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    Clinical Trial Results:
    A Phase III Randomised, Double-Blind, Parallel Group, Multicentre Study to Compare the Efficacy, Safety, Pharmacokinetics and Immunogenicity between SB3 (proposed trastuzumab biosimilar) and Herceptin® in Women with Newly Diagnosed HER2 Positive Early or Locally Advanced Breast Cancer in Neoadjuvant Setting

    Summary
    EudraCT number
    2013-004172-35
    Trial protocol
    CZ   PL   BG   RO  
    Global end of trial date
    17 Jan 2017

    Results information
    Results version number
    v1(current)
    This version publication date
    25 Jan 2019
    First version publication date
    25 Jan 2019
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    SB3-G31-BC
    Additional study identifiers
    ISRCTN number
    -
    US NCT number
    NCT02149524
    WHO universal trial number (UTN)
    -
    Sponsors
    Sponsor organisation name
    Samsung Bioepis Co., Ltd.
    Sponsor organisation address
    107, Cheomdan-daero, Incheon, Korea, Republic of,
    Public contact
    Quintiles Contact Centre, Quintiles Limited, 001 8622613634,
    Scientific contact
    Quintiles Contact Centre, Quintiles Limited, 001 8622613634,
    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
    17 Jan 2017
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    17 Jan 2017
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The primary objective of this study is to demonstrate comparable clinical efficacy of SB3 to Herceptin®, in terms of Pathologic complete response rate of the primary breast tumour in women with HER2 positive Early breast cancer or Locally advanced breast cancer in neoadjuvant setting.
    Protection of trial subjects
    The study and clinical study protocols were reviewed and approved by Independent Ethics Committee (IEC) or Institutional Review Board (IRB). This study was conducted in accordance with the ethical principles that have their origin in the Declaration of Helsinki (2008) and that are consistent with International Conference on Harmonisation (ICH) Good Clinical Practice (GCP) guidelines (ICH E6) and applicable local regulatory requirements and laws. The nature and purpose of the study was fully explained to each subject and written informed consent was obtained at Screening from each subject before any study related procedures were performed. The consent documents for the study was reviewed and approved by the appropriate IEC or IRB prior to use.
    Background therapy
    -
    Evidence for comparator
    -
    Actual start date of recruitment
    14 Apr 2014
    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
    Korea, Republic of: 74
    Country: Number of subjects enrolled
    Malaysia: 21
    Country: Number of subjects enrolled
    Mexico: 1
    Country: Number of subjects enrolled
    Philippines: 52
    Country: Number of subjects enrolled
    Vietnam: 16
    Country: Number of subjects enrolled
    Bosnia and Herzegovina: 7
    Country: Number of subjects enrolled
    Ukraine: 166
    Country: Number of subjects enrolled
    India: 104
    Country: Number of subjects enrolled
    Russian Federation: 211
    Country: Number of subjects enrolled
    Poland: 143
    Country: Number of subjects enrolled
    Romania: 40
    Country: Number of subjects enrolled
    Bulgaria: 4
    Country: Number of subjects enrolled
    Czech Republic: 17
    Country: Number of subjects enrolled
    France: 19
    Worldwide total number of subjects
    875
    EEA total number of subjects
    223
    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)
    856
    From 65 to 84 years
    19
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    -

    Pre-assignment
    Screening details
    Participants who fulfilled the inclusion/exclusion criteria were randomly assigned to 1 of the 2 treatments of this study.

    Period 1
    Period 1 title
    Overall study period (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
    SB3 (proposed trastuzumab biosimilar)
    Arm description
    Participants received SB3 every 3 weeks for a total of 18 cycles (8 cycles of neoadjuvant therapy and 10 cycles of adjuvant therapy).
    Arm type
    Experimental

    Investigational medicinal product name
    SB3
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Powder for concentrate for solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    SB3 was administered intravenously at a loading dose of 8 mg/kg and at a maintenance dose of 6 mg/kg for the subsequent cycles.

