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    Clinical Trial Results:
    A Randomized Double-blind Placebo-Controlled Trial of Neratinib (HKI-272) After Trastuzumab in Women With Early-Stage HER-2/neu Overexpressed/Amplified Breast Cancer.

    Summary
    EudraCT number
    		 2008-007345-31
    Trial protocol
    		 HU   DE   IT   SK   CZ   ES   BE   GB   LT   NL   FR   DK   SE   GR   MT   BG   PT  
    Global end of trial date
    04 Oct 2019

    Results information
    Results version number
    		 v1(current)
    This version publication date
    18 Oct 2020
    First version publication date
    18 Oct 2020
    Other versions

    Trial information

    		 Close Top of page
    Trial identification
    Sponsor protocol code
    3144A2-3004-WW
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT00878709
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Puma Biotechnology, Inc.
    Sponsor organisation address
    10880 Wilshire Blvd, Suite 2150, Los Angeles, United States, 90024
    Public contact
    Clinical Operations Senior Director, Puma Biotechnology, Inc, 1 4242486500, clinicaltrials@pumabiotechnology.com
    Scientific contact
    Clinical Operations Senior Director, Puma Biotechnology, Inc., 1 4242486500, clinicaltrials@pumabiotechnology.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
    04 Oct 2019
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    04 Oct 2019
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The primary objective of the study was to compare invasive disease free survival of women with early-stage HER2-overexpressed/amplified breast cancer who received neratinib or placebo in an extended adjuvant setting after one year of adjuvant trastuzumab.
    Protection of trial subjects
    Study commencement required prior written approval of a properly constituted Institutional Review Board (IRB) or Independent Ethics Committee (IEC). Clinical trial data were monitored at regular intervals by the Sponsor or their representative throughout the study to verify compliance to study protocol, completeness, accuracy and consistency of the data and adherence to local regulations on the conduct of clinical research. Patients were discontinued from study drug treatment (but remained in the study, if appropriate) under the following circumstances: patient completed twelve months of protocol-specified treatment, clinically documented disease recurrence as determined by the investigator, adverse event, patient request, investigator request, protocol violation, lost to follow-up, discontinuation of the study by the sponsor or death.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    09 Jul 2009
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Macedonia, the former Yugoslav Republic of: 19
    Country: Number of subjects enrolled
    United Kingdom: 80
    Country: Number of subjects enrolled
    United States: 899
    Country: Number of subjects enrolled
    Czech Republic: 35
    Country: Number of subjects enrolled
    Netherlands: 27
    Country: Number of subjects enrolled
    Bahamas: 4
    Country: Number of subjects enrolled
    Taiwan: 12
    Country: Number of subjects enrolled
    Korea, Republic of: 37
    Country: Number of subjects enrolled
    Australia: 106
    Country: Number of subjects enrolled
    Belgium: 26
    Country: Number of subjects enrolled
    Bulgaria: 34
    Country: Number of subjects enrolled
    Canada: 93
    Country: Number of subjects enrolled
    China: 49
    Country: Number of subjects enrolled
    Colombia: 21
    Country: Number of subjects enrolled
    Croatia: 47
    Country: Number of subjects enrolled
    Denmark: 112
    Country: Number of subjects enrolled
    France: 112
    Country: Number of subjects enrolled
    Germany: 131
    Country: Number of subjects enrolled
    Greece: 39
    Country: Number of subjects enrolled
    Hong Kong: 30
    Country: Number of subjects enrolled
    Hungary: 61
    Country: Number of subjects enrolled
    Israel: 23
    Country: Number of subjects enrolled
    Italy: 78
    Country: Number of subjects enrolled
    Japan: 205
    Country: Number of subjects enrolled
    Lithuania: 25
    Country: Number of subjects enrolled
    Malaysia: 4
    Country: Number of subjects enrolled
    Malta: 12
    Country: Number of subjects enrolled
    Mexico: 1
    Country: Number of subjects enrolled
    New Zealand: 31
    Country: Number of subjects enrolled
    Peru: 3
    Country: Number of subjects enrolled
    Poland: 68
    Country: Number of subjects enrolled
    Romania: 13
    Country: Number of subjects enrolled
    Serbia: 35
    Country: Number of subjects enrolled
    Singapore: 4
    Country: Number of subjects enrolled
    Slovakia: 21
    Country: Number of subjects enrolled
    Spain: 245
    Country: Number of subjects enrolled
    Sweden: 7
    Country: Number of subjects enrolled
    Switzerland: 13
    Country: Number of subjects enrolled
    Turkey: 78
    Worldwide total number of subjects
    2840
    EEA total number of subjects
    1173
    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)
    2492
    From 65 to 84 years
    348
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 The institutional review board /independent ethics committee must review and approve the protocol and informed consent form (ICF) before any subjects provide consent.

    Pre-assignment
    Screening details
    		 Each subject must participate in the informed consent process and sign and date an ICF for this protocol before any protocol-required procedures are performed.

    Period 1
    Period 1 title
    Treatment (overall period)
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Subject, Investigator, Monitor, Data analyst, Carer, Assessor

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Neratinib
    Arm description
    		 Neratinib 240 mg qd
    Arm type
    		 Experimental

    Investigational medicinal product name
    neratinib
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Six (6) Neratinib 40 mg tablets, given continuously for 1 year (ie, 52 weeks), as long as tolerated, there is no evidence of recurrent breast cancer or a new breast cancer, the subject is lost to follow-up, or withdraws consent.

    Arm title
    		 Placebo
    Arm description
    		 Placebo qd
    Arm type
    		 Placebo

    Investigational medicinal product name
    placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Six (6) Placebo tablets, given continuously for 1 year (ie, 52 weeks), as long as tolerated, there is no evidence of recurrent breast cancer or a new breast cancer, the subject is lost to follow-up, or withdraws consent.

    Number of subjects in period 1
    		Neratinib Placebo
    Started
    1420
    1420
    Completed
    1095
    1183
    Not completed
    325
    237
         Consent withdrawn by subject
    197
    120
         Other reasons
    93
    84
         Lost to follow-up
    35
    33

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Neratinib
    Reporting group description
    		 Neratinib 240 mg qd

    Reporting group title
    Placebo
    Reporting group description
    		 Placebo qd

    Reporting group values
    		 Neratinib Placebo Total
    Number of subjects
    		 1420 1420 2840
    Age categorical
    Units: Subjects
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    		 52.3 ± 10.08 52.3 ± 10.28 -
    Gender categorical
    Units: Subjects
        Female
    		 1420 1420 2840
    Race/Ethnicity
    Units: Subjects
        Asian
    		 188 197 385
        Black or African American
    		 27 47 74
        White
    		 1165 1135 2300
        Other
    		 40 41 81
    Subject analysis sets

    Subject analysis set title
    Intent to treat (ITT) population
    Subject analysis set type
    		 Intention-to-treat
    Subject analysis set description
    The Intent-to-treat (ITT) is defined as all subjects who were randomized.

