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    Clinical Trial Results:
    A Phase III Prospective, Two-Cohort Non-Randomized, Multi-Centre, Multinational, Open-Label Study to Assess the Safety of Assisted- and Self-Administered Subcutaneous Trastuzumab as Therapy in Patients With Operable HER2-Positive Early Breast Cancer (SafeHER)

    Summary
    EudraCT number
    2011-005328-17
    Trial protocol
    IE   CZ   DE   ES   FR   HU   PT   GB   IT   GR   LT   PL   SI   SK   FI   BG   NL   SE  
    Global end of trial date

    Results information
    Results version number
    v1(current)
    This version publication date
    22 Mar 2017
    First version publication date
    22 Mar 2017
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    MO28048
    Additional study identifiers
    ISRCTN number
    -
    US NCT number
    NCT01566721
    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 61 6878333, global.trial_information@roche.com
    Scientific contact
    Roche Trial Information Hotline, F. Hoffmann-La Roche AG, +41 61 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
    10 Mar 2015
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    10 Mar 2015
    Global end of trial reached?
    No
    General information about the trial
    Main objective of the trial
    This multicenter, two-cohort, non-randomized, open-label study is designed to evaluate the safety and tolerability of assisted and self-administered subcutaneous (SC) Herceptin (trastuzumab) as adjuvant therapy in participants with early human epidermal growth factor receptor 2 (HER2)-positive breast cancer following tumor excision.
    Protection of trial subjects
    The study was conducted in accordance with the principles of the “Declaration of Helsinki” and Good Clinical Practice (GCP) guidelines according to the regulations and procedures described in the protocol.
    Background therapy
    -
    Evidence for comparator
    -
    Actual start date of recruitment
    17 May 2012
    Long term follow-up planned
    Yes
    Long term follow-up rationale
    Safety, Efficacy
    Long term follow-up duration
    5 Years
    Independent data monitoring committee (IDMC) involvement?
    No
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Albania: 8
    Country: Number of subjects enrolled
    Algeria: 16
    Country: Number of subjects enrolled
    Argentina: 13
    Country: Number of subjects enrolled
    Australia: 54
    Country: Number of subjects enrolled
    Bosnia and Herzegovina: 5
    Country: Number of subjects enrolled
    Brazil: 31
    Country: Number of subjects enrolled
    Bulgaria: 16
    Country: Number of subjects enrolled
    Canada: 50
    Country: Number of subjects enrolled
    Chile: 25
    Country: Number of subjects enrolled
    Colombia: 6
    Country: Number of subjects enrolled
    Croatia: 7
    Country: Number of subjects enrolled
    Czech Republic: 68
    Country: Number of subjects enrolled
    Dominican Republic: 2
    Country: Number of subjects enrolled
    Ecuador: 13
    Country: Number of subjects enrolled
    Egypt: 34
    Country: Number of subjects enrolled
    El Salvador: 6
    Country: Number of subjects enrolled
    France: 224
    Country: Number of subjects enrolled
    Germany: 235
    Country: Number of subjects enrolled
    Greece: 64
    Country: Number of subjects enrolled
    Guatemala: 16
    Country: Number of subjects enrolled
    Hong Kong: 10
    Country: Number of subjects enrolled
    Hungary: 39
    Country: Number of subjects enrolled
    Indonesia: 61
    Country: Number of subjects enrolled
    Ireland: 26
    Country: Number of subjects enrolled
    Italy: 203
    Country: Number of subjects enrolled
    Korea, Republic of: 59
    Country: Number of subjects enrolled
    Lithuania: 12
    Country: Number of subjects enrolled
    Malaysia: 45
    Country: Number of subjects enrolled
    Mexico: 52
    Country: Number of subjects enrolled
    Morocco: 8
    Country: Number of subjects enrolled
    Netherlands: 81
    Country: Number of subjects enrolled
    New Zealand: 10
    Country: Number of subjects enrolled
    Norway: 29
    Country: Number of subjects enrolled
    Pakistan: 46
    Country: Number of subjects enrolled
    Panama: 8
    Country: Number of subjects enrolled
    Peru: 26
    Country: Number of subjects enrolled
    Philippines: 48
    Country: Number of subjects enrolled
    Poland: 48
    Country: Number of subjects enrolled
    Portugal: 26
    Country: Number of subjects enrolled
    Romania: 43
    Country: Number of subjects enrolled
    Russian Federation: 82
    Country: Number of subjects enrolled
    Saudi Arabia: 3
    Country: Number of subjects enrolled
    Serbia: 23
    Country: Number of subjects enrolled
    Singapore: 8
    Country: Number of subjects enrolled
    Slovakia: 19
    Country: Number of subjects enrolled
    Slovenia: 5
    Country: Number of subjects enrolled
    South Africa: 17
    Country: Number of subjects enrolled
    Spain: 161
    Country: Number of subjects enrolled
    Sweden: 15
    Country: Number of subjects enrolled
    Switzerland: 40
    Country: Number of subjects enrolled
    Taiwan: 32
    Country: Number of subjects enrolled
    Thailand: 28
    Country: Number of subjects enrolled
    Turkey: 47
    Country: Number of subjects enrolled
    Ukraine: 17
    Country: Number of subjects enrolled
    United Arab Emirates: 5
    Country: Number of subjects enrolled
    United Kingdom: 283
    Country: Number of subjects enrolled
    Uruguay: 3
    Country: Number of subjects enrolled
    Venezuela, Bolivarian Republic of: 5
    Country: Number of subjects enrolled
    Vietnam: 11
    Worldwide total number of subjects
    2577
    EEA total number of subjects
    1604
    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)
    2090
    From 65 to 84 years
    483
    85 years and over
    4

    Subject disposition

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    Recruitment
    Recruitment details
    -

    Pre-assignment
    Screening details
    Of the 2984 participants screened, a total of 2577 participants were enrolled into the trial, and 2573 participants received at least one dose of study treatment.

    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
    Cohort A: SC Herceptin by Needle/Syringe
    Arm description
    Participants received SC Herceptin by an assisted administration as 600 milligrams (mg) every 3 weeks for a total of 18 doses/cycles. Each dose of SC Herceptin was taken from a single-use vial and injected by needle/syringe.
    Arm type
    Experimental

    Investigational medicinal product name
    Herceptin
    Investigational medicinal product code
    Other name
    Trastuzumab
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    Herceptin was given as 600 mg SC (into thigh) on Day 1 of each 3-week cycle for up to 18 cycles.

    Arm title
    Cohort B: SC Herceptin by Single-Use Injection Device (SID)
    Arm description
    Participants received SC Herceptin as 600 mg every 3 weeks for a total of 18 doses/cycles. Each dose of SC Herceptin was administered from a pre-filled SID. The first administration was performed by a healthcare professional (HCP). Subsequent doses were self-administered by participants who were willing and judged competent by the HCP.
    Arm type
    Experimental

    Investigational medicinal product name
    Herceptin
    Investigational medicinal product code
    Other name
    Trastuzumab
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    Herceptin was given as 600 mg SC (into thigh) on Day 1 of each 3-week cycle for up to 18 cycles.

