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    Clinical Trial Results:
    A Phase III, Randomized Open-Label Study to Compare Pharmacokinetics, Efficacy and Safety of Subcutaneous (SC) Trastuzumab With Intravenous (IV) Trastuzumab Administered in Women With HER2-Positive Early Breast Cancer (EBC)

    Summary
    EudraCT number
    		 2008-007326-19
    Trial protocol
    		 FR   ES   CZ   EE   DE   GB   SE   IT   SK   HU  
    Global end of trial date
    24 Jan 2017

    Results information
    Results version number
    		 v2(current)
    This version publication date
    05 Jan 2018
    First version publication date
    26 Jun 2015
    Other versions
    		 v1
    Version creation reason

    Trial information

    		 Close Top of page
    Trial identification
    Sponsor protocol code
    BO22227
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT00950300
    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
    Final
    Date of interim/final analysis
    24 Jan 2017
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    24 Jan 2017
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To compare the following parameters between Herceptin (trastuzumab) IV and Herceptin SC in the neoadjuvant setting: a) Serum trough concentrations observed pre-surgery; b) Efficacy (pathological complete response)
    Protection of trial subjects
    The investigator was required to ensure that this study was conducted in full conformance with the principles of the “Declaration of Helsinki” or with the laws and regulations of the country in which the research was conducted, whichever afforded the greater protection to the individual. The study had to fully adhere to the principles outlined in “Guideline for Good Clinical Practice” International Council for Harmonization (ICH) Tripartite Guideline [January 1997] or with local law if it afforded greater protection to the participant. The investigator was also required to ensure compliance with the European Union Clinical Trial Directive [2001/20/EC] and/or Good Clinical Practice (GCP).
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    16 Oct 2009
    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?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Thailand: 28
    Country: Number of subjects enrolled
    Peru: 27
    Country: Number of subjects enrolled
    Spain: 19
    Country: Number of subjects enrolled
    Hungary: 18
    Country: Number of subjects enrolled
    Czech Republic: 17
    Country: Number of subjects enrolled
    Slovakia: 12
    Country: Number of subjects enrolled
    Italy: 11
    Country: Number of subjects enrolled
    Panama: 8
    Country: Number of subjects enrolled
    Turkey: 8
    Country: Number of subjects enrolled
    China: 6
    Country: Number of subjects enrolled
    Colombia: 5
    Country: Number of subjects enrolled
    Sweden: 4
    Country: Number of subjects enrolled
    Canada: 3
    Country: Number of subjects enrolled
    Guatemala: 3
    Country: Number of subjects enrolled
    Estonia: 1
    Country: Number of subjects enrolled
    Mexico: 1
    Country: Number of subjects enrolled
    Russian Federation: 134
    Country: Number of subjects enrolled
    Brazil: 52
    Country: Number of subjects enrolled
    Korea, Democratic People's Republic of: 51
    Country: Number of subjects enrolled
    Poland: 47
    Country: Number of subjects enrolled
    Germany: 44
    Country: Number of subjects enrolled
    Taiwan: 37
    Country: Number of subjects enrolled
    South Africa: 32
    Country: Number of subjects enrolled
    France: 28
    Worldwide total number of subjects
    596
    EEA total number of subjects
    201
    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)
    540
    From 65 to 84 years
    56
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 -

    Pre-assignment
    Screening details
    		 A total of 833 participants were screened, out of which, 596 participants were enrolled into the study.

    Period 1
    Period 1 title
    Neoadjuvant/Adjuvant Treatment Periods
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Not blinded

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Herceptin IV + Chemotherapy
    Arm description
    		 Participants received eight cycles of Herceptin IV plus chemotherapy prior to surgery and ten cycles of Herceptin IV after surgery. Chemotherapy consisted of docetaxel 75 milligrams per meter-squared (mg/m^2) every 21 days for four cycles followed by 5-fluorouracil 500 mg/m^2, epirubicin 75 mg/m^2, and cyclophosphamide 500 mg/m^2 (FEC) every 21 days for four cycles. Herceptin was administered as 8 milligrams per kilogram (mg/kg) on Day 1 and then as 6 mg/kg on Day 22 and every 21 days thereafter. The first eight cycles prior to surgery comprised the Neoadjuvant Treatment Period, and the ten cycles of Herceptin IV after surgery comprised the Adjuvant Treatment Period. Thereafter, participants entered the Treatment-Free Follow-Up (TFFU) Period. Participants who were withdrawn from the Neoadjuvant Treatment Period for any reason, or who experienced disease recurrence during either the Adjuvant Treatment Period or TFFU Period, could be entered into the Survival Follow-Up (SFU) Period.
    Arm type
    		 Active comparator

    Investigational medicinal product name
    Herceptin IV (Trastuzumab)
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Powder for concentrate for solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Herceptin was administered as 8 mg/kg (loading dose during Cycle 1) and 6 mg/kg (subsequent cycles) via IV infusion on Day 1 of each 21-day cycle for a total of 18 cycles.

    Arm title
    		 Herceptin SC + Chemotherapy
    Arm description
    		 Participants received eight cycles of Herceptin SC plus chemotherapy prior to surgery and ten cycles of Herceptin SC after surgery. Chemotherapy consisted of docetaxel 75 mg/m^2 every 21 days for four cycles followed by FEC every 21 days for four cycles. Herceptin was administered as a 600-milligram (mg) fixed dose given every 21 days. The first eight cycles prior to surgery comprised the Neoadjuvant Treatment Period, and the ten cycles of Herceptin IV after surgery comprised the Adjuvant Treatment Period. Thereafter, participants entered the TFFU Period. Participants who were withdrawn from the Neoadjuvant Treatment Period for any reason, or who experienced disease recurrence during either the Adjuvant Treatment Period or TFFU Period, could be entered into the SFU Period.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Herceptin SC (Trastuzumab)
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    Herceptin was administered as fixed dose 600 mg SC on Day 1 of each 21-day cycle for a total of 18 cycles.

    Number of subjects in period 1
    		Herceptin IV + Chemotherapy Herceptin SC + Chemotherapy
    Started
    299
    297
    Received Neoadjuvant Treatment
    298
    297
    Underwent Surgery
    277
    273
    Entered Adjuvant Treatment
    277
    274
    Completed
    257
    255
    Not completed
    42
    42
         Violation of Selection Criteria
    2
    1
         Progression of Disease
    12
    11
         Death
    1
    3
         Recurrence of Disease
    10
    5
         Adverse Event or Intercurrent Illness
    6
    15
         Not Specified
    1
    1
         Participant Refusal/Withdrawal
    4
    5
         Lost to follow-up
    2
    1
         Insufficient Therapeutic Response
    3
    -
         Protocol deviation
    1
    -
    Period 2
    Period 2 title
    TFFU Period
    Is this the baseline period?
    		 No
    Allocation method
    Non-randomised - controlled
    Blinding used
    		 Not blinded

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Herceptin IV + Chemotherapy
    Arm description
    		 Participants received eight cycles of Herceptin IV plus chemotherapy prior to surgery and ten cycles of Herceptin IV after surgery. Chemotherapy consisted of docetaxel 75 mg/m^2 every 21 days for four cycles followed by FEC every 21 days for four cycles. Herceptin was administered as 8 mg/kg on Day 1 and then as 6 mg/kg on Day 22 and every 21 days thereafter. The first eight cycles prior to surgery comprised the Neoadjuvant Treatment Period, and the ten cycles of Herceptin IV after surgery comprised the Adjuvant Treatment Period. Thereafter, participants entered the TFFU Period. Participants who were withdrawn from the Neoadjuvant Treatment Period for any reason, or who experienced disease recurrence during either the Adjuvant Treatment Period or TFFU Period, could be entered into the SFU Period.
    Arm type
    		 Active comparator

    Investigational medicinal product name
    Herceptin IV (Trastuzumab)
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Powder for concentrate for solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Herceptin was administered as 8 mg/kg (loading dose during Cycle 1) and 6 mg/kg (subsequent cycles) via IV infusion on Day 1 of each 21-day cycle for a total of 18 cycles.

    Arm title
    		 Herceptin SC + Chemotherapy
    Arm description
    		 Participants received eight cycles of Herceptin SC plus chemotherapy prior to surgery and ten cycles of Herceptin SC after surgery. Chemotherapy consisted of docetaxel 75 mg/m^2 every 21 days for four cycles followed by FEC every 21 days for four cycles. Herceptin was administered as a 600-mg fixed dose given every 21 days. The first eight cycles prior to surgery comprised the Neoadjuvant Treatment Period, and the ten cycles of Herceptin IV after surgery comprised the Adjuvant Treatment Period. Thereafter, participants entered the TFFU Period. Participants who were withdrawn from the Neoadjuvant Treatment Period for any reason, or who experienced disease recurrence during either the Adjuvant Treatment Period or TFFU Period, could be entered into the SFU Period.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Herceptin SC (Trastuzumab)
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    Herceptin was administered as fixed dose 600 mg SC on Day 1 of each 21-day cycle for a total of 18 cycles.