    Subject analysis sets values
    		 Intent to treat (ITT) population
    Number of subjects
    2840
    Age categorical
    Units: Subjects
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    52.29 ± 10.18
    Gender categorical
    Units: Subjects
        Female
    2840
    Race/Ethnicity
    Units: Subjects
        Asian
    385
        Black or African American
    74
        White
    2300
        Other
    81

    End points

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    End points reporting groups
    Reporting group title
    Neratinib
    Reporting group description
    		 Neratinib 240 mg qd

    Reporting group title
    Placebo
    Reporting group description
    		 Placebo qd

    Subject analysis set title
    Intent to treat (ITT) population
    Subject analysis set type
    		 Intention-to-treat
    Subject analysis set description
    The Intent-to-treat (ITT) is defined as all subjects who were randomized.

    Primary: Invasive Disease-free Survival (iDFS) in Neratinib Arm Compared to Placebo Arm at Year 2

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    End point title
    		 Invasive Disease-free Survival (iDFS) in Neratinib Arm Compared to Placebo Arm at Year 2
    End point description
    Invasive disease-free survival time is defined as the time from date of randomization until the first disease recurrence of the following events: invasive ipsilateral breast tumor recurrence, invasive contralateral breast cancer, local/regional invasive recurrence, distant recurrence and death from any cause.
    End point type
    Primary
    End point timeframe
    From randomization until time of event up to 2 years
    End point values
    		 Neratinib Placebo
    Number of subjects analysed
    1420
    1420
    Units: percentage of patients
        number (not applicable)
    4.7
    7.5
    Statistical analysis title
    		 Invasive Disease-free Survival (iDFS)
    Statistical analysis description
    The 2-sided P-value was based on stratified log-rank test (stratification factors: prior Trastuzumab (concurrent or sequential), nodal status (<=3 or >=4) and ER/PgR status (positive or negative). The hazard ratio and corresponding 95% CI from the stratified cox proportional hazard model were also presented.
    Comparison groups
    Neratinib v Placebo
    Number of subjects included in analysis
    2840
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.008
    Method
    		 Logrank
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.66
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.49
         upper limit
    		 0.9

    Primary: Kaplan-Meier Estimates of Invasive Disease-free Survival (iDFS) at Year 2 by Treatment Arms

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    End point title
    		 Kaplan-Meier Estimates of Invasive Disease-free Survival (iDFS) at Year 2 by Treatment Arms
    End point description
    Invasive disease-free survival time is defined as the time from date of randomization until the first disease recurrence of the following events: invasive ipsilateral breast tumor recurrence, invasive contralateral breast cancer, local/regional invasive recurrence, distant recurrence and death from any cause.
    End point type
    Primary
    End point timeframe
    From randomization until time of event up to 2 years
    End point values
    		 Neratinib Placebo
    Number of subjects analysed
    1420
    1420
    Units: 2-year disease free survival rate
        number (confidence interval 95%)
    94.2 (92.6 to 95.4)
    91.9 (90.2 to 93.2)
    Statistical analysis title
    		 Invasive Disease-free Survival (iDFS)
    Comparison groups
    Neratinib v Placebo
    Number of subjects included in analysis
    2840
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.008
    Method
    		 Logrank
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.66
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.49
         upper limit
    		 0.9

    Secondary: Disease-free Survival Including Ductal Carcinoma in Situ (DFS-DCIS) in Neratinib Arm Compared to Placebo Arm at Year 2

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    End point title
    		 Disease-free Survival Including Ductal Carcinoma in Situ (DFS-DCIS) in Neratinib Arm Compared to Placebo Arm at Year 2
    End point description
    Disease-free survival including DCIS time is defined as the time from date of randomization until the first occurrence of DCIS or an iDFS event (an iDFS event including invasive ipsilateral breast tumor recurrence, invasive contralateral breast cancer, local/regional invasive recurrence, or distant recurrence and death from any cause.
    End point type
    Secondary
    End point timeframe
    From randomization until time of event up to 2 years.
    End point values
    		 Neratinib Placebo
    Number of subjects analysed
    1420
    1420
    Units: percentage
        number (not applicable)
    4.7
    8.0
    Statistical analysis title
    		 DFS-DCIS
    Statistical analysis description
    The hazard ratio is estimated by stratified Cox model. The Cox model is stratified by prior trastuzumab (concurrent or sequential), nodal status (<= 3 or >= 4) and ER/PgR status (positive or negative).
    Comparison groups
    Neratinib v Placebo
    Number of subjects included in analysis
    2840
    Analysis specification
    Pre-specified
    Analysis type
    		 other [1]
    Method
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.61
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.45
         upper limit
    		 0.83
    Notes
    [1] - Estimation

    Secondary: Distant Disease-free Survival (DDFS) in Neratinib Arm Compared to Placebo Arm at Year 2

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    End point title
    		 Distant Disease-free Survival (DDFS) in Neratinib Arm Compared to Placebo Arm at Year 2
    End point description
    Distant disease-free survival time is defined as the time from date of randomization until the first occurrence of distant recurrence or death from any cause.
    End point type
    Secondary
    End point timeframe
    From randomization until time of event up to 2 years
    End point values
    		 Neratinib Placebo
    Number of subjects analysed
    1420
    1420
    Units: percentage
        number (not applicable)
    3.8
    5.4
    Statistical analysis title
    		 DDFS
    Statistical analysis description
    The hazard ratio is estimated by stratified Cox model. The Cox model is stratified by prior trastuzumab (concurrent or sequential), nodal status (<= 3 or >= 4) and ER/PgR status (positive or negative).
    Comparison groups
    Neratinib v Placebo
    Number of subjects included in analysis
    2840
    Analysis specification
    Pre-specified
    Analysis type
    		 other [2]
    Method
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.74
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.52
         upper limit
    		 1.05
    Notes
    [2] - Estimation

    Secondary: Time to Distant Recurrence (TTDR) in Neratinib Arm Compared to Placebo Arm at Year 2

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    End point title
    		 Time to Distant Recurrence (TTDR) in Neratinib Arm Compared to Placebo Arm at Year 2
    End point description
    Time to distant recurrence is defined as the time from date of randomization until the first occurrence of distant recurrence or death from breast cancer.
    End point type
    Secondary
    End point timeframe
    From randomization until time of event up to 2 years.
    End point values
    		 Neratinib Placebo
    Number of subjects analysed
    1420
    1420
    Units: percentage
        number (not applicable)
    3.7
    5.3
    Statistical analysis title
    		 TTDR
    Statistical analysis description
    The hazard ratio is estimated by stratified Cox model. The Cox model is stratified by prior trastuzumab (concurrent or sequential), nodal status (<= 3 or >= 4) and ER/PgR status (positive or negative).
    Comparison groups
    Neratinib v Placebo
    Number of subjects included in analysis
    2840
    Analysis specification
    Pre-specified
    Analysis type
    		 other [3]
    Method
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.73
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.51
         upper limit
    		 1.04
    Notes
    [3] - Estimation

