
        Would continue: Unsure
    5.3
        Would continue: Agree
    31.6
        Would continue: Strongly Agree
    47.4
    No statistical analyses for this end point

    Secondary: Percentage of Health Care Professionals (HCPs) by Response to Health Care Professional Questionnaire (HCPQ)

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    End point title
    		 Percentage of Health Care Professionals (HCPs) by Response to Health Care Professional Questionnaire (HCPQ)
    End point description
    Percentage of HCPs providing responses to various questions related to overall ease of study drug administration was reported in different categories, where categories indicate all possible responses to such questions. HCPQ population included all investigators and study nurses who completed the questionnaire at each site when at least 4 participants from their site had received at least 5 cycles of adjuvant study treatment. Here, '9999' indicates that data were not evaluable as the question applied only to vial group; and '999999' indicates that data were not evaluable as the question applied only to SID group.
    End point type
    Secondary
    End point timeframe
    After at least 4 participants completed 5 cycles of adjuvant treatment (1 cycle = 21 days; maximum up to 1 year)
    End point values
    		 HCPs: Trastuzumab (Vial) HCPs: Trastuzumab (SID)
    Number of subjects analysed
    121 [3]
    119 [4]
    Units: percentage of health care professionals
    number (not applicable)
        Specialization: Oncologist
    17.3
    16
        Specialization: Specialist nurse
    69.2
    76
        Specialization: Other
    11.5
    8
        Specialization: Missing
    1.9
    0
        Personally administered/supervised: Always
    40.4
    48
        Personally administered/supervised: Sometimes
    51.9
    48
        Personally administered/supervised: Never
    7.7
    4
        If ‘Never’, who administered: Specialist nurse
    7.7
    4
        Syringe prepared at: Pharmacy
    55.8
    9999
        Syringe prepared at: Oncology ward
    40.4
    9999
        Syringe prepared at: Missing
    3.8
    9999
        Time to fill syringe: less than (<) 5 minutes
    67.3
    9999
        Time to fill syringe: 6-10 minutes
    13.5
    9999
        Time to fill syringe: 11-15 minutes
    5.8
    9999
        Time to fill syringe: Unknown
    13.5
    9999
        Total time for vial administration: <3 minutes
    1.9
    9999
        Total time for vial administration: <5 minutes
    59.6
    9999
        Total time for vial administration: 6-15 minutes
    38.5
    9999
        Time to prepare SID: <5 minutes
    999999
    72
        Time to prepare SID: 6-10 minutes
    999999
    14
        Time to prepare SID: 11-15 minutes
    999999
    4
        Time to prepare SID: 16-20 minutes
    999999
    2
        Time to prepare SID: >20 minutes
    999999
    8
        Total time for SID administration: <3 minutes
    999999
    26
        Total time for SID administration: <5 minutes
    999999
    30
        Total time for SID administration: 6-15 minutes
    999999
    44
        Injection site: Irritation: A lot
    1.9
    4
        Injection site: Irritation: A few
    46.2
    36
        Injection site: Irritation: None
    51.9
    60
        Injection site: Bruising: A few
    7.7
    10
        Injection site: Bruising: None
    92.3
    90
        Injection site: Infection: None
    100
    100
        Fever,shivering,flu-like,rash,swelling:A few
    15.4
    14
        Fever,shivering,flu-like,rash,swelling:None
    84.6
    86
        Time at hospital for administration: <2 hours
    44.2
    44
        Time at hospital for administration: >2, <3 hours
    23.1
    34
        Time at hospital for administration: >3, <4 hours
    23.1
    12
        Time at hospital for administration: >4 hours
    7.7
    10
        Time at hospital for administration: Missing
    1.9
    0
        Anxiety to participants: None
    82.7
    90
        Anxiety to participants: A fair amount
    17.3
    10
        Ease of vial administration: None
    5.8
    9999
        Ease of vial administration: A fair amount
    38.5
    9999
        Ease of vial administration: A lot
    55.8
    9999
        Subcutaneous route may simplify management: Yes
    94.2
    100
        Subcutaneous route may simplify management: No
    5.8
    0
        Would recommend SID to intravenous route: Yes
    96.2
    96
        Would recommend SID to intravenous route: No
    3.8
    4
        Would recommend subcutaneous route to medics: Yes
    100
    90
        Would recommend subcutaneous route to medics: No
    0
    8
        Would recommend subcutaneous to medics:Missing
    0
    2
        Convenience of using SID by participants: Yes
    94.2
    96
        Convenience of using SID by participants: No
    0
    4
        Convenience of using SID by participants: Yes/No
    5.8
    0
    Notes
    [3] - Total 52 health care professionals were analyzed.