    Number of subjects in period 1
    Cohort A: SC Herceptin by Needle/Syringe Cohort B: SC Herceptin by Single-Use Injection Device (SID)
    Started
    1867
    710
    Received Treatment
    1864
    709
    Completed
    0
    0
    Not completed
    1867
    710
         Death
    6
    3
         Withdrew prior to treatment
    3
    1
         Not specified
    10
    4
         Ongoing study
    1649
    659
         Disease progression/recurrence
    123
    28
         Consent withdrawn by subject
    58
    15
         Lost to follow-up
    18
    -

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Cohort A: SC Herceptin by Needle/Syringe
    Reporting group description
    Participants received SC Herceptin by an assisted administration as 600 milligrams (mg) every 3 weeks for a total of 18 doses/cycles. Each dose of SC Herceptin was taken from a single-use vial and injected by needle/syringe.

    Reporting group title
    Cohort B: SC Herceptin by Single-Use Injection Device (SID)
    Reporting group description
    Participants received SC Herceptin as 600 mg every 3 weeks for a total of 18 doses/cycles. Each dose of SC Herceptin was administered from a pre-filled SID. The first administration was performed by a healthcare professional (HCP). Subsequent doses were self-administered by participants who were willing and judged competent by the HCP.

    Reporting group values
    Cohort A: SC Herceptin by Needle/Syringe Cohort B: SC Herceptin by Single-Use Injection Device (SID) Total
    Number of subjects
    1867 710 2577
    Age categorical
    Units: Subjects
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    54 ± 12.01 53 ± 11.32 -
    Gender categorical
    Units: Subjects
        Female
    1863 710 2573
        Male
    4 0 4

    End points

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    End points reporting groups
    Reporting group title
    Cohort A: SC Herceptin by Needle/Syringe
    Reporting group description
    Participants received SC Herceptin by an assisted administration as 600 milligrams (mg) every 3 weeks for a total of 18 doses/cycles. Each dose of SC Herceptin was taken from a single-use vial and injected by needle/syringe.

    Reporting group title
    Cohort B: SC Herceptin by Single-Use Injection Device (SID)
    Reporting group description
    Participants received SC Herceptin as 600 mg every 3 weeks for a total of 18 doses/cycles. Each dose of SC Herceptin was administered from a pre-filled SID. The first administration was performed by a healthcare professional (HCP). Subsequent doses were self-administered by participants who were willing and judged competent by the HCP.

    Subject analysis set title
    Cohort B: SC Herceptin by SID (Self-Administered)
    Subject analysis set type
    Sub-group analysis
    Subject analysis set description
    Participants received SC Herceptin as 600 mg every 3 weeks for a total of 18 doses/cycles. Each dose of SC Herceptin was administered from a pre-filled SID. Dosing was either performed by self-administration or a qualified HCP. The present subgroup included only participants for whom SC Herceptin was given by self-administration.

    Subject analysis set title
    Cohort B: SC Herceptin by SID (HCP-Administered)
    Subject analysis set type
    Sub-group analysis
    Subject analysis set description
    Participants received SC Herceptin as 600 mg every 3 weeks for a total of 18 doses/cycles. Each dose of SC Herceptin was administered from a pre-filled SID. Dosing was either performed by self-administration or a qualified HCP. The present subgroup included only participants for whom SC Herceptin was administered by an HCP.

    Subject analysis set title
    Cohort A: SC Herceptin by Needle/Syringe (Intent-to-Treat)
    Subject analysis set type
    Intention-to-treat
    Subject analysis set description
    Participants received SC Herceptin by an assisted administration as 600 mg every 3 weeks for a total of 18 doses/cycles. Each dose of SC Herceptin was taken from a single-use vial and injected by needle/syringe. The Intent-to-Treat (ITT) Population included both treated and untreated participants.

    Subject analysis set title
    Cohort B: SC Herceptin by SID (Intent-to-Treat)
    Subject analysis set type
    Intention-to-treat
    Subject analysis set description
    Participants received SC Herceptin as 600 mg every 3 weeks for a total of 18 doses/cycles. Each dose of SC Herceptin was administered from a pre-filled SID. The first administration was performed by an HCP. Subsequent doses were self-administered by participants who were willing and judged competent by the HCP. The ITT Population included both treated and untreated participants.

    Primary: Percentage of Participants With At Least 1 Adverse Event (AE) During the Treatment Period

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    End point title
    Percentage of Participants With At Least 1 Adverse Event (AE) During the Treatment Period [1]
    End point description
    Participants were planned to receive a total of 18 cycles of SC Herceptin. An AE was defined as any untoward medical occurrence in a participant administered SC Herceptin. Examples included unfavorable/unintended signs and symptoms, new or exacerbated disease, recurrence of intermittent condition, deterioration in laboratory value or other clinical test, or adverse procedure-related events. The percentage of participants with at least 1 AE during the treatment period (regardless of severity or seriousness) was reported. Safety Population: All enrolled participants who received at least one dose of study medication according to assigned treatment.
    End point type
    Primary
    End point timeframe
    From Day 1 up to 19 cycles (cycle length 3 weeks) (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: Study data were analyzed by descriptive summaries. No formal hypothesis testing was planned.
    End point values
    Cohort A: SC Herceptin by Needle/Syringe Cohort B: SC Herceptin by Single-Use Injection Device (SID)
    Number of subjects analysed
    1864
    709
    Units: percentage of participants
        number (not applicable)
    88.6
    89
    No statistical analyses for this end point

    Primary: Percentage of Participants With a Grade 3 or Higher AE During the Treatment Period

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    End point title
    Percentage of Participants With a Grade 3 or Higher AE During the Treatment Period [2]
    End point description
    Participants were planned to receive a total of 18 cycles of SC Herceptin. An AE was defined as any untoward medical occurrence in a participant administered SC Herceptin. Examples included unfavorable/unintended signs and symptoms, new or exacerbated disease, recurrence of intermittent condition, deterioration in laboratory value or other clinical test, or adverse procedure-related events. AEs were graded according to National Cancer Institute Common Terminology Criteria Version 4.0. Grade 3 AEs were those considered severe or medically significant but not immediately life-threatening. Grade 4 AEs were those considered life-threatening and/or for which urgent intervention was indicated. Grade 5 AEs were those resulting in death. The percentage of participants with a Grade 3 or higher (i.e., Grade 3 to 5) AE during the treatment period was reported. Safety Population.
    End point type
    Primary
    End point timeframe
    From Day 1 up to 19 cycles (cycle length 3 weeks) (approximately 1 year)
    Notes
    [2] - 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: Study data were analyzed by descriptive summaries. No formal hypothesis testing was planned.
    End point values
    Cohort A: SC Herceptin by Needle/Syringe Cohort B: SC Herceptin by Single-Use Injection Device (SID)
    Number of subjects analysed
    1864
    709
    Units: percentage of participants
        number (confidence interval 95%)
    24 (22.1 to 26)
    21 (18.1 to 24.2)
    No statistical analyses for this end point

    Primary: Percentage of Participants With Treatment Interruption Due to an AE

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    End point title
    Percentage of Participants With Treatment Interruption Due to an AE [3]
    End point description
    Participants were planned to receive a total of 18 cycles of SC Herceptin. An AE was defined as any untoward medical occurrence in a participant administered SC Herceptin. Examples included unfavorable/unintended signs and symptoms, new or exacerbated disease, recurrence of intermittent condition, deterioration in laboratory value or other clinical test, or adverse procedure-related events. The percentage of participants with SC Herceptin treatment interrupted to assess or treat AEs was reported. Safety Population.
    End point type
    Primary
    End point timeframe
    From Day 1 up to 19 cycles (cycle length 3 weeks) (approximately 1 year)
    Notes
    [3] - 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: Study data were analyzed by descriptive summaries. No formal hypothesis testing was planned.
    End point values
    Cohort A: SC Herceptin by Needle/Syringe Cohort B: SC Herceptin by Single-Use Injection Device (SID)
    Number of subjects analysed
    1864
    709
    Units: percentage of participants
        number (not applicable)
    9.8
    10.4
    No statistical analyses for this end point