    Secondary: Cumulative Incidence of Central Nervous System Recurrence (CNS) at Year 2

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    End point title
    		 Cumulative Incidence of Central Nervous System Recurrence (CNS) at Year 2
    End point description
    Cumulative incidence of CNS recurrence as a site of first distant recurrence is defined as time from randomization to CNS recurrence as first distant recurrence. Competing events include distant recurrence at other sites as first distant recurrence and death from any cause prior to distant recurrence.
    End point type
    Secondary
    End point timeframe
    From randomization until time of event up to 2 years.
    End point values
    		 Neratinib Placebo
    Number of subjects analysed
    1420
    1420
    Units: percentage
        number (confidence interval 95%)
    0.92 (0.49 to 1.59)
    1.16 (0.68 to 1.87)
    No statistical analyses for this end point

    Secondary: Kaplan-Meier Estimates of Overall Survival (OS) by Treatment Arms

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    End point title
    		 Kaplan-Meier Estimates of Overall Survival (OS) by Treatment Arms
    End point description
    OS was defined as the time from randomization to death due to any cause, censored at the last date known alive.
    End point type
    Secondary
    End point timeframe
    Randomization until death due to any cause (up to 119 Months)
    End point values
    		 Neratinib Placebo
    Number of subjects analysed
    1420
    1420
    Units: Survival rate at 8 year
        number (confidence interval 95%)
    90.09 (88.27 to 91.64)
    90.20 (88.43 to 91.70)
    Statistical analysis title
    		 OS
    Statistical analysis description
    The 2-sided P-value was based on stratified log-rank test (stratification factors: prior Trastuzumab (concurrent or sequential), nodal status (<=3 or >=4) and ER/PgR status (positive or negative). The hazard ratio and corresponding 95% CI from the stratified Cox proportional hazard model were also presented.
    Comparison groups
    Neratinib v Placebo
    Number of subjects included in analysis
    2840
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.6914
    Method
    		 Logrank
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.952
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.747
         upper limit
    		 1.212

    Other pre-specified: Invasive Disease-free Survival (iDFS) in Neratinib Arm Compared to Placebo Arm at Year 5

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    End point title
    		 Invasive Disease-free Survival (iDFS) in Neratinib Arm Compared to Placebo Arm at Year 5
    End point description
    Invasive disease-free survival time is defined as the time from date of randomization until the first disease recurrence of the following events: invasive ipsilateral breast tumor recurrence, invasive contralateral breast cancer, local/regional invasive recurrence, distant recurrence and death from any cause.
    End point type
    Other pre-specified
    End point timeframe
    From randomization until time of event up to 5 years
    End point values
    		 Neratinib Placebo
    Number of subjects analysed
    1420
    1420
    Units: percent
        number (not applicable)
    8.2
    11.5
    Statistical analysis title
    		 Invasive Disease-free Survival (iDFS)
    Statistical analysis description
    The 2-sided P-value was based on stratified log-rank test (stratification factors: prior Trastuzumab (concurrent or sequential), nodal status (<=3 or >=4) and ER/PgR status (positive or negative). The hazard ratio and corresponding 95% CI from the stratified cox proportional hazard model were also presented.
    Comparison groups
    Neratinib v Placebo
    Number of subjects included in analysis
    2840
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.008
    Method
    		 Logrank
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.73
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.57
         upper limit
    		 0.92

    Other pre-specified: Kaplan-Meier Estimates of Invasive Disease-free Survival (iDFS) at Year 5 by Treatment Arms

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    End point title
    		 Kaplan-Meier Estimates of Invasive Disease-free Survival (iDFS) at Year 5 by Treatment Arms
    End point description
    Invasive disease-free survival time is defined as the time from date of randomization until the first disease recurrence of the following events: invasive ipsilateral breast tumor recurrence, invasive contralateral breast cancer, local/regional invasive recurrence, distant recurrence and death from any cause.
    End point type
    Other pre-specified
    End point timeframe
    From randomization until time of event up to 5 years
    End point values
    		 Neratinib Placebo
    Number of subjects analysed
    1420
    1420
    Units: percent
        number (confidence interval 95%)
    90.2 (88.3 to 91.8)
    87.7 (85.7 to 89.4)
    Statistical analysis title
    		 Invasive Disease-free Survival (iDFS)
    Comparison groups
    Neratinib v Placebo
    Number of subjects included in analysis
    2840
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.008
    Method
    		 Logrank
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.73
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.57
         upper limit
    		 0.92

    Other pre-specified: Disease-free Survival Including Ductal Carcinoma in Situ (DFS-DCIS) in Neratinib Arm Compared to Placebo Arm at Year 5

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    End point title
    		 Disease-free Survival Including Ductal Carcinoma in Situ (DFS-DCIS) in Neratinib Arm Compared to Placebo Arm at Year 5
    End point description
    Disease-free survival including DCIS time is defined as the time from date of randomization until the first occurrence of DCIS or an iDFS event (an iDFS event including invasive ipsilateral breast tumor recurrence, invasive contralateral breast cancer, local/regional invasive recurrence, or distant recurrence and death from any cause.
    End point type
    Other pre-specified
    End point timeframe
    From randomization until time of event up to 5 years.
    End point values
    		 Neratinib Placebo
    Number of subjects analysed
    1420
    1420
    Units: percent
        number (not applicable)
    8.5
    12.3
    Statistical analysis title
    		 DFS-DCIS
    Statistical analysis description
    The hazard ratio is estimated by stratified Cox model. The Cox model is stratified by prior trastuzumab (concurrent or sequential), nodal status (<= 3 or >= 4) and ER/PgR status (positive or negative).
    Comparison groups
    Neratinib v Placebo
    Number of subjects included in analysis
    2840
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    Method
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.71
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.56
         upper limit
    		 0.89

    Other pre-specified: Distant Disease-free Survival (DDFS) in Neratinib Arm Compared to Placebo Arm at Year 5

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    End point title
    		 Distant Disease-free Survival (DDFS) in Neratinib Arm Compared to Placebo Arm at Year 5
    End point description
    Distant disease-free survival time is defined as the time from date of randomization until the first occurrence of distant recurrence or death from any cause.
    End point type
    Other pre-specified
    End point timeframe
    From randomization until time of event up to 5 years
    End point values
    		 Neratinib Placebo
    Number of subjects analysed
    1420
    1420
    Units: percent
        number (not applicable)
    7.0
    9.2
    Statistical analysis title
    		 DDFS
    Statistical analysis description
    The hazard ratio is estimated by stratified Cox model. The Cox model is stratified by prior trastuzumab (concurrent or sequential), nodal status (<= 3 or >= 4) and ER/PgR status (positive or negative).
    Comparison groups
    Neratinib v Placebo
    Number of subjects included in analysis
    2840
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    Method
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.78
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.6
         upper limit
    		 1.01

