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    Clinical Trial Results:
    Pivotal study in breast cancer patients investigating efficacy and safety of LA-EP2006 and Neulasta®

    Summary
    EudraCT number
    		 2012-002039-28
    Trial protocol
    		 ES  
    Global end of trial date
    04 Dec 2013

    Results information
    Results version number
    		 v2(current)
    This version publication date
    21 Jul 2016
    First version publication date
    05 Aug 2015
    Other versions
    		 v1
    Version creation reason
    • Correction of full data set
    These results have been removed from public view by EMA due to a system error. Subsequently, Sponsor reviewed and updated/corrected trial results to restore posting.

    Trial information

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    Trial identification
    Sponsor protocol code
    LA-EP06-302
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 -
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Sandoz GmbH
    Sponsor organisation address
    Biochemiestrasse 10, Kundl, Austria,
    Public contact
    Strategic Planning Biopharma Clinical Development, Sandoz, +49 8024 476 - 0, biopharma.clinicaltrials@sandoz.com
    Scientific contact
    Strategic Planning Biopharma Clinical Development, Sandoz, +49 8024 476 - 0, biopharma.clinicaltrials@sandoz.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
    19 Feb 2015
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    04 Dec 2013
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To assess the efficacy of LA-EP2006 compared to Neulasta® with respect to the mean duration of severe neutropenia (DSN), defined as number of consecutive days with Grade 4 neutropenia (absolute neutrophil count [ANC] less than 0.5 x 10^9/L), during Cycle 1 of the neoadjuvant or adjuvant TAC regimen (Taxotere® [docetaxel] in combination with Adriamycin® [doxorubicin] and Cytoxan® [cyclophosphamide]) in breast cancer patients.
    Protection of trial subjects
    The study was conducted in accordance with the International Conference on Harmonization (ICH) Harmonized Tripartite Guidelines for Good Clinical Practice (GCP), with applicable local regulations (including Food and Drug Administration (FDA) regulations relating to GCP and clinical trials in CFR Title 21; EU legislation on GCP and the conduct of clinical trials: Directive 2001/83/EC, Directive 2001/20/EC), and with the ethical principles laid down in the Declaration of Helsinki. The study protocol and the amendment were reviewed by the Independent Ethics Committee (IEC) or Institutional Review Board (IRB) for each center. A data safety monitoring board (DSMB) monitored the safety of the study.
    Background therapy
    		 The Chemotherapy (TAC) regimen comprised six chemotherapy cycles every 3 weeks and consisted of the three-drug combination of docetaxel, doxorubicin, and cyclophosphamide administered i.v. at Day 1 of each chemotherapy cycle. Doxorubicin was given first at a dose of 50 mg/m² followed by cyclophosphamide at a dose of 500 mg/m². Finally, docetaxel was administered as an infusion at a dose of 75 mg/m². Dose reductions of 25% were to be considered in case of Grade 3 or 4 non-hematological toxicity; Grade 4 thrombocytopenia; episode of febrile neutropenia; or a delay of > 7 days but < 14 days. The chemotherapy doses were calculated according to the baseline body surface area (BSA) for all cycles according to the Mosteller formula. If there was a 10% or greater decrease in body weight compared to baseline, the BSA was to be recalculated. Dose reduction and/or treatment delay and treatment discontinuation were foreseen in the case of severe hematological and/or non hematological toxicities. All study patients were treated with the TAC combination chemotherapy taking into consideration the information about dosage and administration, contraindications, warnings and precautions of the US prescribing information of the three products. In case of disease progression or of intolerable toxicities of the cytotoxic products, the chemotherapy could be discontinued at the discretion of the investigator.
    Evidence for comparator
    		 Neulasta (EU-authorized) is a colorless ready-to-use solution and was provided in pre-filled syringes intended for s.c. administration in the strength of 6 mg/0.6 mL.
    Actual start date of recruitment
    05 Mar 2012
    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
    Spain: 14
    Country: Number of subjects enrolled
    Russian Federation: 138
    Country: Number of subjects enrolled
    India: 96
    Country: Number of subjects enrolled
    Malaysia: 24
    Country: Number of subjects enrolled
    United States: 23
    Country: Number of subjects enrolled
    Puerto Rico: 5
    Country: Number of subjects enrolled
    Chile: 6
    Country: Number of subjects enrolled
    Argentina: 2
    Worldwide total number of subjects
    308
    EEA total number of subjects
    14
    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)
    287
    From 65 to 84 years
    21
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 Between 05-Mar-2012 (first patient first visit) and 04-Dec-2013 (last patient last visit) patients were screened and randomized in 8 countries (Argentina, Chile, India, Malaysia, Puerto Rico, Russia, Spain, USA): 64 study sites were initiated, 53 sites screened patients and 52 sites randomized patients.