    [4] - Total 50 health care professionals were analyzed.
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Day 1 up to 28 days after last dose of trastuzumab (assessed up to cut off date 05 April 2016; up to approximately 1 year)
    Adverse event reporting additional description
    Safety population
    Assessment type
    		 Non-systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    19.0
    Reporting groups
    Reporting group title
    Trastuzumab (Vial)
    Reporting group description
    		 Participants received trastuzumab 600 milligrams (mg) subcutaneously using a vial every 3 weeks (1 cycle) for 1 year (4 cycles in combination with adjuvant or neoadjuvant chemotherapy [consisting of doxorubicin, paclitaxel or docetaxel] and 14 cycles administered alone).

    Reporting group title
    Trastuzumab (SID)
    Reporting group description
    		 Participants received trastuzumab 600 mg subcutaneously using SID every 3 weeks (1 cycle) for 1 year (4 cycles in combination with adjuvant or neoadjuvant chemotherapy [consisting of doxorubicin, paclitaxel or docetaxel] and 14 cycles administered alone).

    Serious adverse events
    		 Trastuzumab (Vial) Trastuzumab (SID)
    Total subjects affected by serious adverse events
         subjects affected / exposed
    8 / 115 (6.96%)
    9 / 113 (7.96%)
         number of deaths (all causes)
    3
    0
         number of deaths resulting from adverse events
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Bladder transitional cell carcinoma
         subjects affected / exposed
    0 / 115 (0.00%)
    1 / 113 (0.88%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Intracranial tumour haemorrhage
         subjects affected / exposed
    1 / 115 (0.87%)
    0 / 113 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Ovarian epithelial cancer metastatic
         subjects affected / exposed
    1 / 115 (0.87%)
    0 / 113 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    General disorders and administration site conditions
    Pryexia
         subjects affected / exposed
    0 / 115 (0.00%)
    1 / 113 (0.88%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Immune system disorders
    Anaphylactic shock
         subjects affected / exposed
    1 / 115 (0.87%)
    1 / 113 (0.88%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Psychiatric disorders
    Generalised anxiety disorder
         subjects affected / exposed
    0 / 115 (0.00%)
    1 / 113 (0.88%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Investigations
    Neutrophil count decreased
         subjects affected / exposed
    0 / 115 (0.00%)
    1 / 113 (0.88%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Fibula fracture
         subjects affected / exposed
    1 / 115 (0.87%)
    0 / 113 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Tibia fracture
         subjects affected / exposed
    1 / 115 (0.87%)
    0 / 113 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac disorders
    Atrial fibrillation
         subjects affected / exposed
    1 / 115 (0.87%)
    0 / 113 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pleuropericarditis
         subjects affected / exposed
    1 / 115 (0.87%)
    0 / 113 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nervous system disorders
    Syncope
         subjects affected / exposed
    1 / 115 (0.87%)
    0 / 113 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    Febrile neutropenia
         subjects affected / exposed
    0 / 115 (0.00%)
    1 / 113 (0.88%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Adenocarcinoma pancreas
         subjects affected / exposed
    0 / 115 (0.00%)
    1 / 113 (0.88%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vomiting
         subjects affected / exposed
    0 / 115 (0.00%)
    1 / 113 (0.88%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal and urinary disorders
    Acute kidney injury
         subjects affected / exposed
    0 / 115 (0.00%)
    1 / 113 (0.88%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Intervertebral disc protrusion
         subjects affected / exposed
    1 / 115 (0.87%)