    Arm title
    Herceptin
    Arm description
    Participants received EU sourced Herceptin® every 3 weeks for a total of 18 cycles (8 cycles of neoadjuvant therapy and 10 cycles of adjuvant therapy)
    Arm type
    Active comparator

    Investigational medicinal product name
    Trastuzumab
    Investigational medicinal product code
    Other name
    Herceptin
    Pharmaceutical forms
    Powder for concentrate for solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Herceptin was administered intravenously at a loading dose of 8 mg/kg and at a maintenance dose of 6 mg/kg for the subsequent cycles.

    Number of subjects in period 1
    SB3 (proposed trastuzumab biosimilar) Herceptin
    Started
    437
    438
    Completed
    380
    384
    Not completed
    57
    54
         Administrative or other reasons
    4
    2
         Protocol deviation
    1
    -
         Progressive disease/disease recurrence
    23
    22
         Adverse event, serious fatal
    1
    5
         Adverse event, non-fatal
    13
    12
         Consent withdrawn by subject
    10
    9
         Lost to follow-up
    5
    4

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    SB3 (proposed trastuzumab biosimilar)
    Reporting group description
    Participants received SB3 every 3 weeks for a total of 18 cycles (8 cycles of neoadjuvant therapy and 10 cycles of adjuvant therapy).

    Reporting group title
    Herceptin
    Reporting group description
    Participants received EU sourced Herceptin® every 3 weeks for a total of 18 cycles (8 cycles of neoadjuvant therapy and 10 cycles of adjuvant therapy)

    Reporting group values
    SB3 (proposed trastuzumab biosimilar) Herceptin Total
    Number of subjects
    437 438 875
    Age categorical
    Units: Subjects
        Less than 60 years
    0
        60 years and over
    0
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    49.5 ± 9.51 49.6 ± 9.38 -
    Gender categorical
    Units: Subjects
        Female
    437 438 875
        Male
    0 0 0

    End points

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    End points reporting groups
    Reporting group title
    SB3 (proposed trastuzumab biosimilar)
    Reporting group description
    Participants received SB3 every 3 weeks for a total of 18 cycles (8 cycles of neoadjuvant therapy and 10 cycles of adjuvant therapy).

    Reporting group title
    Herceptin
    Reporting group description
    Participants received EU sourced Herceptin® every 3 weeks for a total of 18 cycles (8 cycles of neoadjuvant therapy and 10 cycles of adjuvant therapy)

    Subject analysis set title
    Per-protocol set
    Subject analysis set type
    Per protocol
    Subject analysis set description
    The PPS consisted of all FAS subjects who completed the 8 cycles of neoadjuvant therapy and surgery. The PPS was the primary analysis set. Major protocol deviations that led to exclusion from this set were pre-specified prior to unblinding the treatment codes for analyses. Subjects who did not have a pathological response assessment were excluded from the PPS.

    Primary: bpCR

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    End point title
    bpCR
    End point description
    pCR was defined as no histological evidence of residual invasive tumour cells in the breast specimen removed at surgery [breast pCR; bpCR]. Non-invasive breast residuals were allowed and the pathological examination of axillary lymph nodes was not to be considered; ypT0/is, ypN0/+.
    End point type
    Primary
    End point timeframe
    Week 24
    End point values
    SB3 (proposed trastuzumab biosimilar) Herceptin Per-protocol set
    Number of subjects analysed
    402
    398
    800 [1]
    Units: percentage
        number (not applicable)
    51.7
    42.0
    800
    Notes
    [1] - SB3: 402/Herceptin: 398
    Statistical analysis title
    bpCR (per-protocol analysis)
    Comparison groups
    SB3 (proposed trastuzumab biosimilar) v Herceptin
    Number of subjects included in analysis
    800
    Analysis specification
    Pre-specified
    Analysis type
    equivalence [2]
    Method
    Parameter type
    Risk ratio (RR)
    Point estimate
    1.259
    Confidence interval
         level
    90%
         sides
    2-sided
         lower limit
    1.112
         upper limit
    1.426
    Notes
    [2] - - Equivalence margin: [0.785, 1.546]

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Adverse events (AEs) and serious AEs (SAEs) were reported from the time the participant had taken at least 1 dose of study drug and the time of informed consent (TEAEs), respectively, through 30 days after the last dose of study drug (EOS).
    Assessment type
    Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    MedDRA
    Dictionary version
    16.1
    Reporting groups
    Reporting group title
    SB3 (proposed trastuzumab biosimilar)
    Reporting group description
    Participants received SB3 every 3 weeks for a total of 18 cycles (8 cycles of neoadjuvant therapy and 10 cycles of adjuvant therapy).