    Primary: Number of Herceptin Cycles Received

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    End point title
    Number of Herceptin Cycles Received [4]
    End point description
    Participants were planned to receive a total of 18 cycles of SC Herceptin. The median number of cycles actually received was reported. Safety Population. The endpoint also included an analysis of a subgroup of participants from Cohort B who received doses of self-administered SC Herceptin via SID.
    End point type
    Primary
    End point timeframe
    From Day 1 up to 19 cycles (cycle length 3 weeks) (approximately 1 year)
    Notes
    [4] - 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: Study data were analyzed by descriptive summaries. No formal hypothesis testing was planned.
    End point values
    Cohort A: SC Herceptin by Needle/Syringe Cohort B: SC Herceptin by Single-Use Injection Device (SID) Cohort B: SC Herceptin by SID (Self-Administered)
    Number of subjects analysed
    1864
    709
    550
    Units: cycles
        median (full range (min-max))
    18 (1 to 19)
    18 (1 to 18)
    16 (1 to 17)
    No statistical analyses for this end point

    Primary: Percentage of Participants by Total Number of Herceptin Cycles Received

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    End point title
    Percentage of Participants by Total Number of Herceptin Cycles Received [5]
    End point description
    Participants were planned to receive a total of 18 cycles of SC Herceptin. The percentage of participants was reported by the total number of cycles actually received. Because the data are presented non-cumulatively, this table reflects participant distribution by the highest number of cycles received. Safety Population. The endpoint also included an analysis of a subgroup of participants from Cohort B who received doses of self-administered SC Herceptin via SID.
    End point type
    Primary
    End point timeframe
    From Day 1 up to 19 cycles (cycle length 3 weeks) (approximately 1 year)
    Notes
    [5] - 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: Study data were analyzed by descriptive summaries. No formal hypothesis testing was planned.
    End point values
    Cohort A: SC Herceptin by Needle/Syringe Cohort B: SC Herceptin by Single-Use Injection Device (SID) Cohort B: SC Herceptin by SID (Self-Administered)
    Number of subjects analysed
    1864
    709
    550
    Units: percentage of participants
    number (not applicable)
        1 Cycle Received
    1
    0.8
    2.7
        2 Cycles Received
    0.5
    0.4
    1.3
        3 Cycles Received
    0.5
    0.1
    1.1
        4 Cycles Received
    1.2
    0.7
    1.6
        5 Cycles Received
    0.8
    0.6
    1.3
        6 Cycles Received
    0.5
    0.1
    1.6
        7 Cycles Received
    0.7
    0.8
    2.2
        8 Cycles Received
    0.9
    0.3
    2.2
        9 Cycles Received
    0.2
    0.6
    1.8
        10 Cycles Received
    0.3
    0.1
    1.5
        11 Cycles Received
    0.4
    0.3
    3.5
        12 Cycles Received
    0.9
    0.8
    2.5
        13 Cycles Received
    0.2
    0
    4.9
        14 Cycles Received
    0.5
    0.6
    6.9
        15 Cycles Received
    0.5
    0.4
    10.7
        16 Cycles Received
    0.6
    0.3
    21.6
        17 Cycles Received
    1
    1.1
    32.5
        18 Cycles Received
    89.2
    91.8
    0
        19 Cycles Received
    0.2
    0
    0
    No statistical analyses for this end point

    Primary: Percentage of Participants Who Received Concomitant Cancer Therapy

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    End point title
    Percentage of Participants Who Received Concomitant Cancer Therapy [6]
    End point description
    Concomitant cancer treatment included chemotherapy, radiotherapy, and hormone therapy administered during the study. The percentage of participants who received any of these concomitant therapies was reported. Safety Population.
    End point type
    Primary
    End point timeframe
    From Baseline to data cutoff of 10 March 2015 (up to approximately 3 years)
    Notes
    [6] - 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: Study data were analyzed by descriptive summaries. No formal hypothesis testing was planned.
    End point values
    Cohort A: SC Herceptin by Needle/Syringe Cohort B: SC Herceptin by Single-Use Injection Device (SID)
    Number of subjects analysed
    1864
    709
    Units: percentage of participants
    number (not applicable)
        Chemotherapy
    58.2
    63.9
        Radiotherapy
    51.3
    48.5
        Hormone Therapy
    53.5
    50.4
    No statistical analyses for this end point

    Primary: Percentage of Participants Who Received Concomitant Non-Cancer Therapy

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    End point title
    Percentage of Participants Who Received Concomitant Non-Cancer Therapy [7]
    End point description
    Concomitant non-cancer treatment included any pharmacologic interventions administered during the study other than chemotherapy, radiotherapy, or hormone therapy. The percentage of participants who received any concomitant non-cancer therapies was reported. Safety Population.
    End point type
    Primary
    End point timeframe
    From Baseline to data cutoff of 10 March 2015 (up to approximately 3 years)
    Notes
    [7] - 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: Study data were analyzed by descriptive summaries. No formal hypothesis testing was planned.
    End point values
    Cohort A: SC Herceptin by Needle/Syringe Cohort B: SC Herceptin by Single-Use Injection Device (SID)
    Number of subjects analysed
    1864
    709
    Units: percentage of participants
        number (not applicable)
    89.1
    89.7
    No statistical analyses for this end point

    Secondary: Percentage of Participants Who Died by Data Cutoff of 10 March 2015

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    End point title
    Percentage of Participants Who Died by Data Cutoff of 10 March 2015
    End point description
    The percentage of participants who died from any cause was reported. ITT Population: All participants enrolled into the study regardless of whether treatment was received.
    End point type
    Secondary
    End point timeframe
    From Baseline to time of event (maximum follow-up approximately 3 years as of data cutoff of 10 March 2015)
    End point values
    Cohort A: SC Herceptin by Needle/Syringe (Intent-to-Treat) Cohort B: SC Herceptin by SID (Intent-to-Treat)
    Number of subjects analysed
    1867
    710
    Units: percentage of participants
        number (not applicable)
    1.5
    0.8
    No statistical analyses for this end point

    Secondary: Percentage of Participants by Item Response to SID Satisfaction Questionnaire