    Other pre-specified: Time to Distant Recurrence (TTDR) in Neratinib Arm Compared to Placebo Arm at Year 5

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    End point title
    		 Time to Distant Recurrence (TTDR) in Neratinib Arm Compared to Placebo Arm at Year 5
    End point description
    Time to distant recurrence is defined as the time from date of randomization until the first occurrence of distant recurrence or death from breast cancer.
    End point type
    Other pre-specified
    End point timeframe
    From randomization until time of event up to 5 years.
    End point values
    		 Neratinib Placebo
    Number of subjects analysed
    1420
    1420
    Units: percent
        number (not applicable)
    6.8
    8.9
    Statistical analysis title
    		 TTDR
    Statistical analysis description
    The hazard ratio is estimated by stratified Cox model. The Cox model is stratified by prior trastuzumab (concurrent or sequential), nodal status (<= 3 or >= 4) and ER/PgR status (positive or negative).
    Comparison groups
    Neratinib v Placebo
    Number of subjects included in analysis
    2840
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    Method
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.79
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.6
         upper limit
    		 1.03

    Other pre-specified: Cumulative Incidence of Central Nervous System Recurrence (CNS) at Year 5

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    End point title
    		 Cumulative Incidence of Central Nervous System Recurrence (CNS) at Year 5
    End point description
    Cumulative incidence of CNS recurrence as a site of first distant recurrence is defined as time from randomization to CNS recurrence as first distant recurrence. Competing events include distant recurrence at other sites as first distant recurrence and death from any cause prior to distant recurrence.
    End point type
    Other pre-specified
    End point timeframe
    From randomization until time of event up to 5 years.
    End point values
    		 Neratinib Placebo
    Number of subjects analysed
    1420
    1420
    Units: percent
        number (confidence interval 95%)
    1.3 (0.77 to 2.06)
    1.82 (1.19 to 2.68)
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    1st dose through 28 days after last dose
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    17.0
    Reporting groups
    Reporting group title
    Placebo
    Reporting group description
    		 Placebo qd

    Reporting group title
    Neratinib
    Reporting group description
    		 Neratinib 240 mg qd