    Reporting group title
    Herceptin
    Reporting group description
    Participants received EU sourced Herceptin every 3 weeks for a total of 18 cycles (8 cycles of neoadjuvant therapy and 10 cycles of adjuvant therapy).

    Serious adverse events
    SB3 (proposed trastuzumab biosimilar) Herceptin
    Total subjects affected by serious adverse events
         subjects affected / exposed
    56 / 437 (12.81%)
    58 / 438 (13.24%)
         number of deaths (all causes)
    1
    5
         number of deaths resulting from adverse events
    Vascular disorders
    Hypertension
         subjects affected / exposed
    1 / 437 (0.23%)
    0 / 438 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypotension
         subjects affected / exposed
    0 / 437 (0.00%)
    1 / 438 (0.23%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Asthenia
         subjects affected / exposed
    1 / 437 (0.23%)
    0 / 438 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Extravasation
         subjects affected / exposed
    1 / 437 (0.23%)
    0 / 438 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Medical device complication
         subjects affected / exposed
    1 / 437 (0.23%)
    0 / 438 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pyrexia
         subjects affected / exposed
    1 / 437 (0.23%)
    2 / 438 (0.46%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Fatigue
         subjects affected / exposed
    0 / 437 (0.00%)
    1 / 438 (0.23%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Sudden death
         subjects affected / exposed
    0 / 437 (0.00%)
    1 / 438 (0.23%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Psychiatric disorders
    Completed suicide
         subjects affected / exposed
    1 / 437 (0.23%)
    0 / 438 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Hallucination, auditory
         subjects affected / exposed
    1 / 437 (0.23%)
    0 / 438 (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
    Metrorrhagia
         subjects affected / exposed
    1 / 437 (0.23%)
    0 / 438 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ovarian hyperstimulation syndrome
         subjects affected / exposed
    1 / 437 (0.23%)
    0 / 438 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Menorrhagia
         subjects affected / exposed
    0 / 437 (0.00%)
    1 / 438 (0.23%)
         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
    Facial bones fracture
         subjects affected / exposed
    1 / 437 (0.23%)
    0 / 438 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Radiation necrosis
         subjects affected / exposed
    1 / 437 (0.23%)
    0 / 438 (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 / 437 (0.23%)
    0 / 438 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hand fracture
         subjects affected / exposed
    0 / 437 (0.00%)
    1 / 438 (0.23%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infusion related reaction
         subjects affected / exposed
    0 / 437 (0.00%)
    2 / 438 (0.46%)
         occurrences causally related to treatment / all
    0 / 0
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Post procedural complication
         subjects affected / exposed
    0 / 437 (0.00%)
    1 / 438 (0.23%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Post procedural haemorrhage
         subjects affected / exposed
    0 / 437 (0.00%)
    2 / 438 (0.46%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Radiation mucositis
         subjects affected / exposed
    0 / 437 (0.00%)
    1 / 438 (0.23%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Investigations
    Neutrophil count decreased
         subjects affected / exposed
    8 / 437 (1.83%)
    4 / 438 (0.91%)
         occurrences causally related to treatment / all
    0 / 20
    1 / 7
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac disorders
    Cardiac failure congestive
         subjects affected / exposed
    3 / 437 (0.69%)
    0 / 438 (0.00%)
         occurrences causally related to treatment / all
    2 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Supraventricular tachycardia
         subjects affected / exposed
    1 / 437 (0.23%)
    0 / 438 (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
    0 / 437 (0.00%)
    1 / 438 (0.23%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Respiratory, thoracic and mediastinal disorders
    Chronic obstructive pulmonary disease
         subjects affected / exposed
    1 / 437 (0.23%)
    0 / 438 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nasal polyps
         subjects affected / exposed
    1 / 437 (0.23%)