    Number of subjects in period 2
    		Herceptin IV + Chemotherapy Herceptin SC + Chemotherapy
    Started
    257
    255
    Completed
    165
    161
    Not completed
    100
    107
         Death
    4
    1
         Refused Treatment
    10
    11
         Recurrence of Disease
    63
    72
         Not Specified
    4
    3
         Adverse Event or Intercurrent Illness
    3
    4
         Failure to Return
    16
    16
    Joined
    8
    13
         Discontinued Period 1 But Continued in Period 2
    8
    13
    Period 3
    Period 3 title
    SFU Period
    Is this the baseline period?
    		 No
    Allocation method
    Non-randomised - controlled
    Blinding used
    		 Not blinded

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Herceptin IV + Chemotherapy
    Arm description
    		 Participants received eight cycles of Herceptin IV plus chemotherapy prior to surgery and ten cycles of Herceptin IV after surgery. Chemotherapy consisted of docetaxel 75 mg/m^2 every 21 days for four cycles followed by FEC every 21 days for four cycles. Herceptin was administered as 8 mg/kg on Day 1 and then as 6 mg/kg on Day 22 and every 21 days thereafter. The first eight cycles prior to surgery comprised the Neoadjuvant Treatment Period, and the ten cycles of Herceptin IV after surgery comprised the Adjuvant Treatment Period. Thereafter, participants entered the TFFU Period. Participants who were withdrawn from the Neoadjuvant Treatment Period for any reason, or who experienced disease recurrence during either the Adjuvant Treatment Period or TFFU Period, could be entered into the SFU Period.
    Arm type
    		 Active comparator

    Investigational medicinal product name
    Herceptin IV (Trastuzumab)
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Powder for concentrate for solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Herceptin was administered as 8 mg/kg (loading dose during Cycle 1) and 6 mg/kg (subsequent cycles) via IV infusion on Day 1 of each 21-day cycle for a total of 18 cycles.

    Arm title
    		 Herceptin SC + Chemotherapy
    Arm description
    		 Participants received eight cycles of Herceptin SC plus chemotherapy prior to surgery and ten cycles of Herceptin SC after surgery. Chemotherapy consisted of docetaxel 75 mg/m^2 every 21 days for four cycles followed by FEC every 21 days for four cycles. Herceptin was administered as a 600-mg fixed dose given every 21 days. The first eight cycles prior to surgery comprised the Neoadjuvant Treatment Period, and the ten cycles of Herceptin IV after surgery comprised the Adjuvant Treatment Period. Thereafter, participants entered the TFFU Period. Participants who were withdrawn from the Neoadjuvant Treatment Period for any reason, or who experienced disease recurrence during either the Adjuvant Treatment Period or TFFU Period, could be entered into the SFU Period.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Herceptin SC (Trastuzumab)
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    Herceptin was administered as fixed dose 600 mg SC on Day 1 of each 21-day cycle for a total of 18 cycles.

    Number of subjects in period 3 [1]
    		Herceptin IV + Chemotherapy Herceptin SC + Chemotherapy
    Started
    118
    123
    Completed
    40
    45
    Not completed
    78
    78
         Consent withdrawn by subject
    4
    8
         Death
    44
    42
         Lost to follow-up
    30
    28
    Notes
    [1] - The number of subjects starting the period is not consistent with the number completing the preceding period. It is expected the number of subjects starting the subsequent period will be the same as the number completing the preceding period.
    Justification: Only participants who consented for follow-up were included in this period.

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Herceptin IV + Chemotherapy
    Reporting group description
    		 Participants received eight cycles of Herceptin IV plus chemotherapy prior to surgery and ten cycles of Herceptin IV after surgery. Chemotherapy consisted of docetaxel 75 milligrams per meter-squared (mg/m^2) every 21 days for four cycles followed by 5-fluorouracil 500 mg/m^2, epirubicin 75 mg/m^2, and cyclophosphamide 500 mg/m^2 (FEC) every 21 days for four cycles. Herceptin was administered as 8 milligrams per kilogram (mg/kg) on Day 1 and then as 6 mg/kg on Day 22 and every 21 days thereafter. The first eight cycles prior to surgery comprised the Neoadjuvant Treatment Period, and the ten cycles of Herceptin IV after surgery comprised the Adjuvant Treatment Period. Thereafter, participants entered the Treatment-Free Follow-Up (TFFU) Period. Participants who were withdrawn from the Neoadjuvant Treatment Period for any reason, or who experienced disease recurrence during either the Adjuvant Treatment Period or TFFU Period, could be entered into the Survival Follow-Up (SFU) Period.

    Reporting group title
    Herceptin SC + Chemotherapy
    Reporting group description
    		 Participants received eight cycles of Herceptin SC plus chemotherapy prior to surgery and ten cycles of Herceptin SC after surgery. Chemotherapy consisted of docetaxel 75 mg/m^2 every 21 days for four cycles followed by FEC every 21 days for four cycles. Herceptin was administered as a 600-milligram (mg) fixed dose given every 21 days. The first eight cycles prior to surgery comprised the Neoadjuvant Treatment Period, and the ten cycles of Herceptin IV after surgery comprised the Adjuvant Treatment Period. Thereafter, participants entered the TFFU Period. Participants who were withdrawn from the Neoadjuvant Treatment Period for any reason, or who experienced disease recurrence during either the Adjuvant Treatment Period or TFFU Period, could be entered into the SFU Period.

    Reporting group values
    		 Herceptin IV + Chemotherapy Herceptin SC + Chemotherapy Total
    Number of subjects
    		 299 297 596
    Age Categorical
    Units: Subjects
    Age Continuous
    Analysis was performed on Intent-to-Treat (ITT) Population, which included participants with at least one efficacy assessment after administration of the first treatment cycle. (N=297, 294, respectively).
    Units: years
        arithmetic mean (standard deviation)
    		 49.5 ( 10.83 ) 50.3 ( 11.08 ) -
    Gender Categorical
    Units: Subjects
        Female
    		 299 297 596
        Male
    		 0 0 0

    End points

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    End points reporting groups
    Reporting group title
    Herceptin IV + Chemotherapy
    Reporting group description
    		 Participants received eight cycles of Herceptin IV plus chemotherapy prior to surgery and ten cycles of Herceptin IV after surgery. Chemotherapy consisted of docetaxel 75 milligrams per meter-squared (mg/m^2) every 21 days for four cycles followed by 5-fluorouracil 500 mg/m^2, epirubicin 75 mg/m^2, and cyclophosphamide 500 mg/m^2 (FEC) every 21 days for four cycles. Herceptin was administered as 8 milligrams per kilogram (mg/kg) on Day 1 and then as 6 mg/kg on Day 22 and every 21 days thereafter. The first eight cycles prior to surgery comprised the Neoadjuvant Treatment Period, and the ten cycles of Herceptin IV after surgery comprised the Adjuvant Treatment Period. Thereafter, participants entered the Treatment-Free Follow-Up (TFFU) Period. Participants who were withdrawn from the Neoadjuvant Treatment Period for any reason, or who experienced disease recurrence during either the Adjuvant Treatment Period or TFFU Period, could be entered into the Survival Follow-Up (SFU) Period.

    Reporting group title
    Herceptin SC + Chemotherapy
    Reporting group description
    		 Participants received eight cycles of Herceptin SC plus chemotherapy prior to surgery and ten cycles of Herceptin SC after surgery. Chemotherapy consisted of docetaxel 75 mg/m^2 every 21 days for four cycles followed by FEC every 21 days for four cycles. Herceptin was administered as a 600-milligram (mg) fixed dose given every 21 days. The first eight cycles prior to surgery comprised the Neoadjuvant Treatment Period, and the ten cycles of Herceptin IV after surgery comprised the Adjuvant Treatment Period. Thereafter, participants entered the TFFU Period. Participants who were withdrawn from the Neoadjuvant Treatment Period for any reason, or who experienced disease recurrence during either the Adjuvant Treatment Period or TFFU Period, could be entered into the SFU Period.
    Reporting group title
    Herceptin IV + Chemotherapy
    Reporting group description
    		 Participants received eight cycles of Herceptin IV plus chemotherapy prior to surgery and ten cycles of Herceptin IV after surgery. Chemotherapy consisted of docetaxel 75 mg/m^2 every 21 days for four cycles followed by FEC every 21 days for four cycles. Herceptin was administered as 8 mg/kg on Day 1 and then as 6 mg/kg on Day 22 and every 21 days thereafter. The first eight cycles prior to surgery comprised the Neoadjuvant Treatment Period, and the ten cycles of Herceptin IV after surgery comprised the Adjuvant Treatment Period. Thereafter, participants entered the TFFU Period. Participants who were withdrawn from the Neoadjuvant Treatment Period for any reason, or who experienced disease recurrence during either the Adjuvant Treatment Period or TFFU Period, could be entered into the SFU Period.