    Serious adverse events
    		 Placebo Neratinib
    Total subjects affected by serious adverse events
         subjects affected / exposed
    85 / 1408 (6.04%)
    103 / 1408 (7.32%)
         number of deaths (all causes)
    28
    25
         number of deaths resulting from adverse events
    1
    2
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Acute myeloid leukaemia
         subjects affected / exposed
    0 / 1408 (0.00%)
    1 / 1408 (0.07%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    1 / 1
    Basal cell carcinoma
         subjects affected / exposed
    2 / 1408 (0.14%)
    2 / 1408 (0.14%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Benign breast neoplasm
         subjects affected / exposed
    1 / 1408 (0.07%)
    0 / 1408 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Benign female reproductive tract neoplasm
         subjects affected / exposed
    0 / 1408 (0.00%)
    1 / 1408 (0.07%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Breast cancer
         subjects affected / exposed
    2 / 1408 (0.14%)
    0 / 1408 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Breast cancer metastatic
         subjects affected / exposed
    0 / 1408 (0.00%)
    1 / 1408 (0.07%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Breast neoplasm
         subjects affected / exposed
    1 / 1408 (0.07%)
    0 / 1408 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cancer pain
         subjects affected / exposed
    0 / 1408 (0.00%)
    1 / 1408 (0.07%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastric cancer
         subjects affected / exposed
    1 / 1408 (0.07%)
    0 / 1408 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Glioblastoma
         subjects affected / exposed
    0 / 1408 (0.00%)
    1 / 1408 (0.07%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Glioma
         subjects affected / exposed
    0 / 1408 (0.00%)
    1 / 1408 (0.07%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lung adenocarcinoma
         subjects affected / exposed
    1 / 1408 (0.07%)
    0 / 1408 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Malignant melanoma
         subjects affected / exposed
    0 / 1408 (0.00%)
    1 / 1408 (0.07%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Malignant melanoma in situ
         subjects affected / exposed
    0 / 1408 (0.00%)
    1 / 1408 (0.07%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Malignant pleural effusion
         subjects affected / exposed
    0 / 1408 (0.00%)
    1 / 1408 (0.07%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Metastases to eye
         subjects affected / exposed
    1 / 1408 (0.07%)
    0 / 1408 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Metastases to meninges
         subjects affected / exposed
    0 / 1408 (0.00%)
    1 / 1408 (0.07%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    1 / 1
    Sarcoma
         subjects affected / exposed
    1 / 1408 (0.07%)
    0 / 1408 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Sarcoma uterus
         subjects affected / exposed
    1 / 1408 (0.07%)
    0 / 1408 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Uterine leiomyoma
         subjects affected / exposed
    1 / 1408 (0.07%)
    0 / 1408 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vascular neoplasm
         subjects affected / exposed
    1 / 1408 (0.07%)
    0 / 1408 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vascular disorders
    Deep vein thrombosis
         subjects affected / exposed
    1 / 1408 (0.07%)
    0 / 1408 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypertension
         subjects affected / exposed
    1 / 1408 (0.07%)
    0 / 1408 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypotension
         subjects affected / exposed
    0 / 1408 (0.00%)
    1 / 1408 (0.07%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Surgical and medical procedures
    Hysterosalpingo-oophorectomy
         subjects affected / exposed
    1 / 1408 (0.07%)
    0 / 1408 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Asthenia
         subjects affected / exposed
    0 / 1408 (0.00%)
    1 / 1408 (0.07%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Fatigue
         subjects affected / exposed
    0 / 1408 (0.00%)
    3 / 1408 (0.21%)
         occurrences causally related to treatment / all
    0 / 0
    3 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Non-cardiac chest pain
         subjects affected / exposed
    0 / 1408 (0.00%)
    3 / 1408 (0.21%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pyrexia
         subjects affected / exposed
    1 / 1408 (0.07%)
    2 / 1408 (0.14%)
         occurrences causally related to treatment / all
    0 / 1
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Immune system disorders
    Food allergy
         subjects affected / exposed
    1 / 1408 (0.07%)
    0 / 1408 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Reproductive system and breast disorders
    Endometrial hyperplasia
         subjects affected / exposed
    1 / 1408 (0.07%)
    1 / 1408 (0.07%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Endometrial hypertrophy
         subjects affected / exposed
    0 / 1408 (0.00%)
    1 / 1408 (0.07%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Endometriosis
         subjects affected / exposed
    0 / 1408 (0.00%)
    1 / 1408 (0.07%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Metrorrhagia
         subjects affected / exposed
    1 / 1408 (0.07%)
    1 / 1408 (0.07%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ovarian cyst
         subjects affected / exposed
    1 / 1408 (0.07%)
    0 / 1408 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Uterine polyp
         subjects affected / exposed
    1 / 1408 (0.07%)
    0 / 1408 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vulval leukoplakia
         subjects affected / exposed
    1 / 1408 (0.07%)
    0 / 1408 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Atelectasis
         subjects affected / exposed
    0 / 1408 (0.00%)
    1 / 1408 (0.07%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Dyspnoea
         subjects affected / exposed
    1 / 1408 (0.07%)
    2 / 1408 (0.14%)
         occurrences causally related to treatment / all
    0 / 1
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pleural effusion
         subjects affected / exposed
    1 / 1408 (0.07%)
    1 / 1408 (0.07%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonitis
         subjects affected / exposed
    1 / 1408 (0.07%)
    0 / 1408 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumothorax
         subjects affected / exposed
    1 / 1408 (0.07%)
    1 / 1408 (0.07%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pulmonary embolism
         subjects affected / exposed
    3 / 1408 (0.21%)
    3 / 1408 (0.21%)
         occurrences causally related to treatment / all
    1 / 3
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Tachypnoea
         subjects affected / exposed
    1 / 1408 (0.07%)
    0 / 1408 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Psychiatric disorders
    Anxiety
         subjects affected / exposed
    1 / 1408 (0.07%)
    0 / 1408 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Depression
         subjects affected / exposed
    2 / 1408 (0.14%)
    1 / 1408 (0.07%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Mental disorder
         subjects affected / exposed
    1 / 1408 (0.07%)
    0 / 1408 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Mental status changes
         subjects affected / exposed
    0 / 1408 (0.00%)
    2 / 1408 (0.14%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Investigations
    Alanine aminotransferase increased
         subjects affected / exposed
    0 / 1408 (0.00%)
    4 / 1408 (0.28%)
         occurrences causally related to treatment / all
    0 / 0
    5 / 5
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Aspartate aminotransferase increased
         subjects affected / exposed
    0 / 1408 (0.00%)
    4 / 1408 (0.28%)
         occurrences causally related to treatment / all
    0 / 0
    5 / 5
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Blood creatine increased
         subjects affected / exposed
    0 / 1408 (0.00%)
    1 / 1408 (0.07%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Blood thyroid stimulating hormone increased
         subjects affected / exposed
    0 / 1408 (0.00%)
    1 / 1408 (0.07%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ejection fraction decreased
         subjects affected / exposed
    1 / 1408 (0.07%)
    0 / 1408 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Electrocardiogram T wave inversion
         subjects affected / exposed
    0 / 1408 (0.00%)
    1 / 1408 (0.07%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Staphylococcus test positive
         subjects affected / exposed
    0 / 1408 (0.00%)
    1 / 1408 (0.07%)
         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
    Ankle fracture
         subjects affected / exposed
    0 / 1408 (0.00%)
    1 / 1408 (0.07%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Fall
         subjects affected / exposed
    1 / 1408 (0.07%)
    0 / 1408 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Fracture
         subjects affected / exposed
    0 / 1408 (0.00%)
    1 / 1408 (0.07%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hip fracture
         subjects affected / exposed
    1 / 1408 (0.07%)
    0 / 1408 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Humerus fracture
         subjects affected / exposed
    1 / 1408 (0.07%)
    0 / 1408 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Meniscus injury