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    End point title
    Percentage of Participants by Item Response to SID Satisfaction Questionnaire
    End point description
    The SID satisfaction questionnaire was administered twice during study and asked participants to respond to five statements using a Likert scale from "Strongly Disagree" to "Strongly Agree". Questionnaire items were: "I felt comfortable injecting the study drug by myself" (Comfortable), "The SID was convenient and easy to use" (Easy to Use), "I am confident giving myself an injection in the thigh with the SID" (Confident), "Taking all things into account I find self-administration using the SID satisfactory" (Satisfactory), "If given the opportunity I would choose to continue self-injecting the study drug using the SID in the future" (Continue). Participants could select one response per questionnaire item. The percentage of participants was reported by response given for each item on the SID satisfaction questionnaire. Safety Population. Only those who self-administered were included. The number of participants who responded to the questionnaire item at each assessment (n) is shown.
    End point type
    Secondary
    End point timeframe
    Cycle 4 (cycle length 3 weeks) and last safety follow-up (LSFU) (approximately 1 year)
    End point values
    Cohort B: SC Herceptin by SID (Self-Administered)
    Number of subjects analysed
    550
    Units: percentage of participants
    number (not applicable)
        Cycle 4: Comfortable, Strongly Disagree (n=514)
    4.7
        Cycle 4: Comfortable, Disagree (n=514)
    2.3
        Cycle 4: Comfortable, Unsure (n=514)
    7.6
        Cycle 4: Comfortable, Agree (n=514)
    41.6
        Cycle 4: Comfortable, Strongly Agree (n=514)
    43.6
        Cycle 4: Comfortable, Response Missing (n=514)
    0.2
        Cycle 4: Easy to Use, Strongly Disagree (n=514)
    3.7
        Cycle 4: Easy to Use, Disagree (n=514)
    0.6
        Cycle 4: Easy to Use, Unsure (n=514)
    1.8
        Cycle 4: Easy to Use, Agree (n=514)
    37.7
        Cycle 4: Easy to Use, Strongly Agree (n=514)
    56
        Cycle 4: Easy to Use, Response Missing (n=514)
    0.2
        Cycle 4: Confident, Strongly Disagree (n=514)
    3.9
        Cycle 4: Confident, Disagree (n=514)
    0.8
        Cycle 4: Confident, Unsure (n=514)
    7.2
        Cycle 4: Confident, Agree (n=514)
    42.8
        Cycle 4: Confident, Strongly Agree (n=514)
    45.1
        Cycle 4: Confident, Response Missing (n=514)
    0.2
        Cycle 4: Satisfactory, Strongly Disagree (n=514)
    3.9
        Cycle 4: Satisfactory, Disagree (n=514)
    0.6
        Cycle 4: Satisfactory, Unsure (n=514)
    2.7
        Cycle 4: Satisfactory, Agree (n=514)
    38.7
        Cycle 4: Satisfactory, Strongly Agree (n=514)
    53.9
        Cycle 4: Satisfactory, Response Missing (n=514)
    0.2
        Cycle 4: Continue, Strongly Disagree (n=514)
    3.9
        Cycle 4: Continue, Disagree (n=514)
    1.4
        Cycle 4: Continue, Unsure (n=514)
    5.3
        Cycle 4: Continue, Agree (n=514)
    33.5
        Cycle 4: Continue, Strongly Agree (n=514)
    55.8
        Cycle 4: Continue, Response Missing (n=514)
    0.2
        LSFU: Comfortable, Strongly Disagree (n=415)
    3.6
        LSFU: Comfortable, Disagree (n=415)
    3.1
        LSFU: Comfortable, Unsure (n=415)
    5.3
        LSFU: Comfortable, Agree (n=415)
    35.9
        LSFU: Comfortable, Strongly Agree (n=415)
    51.8
        LSFU: Comfortable, Response Missing (n=415)
    0.2
        LSFU: Easy to Use, Strongly Disagree (n=415)
    3.9
        LSFU: Easy to Use, Disagree (n=415)
    1
        LSFU: Easy to Use, Unsure (n=415)
    1.7
        LSFU: Easy to Use, Agree (n=415)
    34.9
        LSFU: Easy to Use, Strongly Agree (n=415)
    58.6
        LSFU: Easy to Use, Response Missing (n=415)
    0
        LSFU: Confident, Strongly Disagree (n=415)
    4.6
        LSFU: Confident, Disagree (n=415)
    1.2
        LSFU: Confident, Unsure (n=415)
    4.3
        LSFU: Confident, Agree (n=415)
    33.3
        LSFU: Confident, Strongly Agree (n=415)
    56.6
        LSFU: Confident, Response Missing (n=415)
    0
        LSFU: Satisfactory, Strongly Disagree (n=415)
    4.3
        LSFU: Satisfactory, Disagree (n=415)
    1.2
        LSFU: Satisfactory, Unsure (n=415)
    2.2
        LSFU: Satisfactory, Agree (n=415)
    30.8
        LSFU: Satisfactory, Strongly Agree (n=415)
    61.2
        LSFU: Satisfactory, Response Missing (n=415)
    0.2
        LSFU: Continue, Strongly Disagree (n=415)
    4.6
        LSFU: Continue, Disagree (n=415)
    1.2
        LSFU: Continue, Unsure (n=415)
    2.9
        LSFU: Continue, Agree (n=415)
    28.2
        LSFU: Continue, Strongly Agree (n=415)
    63.1
        LSFU: Continue, Response Missing (n=415)
    0
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    From Day 1 up to 19 cycles (approximately 1 year)
    Adverse event reporting additional description
    Safety Population. Three AEs with onset during treatment resulted in eventual death and are captured under the respective AE terms in Cohort A as fatal events. One of these deaths occurred during treatment and is captured in "Number of deaths (all causes)" for Cohort A. The remaining 2 deaths occurred in follow-up and are excluded from this count.
    Assessment type
    Non-systematic
    Dictionary used for adverse event reporting
    Dictionary name
    MedDRA
    Dictionary version
    18.0
    Reporting groups
    Reporting group title
    Cohort A: SC Herceptin by Needle/Syringe
    Reporting group description
    Participants received SC Herceptin by an assisted administration as 600 mg every 3 weeks for a total of 18 doses/cycles. Each dose of SC Herceptin was taken from a single-use vial and injected by needle/syringe.

    Reporting group title
    Cohort B: SC Herceptin by Single-Use Injection Device (SID)
    Reporting group description
    Participants received SC Herceptin as 600 mg every 3 weeks for a total of 18 doses/cycles. Each dose of SC Herceptin was administered from a pre-filled SID. The first administration was performed by an HCP. Subsequent doses were self-administered by participants who were willing and judged competent by the HCP.