    Pre-assignment
    Screening details
    		 The study started with a 21-day screening period. During the screening period, the eligibility of the patients to participate in the study was assessed based on safety evaluations. After completion of the screening period and first dose of chemotherapy, eligible patients were randomized to either LA-EP2006 or Neulasta.

    Pre-assignment period milestones
    Number of subjects started
    		 352 [1]
    Number of subjects completed
    		 308

    Pre-assignment subject non-completion reasons
    Reason: Number of subjects
    		 Consent withdrawn by subject: 10
    Reason: Number of subjects
    		 Meet exclusion criteria: 6
    Reason: Number of subjects
    		 Not meet inclision criteria: 18
    Reason: Number of subjects
    		 No study drug available: 7
    Reason: Number of subjects
    		 Screening period expired: 2
    Reason: Number of subjects
    		 Not randomized: 1
    Notes
    [1] - The number of subjects reported to have started the pre-assignment period are not the same as the worldwide number enrolled in the trial. It is expected that these numbers will be the same.
    Justification: The number of subjects started the pre-assignment period is the number of screened subjects. The number of subjects started the enrolment period is the number of randomized subjects.
    Period 1
    Period 1 title
    Double blind (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
    Blinding implementation details
    An unblinded drug administrator (such as a study nurse) injected the entire volume of the IMP. This drug administrator did not participate in any study assessments. The unblinded drug administrator documented in the drug accountability log the type of IMP administered (LA-EP2006 or Neulasta), the batch number, and the kit number. The blinded investigator did not have access to this drug accountability log.

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 LA-EP2006
    Arm description
    		 LA-EP2006 was presented in pre-filled syringes (PFS) for s.c. administration. LA EP2006 as IMP was provided in the strength of 6 mg/0.6 mL.
    Arm type
    		 Experimental

    Investigational medicinal product name
    LA-EP2006
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    LA-EP2006 pre-filled syringes 6 mg/0.6 mL for subcutaneous (s.c.) administration.

    Arm title
    		 Neulasta®
    Arm description
    		 Neulasta® (EU-authorized) was provided in PFS for s.c. administration in the strength of 6 mg/0.6 mL. Commercially available, EU-authorized Neulasta was sourced by Sandoz GmbH and labelled, packaged, and supplied.
    Arm type
    		 Active comparator

    Investigational medicinal product name
    Neulasta®
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    Neulasta® (EU-authorized) pre-filled syringes 6 mg/0.6 mL for s.c. administration.

    Number of subjects in period 1
    		LA-EP2006 Neulasta®
    Started
    155
    153
    Completed
    133
    137
    Not completed
    22
    16
         Adverse event, serious fatal
    3
    1
         Consent withdrawn by subject
    10
    4
         Other
    7
    11
         Lost to follow-up
    2
    -

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    LA-EP2006
    Reporting group description
    		 LA-EP2006 was presented in pre-filled syringes (PFS) for s.c. administration. LA EP2006 as IMP was provided in the strength of 6 mg/0.6 mL.