    Reporting group title
    Herceptin SC + Chemotherapy
    Reporting group description
    		 Participants received eight cycles of Herceptin SC plus chemotherapy prior to surgery and ten cycles of Herceptin SC after surgery. Chemotherapy consisted of docetaxel 75 mg/m^2 every 21 days for four cycles followed by FEC every 21 days for four cycles. Herceptin was administered as a 600-mg fixed dose given every 21 days. The first eight cycles prior to surgery comprised the Neoadjuvant Treatment Period, and the ten cycles of Herceptin IV after surgery comprised the Adjuvant Treatment Period. Thereafter, participants entered the TFFU Period. Participants who were withdrawn from the Neoadjuvant Treatment Period for any reason, or who experienced disease recurrence during either the Adjuvant Treatment Period or TFFU Period, could be entered into the SFU Period.
    Reporting group title
    Herceptin IV + Chemotherapy
    Reporting group description
    		 Participants received eight cycles of Herceptin IV plus chemotherapy prior to surgery and ten cycles of Herceptin IV after surgery. Chemotherapy consisted of docetaxel 75 mg/m^2 every 21 days for four cycles followed by FEC every 21 days for four cycles. Herceptin was administered as 8 mg/kg on Day 1 and then as 6 mg/kg on Day 22 and every 21 days thereafter. The first eight cycles prior to surgery comprised the Neoadjuvant Treatment Period, and the ten cycles of Herceptin IV after surgery comprised the Adjuvant Treatment Period. Thereafter, participants entered the TFFU Period. Participants who were withdrawn from the Neoadjuvant Treatment Period for any reason, or who experienced disease recurrence during either the Adjuvant Treatment Period or TFFU Period, could be entered into the SFU Period.

    Reporting group title
    Herceptin SC + Chemotherapy
    Reporting group description
    		 Participants received eight cycles of Herceptin SC plus chemotherapy prior to surgery and ten cycles of Herceptin SC after surgery. Chemotherapy consisted of docetaxel 75 mg/m^2 every 21 days for four cycles followed by FEC every 21 days for four cycles. Herceptin was administered as a 600-mg fixed dose given every 21 days. The first eight cycles prior to surgery comprised the Neoadjuvant Treatment Period, and the ten cycles of Herceptin IV after surgery comprised the Adjuvant Treatment Period. Thereafter, participants entered the TFFU Period. Participants who were withdrawn from the Neoadjuvant Treatment Period for any reason, or who experienced disease recurrence during either the Adjuvant Treatment Period or TFFU Period, could be entered into the SFU Period.

    Primary: Observed Serum Trough Concentration (Ctrough) of Trastuzumab Prior to Surgery

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    End point title
    		 Observed Serum Trough Concentration (Ctrough) of Trastuzumab Prior to Surgery
    End point description
    Pre-dose samples were obtained prior to surgery (Cycle 8). The observed Ctrough was recorded, averaged among all participants, and expressed in micrograms per milliliter (mcg/mL). Analysis was performed on Primary Pharmacokinetic (PK) Per Protocol (PP) Population, which included all participants with at least one measurable trastuzumab serum concentration and who did not have any major protocol violations related to PK sampling for the primary endpoint.
    End point type
    Primary
    End point timeframe
    Pre-dose (0 hours) on Day 1 of Cycle 8 (cycle length of 21 days)
    End point values
    		 Herceptin IV + Chemotherapy Herceptin SC + Chemotherapy
    Number of subjects analysed
    235
    234
    Units: mcg/mL
        arithmetic mean (standard deviation)
    57.8 ( 30.3 )
    78.7 ( 43.9 )
    Statistical analysis title
    		 Statistical Analysis 1
    Statistical analysis description
    PK sample size calculations based on percentage of coefficient of variation (CV%) for Ctrough of trastuzumab from previous metastatic breast cancer (MBC) and early breast cancer (EBC) studies. Because pre-surgery situation was comparable to MBC setting, interpatient CV% of 60 percent (%) was assumed and 130 participants per arm (260 participants total) were needed to demonstrate Ctrough comparability with 80% power if the true means of the two formulations did not differ by greater than (>) 5%.
    Comparison groups
    Herceptin IV + Chemotherapy v Herceptin SC + Chemotherapy
    Number of subjects included in analysis
    469
    Analysis specification
    Pre-specified
    Analysis type
    		 non-inferiority [1]
    Method
    Parameter type
    		 Geometric mean ratio
    Point estimate
    1.33
    Confidence interval
         level
    		 90%
         sides
    2-sided
         lower limit
    		 1.24
         upper limit
    		 1.44
    Notes
    [1] - Non-inferiority was concluded if the lower limit of the 90% confidence interval (CI) was greater than or equal to (>/=) 0.8 for the geometric mean ratio (ratio of test treatment group [Herceptin SC + Chemotherapy] to reference treatment group [Herceptin IV + Chemotherapy]).

    Primary: Percentage of Participants with Pathological Complete Response (pCR)

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    End point title
    		 Percentage of Participants with Pathological Complete Response (pCR)
    End point description
    Participants were evaluated following eight cycles of treatment and after surgery to assess for pCR, defined as absence of neoplastic invasive cells in the breast according to pathologist examination. The percentage of participants with pCR was reported, and the 95% CI for one-sample binomial was constructed using the Pearson-Clopper method. Analysis was performed on Efficacy (E) PP Population, which included all participants with at least one on-treatment efficacy assessment who received a full eight cycles of study treatment according to randomization and who met additional protocol-specified criteria.
    End point type
    Primary
    End point timeframe
    After surgery following eight cycles of Herceptin + chemotherapy (approximately 6 months from Baseline)
    End point values
    		 Herceptin IV + Chemotherapy Herceptin SC + Chemotherapy
    Number of subjects analysed
    263
    260
    Units: percentage of participants
        number (confidence interval 95%)
    40.7 (34.7 to 46.9)
    45.4 (39.2 to 51.7)
    Statistical analysis title
    		 Statistical Analysis 1
    Statistical analysis description
    Assuming pCR rates of at least 40% in both arms, 552 participants were necessary to conclude non-inferiority in pCR rate with a power of 80% using a one-sided 97.5% CI for the difference of the response rates and a non-inferiority margin of 12.5%.
    Comparison groups
    Herceptin IV + Chemotherapy v Herceptin SC + Chemotherapy
    Number of subjects included in analysis
    523
    Analysis specification
    Pre-specified
    Analysis type
    		 non-inferiority [2]
    Method
    Parameter type
    		 Difference in response rates
    Point estimate
    4.7
    Confidence interval
         level
    		 97.5%
         sides
    1-sided
         lower limit
    		 -4
         upper limit
    		 -
    Notes
    [2] - Non-inferiority was concluded if the lower limit of the one-sided 97.5% CI was above -12.5% for the difference in response (pCR) rates. The one-sided 97.5% CI for the difference in response (pCR) rates was calculated using the Anderson-Hauck continuity correction.

    Secondary: Observed Ctrough of Trastuzumab After Surgery

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    End point title
    		 Observed Ctrough of Trastuzumab After Surgery
    End point description
    Pre-dose samples were obtained after surgery (Cycle 13). The observed Ctrough was recorded, averaged among all participants, and expressed in mcg/mL. Analysis was performed on Secondary PKPP Population, which included all participants with at least one measurable trastuzumab serum concentration and who did not have any major protocol violations related to PK sampling for the secondary endpoint.
    End point type
    Secondary
    End point timeframe
    Pre-dose (0 hours) on Day 1 of Cycle 13 (cycle length of 21 days)
    End point values
    		 Herceptin IV + Chemotherapy Herceptin SC + Chemotherapy
    Number of subjects analysed
    223
    227
    Units: mcg/mL
        arithmetic mean (standard deviation)
    62.1 ( 37.1 )
    90.4 ( 41.9 )
    Statistical analysis title
    		 Statistical Analysis 1
    Statistical analysis description
    Additional supportive analysis
    Comparison groups
    Herceptin IV + Chemotherapy v Herceptin SC + Chemotherapy
    Number of subjects included in analysis
    450
    Analysis specification
    Pre-specified
    Analysis type
    		 other [3]
    Method
    Parameter type
    		 Geometric mean ratio
    Point estimate
    1.51
    Confidence interval
         level
    		 90%
         sides
    2-sided
         lower limit
    		 1.4
         upper limit
    		 1.63
    Notes
    [3] - Geometric mean ratio = ratio of test treatment group (Herceptin SC + Chemotherapy) to reference treatment group (Herceptin IV + Chemotherapy)

    Secondary: Predicted Ctrough of Trastuzumab Prior to Surgery

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    End point title
    		 Predicted Ctrough of Trastuzumab Prior to Surgery
    End point description
    Predicted Ctrough at pre-dose prior to surgery (Cycle 8) was determined on the basis of a population PK model from Study BP22023 (NCT00800436). The mean predicted Ctrough was expressed in mcg/mL. Analysis was performed on PKPP Population.
    End point type
    Secondary
    End point timeframe
    Pre-dose (0 hours) on Day 1 of Cycle 8 (cycle length of 21 days)
    End point values
    		 Herceptin IV + Chemotherapy Herceptin SC + Chemotherapy
    Number of subjects analysed
    276
    278
    Units: mcg/mL
        arithmetic mean (standard deviation)
    51.4 ( 19.4 )
    80.3 ( 33.2 )
    Statistical analysis title
    		 Statistical Analysis 1
    Statistical analysis description
    Additional supportive analysis.
    Comparison groups
    Herceptin IV + Chemotherapy v Herceptin SC + Chemotherapy
    Number of subjects included in analysis
    554
    Analysis specification
    Pre-specified
    Analysis type
    		 other [4]
    Method
    Parameter type
    		 Geometric mean ratio
    Point estimate
    1.55
    Confidence interval
         level
    		 90%
         sides
    2-sided
         lower limit
    		 1.46
         upper limit
    		 1.64
    Notes
    [4] - Geometric mean ratio = ratio of test treatment group (Herceptin SC + Chemotherapy) to reference treatment group (Herceptin IV + Chemotherapy).