         subjects affected / exposed
    2 / 1408 (0.14%)
    0 / 1408 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Multiple injuries
         subjects affected / exposed
    0 / 1408 (0.00%)
    1 / 1408 (0.07%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Patella fracture
         subjects affected / exposed
    1 / 1408 (0.07%)
    0 / 1408 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Sternal fracture
         subjects affected / exposed
    0 / 1408 (0.00%)
    1 / 1408 (0.07%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Wound dehiscence
         subjects affected / exposed
    1 / 1408 (0.07%)
    1 / 1408 (0.07%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Wrist fracture
         subjects affected / exposed
    0 / 1408 (0.00%)
    1 / 1408 (0.07%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac disorders
    Angina pectoris
         subjects affected / exposed
    0 / 1408 (0.00%)
    1 / 1408 (0.07%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Atrial fibrillation
         subjects affected / exposed
    1 / 1408 (0.07%)
    0 / 1408 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Myocardial infarction
         subjects affected / exposed
    1 / 1408 (0.07%)
    1 / 1408 (0.07%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Sinus tachycardia
         subjects affected / exposed
    1 / 1408 (0.07%)
    0 / 1408 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Tachycardia
         subjects affected / exposed
    1 / 1408 (0.07%)
    0 / 1408 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nervous system disorders
    Ageusia
         subjects affected / exposed
    0 / 1408 (0.00%)
    1 / 1408 (0.07%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Anosmia
         subjects affected / exposed
    0 / 1408 (0.00%)
    1 / 1408 (0.07%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Brain oedema
         subjects affected / exposed
    1 / 1408 (0.07%)
    0 / 1408 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Carotid artery stenosis
         subjects affected / exposed
    1 / 1408 (0.07%)
    0 / 1408 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cerebral haemorrhage
         subjects affected / exposed
    0 / 1408 (0.00%)
    1 / 1408 (0.07%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cerebral infarction
         subjects affected / exposed
    0 / 1408 (0.00%)
    1 / 1408 (0.07%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cerebrovascular accident
         subjects affected / exposed
    1 / 1408 (0.07%)
    0 / 1408 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Dizziness
         subjects affected / exposed
    1 / 1408 (0.07%)
    0 / 1408 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Headache
         subjects affected / exposed
    1 / 1408 (0.07%)
    0 / 1408 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Intercostal neuralgia
         subjects affected / exposed
    1 / 1408 (0.07%)
    0 / 1408 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Paresis
         subjects affected / exposed
    0 / 1408 (0.00%)
    1 / 1408 (0.07%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Speech disorder
         subjects affected / exposed
    1 / 1408 (0.07%)
    0 / 1408 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Syncope
         subjects affected / exposed
    2 / 1408 (0.14%)
    3 / 1408 (0.21%)
         occurrences causally related to treatment / all
    0 / 2
    2 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Transient ischaemic attack
         subjects affected / exposed
    1 / 1408 (0.07%)
    0 / 1408 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Tremor
         subjects affected / exposed
    1 / 1408 (0.07%)
    0 / 1408 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    1 / 1408 (0.07%)
    1 / 1408 (0.07%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ear and labyrinth disorders
    Vertigo
         subjects affected / exposed
    1 / 1408 (0.07%)
    0 / 1408 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Abdominal distension
         subjects affected / exposed
    1 / 1408 (0.07%)
    0 / 1408 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Abdominal pain
         subjects affected / exposed
    0 / 1408 (0.00%)
    2 / 1408 (0.14%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Abdominal pain upper
         subjects affected / exposed
    0 / 1408 (0.00%)
    1 / 1408 (0.07%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Abdominal strangulated hernia
         subjects affected / exposed
    0 / 1408 (0.00%)
    1 / 1408 (0.07%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Colitis
         subjects affected / exposed
    2 / 1408 (0.14%)
    0 / 1408 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Colitis ischaemic
         subjects affected / exposed
    1 / 1408 (0.07%)
    0 / 1408 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Constipation
         subjects affected / exposed
    1 / 1408 (0.07%)
    0 / 1408 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Diarrhoea
         subjects affected / exposed
    1 / 1408 (0.07%)
    22 / 1408 (1.56%)
         occurrences causally related to treatment / all
    2 / 2
    29 / 30
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Enterocele
         subjects affected / exposed
    0 / 1408 (0.00%)
    1 / 1408 (0.07%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nausea
         subjects affected / exposed
    1 / 1408 (0.07%)
    4 / 1408 (0.28%)
         occurrences causally related to treatment / all
    1 / 1
    3 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pancreatitis
         subjects affected / exposed
    1 / 1408 (0.07%)
    2 / 1408 (0.14%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Periodontal disease
         subjects affected / exposed
    0 / 1408 (0.00%)
    1 / 1408 (0.07%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Rectal cancer
         subjects affected / exposed
    0 / 1408 (0.00%)
    1 / 1408 (0.07%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vomiting
         subjects affected / exposed
    1 / 1408 (0.07%)
    12 / 1408 (0.85%)
         occurrences causally related to treatment / all
    0 / 1
    13 / 15
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatobiliary disorders
    Cholecystitis
         subjects affected / exposed
    0 / 1408 (0.00%)
    1 / 1408 (0.07%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cholecystitis acute
         subjects affected / exposed
    0 / 1408 (0.00%)
    1 / 1408 (0.07%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cholelithiasis
         subjects affected / exposed
    0 / 1408 (0.00%)
    2 / 1408 (0.14%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatic function abnormal
         subjects affected / exposed
    1 / 1408 (0.07%)
    0 / 1408 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypertransaminasaemia
         subjects affected / exposed
    1 / 1408 (0.07%)
    0 / 1408 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Jaundice cholestatic
         subjects affected / exposed
    1 / 1408 (0.07%)
    0 / 1408 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Skin and subcutaneous tissue disorders
    Dermatitis
         subjects affected / exposed
    0 / 1408 (0.00%)
    1 / 1408 (0.07%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Erythema
         subjects affected / exposed
    0 / 1408 (0.00%)
    1 / 1408 (0.07%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Skin disorder
         subjects affected / exposed
    1 / 1408 (0.07%)
    0 / 1408 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Skin necrosis
         subjects affected / exposed
    1 / 1408 (0.07%)
    1 / 1408 (0.07%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal and urinary disorders
    Bladder prolapse
         subjects affected / exposed
    1 / 1408 (0.07%)
    0 / 1408 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hyperuricosuria
         subjects affected / exposed
    0 / 1408 (0.00%)
    1 / 1408 (0.07%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal colic
         subjects affected / exposed
    0 / 1408 (0.00%)
    1 / 1408 (0.07%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal failure
         subjects affected / exposed
    0 / 1408 (0.00%)
    2 / 1408 (0.14%)
         occurrences causally related to treatment / all
    0 / 0
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal failure acute
         subjects affected / exposed
    0 / 1408 (0.00%)
    3 / 1408 (0.21%)
         occurrences causally related to treatment / all
    0 / 0
    2 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Lumbar spinal stenosis
         subjects affected / exposed
    1 / 1408 (0.07%)
    0 / 1408 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Muscle spasms
         subjects affected / exposed
    1 / 1408 (0.07%)
    0 / 1408 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Muscular weakness
         subjects affected / exposed
    1 / 1408 (0.07%)
    0 / 1408 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Musculoskeletal chest pain
         subjects affected / exposed
    1 / 1408 (0.07%)
    0 / 1408 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Osteoarthritis
         subjects affected / exposed
    1 / 1408 (0.07%)
    1 / 1408 (0.07%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pain in extremity
         subjects affected / exposed
    1 / 1408 (0.07%)
    0 / 1408 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infections and infestations
    Abdominal wall abscess
         subjects affected / exposed
    1 / 1408 (0.07%)