    Reporting group title
    Neulasta®
    Reporting group description
    		 Neulasta® (EU-authorized) was provided in PFS for s.c. administration in the strength of 6 mg/0.6 mL. Commercially available, EU-authorized Neulasta was sourced by Sandoz GmbH and labelled, packaged, and supplied.

    Reporting group values
    		 LA-EP2006 Neulasta® Total
    Number of subjects
    		 155 153 308
    Age categorical
    Units: Subjects
        18 - 64
    		 144 143 287
        65-84
    		 11 10 21
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    		 48.8 ( 10.5 ) 49.1 ( 10.07 ) -
    Gender categorical
    Units: Subjects
        Female
    		 155 153 308
    Subject analysis sets

    Subject analysis set title
    FAS
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    All randomized patients who received at least one dose of either LA-EP2006 or Neulasta. Following the intent-to-treat principle, patients were analyzed according to the treatment they had been assigned to at randomization.

    Subject analysis sets values
    		 FAS
    Number of subjects
    308
    Age categorical
    Units: Subjects
        18 - 64
    287
        65-84
    21
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    48.9 ( 10.27 )
    Gender categorical
    Units: Subjects
        Female
    308

    End points

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    End points reporting groups
    Reporting group title
    LA-EP2006
    Reporting group description
    		 LA-EP2006 was presented in pre-filled syringes (PFS) for s.c. administration. LA EP2006 as IMP was provided in the strength of 6 mg/0.6 mL.

    Reporting group title
    Neulasta®
    Reporting group description
    		 Neulasta® (EU-authorized) was provided in PFS for s.c. administration in the strength of 6 mg/0.6 mL. Commercially available, EU-authorized Neulasta was sourced by Sandoz GmbH and labelled, packaged, and supplied.

    Subject analysis set title
    FAS
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    All randomized patients who received at least one dose of either LA-EP2006 or Neulasta. Following the intent-to-treat principle, patients were analyzed according to the treatment they had been assigned to at randomization.

    Primary: DSN (duration of severe neutropenia)

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    End point title
    		 DSN (duration of severe neutropenia)
    End point description
    Number of consecutive days from the first day when a patient’s ANC was < 0.5 × 10^9/L until the patient reached an ANC ≥ 0.5 × 10^9/L.
    End point type
    Primary
    End point timeframe
    During the Chemotherapy Cycle 1
    End point values
    		 LA-EP2006 Neulasta® FAS
    Number of subjects analysed
    151
    149
    300 [1]
    Units: Days
        arithmetic mean (standard deviation)
    1.36 ( 1.133 )
    1.19 ( 0.984 )
    1.28 ( 1.063 )
    Notes
    [1] - Number differs from subject completed number due to BDRM decision (no ANC profiles available).
    Statistical analysis title
    		 Primary Efficacy Analysis
    Comparison groups
    Neulasta® v LA-EP2006
    Number of subjects included in analysis
    300
    Analysis specification
    Pre-specified
    Analysis type
    		 equivalence
    Method
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -0.16
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.4
         upper limit
    		 0.08

    Secondary: Incidence of febrile neutropenia

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    End point title
    		 Incidence of febrile neutropenia
    End point description
    Febrile neutropenia was defined as oral temperature ≥ 38.3°C while having an ANC < 0.5 × 10^9/L
    End point type
    Secondary
    End point timeframe
    Across all chemotherapy cycles
    End point values
    		 LA-EP2006 Neulasta® FAS
    Number of subjects analysed
    155
    153
    308
    Units: Subjects
        At least one incidence
    16
    20
    36
    No statistical analyses for this end point

    Secondary: Number of patients with at least one fever episode

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    End point title
    		 Number of patients with at least one fever episode
    End point description
    Fever was defined as an oral body temperature of ≥ 38.3°C.
    End point type
    Secondary
    End point timeframe
    Across all chemotherapy cycles.
    End point values
    		 LA-EP2006 Neulasta® FAS
    Number of subjects analysed
    155
    153
    308
    Units: Subjects
        At least one fever episode
    32
    35
    67
    No statistical analyses for this end point