    Secondary: Predicted Ctrough of Trastuzumab After Surgery

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    End point title
    		 Predicted Ctrough of Trastuzumab After Surgery
    End point description
    Predicted Ctrough at pre-dose after surgery (Cycle 13) was determined on the basis of a population PK model from Study BP22023 (NCT00800436). The mean predicted Ctrough was expressed in mcg/mL. Analysis was performed on PKPP Population. Only participants with a Cycle 13 pre-dose PK measurement were included in the analysis.
    End point type
    Secondary
    End point timeframe
    Pre-dose (0 hours) on Day 1 of Cycle 13 (cycle length of 21 days)
    End point values
    		 Herceptin IV + Chemotherapy Herceptin SC + Chemotherapy
    Number of subjects analysed
    236
    236
    Units: mcg/mL
        arithmetic mean (standard deviation)
    51.7 ( 20.0 )
    80.6 ( 33.4 )
    Statistical analysis title
    		 Statistical Analysis 1
    Statistical analysis description
    Additional supportive analysis
    Comparison groups
    Herceptin IV + Chemotherapy v Herceptin SC + Chemotherapy
    Number of subjects included in analysis
    472
    Analysis specification
    Pre-specified
    Analysis type
    		 other [5]
    Method
    Parameter type
    		 Geometric mean ratio
    Point estimate
    1.55
    Confidence interval
         level
    		 90%
         sides
    2-sided
         lower limit
    		 1.45
         upper limit
    		 1.64
    Notes
    [5] - Geometric mean ratio = ratio of test treatment group (Herceptin SC + Chemotherapy) to reference treatment group (Herceptin IV + Chemotherapy).

    Secondary: Number of Participants with Ctrough of Trastuzumab >20 mcg/mL Prior to Surgery

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    End point title
    		 Number of Participants with Ctrough of Trastuzumab >20 mcg/mL Prior to Surgery
    End point description
    Pre-dose samples were obtained prior to surgery (Cycle 8). The number of participants who had an observed Ctrough >20 mcg/mL was reported. Analysis was performed on primary PKPP Population.
    End point type
    Secondary
    End point timeframe
    Pre-dose (0 hours) on Day 1 of Cycle 8 (cycle length of 21 days)
    End point values
    		 Herceptin IV + Chemotherapy Herceptin SC + Chemotherapy
    Number of subjects analysed
    235
    234
    Units: participants
    232
    227
    No statistical analyses for this end point

    Secondary: Number of Participants with Ctrough of Trastuzumab >20 mcg/mL After Surgery

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    End point title
    		 Number of Participants with Ctrough of Trastuzumab >20 mcg/mL After Surgery
    End point description
    Pre-dose samples were obtained after surgery (Cycle 13). The number of participants who had an observed Ctrough >20 mcg/mL was reported. Analysis was performed on secondary PKPP population.
    End point type
    Secondary
    End point timeframe
    Pre-dose (0 hours) on Day 1 of Cycle 13 (cycle length of 21 days)
    End point values
    		 Herceptin IV + Chemotherapy Herceptin SC + Chemotherapy
    Number of subjects analysed
    223
    227
    Units: participants
    216
    227
    No statistical analyses for this end point

    Secondary: Maximum Serum Concentration (Cmax) of Trastuzumab Prior to Surgery

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    End point title
    		 Maximum Serum Concentration (Cmax) of Trastuzumab Prior to Surgery
    End point description
    PK samples were obtained prior to surgery (Cycle 7). The Cmax during Cycle 7 was recorded, averaged among all participants, and expressed in mcg/mL. Analysis was performed on Primary PKPP Population. Only those participants who provided evaluable data were included in the analysis.
    End point type
    Secondary
    End point timeframe
    Pre-dose (0 hours) and at end of 30-minute infusion (Herceptin IV only) on Day 1 of Cycle 7; on Days 2, 4, 8, 15 of Cycle 7; pre-dose (0 hours) on Day 1 of Cycle 8 (cycle length of 21 days)
    End point values
    		 Herceptin IV + Chemotherapy Herceptin SC + Chemotherapy
    Number of subjects analysed
    235
    233
    Units: mcg/mL
        arithmetic mean (standard deviation)
    221 ( 118 )
    149 ( 64.8 )
    No statistical analyses for this end point

    Secondary: Time of Maximum Serum Concentration (Tmax) of Trastuzumab Prior to Surgery

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    End point title
    		 Time of Maximum Serum Concentration (Tmax) of Trastuzumab Prior to Surgery
    End point description
    PK samples were obtained prior to surgery (Cycle 7). The Tmax during Cycle 7 was recorded, averaged among all participants, and expressed in days. Analysis was performed on Primary PKPP Population. Only those participants who provided evaluable data were included in the analysis.
    End point type
    Secondary
    End point timeframe
    Pre-dose (0 hours) and at end of 30-minute infusion (Herceptin IV only) on Day 1 of Cycle 7; on Days 2, 4, 8, 15 of Cycle 7; pre-dose (0 hours) on Day 1 of Cycle 8 (cycle length of 21 days)
    End point values
    		 Herceptin IV + Chemotherapy Herceptin SC + Chemotherapy
    Number of subjects analysed
    235
    233
    Units: days
        arithmetic mean (standard deviation)
    0.05 ( 0.04 )
    4.12 ( 2.91 )
    No statistical analyses for this end point

    Secondary: Area Under the Concentration-Time Curve from 0 to 21 Days (AUC21d) of Trastuzumab Prior to Surgery

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    End point title
    		 Area Under the Concentration-Time Curve from 0 to 21 Days (AUC21d) of Trastuzumab Prior to Surgery
    End point description
    PK samples were obtained prior to surgery (Cycle 7). Values were extrapolated beyond Day 15 to produce the area over the full 21-day cycle. The AUC21d value at Cycle 7 was calculated from trastuzumab concentration-time profiles using standard non-compartmental PK methods, averaged among all participants, and expressed in days multiplied by micrograms per milliliter (d*mcg/mL). Analysis was performed on Primary PKPP Population. Only those participants who provided evaluable data were included in the analysis.
    End point type
    Secondary
    End point timeframe
    Pre-dose (0 hours) and at end of 30-minute infusion (Herceptin IV only) on Day 1 of Cycle 7; on Days 2, 4, 8, 15 of Cycle 7; pre-dose (0 hours) on Day 1 of Cycle 8 (cycle length of 21 days)
    End point values
    		 Herceptin IV + Chemotherapy Herceptin SC + Chemotherapy
    Number of subjects analysed
    235
    233
    Units: d*mcg/mL
        arithmetic mean (standard deviation)
    2056 ( 598 )
    2268 ( 875 )
    No statistical analyses for this end point

    Secondary: Cmax of Trastuzumab After Surgery

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    End point title
    		 Cmax of Trastuzumab After Surgery
    End point description
    PK samples were obtained after surgery (Cycle 12). The Cmax during Cycle 12 was recorded, averaged among all participants, and expressed in mcg/mL. Analysis was performed on Secondary PKPP population. Only those participants who provided evaluable data were included in the analysis.
    End point type
    Secondary
    End point timeframe
    Pre-dose (0 hours) and at end of 30-minute infusion (Herceptin IV only) on Day 1 of Cycle 12; on Days 2, 4, 8, 15 of Cycle 12; pre-dose (0 hours) on Day 1 of Cycle 13 (cycle length of 21 days)
    End point values
    		 Herceptin IV + Chemotherapy Herceptin SC + Chemotherapy
    Number of subjects analysed
    223
    223
    Units: mcg/mL
        arithmetic mean (standard deviation)
    230 ( 118 )
    166 ( 58.8 )
    No statistical analyses for this end point

    Secondary: Tmax of Trastuzumab After Surgery

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    End point title
    		 Tmax of Trastuzumab After Surgery
    End point description
    PK samples were obtained after surgery (Cycle 12). The Tmax during Cycle 12 was recorded, averaged among all participants, and expressed in days. Analysis was performed on Secondary PKPP population. Only those participants who provided evaluable data were included in the analysis.
    End point type
    Secondary
    End point timeframe
    Pre-dose (0 hours) and at end of 30-minute infusion (Herceptin IV only) on Day 1 of Cycle 12; on Days 2, 4, 8, 15 of Cycle 12; pre-dose (0 hours) on Day 1 of Cycle 13 (cycle length of 21 days)
    End point values
    		 Herceptin IV + Chemotherapy Herceptin SC + Chemotherapy
    Number of subjects analysed
    223
    222
    Units: days
        arithmetic mean (standard deviation)
    0.06 ( 0.13 )
    4.08 ( 2.87 )
    No statistical analyses for this end point