    0 / 438 (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
    1 / 437 (0.23%)
    2 / 438 (0.46%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Pneumonitis
         subjects affected / exposed
    0 / 437 (0.00%)
    1 / 438 (0.23%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Blood and lymphatic system disorders
    Febrile neutropenia
         subjects affected / exposed
    10 / 437 (2.29%)
    13 / 438 (2.97%)
         occurrences causally related to treatment / all
    1 / 11
    1 / 14
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Neutropenia
         subjects affected / exposed
    7 / 437 (1.60%)
    5 / 438 (1.14%)
         occurrences causally related to treatment / all
    2 / 7
    1 / 5
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Anaemia
         subjects affected / exposed
    2 / 437 (0.46%)
    0 / 438 (0.00%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Thrombocytopenia
         subjects affected / exposed
    1 / 437 (0.23%)
    0 / 438 (0.00%)
         occurrences causally related to treatment / all
    2 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Haemolytic anaemia
         subjects affected / exposed
    0 / 437 (0.00%)
    1 / 438 (0.23%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Leukopenia
         subjects affected / exposed
    0 / 437 (0.00%)
    1 / 438 (0.23%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nervous system disorders
    Polyneuropathy
         subjects affected / exposed
    1 / 437 (0.23%)
    0 / 438 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Carpal tunnel syndrome
         subjects affected / exposed
    0 / 437 (0.00%)
    1 / 438 (0.23%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Convulsion
         subjects affected / exposed
    0 / 437 (0.00%)
    2 / 438 (0.46%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Haemorrhagic stroke
         subjects affected / exposed
    0 / 437 (0.00%)
    1 / 438 (0.23%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Ischaemic stroke
         subjects affected / exposed
    0 / 437 (0.00%)
    1 / 438 (0.23%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Transient ischaemic attack
         subjects affected / exposed
    0 / 437 (0.00%)
    1 / 438 (0.23%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Eye disorders
    Retinal haemorrhage
         subjects affected / exposed
    0 / 437 (0.00%)
    1 / 438 (0.23%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ear and labyrinth disorders
    Vertigo
         subjects affected / exposed
    1 / 437 (0.23%)
    0 / 438 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Diarrhoea
         subjects affected / exposed
    3 / 437 (0.69%)
    3 / 438 (0.68%)
         occurrences causally related to treatment / all
    1 / 5
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrooesophageal reflux disease
         subjects affected / exposed
    2 / 437 (0.46%)
    0 / 438 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Abdominal pain upper
         subjects affected / exposed
    1 / 437 (0.23%)
    0 / 438 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nausea
         subjects affected / exposed
    1 / 437 (0.23%)
    0 / 438 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Stomatitis
         subjects affected / exposed
    1 / 437 (0.23%)
    0 / 438 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vomiting
         subjects affected / exposed
    1 / 437 (0.23%)
    2 / 438 (0.46%)
         occurrences causally related to treatment / all
    0 / 1
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastritis
         subjects affected / exposed
    0 / 437 (0.00%)
    1 / 438 (0.23%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Haemorrhoids
         subjects affected / exposed
    0 / 437 (0.00%)
    1 / 438 (0.23%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal and urinary disorders
    Renal failure acute
         subjects affected / exposed
    1 / 437 (0.23%)
    0 / 438 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatobiliary disorders
    Hepatic function abnormal
         subjects affected / exposed
    1 / 437 (0.23%)
    0 / 438 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Myalgia
         subjects affected / exposed
    2 / 437 (0.46%)
    0 / 438 (0.00%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pathological fracture
         subjects affected / exposed
    0 / 437 (0.00%)
    1 / 438 (0.23%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Diabetes mellitus
         subjects affected / exposed
    1 / 437 (0.23%)
    1 / 438 (0.23%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypokalaemia
         subjects affected / exposed