    Serious adverse events
    Cohort A: SC Herceptin by Needle/Syringe Cohort B: SC Herceptin by Single-Use Injection Device (SID)
    Total subjects affected by serious adverse events
         subjects affected / exposed
    242 / 1864 (12.98%)
    84 / 709 (11.85%)
         number of deaths (all causes)
    1
    2
         number of deaths resulting from adverse events
    Vascular disorders
    Hypertension
         subjects affected / exposed
    2 / 1864 (0.11%)
    0 / 709 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypertensive crisis
         subjects affected / exposed
    1 / 1864 (0.05%)
    1 / 709 (0.14%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Aortic aneurysm
         subjects affected / exposed
    1 / 1864 (0.05%)
    0 / 709 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Arterial stenosis
         subjects affected / exposed
    0 / 1864 (0.00%)
    1 / 709 (0.14%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Deep vein thrombosis
         subjects affected / exposed
    0 / 1864 (0.00%)
    1 / 709 (0.14%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Orthostatic hypotension
         subjects affected / exposed
    0 / 1864 (0.00%)
    1 / 709 (0.14%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Phlebitis
         subjects affected / exposed
    1 / 1864 (0.05%)
    0 / 709 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Venous thrombosis
         subjects affected / exposed
    1 / 1864 (0.05%)
    0 / 709 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Venous thrombosis limb
         subjects affected / exposed
    1 / 1864 (0.05%)
    0 / 709 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Uterine leiomyoma
         subjects affected / exposed
    1 / 1864 (0.05%)
    2 / 709 (0.28%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Benign pancreatic neoplasm
         subjects affected / exposed
    1 / 1864 (0.05%)
    0 / 709 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Borderline serous tumour of ovary
         subjects affected / exposed
    1 / 1864 (0.05%)
    0 / 709 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Breast cancer
         subjects affected / exposed
    1 / 1864 (0.05%)
    0 / 709 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Clear cell renal cell carcinoma
         subjects affected / exposed
    1 / 1864 (0.05%)
    0 / 709 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Colon cancer
         subjects affected / exposed
    0 / 1864 (0.00%)
    1 / 709 (0.14%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Endometrial cancer
         subjects affected / exposed
    1 / 1864 (0.05%)
    0 / 709 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Intraductal proliferative breast lesion
         subjects affected / exposed
    1 / 1864 (0.05%)
    0 / 709 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lung adenocarcinoma
         subjects affected / exposed
    0 / 1864 (0.00%)
    1 / 709 (0.14%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ovarian fibroma
         subjects affected / exposed
    1 / 1864 (0.05%)
    0 / 709 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Rectal adenocarcinoma
         subjects affected / exposed
    1 / 1864 (0.05%)
    0 / 709 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Schwannoma
         subjects affected / exposed
    1 / 1864 (0.05%)
    0 / 709 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Thyroid adenoma
         subjects affected / exposed
    1 / 1864 (0.05%)
    0 / 709 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Immune system disorders
    Drug hypersensitivity
         subjects affected / exposed
    2 / 1864 (0.11%)
    0 / 709 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypersensitivity
         subjects affected / exposed
    0 / 1864 (0.00%)
    2 / 709 (0.28%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Pyrexia
         subjects affected / exposed
    11 / 1864 (0.59%)
    7 / 709 (0.99%)
         occurrences causally related to treatment / all
    0 / 12
    0 / 8
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Device breakage
         subjects affected / exposed
    1 / 1864 (0.05%)
    1 / 709 (0.14%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    General physical health deterioration
         subjects affected / exposed
    1 / 1864 (0.05%)
    1 / 709 (0.14%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Asthenia
         subjects affected / exposed
    1 / 1864 (0.05%)
    0 / 709 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Chest discomfort
         subjects affected / exposed
    0 / 1864 (0.00%)
    1 / 709 (0.14%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Chest pain
         subjects affected / exposed
    1 / 1864 (0.05%)
    0 / 709 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Death
         subjects affected / exposed
    0 / 1864 (0.00%)
    1 / 709 (0.14%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Device defective
         subjects affected / exposed
    1 / 1864 (0.05%)
    0 / 709 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Fatigue
         subjects affected / exposed
    1 / 1864 (0.05%)
    0 / 709 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Influenza like illness
         subjects affected / exposed
    1 / 1864 (0.05%)
    0 / 709 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Mucosal inflammation
         subjects affected / exposed
    1 / 1864 (0.05%)
    0 / 709 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Non-cardiac chest pain
         subjects affected / exposed
    1 / 1864 (0.05%)
    0 / 709 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Oedema peripheral
         subjects affected / exposed
    1 / 1864 (0.05%)
    0 / 709 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Psychiatric disorders
    Anxiety
         subjects affected / exposed
    2 / 1864 (0.11%)
    0 / 709 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Depression
         subjects affected / exposed
    1 / 1864 (0.05%)
    1 / 709 (0.14%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Panic attack
         subjects affected / exposed
    1 / 1864 (0.05%)
    0 / 709 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Psychotic disorder
         subjects affected / exposed
    1 / 1864 (0.05%)
    0 / 709 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Reproductive system and breast disorders
    Uterine polyp
         subjects affected / exposed
    2 / 1864 (0.11%)
    0 / 709 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Breast fibrosis
         subjects affected / exposed
    1 / 1864 (0.05%)
    0 / 709 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Endometrial hypertrophy
         subjects affected / exposed
    1 / 1864 (0.05%)
    0 / 709 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ovarian cyst
         subjects affected / exposed
    1 / 1864 (0.05%)
    0 / 709 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Postmenopausal haemorrhage
         subjects affected / exposed
    1 / 1864 (0.05%)
    0 / 709 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Uterine haemorrhage
         subjects affected / exposed
    1 / 1864 (0.05%)
    0 / 709 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Radiation pneumonitis
         subjects affected / exposed
    2 / 1864 (0.11%)
    0 / 709 (0.00%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hip fracture
         subjects affected / exposed
    1 / 1864 (0.05%)
    1 / 709 (0.14%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Wound dehiscence
         subjects affected / exposed
    0 / 1864 (0.00%)
    1 / 709 (0.14%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Concussion
         subjects affected / exposed
    1 / 1864 (0.05%)
    0 / 709 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Fibula fracture
         subjects affected / exposed
    1 / 1864 (0.05%)
    0 / 709 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Fracture displacement
         subjects affected / exposed
    1 / 1864 (0.05%)
    0 / 709 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Laceration
         subjects affected / exposed
    0 / 1864 (0.00%)
    1 / 709 (0.14%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lumbar vertebral fracture
         subjects affected / exposed
    1 / 1864 (0.05%)
    0 / 709 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Patella fracture
         subjects affected / exposed
    0 / 1864 (0.00%)
    1 / 709 (0.14%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pelvic fracture
         subjects affected / exposed
    1 / 1864 (0.05%)
    0 / 709 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Radius fracture
         subjects affected / exposed
    1 / 1864 (0.05%)
    0 / 709 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Seroma
         subjects affected / exposed
    1 / 1864 (0.05%)
    0 / 709 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Spinal fracture
         subjects affected / exposed
    1 / 1864 (0.05%)
    0 / 709 (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 / 1864 (0.05%)
    0 / 709 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Traumatic arthropathy
         subjects affected / exposed
    0 / 1864 (0.00%)
    1 / 709 (0.14%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ulna fracture
         subjects affected / exposed
    1 / 1864 (0.05%)
    0 / 709 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Wound
         subjects affected / exposed
    1 / 1864 (0.05%)
    0 / 709 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Investigations