    Secondary: AUC21d of Trastuzumab After Surgery

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    End point title
    		 AUC21d of Trastuzumab After Surgery
    End point description
    PK samples were obtained after surgery (Cycle 12). Values were extrapolated beyond Day 15 to produce the area over the full 21-day cycle. The AUC21d value at Cycle 12 was calculated from trastuzumab concentration-time profiles using standard non-compartmental PK methods, averaged among all participants, and expressed in d*mcg/mL. Analysis was performed on Secondary PKPP population. Only those participants who provided evaluable data were included in the analysis.
    End point type
    Secondary
    End point timeframe
    Pre-dose (0 hours) and at end of 30-minute infusion (Herceptin IV only) on Day 1 of Cycle 12; on Days 2, 4, 8, 15 of Cycle 12; pre-dose (0 hours) on Day 1 of Cycle 13 (cycle length of 21 days)
    End point values
    		 Herceptin IV + Chemotherapy Herceptin SC + Chemotherapy
    Number of subjects analysed
    223
    223
    Units: d*mcg/mL
        arithmetic mean (standard deviation)
    2179 ( 725 )
    2610 ( 945 )
    No statistical analyses for this end point

    Secondary: Percentage of Participants with Total Pathological Complete Response (tpCR)

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    End point title
    		 Percentage of Participants with Total Pathological Complete Response (tpCR)
    End point description
    Participants were evaluated following eight cycles of treatment and after surgery to assess for tpCR, defined as absence of neoplastic invasive cells in the breast and axillary lymph nodes according to pathologist examination. The percentage of participants with tpCR was reported, and the 95% CI for one-sample binomial was constructed using the Pearson-Clopper method. Analysis was performed on EPP Population.
    End point type
    Secondary
    End point timeframe
    After surgery following eight cycles of Herceptin + chemotherapy (approximately 6 months from Baseline)
    End point values
    		 Herceptin IV + Chemotherapy Herceptin SC + Chemotherapy
    Number of subjects analysed
    263
    260
    Units: percentage of participants
        number (confidence interval 95%)
    34.2 (28.5 to 40.3)
    39.2 (33.3 to 45.5)
    Statistical analysis title
    		 Statistical Analysis 1
    Statistical analysis description
    The 95% CI for the difference in response (tpCR) rates was calculated using the Anderson-Hauck continuity correction.
    Comparison groups
    Herceptin IV + Chemotherapy v Herceptin SC + Chemotherapy
    Number of subjects included in analysis
    523
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    Method
    Parameter type
    		 Difference in response rates
    Point estimate
    5.01
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -3.5
         upper limit
    		 13.5

    Secondary: Percentage of Participants with Complete Response (CR) or Partial Response (PR) According to Response Evaluation Criteria in Solid Tumors (RECIST) Version 1.0, Among Those with Measurable Disease at Baseline

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    End point title
    		 Percentage of Participants with Complete Response (CR) or Partial Response (PR) According to Response Evaluation Criteria in Solid Tumors (RECIST) Version 1.0, Among Those with Measurable Disease at Baseline
    End point description
    Tumor response was assessed using RECIST version 1.0. CR was defined as disappearance of all target lesions and short axis reduction of any pathological lymph nodes to less than (<) 10 millimeters (mm) with no prior assessment of progressive disease (PD). PR was defined as greater than or equal to (>/=) 30% decrease from Baseline in sum diameter (SD) of target lesions with no prior assessment of PD. PD was defined as >/=20% relative increase and >/=5 mm of absolute increase in the SD of target lesions, taking as reference the smallest SD recorded since treatment started; or appearance of 1 or more new lesions. The percentage of participants with overall response of CR or PR at the end of neoadjuvant treatment was reported, and the 95% CI for one-sample binomial was constructed using the Pearson-Clopper method. Analysis was performed on EPP Population. Only participants with measurable disease at Baseline were included.
    End point type
    Secondary
    End point timeframe
    Tumor assessments at Baseline; on Day 1 of Cycles 3, 5, 7 (cycle length of 21 days); and at time of surgery following eight cycles of Herceptin + chemotherapy (approximately 6 months overall)
    End point values
    		 Herceptin IV + Chemotherapy Herceptin SC + Chemotherapy
    Number of subjects analysed
    260
    258
    Units: percentage of participants
        number (confidence interval 95%)
    88.8 (84.4 to 92.4)
    87.2 (82.5 to 91.0)
    Statistical analysis title
    		 Statistical Analysis 2
    Statistical analysis description
    Odds Ratio (OR) = ratio of test treatment group (Herceptin SC + Chemotherapy) to reference treatment group (Herceptin IV + Chemotherapy).
    Comparison groups
    Herceptin IV + Chemotherapy v Herceptin SC + Chemotherapy
    Number of subjects included in analysis
    518
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    Method
    Parameter type
    		 Odds ratio (OR)
    Point estimate
    0.86
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.5
         upper limit
    		 1.46
    Statistical analysis title
    		 Statistical Analysis 1
    Statistical analysis description
    The 95% CI for the difference in response (CR+PR) rates was calculated using the Anderson-Hauck continuity correction.
    Comparison groups
    Herceptin IV + Chemotherapy v Herceptin SC + Chemotherapy
    Number of subjects included in analysis
    518
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    Method
    Parameter type
    		 Difference in response rates
    Point estimate
    -1.64
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -7.4
         upper limit
    		 4.2

    Secondary: Time to Response According to RECIST Version 1.0, Among Those with Measurable Disease at Baseline

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    End point title
    		 Time to Response According to RECIST Version 1.0, Among Those with Measurable Disease at Baseline
    End point description
    Tumor response was assessed using RECIST version 1.0. CR was defined as disappearance of all target lesions and short-axis reduction of any pathological lymph nodes to <10 mm with no prior assessment of PD. PR was defined as >/=30% decrease from Baseline in SD of target lesions with no prior assessment of PD. PD was defined as >/=20% relative increase and >/=5 mm of absolute increase in the SD of target lesions, taking as reference the smallest SD recorded since treatment started; or appearance of 1 or more new lesions. Time to response was defined as the time from first dose of study medication to the first assessment of CR or PR, which was the date the response was first documented by objective evidence, among participants with an overall response of CR or PR. Analysis was performed on EPP Population. Only participants with measurable disease at Baseline and a response of CR or PR were included.
    End point type
    Secondary
    End point timeframe
    Tumor assessments at Baseline; on Day 1 Cycles 3, 5, 7 (cycle length of 21 days); and at time of surgery following eight cycles of chemotherapy (approximately 6 months overall)
    End point values
    		 Herceptin IV + Chemotherapy Herceptin SC + Chemotherapy
    Number of subjects analysed
    231
    225
    Units: weeks
        median (full range (min-max))
    6.14 (3 to 25)
    6.14 (3 to 28)
    No statistical analyses for this end point

    Secondary: Percentage of Participants Who Experienced a Protocol-Defined Event

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    End point title
    		 Percentage of Participants Who Experienced a Protocol-Defined Event
    End point description
    Protocol-defined events included disease recurrence/progression (local, regional, distant, contralateral) or death from any cause. Imaging was performed at specified visits for up to 5 years after last dose. Thereafter, participants were followed for survival only. The percentage of participants who experienced a protocol-defined event at any time during the study was reported. Analysis was performed on ITT Population.
    End point type
    Secondary
    End point timeframe
    Screening; Day 1 of Cycle 18 (cycle length of 21 days); and Months 6, 12, 24, 36, 48, 60 from last dose of Cycle 18; then every 6 months until withdrawal for any reason (up to approximately 87 months overall)
    End point values
    		 Herceptin IV + Chemotherapy Herceptin SC + Chemotherapy
    Number of subjects analysed
    297
    294
    Units: percentage of participants
        number (not applicable)
    33.3
    32.7
    No statistical analyses for this end point

    Secondary: Event-Free Survival (EFS)

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    End point title
    		 Event-Free Survival (EFS)
    End point description
    Protocol-defined events included disease recurrence or progression (local, regional, distant, contralateral) or death from any cause. Imaging was performed at specified visits for up to 5 years after last dose. Thereafter, participants were followed for survival only. EFS was estimated by Kaplan-Meier analysis and defined as the time from randomization to the first protocol-defined event. Analysis was performed on ITT Population. The value “9.9999” in results indicate that median time to event could not be determined because of a high number (>50%) of censored observations. Full range includes censored observations.
    End point type
    Secondary
    End point timeframe
    Screening; Day 1 of Cycle 18 (cycle length of 21 days); and Months 6, 12, 24, 36, 48, 60 from last dose of Cycle 18; then every 6 months until withdrawal for any reason (up to approximately 87 months overall)
    End point values
    		 Herceptin IV + Chemotherapy Herceptin SC + Chemotherapy
    Number of subjects analysed
    297
    294
    Units: months
        median (full range (min-max))
    9.9999 (1 to 82)
    9.9999 (1 to 76)
    Statistical analysis title
    		 Statistical Analysis 1
    Statistical analysis description
    Hazard Ratio (HR): ratio of test treatment group (Herceptin SC + Chemotherapy) to reference treatment group (Herceptin IV + Chemotherapy)
    Comparison groups
    Herceptin IV + Chemotherapy v Herceptin SC + Chemotherapy
    Number of subjects included in analysis
    591
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.8651
    Method
    		 Logrank
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.98
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.74
         upper limit
    		 1.29