    1 / 437 (0.23%)
    1 / 438 (0.23%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hyponatraemia
         subjects affected / exposed
    1 / 437 (0.23%)
    1 / 438 (0.23%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Malnutrition
         subjects affected / exposed
    0 / 437 (0.00%)
    1 / 438 (0.23%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infections and infestations
    Pneumonia
         subjects affected / exposed
    4 / 437 (0.92%)
    0 / 438 (0.00%)
         occurrences causally related to treatment / all
    0 / 5
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Urinary tract infection
         subjects affected / exposed
    2 / 437 (0.46%)
    0 / 438 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bronchitis
         subjects affected / exposed
    1 / 437 (0.23%)
    0 / 438 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cellulitis
         subjects affected / exposed
    1 / 437 (0.23%)
    1 / 438 (0.23%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Furuncle
         subjects affected / exposed
    1 / 437 (0.23%)
    0 / 438 (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 / 437 (0.23%)
    1 / 438 (0.23%)
         occurrences causally related to treatment / all
    0 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Neutropenic sepsis
         subjects affected / exposed
    1 / 437 (0.23%)
    1 / 438 (0.23%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Soft tissue infection
         subjects affected / exposed
    1 / 437 (0.23%)
    0 / 438 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Tuberculosis
         subjects affected / exposed
    1 / 437 (0.23%)
    0 / 438 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Upper respiratory tract infection
         subjects affected / exposed
    1 / 437 (0.23%)
    0 / 438 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bronchopneumonia
         subjects affected / exposed
    0 / 437 (0.00%)
    1 / 438 (0.23%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Dengue fever
         subjects affected / exposed
    0 / 437 (0.00%)
    2 / 438 (0.46%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Erysipelas
         subjects affected / exposed
    0 / 437 (0.00%)
    1 / 438 (0.23%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Influenza
         subjects affected / exposed
    0 / 437 (0.00%)
    2 / 438 (0.46%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Intraspinal abscess
         subjects affected / exposed
    0 / 437 (0.00%)
    1 / 438 (0.23%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lobar pneumonia
         subjects affected / exposed
    0 / 437 (0.00%)
    1 / 438 (0.23%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Neutropenic infection
         subjects affected / exposed
    0 / 437 (0.00%)
    1 / 438 (0.23%)
         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 / 437 (0.00%)
    1 / 438 (0.23%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Wound infection
         subjects affected / exposed
    0 / 437 (0.00%)
    1 / 438 (0.23%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    SB3 (proposed trastuzumab biosimilar) Herceptin
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    420 / 437 (96.11%)
    414 / 438 (94.52%)
    Vascular disorders
    Lymphorrhoea
         subjects affected / exposed
    32 / 437 (7.32%)
    30 / 438 (6.85%)
         occurrences all number
    58
    51
    Injury, poisoning and procedural complications
    Radiation skin injury
         subjects affected / exposed
    48 / 437 (10.98%)
    38 / 438 (8.68%)
         occurrences all number
    48
    47
    Procedural pain
         subjects affected / exposed
    39 / 437 (8.92%)
    53 / 438 (12.10%)
         occurrences all number
    41
    54
    Infusion related reaction
         subjects affected / exposed
    37 / 437 (8.47%)
    42 / 438 (9.59%)
         occurrences all number
    53
    62
    Postoperative wound complication
         subjects affected / exposed
    27 / 437 (6.18%)
    21 / 438 (4.79%)
         occurrences all number
    27
    21
    Investigations
    Alanine aminotransferase increased
         subjects affected / exposed
    84 / 437 (19.22%)
    83 / 438 (18.95%)
         occurrences all number
    150
    150
    Aspartate aminotransferase increased
         subjects affected / exposed
    68 / 437 (15.56%)
    63 / 438 (14.38%)
         occurrences all number
    102
    110
    Neutrophil count decreased
         subjects affected / exposed
    53 / 437 (12.13%)
    53 / 438 (12.10%)
         occurrences all number
    124
    162
    White blood cell count decreased