    Secondary: Depth of ANC (absolute neutrophil count) nadir

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    End point title
    		 Depth of ANC (absolute neutrophil count) nadir
    End point description
    The depth of ANC nadir was defined as the patient’s lowest ANC (10^9/L) in Cycle 1
    End point type
    Secondary
    End point timeframe
    Across all chemotherapy cycles.
    End point values
    		 LA-EP2006 Neulasta® FAS
    Number of subjects analysed
    155
    153
    308
    Units: Absolute Neutrophil Count
        arithmetic mean (standard deviation)
    0.49 ( 0.7205 )
    0.444 ( 0.5684 )
    0.467 ( 0.649 )
    No statistical analyses for this end point

    Secondary: Time to ANC (absolute neutrophil count) recovery

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    End point title
    		 Time to ANC (absolute neutrophil count) recovery
    End point description
    Time to ANC recovery was defined as the time in days from ANC nadir until the patient’s ANC had increased to ≥ 2 × 10^9/L after the nadir.
    End point type
    Secondary
    End point timeframe
    During Cycle 1
    End point values
    		 LA-EP2006 Neulasta® FAS
    Number of subjects analysed
    155
    153
    Units: Days
        median (full range (min-max))
    2 (0 to 4)
    2 (0 to 6)
    2 (0 to 6)
    No statistical analyses for this end point

    Secondary: Frequency of infections

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    End point title
    		 Frequency of infections
    End point description
    Infections were identified by the AE documentation page selecting all events coded with SOC “Infections and Infestations”.
    End point type
    Secondary
    End point timeframe
    Across all chemotherapy cycles
    End point values
    		 LA-EP2006 Neulasta® FAS
    Number of subjects analysed
    155
    153
    308
    Units: Subjects
        At least one infection
    26
    32
    58
    No statistical analyses for this end point

    Secondary: Mortality due to infection

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    End point title
    		 Mortality due to infection
    End point description
    Number of subjects who died due to infection
    End point type
    Secondary
    End point timeframe
    Across all chemotherapy cycles
    End point values
    		 LA-EP2006 Neulasta® FAS
    Number of subjects analysed
    155
    153
    308
    Units: Subjects
        Mortality due to infection
    0
    0
    0
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Treatment emergent adverse events
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    16.1
    Reporting groups
    Reporting group title
    Neulasta®
    Reporting group description
    		 treatment emergent adverse events in patients treated with Neulasta®

    Reporting group title
    LA-EP2006
    Reporting group description
    		 Treatment emergent adverse evente in patients treated with LA-EP2006 .