    Secondary: Percentage of Participants Who Died

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    End point title
    		 Percentage of Participants Who Died
    End point description
    The percentage of participants who died at any time during the study was reported. Analysis was performed on ITT Population.
    End point type
    Secondary
    End point timeframe
    Continuously during treatment (up to 12 months); at Months 1, 3, 6 from last dose of Cycle 18 (cycle length of 21 days); then every 6 months until withdrawal for any reason (up to approximately 87 months overall)
    End point values
    		 Herceptin IV + Chemotherapy Herceptin SC + Chemotherapy
    Number of subjects analysed
    297
    294
    Units: percentage of participants
        number (not applicable)
    14.5
    13.6
    No statistical analyses for this end point

    Secondary: Overall Survival (OS)

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    End point title
    		 Overall Survival (OS)
    End point description
    OS was estimated by Kaplan-Meier analysis and defined as the time from randomization to death from any cause. Analysis was performed on ITT Population. The value “9.9999” in results indicate that median OS could not be determined because of a high number (>50%) of censored observations. Full range includes censored observations.
    End point type
    Secondary
    End point timeframe
    Continuously during treatment (up to 12 months); at Months 1, 3, 6 from last dose of Cycle 18 (cycle length of 21 days); then every 6 months until withdrawal for any reason (up to approximately 87 months overall)
    End point values
    		 Herceptin IV + Chemotherapy Herceptin SC + Chemotherapy
    Number of subjects analysed
    297
    294
    Units: months
        median (full range (min-max))
    9.9999 (2 to 82)
    9.9999 (3 to 79)
    Statistical analysis title
    		 Statistical Analysis 1
    Statistical analysis description
    Hazard Ratio (HR): ratio of test treatment group (Herceptin SC + Chemotherapy) to reference treatment group (Herceptin IV + Chemotherapy)
    Comparison groups
    Herceptin IV + Chemotherapy v Herceptin SC + Chemotherapy
    Number of subjects included in analysis
    591
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.7767
    Method
    		 Logrank
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.94
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.61
         upper limit
    		 1.45

    Secondary: Number of Participants with Anti-Drug Antibodies (ADAs) Against Trastuzumab

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    End point title
    		 Number of Participants with Anti-Drug Antibodies (ADAs) Against Trastuzumab
    End point description
    Participants provided PK samples for evaluation of anti-trastuzumab antibodies. The number of participants with “Treatment-induced ADAs” and “Treatment-enhanced ADA” against trastuzumab at any time during or after treatment was reported. Treatment-induced ADA = a participant with negative or missing Baseline ADA result(s) and at least one positive post-Baseline ADA result. Treatment-enhanced ADA = a participant with positive ADA result at Baseline who has one or more post Baseline titer results that are at least 0.60 titer unit greater than the Baseline titer result (four-fold increase of titer). Analysis was performed on Safety Population, which included all participants who received at least one dose of study medication. Here, Number of Subjects Analysed = participants who were evaluable for this outcome measure.
    End point type
    Secondary
    End point timeframe
    Baseline; pre-dose (0 hours) on Day 1 of Cycles 2, 5, 13, 18 (cycle length of 21 days); and Months 3, 6, 12, 18, 24, 30, 36, 42, 48, 54, 60 from last dose of Cycle 18
    End point values
    		 Herceptin IV + Chemotherapy Herceptin SC + Chemotherapy
    Number of subjects analysed
    296
    295
    Units: participants
        Treatment-induced ADAs
    28
    46
        Treatment-enhanced ADA
    2
    1
    No statistical analyses for this end point

    Secondary: Number of Participants with ADAs Against Recombinant Human Hyaluronidase (rHuPH20)

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    End point title
    		 Number of Participants with ADAs Against Recombinant Human Hyaluronidase (rHuPH20) [6]
    End point description
    Participants in the Herceptin SC arm provided PK samples for evaluation of anti-rHuPH20 antibodies. The number of participants with “Treatment-induced ADAs” and “Treatment-enhanced ADA” against rHuPH20 (an excipient unique to the SC formulation) at any time during or after treatment was reported. Treatment-induced ADA = a participant with negative or missing Baseline ADA result(s) and at least one positive post-Baseline ADA result. Treatment-enhanced ADA = a participant with positive ADA result at Baseline who has one or more post Baseline titer results that are at least 0.60 titer unit greater than the Baseline titer result (four-fold increase of titer). Analysis was performed on Safety Population. Here, Number of Subjects Analysed = participants who were evaluable for this outcome measure. As rHuPH20 is unique to SC formulation, this outcome measure was applicable for “Herceptin SC + Chemotherapy” arm only.
    End point type
    Secondary
    End point timeframe
    Baseline; pre-dose (0 hours) on Day 1 of Cycles 2, 5, 13, 18 (cycle length of 21 days); and Months 3, 6, 12, 18, 24, 30, 36, 42, 48, 54, 60 from last dose of Cycle 18
    Notes
    [6] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Reported analysis was planned to be carried out in the indicated arm only.
    End point values
    		 Herceptin SC + Chemotherapy
    Number of subjects analysed
    295
    Units: participants
        Treatment-induced ADA
    49
        Treatment-enhanced ADA
    13
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Approximately 87 months overall
    Adverse event reporting additional description
    Analysis was performed on Safety Population.
    Assessment type
    		 Non-systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    19.1
    Reporting groups
    Reporting group title
    Herceptin IV + Chemotherapy
    Reporting group description
    		 Participants received eight cycles of Herceptin IV plus chemotherapy prior to surgery and ten cycles of Herceptin IV after surgery. Chemotherapy consisted of docetaxel 75 mg/m^2 every 21 days for four cycles followed by FEC every 21 days for four cycles. Herceptin was administered as 8 mg/kg on Day 1 and then as 6 mg/kg on Day 22 and every 21 days thereafter. The first eight cycles prior to surgery comprised the Neoadjuvant Treatment Period, and the ten cycles of Herceptin IV after surgery comprised the Adjuvant Treatment Period. Thereafter, participants entered the TFFU Period. Participants who were withdrawn from the Neoadjuvant Treatment Period for any reason, or who experienced disease recurrence during either the Adjuvant Treatment Period or TFFU Period, could be entered into the SFU Period.

    Reporting group title
    Herceptin SC + Chemotherapy
    Reporting group description
    		 Participants received eight cycles of Herceptin SC plus chemotherapy prior to surgery and ten cycles of Herceptin SC after surgery. Chemotherapy consisted of docetaxel 75 mg/m^2 every 21 days for four cycles followed by FEC every 21 days for four cycles. Herceptin was administered as a 600-mg fixed dose given every 21 days. The first eight cycles prior to surgery comprised the Neoadjuvant Treatment Period, and the ten cycles of Herceptin IV after surgery comprised the Adjuvant Treatment Period. Thereafter, participants entered the TFFU Period. Participants who were withdrawn from the Neoadjuvant Treatment Period for any reason, or who experienced disease recurrence during either the Adjuvant Treatment Period or TFFU Period, could be entered into the SFU Period.