         subjects affected / exposed
    25 / 437 (5.72%)
    32 / 438 (7.31%)
         occurrences all number
    69
    71
    Blood alkaline phosphatase increased
         subjects affected / exposed
    22 / 437 (5.03%)
    29 / 438 (6.62%)
         occurrences all number
    40
    43
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    41 / 437 (9.38%)
    27 / 438 (6.16%)
         occurrences all number
    46
    34
    Oropharyngeal pain
         subjects affected / exposed
    25 / 437 (5.72%)
    19 / 438 (4.34%)
         occurrences all number
    28
    22
    Blood and lymphatic system disorders
    Neutropenia
         subjects affected / exposed
    239 / 437 (54.69%)
    280 / 438 (63.93%)
         occurrences all number
    654
    634
    Leukopenia
         subjects affected / exposed
    125 / 437 (28.60%)
    113 / 438 (25.80%)
         occurrences all number
    259
    237
    Anaemia
         subjects affected / exposed
    96 / 437 (21.97%)
    95 / 438 (21.69%)
         occurrences all number
    180
    198
    Nervous system disorders
    Headache
         subjects affected / exposed
    31 / 437 (7.09%)
    32 / 438 (7.31%)
         occurrences all number
    55
    51
    Peripheral sensory neuropathy
         subjects affected / exposed
    30 / 437 (6.86%)
    23 / 438 (5.25%)
         occurrences all number
    42
    40
    Neuropathy peripheral
         subjects affected / exposed
    22 / 437 (5.03%)
    12 / 438 (2.74%)
         occurrences all number
    24
    12
    Psychiatric disorders
         subjects affected / exposed
    22 / 437 (5.03%)
    22 / 438 (5.02%)
         occurrences all number
    32
    31
    Insomnia
         subjects affected / exposed
    22 / 437 (5.03%)
    22 / 438 (5.02%)
         occurrences all number
    32
    31
    General disorders and administration site conditions
    Fatigue
         subjects affected / exposed
    88 / 437 (20.14%)
    79 / 438 (18.04%)
         occurrences all number
    186
    182
    Asthenia
         subjects affected / exposed
    57 / 437 (13.04%)
    55 / 438 (12.56%)
         occurrences all number
    145
    162
    Pyrexia
         subjects affected / exposed
    39 / 437 (8.92%)
    37 / 438 (8.45%)
         occurrences all number
    50
    48
    Oedema peripheral
         subjects affected / exposed
    18 / 437 (4.12%)
    31 / 438 (7.08%)
         occurrences all number
    27
    34
    Gastrointestinal disorders
    Nausea
         subjects affected / exposed
    143 / 437 (32.72%)
    135 / 438 (30.82%)
         occurrences all number
    362
    388
    Diarrhoea
         subjects affected / exposed
    91 / 437 (20.82%)
    65 / 438 (14.84%)
         occurrences all number
    143
    90
    Stomatitis
         subjects affected / exposed
    61 / 437 (13.96%)
    51 / 438 (11.64%)
         occurrences all number
    107
    88
    Vomiting
         subjects affected / exposed
    61 / 437 (13.96%)
    50 / 438 (11.42%)
         occurrences all number
    110
    87
    Dyspepsia
         subjects affected / exposed
    26 / 437 (5.95%)
    22 / 438 (5.02%)
         occurrences all number
    39
    27
    Skin and subcutaneous tissue disorders
    Alopecia
         subjects affected / exposed
    299 / 437 (68.42%)
    283 / 438 (64.61%)
         occurrences all number
    349
    324
    Rash
         subjects affected / exposed
    47 / 437 (10.76%)
    45 / 438 (10.27%)
         occurrences all number
    61
    62
    Nail disorder
         subjects affected / exposed
    22 / 437 (5.03%)
    23 / 438 (5.25%)
         occurrences all number
    23
    23
    Musculoskeletal and connective tissue disorders
    Myalgia
         subjects affected / exposed
    63 / 437 (14.42%)
    66 / 438 (15.07%)
         occurrences all number
    148
    138
    Arthralgia
         subjects affected / exposed
    48 / 437 (10.98%)
    47 / 438 (10.73%)
         occurrences all number
    74
    70
    Joint range of motion decreased
         subjects affected / exposed
    27 / 437 (6.18%)
    20 / 438 (4.57%)
         occurrences all number
    33
    21
    Bone pain
         subjects affected / exposed
    23 / 437 (5.26%)
    24 / 438 (5.48%)
         occurrences all number
    39
    39
    Metabolism and nutrition disorders
    Decreased appetite
         subjects affected / exposed
    40 / 437 (9.15%)
    41 / 438 (9.36%)
         occurrences all number
    78
    103
    Infections and infestations
    Upper respiratory tract infection
         subjects affected / exposed
    44 / 437 (10.07%)
    40 / 438 (9.13%)
         occurrences all number
    66
    64