    0 / 113 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infections and infestations
    Gastroenteritis
         subjects affected / exposed
    1 / 115 (0.87%)
    0 / 113 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Trastuzumab (Vial) Trastuzumab (SID)
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    112 / 115 (97.39%)
    95 / 113 (84.07%)
    Investigations
    Ejection fraction decreased
         subjects affected / exposed
    14 / 115 (12.17%)
    5 / 113 (4.42%)
         occurrences all number
    14
    5
    Neutrophil count decreased
         subjects affected / exposed
    3 / 115 (2.61%)
    8 / 113 (7.08%)
         occurrences all number
    9
    10
    White blood cell count decreased
         subjects affected / exposed
    2 / 115 (1.74%)
    6 / 113 (5.31%)
         occurrences all number
    4
    11
    Vascular disorders
    Hot flush
         subjects affected / exposed
    12 / 115 (10.43%)
    9 / 113 (7.96%)
         occurrences all number
    12
    9
    Hypertension
         subjects affected / exposed
    12 / 115 (10.43%)
    9 / 113 (7.96%)
         occurrences all number
    12
    10
    Lymphoedema
         subjects affected / exposed
    6 / 115 (5.22%)
    2 / 113 (1.77%)
         occurrences all number
    6
    2
    Nervous system disorders
    Paraesthesia
         subjects affected / exposed
    51 / 115 (44.35%)
    28 / 113 (24.78%)
         occurrences all number
    77
    34
    Headache
         subjects affected / exposed
    8 / 115 (6.96%)
    4 / 113 (3.54%)
         occurrences all number
    9
    4
    Dysgeusia
         subjects affected / exposed
    6 / 115 (5.22%)
    7 / 113 (6.19%)
         occurrences all number
    6
    7
    Neurotoxicity
         subjects affected / exposed
    6 / 115 (5.22%)
    6 / 113 (5.31%)
         occurrences all number
    10
    6
    Blood and lymphatic system disorders
    Neutropenia
         subjects affected / exposed
    24 / 115 (20.87%)
    4 / 113 (3.54%)
         occurrences all number
    38
    4
    Anaemia
         subjects affected / exposed
    16 / 115 (13.91%)
    11 / 113 (9.73%)
         occurrences all number
    18
    12
    Leukopenia
         subjects affected / exposed
    13 / 115 (11.30%)
    6 / 113 (5.31%)
         occurrences all number
    19
    7
    General disorders and administration site conditions
    Asthenia
         subjects affected / exposed
    35 / 115 (30.43%)
    27 / 113 (23.89%)
         occurrences all number
    55
    36
    Pyrexia
         subjects affected / exposed
    22 / 115 (19.13%)
    17 / 113 (15.04%)
         occurrences all number
    36
    20
    Fatigue
         subjects affected / exposed
    12 / 115 (10.43%)
    13 / 113 (11.50%)
         occurrences all number
    18
    22
    Oedema peripheral
         subjects affected / exposed
    10 / 115 (8.70%)
    12 / 113 (10.62%)
         occurrences all number
    11
    17
    Mucosal inflammation
         subjects affected / exposed
    9 / 115 (7.83%)
    8 / 113 (7.08%)
         occurrences all number
    9
    11
    Chest pain
         subjects affected / exposed
    7 / 115 (6.09%)
    1 / 113 (0.88%)
         occurrences all number
    7
    1
    Pain
         subjects affected / exposed
    7 / 115 (6.09%)
    4 / 113 (3.54%)
         occurrences all number
    8
    5
    Influenza like illness
         subjects affected / exposed
    6 / 115 (5.22%)
    3 / 113 (2.65%)
         occurrences all number
    6
    3
    Oedema
         subjects affected / exposed
    6 / 115 (5.22%)
    2 / 113 (1.77%)
         occurrences all number
    6
    2
    Gastrointestinal disorders
    Diarrhoea
         subjects affected / exposed
    28 / 115 (24.35%)
    21 / 113 (18.58%)
         occurrences all number
    51
    23
    Nausea
         subjects affected / exposed
    10 / 115 (8.70%)
    16 / 113 (14.16%)
         occurrences all number
    19
    19
    Stomatitis
         subjects affected / exposed
    9 / 115 (7.83%)
    10 / 113 (8.85%)
         occurrences all number
    12
    11
    Abdominal pain upper