    Ejection fraction decreased
         subjects affected / exposed
    3 / 1864 (0.16%)
    0 / 709 (0.00%)
         occurrences causally related to treatment / all
    2 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    White blood cell count decreased
         subjects affected / exposed
    1 / 1864 (0.05%)
    1 / 709 (0.14%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Blood urea increased
         subjects affected / exposed
    1 / 1864 (0.05%)
    0 / 709 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Electrocardiogram QT prolonged
         subjects affected / exposed
    1 / 1864 (0.05%)
    0 / 709 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Neutrophil count decreased
         subjects affected / exposed
    1 / 1864 (0.05%)
    0 / 709 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac disorders
    Cardiac failure congestive
         subjects affected / exposed
    10 / 1864 (0.54%)
    1 / 709 (0.14%)
         occurrences causally related to treatment / all
    9 / 10
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Atrial fibrillation
         subjects affected / exposed
    2 / 1864 (0.11%)
    0 / 709 (0.00%)
         occurrences causally related to treatment / all
    2 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Angina unstable
         subjects affected / exposed
    2 / 1864 (0.11%)
    0 / 709 (0.00%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Coronary artery disease
         subjects affected / exposed
    2 / 1864 (0.11%)
    0 / 709 (0.00%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Left ventricular dysfunction
         subjects affected / exposed
    1 / 1864 (0.05%)
    1 / 709 (0.14%)
         occurrences causally related to treatment / all
    1 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Myocardial ischaemia
         subjects affected / exposed
    2 / 1864 (0.11%)
    0 / 709 (0.00%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pericarditis
         subjects affected / exposed
    1 / 1864 (0.05%)
    1 / 709 (0.14%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Supraventricular tachycardia
         subjects affected / exposed
    2 / 1864 (0.11%)
    0 / 709 (0.00%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Acute myocardial infarction
         subjects affected / exposed
    1 / 1864 (0.05%)
    0 / 709 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Atrial thrombosis
         subjects affected / exposed
    1 / 1864 (0.05%)
    0 / 709 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Atrioventricular block second degree
         subjects affected / exposed
    1 / 1864 (0.05%)
    0 / 709 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Myocarditis
         subjects affected / exposed
    1 / 1864 (0.05%)
    0 / 709 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Palpitations
         subjects affected / exposed
    1 / 1864 (0.05%)
    0 / 709 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Stress cardiomyopathy
         subjects affected / exposed
    1 / 1864 (0.05%)
    0 / 709 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ventricular arrhythmia
         subjects affected / exposed
    1 / 1864 (0.05%)
    0 / 709 (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
    39 / 1864 (2.09%)
    14 / 709 (1.97%)
         occurrences causally related to treatment / all
    5 / 39
    1 / 17
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Neutropenia
         subjects affected / exposed
    9 / 1864 (0.48%)
    6 / 709 (0.85%)
         occurrences causally related to treatment / all
    0 / 11
    1 / 6
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Febrile bone marrow aplasia
         subjects affected / exposed
    2 / 1864 (0.11%)
    2 / 709 (0.28%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Anaemia
         subjects affected / exposed
    3 / 1864 (0.16%)
    0 / 709 (0.00%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Leukocytosis
         subjects affected / exposed
    2 / 1864 (0.11%)
    0 / 709 (0.00%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Leukopenia
         subjects affected / exposed
    2 / 1864 (0.11%)
    0 / 709 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pancytopenia
         subjects affected / exposed
    1 / 1864 (0.05%)
    0 / 709 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Thymus enlargement
         subjects affected / exposed
    1 / 1864 (0.05%)
    0 / 709 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Asthma
         subjects affected / exposed
    2 / 1864 (0.11%)
    0 / 709 (0.00%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Dyspnoea
         subjects affected / exposed
    2 / 1864 (0.11%)
    0 / 709 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonitis
         subjects affected / exposed
    1 / 1864 (0.05%)
    1 / 709 (0.14%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pulmonary embolism
         subjects affected / exposed
    0 / 1864 (0.00%)
    2 / 709 (0.28%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Dyspnoea exertional
         subjects affected / exposed
    0 / 1864 (0.00%)
    1 / 709 (0.14%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Organising pneumonia
         subjects affected / exposed
    0 / 1864 (0.00%)
    1 / 709 (0.14%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Painful respiration
         subjects affected / exposed
    1 / 1864 (0.05%)
    0 / 709 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pleurisy
         subjects affected / exposed
    0 / 1864 (0.00%)
    1 / 709 (0.14%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pulmonary oedema
         subjects affected / exposed
    1 / 1864 (0.05%)
    0 / 709 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory failure
         subjects affected / exposed
    1 / 1864 (0.05%)
    0 / 709 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nervous system disorders
    Headache
         subjects affected / exposed
    2 / 1864 (0.11%)
    0 / 709 (0.00%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Syncope
         subjects affected / exposed
    1 / 1864 (0.05%)
    1 / 709 (0.14%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Aphasia
         subjects affected / exposed
    1 / 1864 (0.05%)
    0 / 709 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Carotid sinus syndrome
         subjects affected / exposed
    1 / 1864 (0.05%)
    0 / 709 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cerebral ischaemia
         subjects affected / exposed
    1 / 1864 (0.05%)
    0 / 709 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cerebrovascular accident
         subjects affected / exposed
    1 / 1864 (0.05%)
    0 / 709 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Depressed level of consciousness
         subjects affected / exposed
    1 / 1864 (0.05%)
    0 / 709 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Epilepsy
         subjects affected / exposed
    0 / 1864 (0.00%)
    1 / 709 (0.14%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Generalised tonic-clonic seizure
         subjects affected / exposed
    0 / 1864 (0.00%)
    1 / 709 (0.14%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Peripheral sensorimotor neuropathy
         subjects affected / exposed
    1 / 1864 (0.05%)
    0 / 709 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Presyncope
         subjects affected / exposed
    1 / 1864 (0.05%)
    0 / 709 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Tension headache
         subjects affected / exposed
    0 / 1864 (0.00%)
    1 / 709 (0.14%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Transient ischaemic attack
         subjects affected / exposed
    1 / 1864 (0.05%)
    0 / 709 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ear and labyrinth disorders
    Vertigo
         subjects affected / exposed
    2 / 1864 (0.11%)
    0 / 709 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Meniere's disease
         subjects affected / exposed
    1 / 1864 (0.05%)
    0 / 709 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Diarrhoea
         subjects affected / exposed
    8 / 1864 (0.43%)
    4 / 709 (0.56%)
         occurrences causally related to treatment / all
    0 / 9
    0 / 5
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nausea
         subjects affected / exposed
    5 / 1864 (0.27%)
    0 / 709 (0.00%)
         occurrences causally related to treatment / all
    0 / 6
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pancreatitis
         subjects affected / exposed
    3 / 1864 (0.16%)
    0 / 709 (0.00%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Abdominal pain upper
         subjects affected / exposed
    1 / 1864 (0.05%)
    1 / 709 (0.14%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pancreatitis acute
         subjects affected / exposed
    2 / 1864 (0.11%)
    0 / 709 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vomiting
         subjects affected / exposed
    2 / 1864 (0.11%)
    0 / 709 (0.00%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Abdominal pain
         subjects affected / exposed
    1 / 1864 (0.05%)
    0 / 709 (0.00%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Abdominal discomfort
         subjects affected / exposed
    1 / 1864 (0.05%)
    0 / 709 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Colitis
         subjects affected / exposed
    1 / 1864 (0.05%)
    0 / 709 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Constipation
         subjects affected / exposed
    1 / 1864 (0.05%)