    0 / 1408 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Anal abscess
         subjects affected / exposed
    0 / 1408 (0.00%)
    1 / 1408 (0.07%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Anorectal cellulitis
         subjects affected / exposed
    0 / 1408 (0.00%)
    1 / 1408 (0.07%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Appendicitis
         subjects affected / exposed
    1 / 1408 (0.07%)
    1 / 1408 (0.07%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Appendicitis perforated
         subjects affected / exposed
    0 / 1408 (0.00%)
    1 / 1408 (0.07%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Breast abscess
         subjects affected / exposed
    1 / 1408 (0.07%)
    0 / 1408 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Breast cellulitis
         subjects affected / exposed
    1 / 1408 (0.07%)
    1 / 1408 (0.07%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bronchitis
         subjects affected / exposed
    1 / 1408 (0.07%)
    2 / 1408 (0.14%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cellulitis
         subjects affected / exposed
    4 / 1408 (0.28%)
    6 / 1408 (0.43%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 6
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cystitis
         subjects affected / exposed
    0 / 1408 (0.00%)
    1 / 1408 (0.07%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Device related infection
         subjects affected / exposed
    3 / 1408 (0.21%)
    0 / 1408 (0.00%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Diverticulitis
         subjects affected / exposed
    1 / 1408 (0.07%)
    0 / 1408 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Erysipelas
         subjects affected / exposed
    0 / 1408 (0.00%)
    5 / 1408 (0.36%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 5
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Escherichia urinary tract infection
         subjects affected / exposed
    0 / 1408 (0.00%)
    1 / 1408 (0.07%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastroenteritis
         subjects affected / exposed
    0 / 1408 (0.00%)
    1 / 1408 (0.07%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastroenteritis salmonella
         subjects affected / exposed
    0 / 1408 (0.00%)
    1 / 1408 (0.07%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal viral infection
         subjects affected / exposed
    0 / 1408 (0.00%)
    1 / 1408 (0.07%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Herpes zoster
         subjects affected / exposed
    0 / 1408 (0.00%)
    1 / 1408 (0.07%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Incision site cellulitis
         subjects affected / exposed
    1 / 1408 (0.07%)
    0 / 1408 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Localised infection
         subjects affected / exposed
    0 / 1408 (0.00%)
    1 / 1408 (0.07%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Mastitis
         subjects affected / exposed
    1 / 1408 (0.07%)
    0 / 1408 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ophthalmic herpes zoster
         subjects affected / exposed
    0 / 1408 (0.00%)
    1 / 1408 (0.07%)
         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 / 1408 (0.28%)
    1 / 1408 (0.07%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Rectal abscess
         subjects affected / exposed
    0 / 1408 (0.00%)
    1 / 1408 (0.07%)
         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
    1 / 1408 (0.07%)
    0 / 1408 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Streptococcal sepsis
         subjects affected / exposed
    0 / 1408 (0.00%)
    1 / 1408 (0.07%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Viral infection
         subjects affected / exposed
    0 / 1408 (0.00%)
    1 / 1408 (0.07%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Dehydration
         subjects affected / exposed
    1 / 1408 (0.07%)
    9 / 1408 (0.64%)
         occurrences causally related to treatment / all
    0 / 1
    8 / 9
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Electrolyte imbalance
         subjects affected / exposed
    1 / 1408 (0.07%)
    0 / 1408 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypoglycaemia
         subjects affected / exposed
    1 / 1408 (0.07%)
    0 / 1408 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypokalaemia
         subjects affected / exposed
    0 / 1408 (0.00%)
    1 / 1408 (0.07%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypomagnesaemia
         subjects affected / exposed
    0 / 1408 (0.00%)
    1 / 1408 (0.07%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hyponatraemia
         subjects affected / exposed
    1 / 1408 (0.07%)
    1 / 1408 (0.07%)
         occurrences causally related to treatment / all
    0 / 1
    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
    		 Placebo Neratinib
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    1234 / 1408 (87.64%)
    1386 / 1408 (98.44%)
    Investigations
    Alanine aminotransferase increased
         subjects affected / exposed
    45 / 1408 (3.20%)
    118 / 1408 (8.38%)
         occurrences all number
    63
    170
    Aspartate aminotransferase increased
         subjects affected / exposed
    46 / 1408 (3.27%)
    101 / 1408 (7.17%)
         occurrences all number
    65
    152
    Electrocardiogram QT prolonged
         subjects affected / exposed
    93 / 1408 (6.61%)
    49 / 1408 (3.48%)
         occurrences all number
    128
    64
    Vascular disorders
    Hot flush
         subjects affected / exposed
    84 / 1408 (5.97%)
    40 / 1408 (2.84%)
         occurrences all number
    109
    49
    Nervous system disorders
    Dizziness
         subjects affected / exposed
    127 / 1408 (9.02%)
    146 / 1408 (10.37%)
         occurrences all number
    211
    241
    Headache
         subjects affected / exposed
    275 / 1408 (19.53%)
    278 / 1408 (19.74%)
         occurrences all number
    764
    707
    General disorders and administration site conditions
    Asthenia
         subjects affected / exposed
    110 / 1408 (7.81%)
    107 / 1408 (7.60%)
         occurrences all number
    194
    237
    Fatigue
         subjects affected / exposed
    283 / 1408 (20.10%)
    381 / 1408 (27.06%)
         occurrences all number
    490
    805
    Pyrexia
         subjects affected / exposed
    54 / 1408 (3.84%)
    77 / 1408 (5.47%)
         occurrences all number
    73
    95
    Gastrointestinal disorders
    Abdominal distension
         subjects affected / exposed
    49 / 1408 (3.48%)
    73 / 1408 (5.18%)
         occurrences all number
    79
    160
    Abdominal pain
         subjects affected / exposed
    144 / 1408 (10.23%)
    339 / 1408 (24.08%)
         occurrences all number
    256
    924
    Abdominal pain upper
         subjects affected / exposed
    96 / 1408 (6.82%)
    212 / 1408 (15.06%)
         occurrences all number
    195
    607
    Constipation
         subjects affected / exposed
    134 / 1408 (9.52%)
    115 / 1408 (8.17%)
         occurrences all number
    290
    245
    Diarrhoea
         subjects affected / exposed
    499 / 1408 (35.44%)
    1341 / 1408 (95.24%)
         occurrences all number
    3215
    25625
    Dyspepsia
         subjects affected / exposed
    59 / 1408 (4.19%)
    139 / 1408 (9.87%)
         occurrences all number
    113
    253
    Nausea
         subjects affected / exposed
    303 / 1408 (21.52%)
    605 / 1408 (42.97%)
         occurrences all number
    593
    1377
    Stomatitis
         subjects affected / exposed
    29 / 1408 (2.06%)
    85 / 1408 (6.04%)
         occurrences all number
    62
    151
    Vomiting
         subjects affected / exposed
    113 / 1408 (8.03%)
    364 / 1408 (25.85%)
         occurrences all number
    161
    627
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    92 / 1408 (6.53%)
    69 / 1408 (4.90%)
         occurrences all number
    122
    81
    Epistaxis
         subjects affected / exposed
    18 / 1408 (1.28%)
    71 / 1408 (5.04%)
         occurrences all number
    33
    120
    Skin and subcutaneous tissue disorders
    Dry skin
         subjects affected / exposed
    33 / 1408 (2.34%)
    85 / 1408 (6.04%)
         occurrences all number
    35
    101
    Rash
         subjects affected / exposed
    100 / 1408 (7.10%)
    211 / 1408 (14.99%)
         occurrences all number
    142
    369
    Psychiatric disorders
    Insomnia
         subjects affected / exposed
    73 / 1408 (5.18%)
    44 / 1408 (3.13%)
         occurrences all number
    90
    56
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    162 / 1408 (11.51%)
    86 / 1408 (6.11%)
         occurrences all number
    240
    123
    Back pain
         subjects affected / exposed
    134 / 1408 (9.52%)
    79 / 1408 (5.61%)
         occurrences all number
    168
    127
    Muscle spasms
         subjects affected / exposed
    44 / 1408 (3.13%)
    159 / 1408 (11.29%)
         occurrences all number
    70
    303
    Pain in extremity
         subjects affected / exposed
    98 / 1408 (6.96%)
    58 / 1408 (4.12%)
         occurrences all number
    159
    108
    Infections and infestations
    Nasopharyngitis
         subjects affected / exposed
    126 / 1408 (8.95%)
    84 / 1408 (5.97%)
         occurrences all number
    188
    143
    Urinary tract infection
         subjects affected / exposed
    23 / 1408 (1.63%)
    72 / 1408 (5.11%)
         occurrences all number
    26
    86
    Metabolism and nutrition disorders
    Decreased appetite
         subjects affected / exposed
    40 / 1408 (2.84%)
    170 / 1408 (12.07%)
         occurrences all number
    51
    226