         subjects affected / exposed
    8 / 115 (6.96%)
    5 / 113 (4.42%)
         occurrences all number
    9
    5
    Constipation
         subjects affected / exposed
    8 / 115 (6.96%)
    7 / 113 (6.19%)
         occurrences all number
    10
    7
    Vomiting
         subjects affected / exposed
    7 / 115 (6.09%)
    7 / 113 (6.19%)
         occurrences all number
    7
    9
    Abdominal pain
         subjects affected / exposed
    6 / 115 (5.22%)
    3 / 113 (2.65%)
         occurrences all number
    7
    3
    Dyspepsia
         subjects affected / exposed
    6 / 115 (5.22%)
    4 / 113 (3.54%)
         occurrences all number
    10
    4
    Reproductive system and breast disorders
    Amenorrhoea
         subjects affected / exposed
    3 / 115 (2.61%)
    6 / 113 (5.31%)
         occurrences all number
    3
    6
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    15 / 115 (13.04%)
    17 / 113 (15.04%)
         occurrences all number
    16
    19
    Epistaxis
         subjects affected / exposed
    14 / 115 (12.17%)
    10 / 113 (8.85%)
         occurrences all number
    18
    10
    Skin and subcutaneous tissue disorders
    Erythema
         subjects affected / exposed
    25 / 115 (21.74%)
    16 / 113 (14.16%)
         occurrences all number
    30
    17
    Nail disorder
         subjects affected / exposed
    13 / 115 (11.30%)
    9 / 113 (7.96%)
         occurrences all number
    13
    9
    Nail ridging
         subjects affected / exposed
    7 / 115 (6.09%)
    1 / 113 (0.88%)
         occurrences all number
    7
    1
    Pruritus
         subjects affected / exposed
    7 / 115 (6.09%)
    7 / 113 (6.19%)
         occurrences all number
    7
    7
    Rash
         subjects affected / exposed
    6 / 115 (5.22%)
    7 / 113 (6.19%)
         occurrences all number
    6
    8
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    32 / 115 (27.83%)
    32 / 113 (28.32%)
         occurrences all number
    39
    38
    Myalgia
         subjects affected / exposed
    13 / 115 (11.30%)
    10 / 113 (8.85%)
         occurrences all number
    14
    14
    Back Pain
         subjects affected / exposed
    11 / 115 (9.57%)
    7 / 113 (6.19%)
         occurrences all number
    12
    8
    Pain in extremity
         subjects affected / exposed
    9 / 115 (7.83%)
    4 / 113 (3.54%)
         occurrences all number
    9
    5
    Musculoskeletal pain
         subjects affected / exposed
    7 / 115 (6.09%)
    9 / 113 (7.96%)
         occurrences all number
    9
    9
    Infections and infestations
    Cystitis
         subjects affected / exposed
    7 / 115 (6.09%)
    9 / 113 (7.96%)
         occurrences all number
    12
    11
    Influenza
         subjects affected / exposed
    3 / 115 (2.61%)
    12 / 113 (10.62%)
         occurrences all number
    3
    13
    Metabolism and nutrition disorders
    Decreased appetite
         subjects affected / exposed
    3 / 115 (2.61%)
    6 / 113 (5.31%)
         occurrences all number
    5
    8

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    27 May 2014
    - Modifications were done in eligibility criteria. - For the purpose of fertility preservation (adjuvant participants only), luteinizing hormone-releasing hormone analogous administration was allowed without limitation. - Clarification was added on the time points for mammography, radiological examinations, and centralized analysis of tissue and blood samples at baseline, and on the process of left ventricular ejection fraction (LVEF) assessments. - An additional blood pressure assessment was included after study drug administration. - Allowed contraception was updated to align with exclusion criteria. - Timelines and procedures to assess breast cancer at screening was added to the Schedule of Assessments to align with the text in the protocol. - The lowest dose of docetaxel (75 milligrams per square meter [mg/m^2]) was to be permitted because it is routine medical practice.

    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
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