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    Substantial protocol amendments (globally)

    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    08 May 2014
    • Text was added to the section on administration of neoadjuvant chemotherapy to be in line with the French regulatory authority’s recommendation. • Administrative changes were made.
    08 Jul 2014
    • Three exclusion criteria were clarified. • To avoid repetition of procedures at Screening, an update was made to allow results from previous assessments (even if they had occurred before the signing of informed consent) to be used as screening procedures as long as they were within 28 days of randomisation. • Text was clarified and editorial/administrative changes were implemented where appropriate.
    26 Aug 2014
    • The period that women of childbearing potential had to agree to use contraception was increased from 6 to 7 months in line with updated SmPC for Herceptin®. • Results from a bilateral mammography performed within 6 weeks before randomisation was now acceptable as a screening procedure because significant changes in a few weeks were unlikely. • A definition of disease stage when tumour size was 2.0 cm (T1) was added to the stratification factors. • A paragraph on pooling data from centres for the efficacy analysis was deleted because subjects were randomised by country not centre. • The axillary staging procedures were updated in accordance with recent breast surgery guidelines. • Text was further clarified and editorial/administrative changes were implemented where appropriate.
    17 Dec 2014
    • Determination of sample size and its rationale was updated as a result of newly found literature and references added to the bibliography [Chang, 2008]. The expected bpCR rate was changed from 40% to 37.5%, the number of evaluable subjects to meet an 80% power changed from 220 to 358 subjects per arm and the equivalence margin changed from within 15% to 0.785 to 1.546. The number of subjects to be randomised was therefore changed from 249 to 403 per arm and the expected dropout rate changed from 12% to 11%. • The number of subjects to be randomised was increased from 498 to 806 and the expected recruitment period increased from 12 to 15 months. • The criteria for declaring equivalence between the two treatments (primary efficacy endpoint) was modified: From: Equivalence between the two treatment groups will be declared if the two-sided 95% (CI) of the difference in the pCR rate between treatments is entirely contained within the equivalence margin of [-15%, 15%]. The two-sided 95% CI of the difference will be estimated for the PPS. To: To demonstrate equivalence in the pCR rate between the two treatment groups in accordance with both FDA and EMA recommendation, the ratio and the difference in pCR rate will be analysed for the primary analysis. Equivalence will be declared if the two-sided 95% (CI) of the ratio in the pCR rate between treatments is entirely contained within the equivalence margin of [0.785, 1.546] or, if the 95% CI of the difference in the pCR rate between treatments is entirely contained within the equivalence margin of [-13%, 13%]. The 95% CIs of the difference will be estimated for the PPS. The difference of pCR will be used for EMA submission and the relative ratio of pCR will be used for FDA submission.
    23 Apr 2015
    • References (different versions of NCI-CTCAE) to be used to grade the severity of AEs of CHF, left ventricular dysfunction and febrile neutropenia were added. • Sample size for PK Population was amended from 270 (135 per arm) to 300 subjects (150 per arm). The expected non-evaluable rate was updated from 22% to 30%. • Clarifications were made to PK sample procedures. • More detail and clarification was added to the sections on dose modification and delays of IP and non-IP. • Premature withdrawal criteria were updated with regard to allowed treatment delays. • In Appendix 4 of the protocol, a section was added on quality control of pCR by central review. • In the case of high-risk subjects, G-CSF was allowed as a primary prophylaxis for neutropenic events. • Text was further clarified and editorial/administrative changes were implemented where appropriate.

    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/29373094
    http://www.ncbi.nlm.nih.gov/pubmed/29448072
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