    0 / 709 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastritis erosive
         subjects affected / exposed
    1 / 1864 (0.05%)
    0 / 709 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal pain
         subjects affected / exposed
    1 / 1864 (0.05%)
    0 / 709 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Intestinal polyp
         subjects affected / exposed
    0 / 1864 (0.00%)
    1 / 709 (0.14%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Neutropenic colitis
         subjects affected / exposed
    0 / 1864 (0.00%)
    1 / 709 (0.14%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Subileus
         subjects affected / exposed
    1 / 1864 (0.05%)
    0 / 709 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatobiliary disorders
    Cholelithiasis
         subjects affected / exposed
    2 / 1864 (0.11%)
    1 / 709 (0.14%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cholecystitis chronic
         subjects affected / exposed
    0 / 1864 (0.00%)
    1 / 709 (0.14%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal and urinary disorders
    Renal failure
         subjects affected / exposed
    2 / 1864 (0.11%)
    0 / 709 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hydronephrosis
         subjects affected / exposed
    1 / 1864 (0.05%)
    0 / 709 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Urinary incontinence
         subjects affected / exposed
    1 / 1864 (0.05%)
    0 / 709 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Urinary retention
         subjects affected / exposed
    1 / 1864 (0.05%)
    0 / 709 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Skin and subcutaneous tissue disorders
    Dermatitis
         subjects affected / exposed
    0 / 1864 (0.00%)
    1 / 709 (0.14%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Dermatitis bullous
         subjects affected / exposed
    0 / 1864 (0.00%)
    1 / 709 (0.14%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Erythema nodosum
         subjects affected / exposed
    0 / 1864 (0.00%)
    1 / 709 (0.14%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Rash
         subjects affected / exposed
    1 / 1864 (0.05%)
    0 / 709 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Toxic skin eruption
         subjects affected / exposed
    0 / 1864 (0.00%)
    1 / 709 (0.14%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Transient acantholytic dermatosis
         subjects affected / exposed
    0 / 1864 (0.00%)
    1 / 709 (0.14%)
         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
    Osteoarthritis
         subjects affected / exposed
    2 / 1864 (0.11%)
    0 / 709 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Arthritis
         subjects affected / exposed
    1 / 1864 (0.05%)
    0 / 709 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Intervertebral disc protrusion
         subjects affected / exposed
    1 / 1864 (0.05%)
    0 / 709 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lumbar spinal stenosis
         subjects affected / exposed
    1 / 1864 (0.05%)
    0 / 709 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Myalgia
         subjects affected / exposed
    1 / 1864 (0.05%)
    0 / 709 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Rheumatoid arthritis
         subjects affected / exposed
    1 / 1864 (0.05%)
    0 / 709 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Endocrine disorders
    Hypothyroidism
         subjects affected / exposed
    0 / 1864 (0.00%)
    1 / 709 (0.14%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Hyperglycaemia
         subjects affected / exposed
    2 / 1864 (0.11%)
    0 / 709 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Electrolyte imbalance
         subjects affected / exposed
    1 / 1864 (0.05%)
    0 / 709 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gout
         subjects affected / exposed
    1 / 1864 (0.05%)
    0 / 709 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypokalaemia
         subjects affected / exposed
    1 / 1864 (0.05%)
    0 / 709 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hyponatraemia
         subjects affected / exposed
    1 / 1864 (0.05%)
    0 / 709 (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
    Neutropenic sepsis
         subjects affected / exposed
    9 / 1864 (0.48%)
    1 / 709 (0.14%)
         occurrences causally related to treatment / all
    1 / 9
    0 / 1
         deaths causally related to treatment / all
    1 / 1
    0 / 0
    Device related infection
         subjects affected / exposed
    6 / 1864 (0.32%)
    0 / 709 (0.00%)
         occurrences causally related to treatment / all
    1 / 6
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonia
         subjects affected / exposed
    5 / 1864 (0.27%)
    1 / 709 (0.14%)
         occurrences causally related to treatment / all
    0 / 5
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Urinary tract infection
         subjects affected / exposed
    3 / 1864 (0.16%)
    2 / 709 (0.28%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Mastitis
         subjects affected / exposed
    3 / 1864 (0.16%)
    2 / 709 (0.28%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cellulitis
         subjects affected / exposed
    4 / 1864 (0.21%)
    0 / 709 (0.00%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastroenteritis
         subjects affected / exposed
    3 / 1864 (0.16%)
    1 / 709 (0.14%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lower respiratory tract infection
         subjects affected / exposed
    4 / 1864 (0.21%)
    0 / 709 (0.00%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Appendicitis
         subjects affected / exposed
    2 / 1864 (0.11%)
    1 / 709 (0.14%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Upper respiratory tract infection
         subjects affected / exposed
    2 / 1864 (0.11%)
    1 / 709 (0.14%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Breast abscess
         subjects affected / exposed
    2 / 1864 (0.11%)
    0 / 709 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Erysipelas
         subjects affected / exposed
    2 / 1864 (0.11%)
    0 / 709 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infectious colitis
         subjects affected / exposed
    2 / 1864 (0.11%)
    0 / 709 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pyelonephritis acute
         subjects affected / exposed
    2 / 1864 (0.11%)
    0 / 709 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Viral infection
         subjects affected / exposed
    1 / 1864 (0.05%)
    1 / 709 (0.14%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infective exacerbation of chronic obstructive airways disease
         subjects affected / exposed
    0 / 1864 (0.00%)
    1 / 709 (0.14%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Abscess of external auditory meatus
         subjects affected / exposed
    1 / 1864 (0.05%)
    0 / 709 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Appendiceal abscess
         subjects affected / exposed
    1 / 1864 (0.05%)
    0 / 709 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bartholin's abscess
         subjects affected / exposed
    1 / 1864 (0.05%)
    0 / 709 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Breast cellulitis
         subjects affected / exposed
    0 / 1864 (0.00%)
    1 / 709 (0.14%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bronchitis
         subjects affected / exposed
    0 / 1864 (0.00%)
    1 / 709 (0.14%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bronchopneumonia
         subjects affected / exposed
    1 / 1864 (0.05%)
    0 / 709 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Clostridium difficile infection
         subjects affected / exposed
    1 / 1864 (0.05%)
    0 / 709 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Dengue fever
         subjects affected / exposed
    1 / 1864 (0.05%)
    0 / 709 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Diverticulitis
         subjects affected / exposed
    1 / 1864 (0.05%)
    0 / 709 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Febrile infection
         subjects affected / exposed
    1 / 1864 (0.05%)
    0 / 709 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastroenteritis rotavirus
         subjects affected / exposed
    0 / 1864 (0.00%)
    1 / 709 (0.14%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatitis B
         subjects affected / exposed
    0 / 1864 (0.00%)
    1 / 709 (0.14%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Herpes zoster
         subjects affected / exposed
    1 / 1864 (0.05%)
    0 / 709 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Intestinal sepsis
         subjects affected / exposed
    0 / 1864 (0.00%)
    1 / 709 (0.14%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Lobar pneumonia
         subjects affected / exposed
    1 / 1864 (0.05%)
    0 / 709 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Localised infection
         subjects affected / exposed
    1 / 1864 (0.05%)
    0 / 709 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lung infection
         subjects affected / exposed
    1 / 1864 (0.05%)
    0 / 709 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lymph node tuberculosis
         subjects affected / exposed
    1 / 1864 (0.05%)
    0 / 709 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Meningoencephalitis bacterial
         subjects affected / exposed
    1 / 1864 (0.05%)
    0 / 709 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Periorbital cellulitis