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    25 Feb 2010
    This amendment included the following updates: restricted eligibility criteria to only include patients with a higher risk of recurrence: node positive patients only, within 1 year from completion of prior trastuzumab therapy; excluded patients with prior neoadjuvant therapy if they achieved a pathologic complete response (pCR) in breast and/or axilla, or if they had only residual in situ disease; removed node-negative stratum, and revised randomization stratification to include the following factors: ER- and/or PR-positive versus ER- and PR-negative; nodal status (1-3 versus 4 or more); and trastuzumab given sequentially versus concurrently with chemotherapy; mandated the availability of an archived diagnostic tumor sample for central ERBB2 testing and the patient’s written consent for this testing; revised dose adjustment guidelines for neratinib-related toxicities; revised guidelines for the management of asymptomatic LVEF declines; increased frequency of safety monitoring for hepatotoxicity and added guidelines for the management of changes in liver function tests; updated the statistical analysis section to reflect changes in trial design and underlying assumptions; allowed concomitant therapy with bisphosphonates at any time regardless of the indication; and other nonadministrative and administrative changes, including changing the sponsor due to the acquisition of Wyeth by Pfizer Inc.
    14 Jun 2010
    This amendment included the following updates: clarified eligibility criteria to state that patients who are node negative or have an unknown nodal status in the axilla after neoadjuvant therapy, but have residual invasive disease in the breast, are eligible. These patients must be stratified as “1-3” positive nodes, revised the definition of the amended intent-to-treat (aITT) population include patients who are node-negative or have an unknown nodal status after neoadjuvant therapy, but have residual disease in the breast; added additional complete blood count (CBC) collection time points at months 2 and 4.5 as a precaution per recommendation of the Independent Data Monitoring Committee (IDMC) after bone marrow suppression (resulting in neutropenia and thrombocytopenia, without any other clear cause) was reported in another neratinib trial in one patient who had taken neratinib monotherapy for 4 months; refined exclusion criterion number 17 to state “On treatment or in followup of any other neoadjuvant or adjuvant breast cancer trial with DFS as an endpoint”; and clarified that missed doses or underdosing of investigational product are not considered medication errors; updated blood volumes to be drawn from each patient; and specified acceptable fixation methods for tumor samples and the minimum number of slides required for central ERBB2 testing.
    18 Nov 2010
    This amendment included the following updates per recommendation of the independent monitoring committee. Additional measures were implemented and existing tools were modified to improve the monitoring and clinical management of diarrhea, the dominant adverse event (AE) seen in the study. The key changes were: Patients must have loperamide on hand when taking the first dose of investigational product (IP). Options included: dispense loperamide along with IP, the investigator provides a prescription for loperamide when dispensing IP on day 1, or the patient obtains loperamide over-the-counter. The following documents were implemented at each site: new investigator checklist for each patient prior to randomizing, modified patient instructions for the management of diarrhea, and modified patient diary for recording of IP intake, AEs (including diarrhea), number of daily stools, and the use of loperamide and/or other anti-diarrheals. The investigator/designee were to call the patient between days 3-5 to confirm that the patient has loperamide available; to inquire about the first dose of IP and any AEs, especially diarrhea; and to provide guidance for immediate medical management of the AEs, if any. Guidelines for diarrhea management with loperamide and for neratinib dose adjustment were revised and consolidated in one place in the protocol. Guidelines for unblinding were updated per recent administrative letter. Other administrative updates were made throughout the document due to the acquisition of Wyeth by Pfizer Inc. These changes included updates in contact information, a new global Serious AE reporting fax number, and removal of the Sponsor and investigator signature pages due to revised approval process.
    14 Oct 2011
    This amendment included the following updates due to changes in organizational strategy. Enrollment of new patients was stopped, and several study design changes were implemented, including reductions to the number of randomized patients, the duration of patient participation, study duration, follow-up period and the scope of exploratory objectives. Patient-reported outcome data (FACT-B, EQ-5D) and tumor samples for biomarker analysis were removed. Statistical assumptions were adjusted due to the reduction in sample size and shortened follow-up time; the prespecified total number of disease-free survival events required for final analysis and the previously-planned interim analyses were removed. Guidelines for the management of diarrhea were revised. Guidelines for the management of changes in liver function tests were revised. Option for dose re-escalation was removed globally. The mandate to discontinue study treatment after unblinding in case of a Suspected Unexpected Serious Adverse Reaction was removed. Adverse Event Reporting was adjusted to standard Legacy-Pfizer safety language, and a new SAE reporting form was adopted. Language providing an option for patients in the placebo arm to receive IP after study completion/termination was removed in anticipation that the reduced sample size will affect the ability to draw efficacy conclusions from the study. References to the 240-mg tablet were removed because the formulation had not been provided for the study. Storage conditions for the IP were clarified. The sponsorship of the study was transferred from Wyeth, a Pfizer Company, to Puma starting on 01-JAN-2012, following a development and commercialization agreement for the IP (neratinib) between Pfizer Inc. and Puma Biotechnology, Inc. on 05-OCT-2011.
    21 Mar 2012
    This amendment included the following updates: Safety reporting wording was updated to comply with the most recent Sponsor-approved safety language. The requirement to collect a PK sample in case of suspected severe hepatotoxicity was removed due to a very small number of suspected hepatotoxicities reported in the study to date (5 out of 2842 randomized patients). Synopsis, Flowchart, and other pertinent sections were updated to reflect changes made in the body of the protocol. Reference to the Academic Steering Committee was removed since the committee is no longer in place. Administrative changes were made due to the transfer of sponsorship from Wyeth, a Pfizer Company, to Puma, including revisions in the emergency contact information.
    16 Jan 2014
    The purpose of the Amendment was to obtain additional Disease Free Survival (DFS) and Overall Survival (OS) data in order to evaluate the long-term efficacy of neratinib in the adjuvant setting. The study follow-up (FU) period was extended to 5 years, and all randomized patients who had discontinued FU at 2 years will be re-consented to obtain survival data. All randomized patients will be included in the analysis of efficacy endpoints. The study design was revised to indicate how recurrent disease events and deaths will be ascertained for the Intent to Treat (ITT) population: Part A: Data collected during the FU period of 2 years post randomization will form the primary analysis. DFS and OS endpoints will be based upon the recurrent disease events and deaths that occurred during this 2-year period. Part B: The expanded FU period from years 2 through 5 years post randomization will evaluate the durability of the treatment effect on DFS and the impact on OS. Recurrent disease events and deaths will be ascertained from patients’ medical records. Statistical evaluations for this part of the study will be considered sensitivity analyses. Part C: Long-term FU of OS will continue for patients who re-consented and will start from 5 years post randomization. Sensitivity analyses of DFS will be included on patient subsets according to the following criteria: Patients in the amended ITT population (aITT) consisting of all patients randomized under Amendment 3 or later, and all patients randomized prior to implementation of Amendment 3 if they had node-positive disease and were treated with trastuzumab ≤1 year prior to randomization; All randomized patients who had node-positive disease; All randomized patients who entered the trial within 1 year of completion of prior trastuzumab; All randomized patients who were ERBB2-positive by central testing. Statistical methods and considerations were revised and a description of the sensitivity analysis was added.

    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

    Online references
    http://www.ncbi.nlm.nih.gov/pubmed/31140297
    http://www.ncbi.nlm.nih.gov/pubmed/30867034
    http://www.ncbi.nlm.nih.gov/pubmed/30813966
    http://www.ncbi.nlm.nih.gov/pubmed/30689703
    http://www.ncbi.nlm.nih.gov/pubmed/29146401
    http://www.ncbi.nlm.nih.gov/pubmed/26874901
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