    Serious adverse events
    		 Neulasta® LA-EP2006
    Total subjects affected by serious adverse events
         subjects affected / exposed
    32 / 153 (20.92%)
    29 / 155 (18.71%)
         number of deaths (all causes)
    2
    3
         number of deaths resulting from adverse events
    0
    0
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Breast cancer
         subjects affected / exposed
    1 / 153 (0.65%)
    0 / 155 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Lung neoplasm
         subjects affected / exposed
    0 / 153 (0.00%)
    1 / 155 (0.65%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vascular disorders
    Hypotension
         subjects affected / exposed
    1 / 153 (0.65%)
    0 / 155 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Shock hemorrhagic
         subjects affected / exposed
    0 / 153 (0.00%)
    1 / 155 (0.65%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Asthenia
         subjects affected / exposed
    3 / 153 (1.96%)
    0 / 155 (0.00%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pyrexia
         subjects affected / exposed
    2 / 153 (1.31%)
    1 / 155 (0.65%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Non-cardiac chest pain
         subjects affected / exposed
    1 / 153 (0.65%)
    0 / 155 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Reproductive system and breast disorders
    Uterine hemorrhage
         subjects affected / exposed
    1 / 153 (0.65%)
    0 / 155 (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
    Pulmonary embolism
         subjects affected / exposed
    0 / 153 (0.00%)
    2 / 155 (1.29%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Dyspnea
         subjects affected / exposed
    1 / 153 (0.65%)
    0 / 155 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Organizing pneumonia
         subjects affected / exposed
    1 / 153 (0.65%)
    0 / 155 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pleural effusion
         subjects affected / exposed
    1 / 153 (0.65%)
    0 / 155 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Psychiatric disorders
    Completed suicide
         subjects affected / exposed
    1 / 153 (0.65%)
    0 / 155 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Investigations
    Neutrophil count decreased
         subjects affected / exposed
    0 / 153 (0.00%)
    1 / 155 (0.65%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Platelet count decreased
         subjects affected / exposed
    0 / 153 (0.00%)
    1 / 155 (0.65%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    White blood cell count decreased
         subjects affected / exposed
    0 / 153 (0.00%)
    1 / 155 (0.65%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac disorders
    Atrial fibrillation
         subjects affected / exposed
    1 / 153 (0.65%)
    0 / 155 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac arrest
         subjects affected / exposed
    0 / 153 (0.00%)
    1 / 155 (0.65%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Cardio-respiratory arrest
         subjects affected / exposed
    0 / 153 (0.00%)
    1 / 155 (0.65%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Pericardial hemorrhage
         subjects affected / exposed
    0 / 153 (0.00%)
    1 / 155 (0.65%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nervous system disorders
    Convulsion
         subjects affected / exposed
    0 / 153 (0.00%)
    1 / 155 (0.65%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Neuropathy peripheral
         subjects affected / exposed
    0 / 153 (0.00%)
    1 / 155 (0.65%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Dizziness
         subjects affected / exposed
    0 / 153 (0.00%)
    1 / 155 (0.65%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lethargy
         subjects affected / exposed
    0 / 153 (0.00%)
    1 / 155 (0.65%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    Febrile neutropenia
         subjects affected / exposed
    19 / 153 (12.42%)
    16 / 155 (10.32%)
         occurrences causally related to treatment / all
    0 / 21
    2 / 18
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Neutropenia
         subjects affected / exposed
    6 / 153 (3.92%)
    4 / 155 (2.58%)
         occurrences causally related to treatment / all
    0 / 7
    1 / 5
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Thrombocytopenia
         subjects affected / exposed
    1 / 153 (0.65%)
    1 / 155 (0.65%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Anemia
         subjects affected / exposed
    0 / 153 (0.00%)
    1 / 155 (0.65%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Eye disorders
    Eye irritation
         subjects affected / exposed
    1 / 153 (0.65%)
    0 / 155 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Abdominal pain
         subjects affected / exposed