         subjects affected / exposed
    1 / 1864 (0.05%)
    0 / 709 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonia bacterial
         subjects affected / exposed
    1 / 1864 (0.05%)
    0 / 709 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Postoperative wound infection
         subjects affected / exposed
    1 / 1864 (0.05%)
    0 / 709 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pyelonephritis
         subjects affected / exposed
    1 / 1864 (0.05%)
    0 / 709 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory tract infection
         subjects affected / exposed
    1 / 1864 (0.05%)
    0 / 709 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Skin infection
         subjects affected / exposed
    0 / 1864 (0.00%)
    1 / 709 (0.14%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Soft tissue infection
         subjects affected / exposed
    1 / 1864 (0.05%)
    0 / 709 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Staphylococcal infection
         subjects affected / exposed
    0 / 1864 (0.00%)
    1 / 709 (0.14%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Tracheobronchitis
         subjects affected / exposed
    1 / 1864 (0.05%)
    0 / 709 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Urosepsis
         subjects affected / exposed
    0 / 1864 (0.00%)
    1 / 709 (0.14%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vaginal infection
         subjects affected / exposed
    1 / 1864 (0.05%)
    0 / 709 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Wound infection
         subjects affected / exposed
    0 / 1864 (0.00%)
    1 / 709 (0.14%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    Cohort A: SC Herceptin by Needle/Syringe Cohort B: SC Herceptin by Single-Use Injection Device (SID)
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    1499 / 1864 (80.42%)
    576 / 709 (81.24%)
    Injury, poisoning and procedural complications
    Radiation skin injury
         subjects affected / exposed
    161 / 1864 (8.64%)
    68 / 709 (9.59%)
         occurrences all number
    172
    78
    Vascular disorders
    Hot flush
         subjects affected / exposed
    164 / 1864 (8.80%)
    72 / 709 (10.16%)
         occurrences all number
    179
    77
    Hypertension
         subjects affected / exposed
    142 / 1864 (7.62%)
    35 / 709 (4.94%)
         occurrences all number
    183
    50
    Investigations
    Ejection fraction decreased
         subjects affected / exposed
    80 / 1864 (4.29%)
    36 / 709 (5.08%)
         occurrences all number
    85
    43
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    130 / 1864 (6.97%)
    43 / 709 (6.06%)
         occurrences all number
    159
    53
    Neutropenia
         subjects affected / exposed
    101 / 1864 (5.42%)
    36 / 709 (5.08%)
         occurrences all number
    156
    45
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    190 / 1864 (10.19%)
    56 / 709 (7.90%)
         occurrences all number
    223
    59
    Dyspnoea
         subjects affected / exposed
    115 / 1864 (6.17%)
    47 / 709 (6.63%)
         occurrences all number
    126
    49
    Epistaxis
         subjects affected / exposed
    109 / 1864 (5.85%)
    30 / 709 (4.23%)
         occurrences all number
    135
    35
    Nervous system disorders
    Headache
         subjects affected / exposed
    228 / 1864 (12.23%)
    73 / 709 (10.30%)
         occurrences all number
    344
    89
    Neuropathy peripheral
         subjects affected / exposed
    140 / 1864 (7.51%)
    56 / 709 (7.90%)
         occurrences all number
    164
    65
    Paraesthesia
         subjects affected / exposed
    112 / 1864 (6.01%)
    70 / 709 (9.87%)
         occurrences all number
    130
    87
    Dizziness
         subjects affected / exposed
    111 / 1864 (5.95%)
    32 / 709 (4.51%)
         occurrences all number
    143
    35
    Peripheral sensory neuropathy
         subjects affected / exposed
    94 / 1864 (5.04%)
    21 / 709 (2.96%)
         occurrences all number
    102
    25
    General disorders and administration site conditions
    Fatigue
         subjects affected / exposed
    381 / 1864 (20.44%)
    132 / 709 (18.62%)
         occurrences all number
    496
    168
    Asthenia
         subjects affected / exposed
    221 / 1864 (11.86%)
    85 / 709 (11.99%)
         occurrences all number
    327
    107
    Pyrexia
         subjects affected / exposed
    185 / 1864 (9.92%)
    55 / 709 (7.76%)
         occurrences all number
    231
    67
    Oedema peripheral
         subjects affected / exposed
    160 / 1864 (8.58%)
    45 / 709 (6.35%)
         occurrences all number
    185
    49
    Injection site erythema
         subjects affected / exposed
    128 / 1864 (6.87%)
    52 / 709 (7.33%)
         occurrences all number
    326
    124
    Mucosal inflammation
         subjects affected / exposed
    105 / 1864 (5.63%)
    53 / 709 (7.48%)
         occurrences all number
    126
    64
    Injection site pain
         subjects affected / exposed
    117 / 1864 (6.28%)
    37 / 709 (5.22%)
         occurrences all number
    190
    107
    Injection site reaction
         subjects affected / exposed
    101 / 1864 (5.42%)
    36 / 709 (5.08%)
         occurrences all number
    279
    58
    Pain
         subjects affected / exposed
    63 / 1864 (3.38%)
    36 / 709 (5.08%)
         occurrences all number
    70
    41
    Psychiatric disorders
    Insomnia
         subjects affected / exposed
    108 / 1864 (5.79%)
    50 / 709 (7.05%)
         occurrences all number
    125
    52
    Gastrointestinal disorders
    Diarrhoea
         subjects affected / exposed
    380 / 1864 (20.39%)
    130 / 709 (18.34%)
         occurrences all number
    540
    184
    Nausea
         subjects affected / exposed
    274 / 1864 (14.70%)
    102 / 709 (14.39%)
         occurrences all number
    362
    133
    Constipation
         subjects affected / exposed
    153 / 1864 (8.21%)
    62 / 709 (8.74%)
         occurrences all number
    200
    73
    Vomiting
         subjects affected / exposed
    129 / 1864 (6.92%)
    38 / 709 (5.36%)
         occurrences all number
    160
    45
    Stomatitis
         subjects affected / exposed
    116 / 1864 (6.22%)
    42 / 709 (5.92%)
         occurrences all number
    140
    47
    Abdominal pain
         subjects affected / exposed
    87 / 1864 (4.67%)
    36 / 709 (5.08%)
         occurrences all number
    104
    45
    Dyspepsia
         subjects affected / exposed
    69 / 1864 (3.70%)
    44 / 709 (6.21%)
         occurrences all number
    80
    50
    Skin and subcutaneous tissue disorders
    Rash
         subjects affected / exposed
    177 / 1864 (9.50%)
    74 / 709 (10.44%)
         occurrences all number
    251
    113
    Erythema
         subjects affected / exposed
    156 / 1864 (8.37%)
    74 / 709 (10.44%)
         occurrences all number
    223
    86
    Alopecia
         subjects affected / exposed
    163 / 1864 (8.74%)
    49 / 709 (6.91%)
         occurrences all number
    170
    50
    Pruritus
         subjects affected / exposed
    115 / 1864 (6.17%)
    35 / 709 (4.94%)
         occurrences all number
    136
    40
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    362 / 1864 (19.42%)
    133 / 709 (18.76%)
         occurrences all number
    471
    160
    Myalgia
         subjects affected / exposed
    260 / 1864 (13.95%)
    84 / 709 (11.85%)
         occurrences all number
    349
    107
    Pain in extremity
         subjects affected / exposed
    194 / 1864 (10.41%)
    49 / 709 (6.91%)
         occurrences all number
    248
    63
    Back pain
         subjects affected / exposed
    114 / 1864 (6.12%)
    42 / 709 (5.92%)
         occurrences all number
    136
    44
    Musculoskeletal pain
         subjects affected / exposed
    89 / 1864 (4.77%)
    36 / 709 (5.08%)
         occurrences all number
    107
    40
    Bone pain
         subjects affected / exposed
    70 / 1864 (3.76%)
    40 / 709 (5.64%)
         occurrences all number
    80
    53
    Infections and infestations
    Nasopharyngitis
         subjects affected / exposed
    146 / 1864 (7.83%)
    58 / 709 (8.18%)
         occurrences all number
    190
    79
    Upper respiratory tract infection
         subjects affected / exposed
    113 / 1864 (6.06%)
    21 / 709 (2.96%)
         occurrences all number
    132
    25
    Urinary tract infection
         subjects affected / exposed
    94 / 1864 (5.04%)
    32 / 709 (4.51%)
         occurrences all number
    114
    43

    More information

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    Substantial protocol amendments (globally)

    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    19 Nov 2012
    The amendment allowed participants to be treated with SC Herceptin according to indication and to allow a sub-population of participants to be enrolled to provide complementary safety data for regulatory purposes. The duration of treatment-free follow-up was extended from a minimum of 2 years to a minimum of 5 years, and the AE reporting timeframe was revised.
    18 Mar 2013
    The protocol was amended to clarify the timeframe for AE reporting as well as the definition of "treatment period". Participants were also allowed the opportunity to self-administer SC Herceptin via SID at the discretion and supervision of the HCP.

    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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