    Serious adverse events
    		 Herceptin IV + Chemotherapy Herceptin SC + Chemotherapy
    Total subjects affected by serious adverse events
         subjects affected / exposed
    45 / 298 (15.10%)
    65 / 297 (21.89%)
         number of deaths (all causes)
    43
    42
         number of deaths resulting from adverse events
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Endometrial cancer
         subjects affected / exposed
    0 / 298 (0.00%)
    2 / 297 (0.67%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Myeloid leukaemia
         subjects affected / exposed
    1 / 298 (0.34%)
    0 / 297 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Thyroid cancer
         subjects affected / exposed
    0 / 298 (0.00%)
    1 / 297 (0.34%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vascular disorders
    Haematoma
         subjects affected / exposed
    1 / 298 (0.34%)
    1 / 297 (0.34%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lymphorrhoea
         subjects affected / exposed
    0 / 298 (0.00%)
    1 / 297 (0.34%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Thrombophlebitis
         subjects affected / exposed
    0 / 298 (0.00%)
    1 / 297 (0.34%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pregnancy, puerperium and perinatal conditions
    Abortion spontaneous
         subjects affected / exposed
    0 / 298 (0.00%)
    1 / 297 (0.34%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pregnancy
         subjects affected / exposed
    0 / 298 (0.00%)
    1 / 297 (0.34%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Death
         subjects affected / exposed
    1 / 298 (0.34%)
    0 / 297 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Pyrexia
         subjects affected / exposed
    0 / 298 (0.00%)
    2 / 297 (0.67%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    General physical health deterioration
         subjects affected / exposed
    0 / 298 (0.00%)
    1 / 297 (0.34%)
         occurrences causally related to treatment / all
    0 / 0
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Sudden death
         subjects affected / exposed
    0 / 298 (0.00%)
    1 / 297 (0.34%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Immune system disorders
    Hypersensitivity
         subjects affected / exposed
    2 / 298 (0.67%)
    0 / 297 (0.00%)
         occurrences causally related to treatment / all
    2 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Reproductive system and breast disorders
    Menorrhagia
         subjects affected / exposed
    0 / 298 (0.00%)
    1 / 297 (0.34%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ovarian haemorrhage
         subjects affected / exposed
    0 / 298 (0.00%)
    1 / 297 (0.34%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ovarian mass
         subjects affected / exposed
    1 / 298 (0.34%)
    0 / 297 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vaginal prolapse
         subjects affected / exposed
    0 / 298 (0.00%)
    1 / 297 (0.34%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Emphysema
         subjects affected / exposed
    1 / 298 (0.34%)
    0 / 297 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Pleural effusion
         subjects affected / exposed
    0 / 298 (0.00%)
    2 / 297 (0.67%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumothorax
         subjects affected / exposed
    1 / 298 (0.34%)
    0 / 297 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pulmonary embolism
         subjects affected / exposed
    0 / 298 (0.00%)
    2 / 297 (0.67%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Psychiatric disorders
    Anxiety
         subjects affected / exposed
    1 / 298 (0.34%)
    0 / 297 (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
    0 / 298 (0.00%)
    1 / 297 (0.34%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Schizophrenia
         subjects affected / exposed
    0 / 298 (0.00%)
    1 / 297 (0.34%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Investigations
    Ejection fraction
         subjects affected / exposed
    0 / 298 (0.00%)
    1 / 297 (0.34%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Tumour marker increased
         subjects affected / exposed
    0 / 298 (0.00%)
    1 / 297 (0.34%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Humerus fracture
         subjects affected / exposed
    1 / 298 (0.34%)
    0 / 297 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Incision site haematoma
         subjects affected / exposed
    1 / 298 (0.34%)
    0 / 297 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lumbar vertebral fracture
         subjects affected / exposed
    0 / 298 (0.00%)
    1 / 297 (0.34%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Post procedural haematoma
         subjects affected / exposed
    1 / 298 (0.34%)
    0 / 297 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Radiation pneumonitis
         subjects affected / exposed
    1 / 298 (0.34%)
    0 / 297 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pulmonary radiation injury
         subjects affected / exposed
    0 / 298 (0.00%)
    1 / 297 (0.34%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Radius fracture
         subjects affected / exposed
    1 / 298 (0.34%)
    1 / 297 (0.34%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac disorders
    Angina pectoris
         subjects affected / exposed
    1 / 298 (0.34%)
    0 / 297 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Arrhythmia
         subjects affected / exposed
    0 / 298 (0.00%)
    1 / 297 (0.34%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Atrial fibrillation
         subjects affected / exposed
    0 / 298 (0.00%)
    1 / 297 (0.34%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac failure congestive
         subjects affected / exposed
    0 / 298 (0.00%)
    2 / 297 (0.67%)
         occurrences causally related to treatment / all
    0 / 0
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Myocardial infarction
         subjects affected / exposed
    1 / 298 (0.34%)
    1 / 297 (0.34%)
         occurrences causally related to treatment / all
    0 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 1
    1 / 1
    Coronary artery disease
         subjects affected / exposed
    1 / 298 (0.34%)
    0 / 297 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Myocardial ischaemia
         subjects affected / exposed
    0 / 298 (0.00%)
    1 / 297 (0.34%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nervous system disorders
    Cerebrovascular accident
         subjects affected / exposed
    0 / 298 (0.00%)
    1 / 297 (0.34%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Dizziness
         subjects affected / exposed
    0 / 298 (0.00%)
    1 / 297 (0.34%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    Febrile neutropenia
         subjects affected / exposed
    10 / 298 (3.36%)
    13 / 297 (4.38%)
         occurrences causally related to treatment / all
    10 / 10
    13 / 13
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Leukopenia
         subjects affected / exposed
    0 / 298 (0.00%)
    1 / 297 (0.34%)
         occurrences causally related to treatment / all
    0 / 0
    3 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lymphadenopathy
         subjects affected / exposed
    1 / 298 (0.34%)
    0 / 297 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Neutropenia
         subjects affected / exposed
    9 / 298 (3.02%)
    7 / 297 (2.36%)
         occurrences causally related to treatment / all
    11 / 11
    8 / 8
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Thrombocytopenia
         subjects affected / exposed
    0 / 298 (0.00%)
    1 / 297 (0.34%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Diarrhoea
         subjects affected / exposed
    1 / 298 (0.34%)
    0 / 297 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Haemorrhoids
         subjects affected / exposed
    1 / 298 (0.34%)
    1 / 297 (0.34%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nausea
         subjects affected / exposed
    1 / 298 (0.34%)
    1 / 297 (0.34%)
         occurrences causally related to treatment / all
    1 / 1
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vomiting
         subjects affected / exposed
    1 / 298 (0.34%)
    0 / 297 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Skin and subcutaneous tissue disorders
    Erythema multiforme
         subjects affected / exposed
    0 / 298 (0.00%)
    1 / 297 (0.34%)
         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 colic
         subjects affected / exposed
    0 / 298 (0.00%)
    1 / 297 (0.34%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Endocrine disorders
    Goitre
         subjects affected / exposed
    1 / 298 (0.34%)
    0 / 297 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Back pain
         subjects affected / exposed
    0 / 298 (0.00%)
    1 / 297 (0.34%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Spinal pain
         subjects affected / exposed
    0 / 298 (0.00%)
    1 / 297 (0.34%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infections and infestations
    Abscess
         subjects affected / exposed
    0 / 298 (0.00%)
    1 / 297 (0.34%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Atypical pneumonia
         subjects affected / exposed
    0 / 298 (0.00%)
    1 / 297 (0.34%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Breast abscess
         subjects affected / exposed
    1 / 298 (0.34%)
    1 / 297 (0.34%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cellulitis
         subjects affected / exposed
    0 / 298 (0.00%)
    2 / 297 (0.67%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Encephalitis viral
         subjects affected / exposed
    0 / 298 (0.00%)
    1 / 297 (0.34%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cystitis
         subjects affected / exposed
    0 / 298 (0.00%)
    1 / 297 (0.34%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Febrile infection
         subjects affected / exposed
    1 / 298 (0.34%)
    0 / 297 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastroenteritis
         subjects affected / exposed
    1 / 298 (0.34%)
    0 / 297 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    H1N1 influenza
         subjects affected / exposed
    1 / 298 (0.34%)
    0 / 297 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Herpes zoster
         subjects affected / exposed
    0 / 298 (0.00%)
    1 / 297 (0.34%)
         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
    1 / 298 (0.34%)
    0 / 297 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infected lymphocele
         subjects affected / exposed
    1 / 298 (0.34%)
    0 / 297 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infection
         subjects affected / exposed
    1 / 298 (0.34%)
    0 / 297 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lower respiratory tract infection
         subjects affected / exposed
    0 / 298 (0.00%)
    2 / 297 (0.67%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Mastitis
         subjects affected / exposed
    1 / 298 (0.34%)
    1 / 297 (0.34%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Periorbital cellulitis
         subjects affected / exposed
    0 / 298 (0.00%)
    1 / 297 (0.34%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonia
         subjects affected / exposed
    4 / 298 (1.34%)
    2 / 297 (0.67%)
         occurrences causally related to treatment / all
    1 / 4
    0 / 2
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Post procedural infection
         subjects affected / exposed
    0 / 298 (0.00%)