    5 / 153 (3.27%)
    3 / 155 (1.94%)
         occurrences causally related to treatment / all
    0 / 6
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Diarrhoea
         subjects affected / exposed
    5 / 153 (3.27%)
    2 / 155 (1.29%)
         occurrences causally related to treatment / all
    0 / 6
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vomiting
         subjects affected / exposed
    4 / 153 (2.61%)
    2 / 155 (1.29%)
         occurrences causally related to treatment / all
    0 / 6
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Abdominal discomfort
         subjects affected / exposed
    0 / 153 (0.00%)
    1 / 155 (0.65%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Constipation
         subjects affected / exposed
    1 / 153 (0.65%)
    0 / 155 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastric ulcer hemorrhage
         subjects affected / exposed
    0 / 153 (0.00%)
    1 / 155 (0.65%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastritis
         subjects affected / exposed
    0 / 153 (0.00%)
    1 / 155 (0.65%)
         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 / 153 (0.65%)
    0 / 155 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Peptic ulcer
         subjects affected / exposed
    1 / 153 (0.65%)
    0 / 155 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Proctalgia
         subjects affected / exposed
    1 / 153 (0.65%)
    0 / 155 (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 / 153 (0.65%)
    0 / 155 (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 hemorrhage
         subjects affected / exposed
    0 / 153 (0.00%)
    1 / 155 (0.65%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatic necrosis
         subjects affected / exposed
    0 / 153 (0.00%)
    1 / 155 (0.65%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Renal and urinary disorders
    Renal failure
         subjects affected / exposed
    0 / 153 (0.00%)
    1 / 155 (0.65%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal hemorrhage
         subjects affected / exposed
    0 / 153 (0.00%)
    1 / 155 (0.65%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Musculoskeletal chest pain
         subjects affected / exposed
    2 / 153 (1.31%)
    0 / 155 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infections and infestations
    Gastroenteritis
         subjects affected / exposed
    2 / 153 (1.31%)
    0 / 155 (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 / 153 (0.65%)
    0 / 155 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Clostridium difficile infection
         subjects affected / exposed
    0 / 153 (0.00%)
    1 / 155 (0.65%)
         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 / 153 (0.65%)
    0 / 155 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Staphylococcal infection
         subjects affected / exposed
    1 / 153 (0.65%)
    0 / 155 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Neutropenic sepsis
         subjects affected / exposed
    1 / 153 (0.65%)
    0 / 155 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Upper respiratory tract infection
         subjects affected / exposed
    1 / 153 (0.65%)
    0 / 155 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Dehydration
         subjects affected / exposed
    0 / 153 (0.00%)
    2 / 155 (1.29%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Decreased appetite
         subjects affected / exposed
    0 / 153 (0.00%)
    1 / 155 (0.65%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 3%
    Non-serious adverse events
    		 Neulasta® LA-EP2006
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    146 / 153 (95.42%)
    149 / 155 (96.13%)
    Investigations
    Alanine aminotransferase increased
         subjects affected / exposed
    4 / 153 (2.61%)
    8 / 155 (5.16%)
         occurrences all number
    6
    10
    Aspartate aminotransferase increased
         subjects affected / exposed
    3 / 153 (1.96%)
    5 / 155 (3.23%)
         occurrences all number
    3
    8
    Nervous system disorders
    Headache
         subjects affected / exposed
    13 / 153 (8.50%)
    21 / 155 (13.55%)
         occurrences all number
    16
    27
    Neuropathy peripheral
         subjects affected / exposed
    7 / 153 (4.58%)
    5 / 155 (3.23%)
         occurrences all number
    15
    9
    Blood and lymphatic system disorders
    Neutropenia
         subjects affected / exposed
    60 / 153 (39.22%)
    71 / 155 (45.81%)
         occurrences all number
    91
    107
    Leukopenia
         subjects affected / exposed
    29 / 153 (18.95%)
    34 / 155 (21.94%)
         occurrences all number
    65
    68
    Anemia
         subjects affected / exposed
    17 / 153 (11.11%)
    14 / 155 (9.03%)
         occurrences all number
    24
    23
    Thrombocytopenia
         subjects affected / exposed
    10 / 153 (6.54%)
    14 / 155 (9.03%)
         occurrences all number
    13
    16
    Leukocytosis
         subjects affected / exposed
    6 / 153 (3.92%)
    7 / 155 (4.52%)
         occurrences all number
    6
    9
    Neutrophilia
         subjects affected / exposed
    5 / 153 (3.27%)
    6 / 155 (3.87%)
         occurrences all number
    5
    8
    General disorders and administration site conditions
    Asthenia
         subjects affected / exposed
    54 / 153 (35.29%)
    58 / 155 (37.42%)
         occurrences all number
    139
    160
    Pyrexia
         subjects affected / exposed
    21 / 153 (13.73%)
    22 / 155 (14.19%)
         occurrences all number
    28
    28
    Fatigue
         subjects affected / exposed
    21 / 153 (13.73%)
    19 / 155 (12.26%)
         occurrences all number
    31
    22
    Pain
         subjects affected / exposed
    12 / 153 (7.84%)
    12 / 155 (7.74%)
         occurrences all number
    22
    19
    Edema peripheral
         subjects affected / exposed
    3 / 153 (1.96%)
    6 / 155 (3.87%)
         occurrences all number
    3
    7
    Gastrointestinal disorders
    Nausea
         subjects affected / exposed
    57 / 153 (37.25%)
    73 / 155 (47.10%)
         occurrences all number
    129
    151
    Vomiting
         subjects affected / exposed
    39 / 153 (25.49%)
    44 / 155 (28.39%)
         occurrences all number
    67
    65
    Diarrhoea
         subjects affected / exposed
    36 / 153 (23.53%)
    32 / 155 (20.65%)
         occurrences all number
    56
    46
    Abdominal pain
         subjects affected / exposed
    11 / 153 (7.19%)
    15 / 155 (9.68%)
         occurrences all number
    14
    19
    Stomatitis
         subjects affected / exposed
    14 / 153 (9.15%)
    12 / 155 (7.74%)
         occurrences all number
    23
    21
    Constipation
         subjects affected / exposed
    8 / 153 (5.23%)
    6 / 155 (3.87%)
         occurrences all number
    9
    6
    Abdominal pain upper
         subjects affected / exposed
    5 / 153 (3.27%)
    8 / 155 (5.16%)
         occurrences all number
    6
    9
    Dyspepsia
         subjects affected / exposed
    6 / 153 (3.92%)
    5 / 155 (3.23%)
         occurrences all number
    8
    5
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    8 / 153 (5.23%)
    12 / 155 (7.74%)
         occurrences all number
    9
    15
    Dyspnoea
         subjects affected / exposed
    3 / 153 (1.96%)
    6 / 155 (3.87%)
         occurrences all number
    3
    8
    Skin and subcutaneous tissue disorders
    Alopecia
         subjects affected / exposed
    66 / 153 (43.14%)
    77 / 155 (49.68%)
         occurrences all number
    69
    91
    Musculoskeletal and connective tissue disorders
    Bone pain
         subjects affected / exposed
    17 / 153 (11.11%)
    10 / 155 (6.45%)
         occurrences all number
    26
    10
    Myalgia
         subjects affected / exposed
    16 / 153 (10.46%)
    11 / 155 (7.10%)
         occurrences all number
    19
    15
    Pain in extremity
         subjects affected / exposed
    7 / 153 (4.58%)
    12 / 155 (7.74%)
         occurrences all number
    20
    40
    Arthralgia
         subjects affected / exposed
    6 / 153 (3.92%)
    10 / 155 (6.45%)
         occurrences all number
    8
    18
    Back pain
         subjects affected / exposed
    5 / 153 (3.27%)
    8 / 155 (5.16%)
         occurrences all number
    5
    9
    Metabolism and nutrition disorders
    Decreased appetite
         subjects affected / exposed
    13 / 153 (8.50%)
    9 / 155 (5.81%)
         occurrences all number
    14
    10

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    10 May 2012
    Amendment 1 introduced the following changes: • Extension of the total study duration for the individual patient from 20 to 22 weeks. • Implementation of re-screening • Corrections/implementations in the visit schedule • Changes to the wording of inclusion criterion 11 and exclusion criteria 4 and 12 • Implementation of 2D-Echocardiography (2D-Echo) and MUGA • Revisions to the assessments by visit • Clarification of protocol specific SAE requirements • Administrative corrections/corrections of typing errors • In the ECG/PK sub-study (Appendix 1 to the study protocol): • Implementation of weighing the syringes

    Interruptions (globally)
    Were there any global interruptions to the trial? No

    Limitations and caveats
    Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.
    None reported
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    The status and protocol content of GB trials is no longer updated since 1 January 2021. For the UK, as of 31 January 2021, EU Law applies only to the territory of Northern Ireland (NI) to the extent foreseen in the Protocol on Ireland/NI. Legal notice
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