    1 / 297 (0.34%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Postoperative wound infection
         subjects affected / exposed
    0 / 298 (0.00%)
    2 / 297 (0.67%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pyelonephritis acute
         subjects affected / exposed
    0 / 298 (0.00%)
    1 / 297 (0.34%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory tract infection
         subjects affected / exposed
    0 / 298 (0.00%)
    1 / 297 (0.34%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory tract infection viral
         subjects affected / exposed
    0 / 298 (0.00%)
    1 / 297 (0.34%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Septic shock
         subjects affected / exposed
    0 / 298 (0.00%)
    1 / 297 (0.34%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    1 / 1
    Sepsis
         subjects affected / exposed
    0 / 298 (0.00%)
    1 / 297 (0.34%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Tonsillitis bacterial
         subjects affected / exposed
    0 / 298 (0.00%)
    1 / 297 (0.34%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Tonsillitis
         subjects affected / exposed
    0 / 298 (0.00%)
    2 / 297 (0.67%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Urinary tract infection
         subjects affected / exposed
    1 / 298 (0.34%)
    0 / 297 (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 / 298 (0.00%)
    1 / 297 (0.34%)
         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
    		 Herceptin IV + Chemotherapy Herceptin SC + Chemotherapy
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    277 / 298 (92.95%)
    283 / 297 (95.29%)
    Vascular disorders
    Hot flush
         subjects affected / exposed
    31 / 298 (10.40%)
    30 / 297 (10.10%)
         occurrences all number
    40
    34
    Hypertension
         subjects affected / exposed
    14 / 298 (4.70%)
    24 / 297 (8.08%)
         occurrences all number
    14
    33
    General disorders and administration site conditions
    Asthenia
         subjects affected / exposed
    75 / 298 (25.17%)
    75 / 297 (25.25%)
         occurrences all number
    150
    137
    Fatigue
         subjects affected / exposed
    80 / 298 (26.85%)
    70 / 297 (23.57%)
         occurrences all number
    179
    158
    Mucosal inflammation
         subjects affected / exposed
    39 / 298 (13.09%)
    31 / 297 (10.44%)
         occurrences all number
    64
    41
    Pyrexia
         subjects affected / exposed
    35 / 298 (11.74%)
    35 / 297 (11.78%)
         occurrences all number
    41
    52
    Pain
         subjects affected / exposed
    15 / 298 (5.03%)
    12 / 297 (4.04%)
         occurrences all number
    19
    13
    Oedema peripheral
         subjects affected / exposed
    30 / 298 (10.07%)
    23 / 297 (7.74%)
         occurrences all number
    44
    25
    Injection site pain
         subjects affected / exposed
    0 / 298 (0.00%)
    18 / 297 (6.06%)
         occurrences all number
    0
    49
    Oedema
         subjects affected / exposed
    15 / 298 (5.03%)
    10 / 297 (3.37%)
         occurrences all number
    15
    11
    Reproductive system and breast disorders
    Amenorrhoea
         subjects affected / exposed
    10 / 298 (3.36%)
    15 / 297 (5.05%)
         occurrences all number
    10
    15
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    24 / 298 (8.05%)
    35 / 297 (11.78%)
         occurrences all number
    27
    41
    Oropharyngeal pain
         subjects affected / exposed
    19 / 298 (6.38%)
    19 / 297 (6.40%)
         occurrences all number
    20
    24
    Dyspnoea
         subjects affected / exposed
    22 / 298 (7.38%)
    21 / 297 (7.07%)
         occurrences all number
    25
    28
    Epistaxis
         subjects affected / exposed
    18 / 298 (6.04%)
    19 / 297 (6.40%)
         occurrences all number
    23
    21
    Psychiatric disorders
    Insomnia
         subjects affected / exposed
    31 / 298 (10.40%)
    26 / 297 (8.75%)
         occurrences all number
    35
    30
    Investigations
    Alanine aminotransferase increased
         subjects affected / exposed
    19 / 298 (6.38%)
    16 / 297 (5.39%)
         occurrences all number
    22
    23
    Injury, poisoning and procedural complications
    Radiation skin injury
         subjects affected / exposed
    34 / 298 (11.41%)
    41 / 297 (13.80%)
         occurrences all number
    34
    42
    Incision site pain
         subjects affected / exposed
    24 / 298 (8.05%)
    33 / 297 (11.11%)
         occurrences all number
    26
    35
    Procedural pain
         subjects affected / exposed
    16 / 298 (5.37%)
    18 / 297 (6.06%)
         occurrences all number
    17
    19
    Nervous system disorders
    Headache
         subjects affected / exposed
    44 / 298 (14.77%)
    50 / 297 (16.84%)
         occurrences all number
    72
    69
    Peripheral sensory neuropathy
         subjects affected / exposed
    27 / 298 (9.06%)
    33 / 297 (11.11%)
         occurrences all number
    30
    34
    Dizziness
         subjects affected / exposed
    28 / 298 (9.40%)
    29 / 297 (9.76%)
         occurrences all number
    36
    38
    Neuropathy peripheral
         subjects affected / exposed
    18 / 298 (6.04%)
    24 / 297 (8.08%)
         occurrences all number
    18
    25
    Dysgeusia
         subjects affected / exposed
    22 / 298 (7.38%)
    24 / 297 (8.08%)
         occurrences all number
    39
    38
    Blood and lymphatic system disorders
    Neutropenia
         subjects affected / exposed
    135 / 298 (45.30%)
    128 / 297 (43.10%)
         occurrences all number
    302
    269
    Anaemia
         subjects affected / exposed
    41 / 298 (13.76%)
    34 / 297 (11.45%)
         occurrences all number
    49
    43
    Leukopenia
         subjects affected / exposed
    46 / 298 (15.44%)
    30 / 297 (10.10%)
         occurrences all number
    105
    52
    Gastrointestinal disorders
    Diarrhoea
         subjects affected / exposed
    109 / 298 (36.58%)
    101 / 297 (34.01%)
         occurrences all number
    189
    178
    Nausea
         subjects affected / exposed
    147 / 298 (49.33%)
    145 / 297 (48.82%)
         occurrences all number
    316
    290
    Vomiting
         subjects affected / exposed
    69 / 298 (23.15%)
    69 / 297 (23.23%)
         occurrences all number
    108
    114
    Stomatitis
         subjects affected / exposed
    51 / 298 (17.11%)
    57 / 297 (19.19%)
         occurrences all number
    70
    96
    Constipation
         subjects affected / exposed
    45 / 298 (15.10%)
    43 / 297 (14.48%)
         occurrences all number
    74
    59
    Dyspepsia
         subjects affected / exposed
    30 / 298 (10.07%)
    33 / 297 (11.11%)
         occurrences all number
    44
    44
    Abdominal pain upper
         subjects affected / exposed
    27 / 298 (9.06%)
    21 / 297 (7.07%)
         occurrences all number
    37
    31
    Abdominal pain
         subjects affected / exposed
    16 / 298 (5.37%)
    22 / 297 (7.41%)
         occurrences all number
    20
    32
    Skin and subcutaneous tissue disorders
    Nail disorder
         subjects affected / exposed
    31 / 298 (10.40%)
    29 / 297 (9.76%)
         occurrences all number
    31
    29
    Alopecia
         subjects affected / exposed
    188 / 298 (63.09%)
    187 / 297 (62.96%)
         occurrences all number
    193
    192
    Pruritus
         subjects affected / exposed
    27 / 298 (9.06%)
    26 / 297 (8.75%)
         occurrences all number
    31
    30
    Skin hyperpigmentation
         subjects affected / exposed
    24 / 298 (8.05%)
    20 / 297 (6.73%)
         occurrences all number
    25
    36
    Palmar−plantar erythrodysaesthesia syndrome
         subjects affected / exposed
    18 / 298 (6.04%)
    20 / 297 (6.73%)
         occurrences all number
    19
    25
    Erythema
         subjects affected / exposed
    8 / 298 (2.68%)
    21 / 297 (7.07%)
         occurrences all number
    8
    25
    Dermatitis
         subjects affected / exposed
    15 / 298 (5.03%)
    14 / 297 (4.71%)
         occurrences all number
    24
    14
    Rash
         subjects affected / exposed
    44 / 298 (14.77%)
    48 / 297 (16.16%)
         occurrences all number
    68
    74
    Musculoskeletal and connective tissue disorders
    Myalgia
         subjects affected / exposed
    54 / 298 (18.12%)
    61 / 297 (20.54%)
         occurrences all number
    96
    109
    Arthralgia
         subjects affected / exposed
    60 / 298 (20.13%)
    53 / 297 (17.85%)
         occurrences all number
    91
    86
    Pain in extremity
         subjects affected / exposed
    26 / 298 (8.72%)
    29 / 297 (9.76%)
         occurrences all number
    33
    42
    Back pain
         subjects affected / exposed
    25 / 298 (8.39%)
    26 / 297 (8.75%)
         occurrences all number
    32
    31
    Musculoskeletal pain
         subjects affected / exposed
    22 / 298 (7.38%)
    18 / 297 (6.06%)
         occurrences all number
    28
    29
    Bone pain
         subjects affected / exposed
    10 / 298 (3.36%)
    19 / 297 (6.40%)
         occurrences all number
    10
    24
    Infections and infestations
    Nasopharyngitis
         subjects affected / exposed
    40 / 298 (13.42%)
    24 / 297 (8.08%)
         occurrences all number
    55
    39
    Urinary tract infection
         subjects affected / exposed
    22 / 298 (7.38%)
    10 / 297 (3.37%)
         occurrences all number
    24
    13
    Upper respiratory tract infection
         subjects affected / exposed
    30 / 298 (10.07%)
    30 / 297 (10.10%)
         occurrences all number
    44
    37
    Pharyngitis
         subjects affected / exposed
    11 / 298 (3.69%)
    15 / 297 (5.05%)
         occurrences all number
    12
    15
    Metabolism and nutrition disorders
    Decreased appetite
         subjects affected / exposed
    59 / 298 (19.80%)
    58 / 297 (19.53%)
         occurrences all number
    95
    98

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    29 Jun 2009
    Following the availability of PK modeling data from 58 participants treated with trastuzumab SC in study BP22023 (NCT00800436), the protocol was updated to change the body weight-adjusted SC dosing to a fixed SC dose; The lymph node status as a stratification factor was deleted; Anti-rHuPH20 analysis was included and blood sampling for antibody testing was extended to include the treatment phase; A secondary analysis was added for the number of participants exceeding the target trastuzumab trough serum concentration of 20 mcg/mL; The inclusion of participants with inflammatory breast cancer without a measurable primary tumor was allowed.
    04 Oct 2012
    Following Health Authority request the treatment-free follow-up phase was extended to 5 years (60 months) in order to continue collection of safety and efficacy data; All participants in survival would be followed until the end of the study; Follow up analyses for safety and efficacy were to be run once all participants had completed 24 months of treatment-free follow-up and at the end of the study; The need to perform a confirmatory left ventricular ejection fraction (LVEF) assessment after a significant LVEF drop was applied throughout the full course of the study; Luteinizing Hormone Releasing Hormone agonists were added to the permitted concomitant hormonal therapy; In order to be consistent with requirements for the June 2011 update of the EU guideline, the timeline for serious adverse events reporting was changed from “one working day” to “within 24 hours”.

    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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