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    Clinical Trial Results:
    A PHASE III, RANDOMIZED, ACTIVE CONTROLLED, ASSESSOR-BLINDED STUDY OF SAFETY AND EFFICACY OF PEGYLATED APO-FILGRASTIM VERSUS US AND EU LICENSED NEULASTA® IN SUBJECTS WITH STAGE IIA, IIB OR IIIA BREAST CANCER RECEIVING TAC ANTICANCER CHEMOTHERAPY IN ADJUVANT SETTING

    Summary
    EudraCT number
    		 2011-002678-21
    Trial protocol
    		 HU   CZ   BG   GR   SK  
    Global end of trial date
    30 May 2014

    Results information
    Results version number
    		 v1(current)
    This version publication date
    28 Nov 2018
    First version publication date
    28 Nov 2018
    Other versions

    Trial information

    		 Close Top of page
    Trial identification
    Sponsor protocol code
    APO-Peg-03
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 -
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Apotex Inc.
    Sponsor organisation address
    150 Signet Drive, Toronto, Canada, M9L 1T9
    Public contact
    Preclinical and Clinical Programs, Apotex Inc., +1 416-749-9300,
    Scientific contact
    Preclinical and Clinical Programs, Apotex Inc., +1 416-749-9300,
    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
    30 May 2014
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    22 Jul 2013
    Global end of trial reached?
    Yes
    Global end of trial date
    30 May 2014
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The primary objective of this study was to demonstrate an equivalent efficacy of Pegylated Apo-Filgrastim (APO-Peg) as compared to US-licensed and EU-approved Neulasta® products (referred to as Neulasta US and Neulasta EU) in subjects suffering from early breast cancer and receiving TAC (docetaxel, doxorubicin, cyclophosphamide) anticancer chemotherapy in adjuvant setting.
    Protection of trial subjects
    This study was conducted in accordance with the current ICH/EMA/FDA/BGTD guidance documents, Good Clinical Practice (GCP) as established by the International Conference on Harmonization (ICH) ICH E6 GCP, the EU Clinical Trials Directive 2001/20/EC, US 21 Code of Federal Regulations dealing with clinical studies, as well as applicable federal, state and/or local laws and regulations in the country where the clinical study was conducted, clinical study contractual obligations and the principles enunciated in the World Medical Association Declaration of Helsinki. When signing the protocol, the investigator agreed to adhere to the instructions and procedures described in it and thereby to adhere to the principles of ICH GCP. Additionally, the investigator ensured that all persons assisting in this trial were adequately qualified and well informed about the protocol, the study treatments, and their trial-related duties and functions.
    Background therapy
    		 All eligible subjects received up to 6 cycles of TAC chemotherapy (docetaxel 75 mg/m2, doxorubicin 50 mg/m2, cyclophosphamide 500 mg/m2). Cycles of chemotherapy were administered every 3 weeks; the first day of each cycle was the Day 22 of the previous cycle. Premedication with dexamethasone 6 doses of 8 mg by mouth, twice daily) was initiated before administration of each chemotherapy cycle to prevent docetaxel-related hypersensitivity and fluid retention. Ondansetron premedication was given to prevent chemotherapy related nausea and vomiting. It could be given either orally or intravenously.
    Evidence for comparator
    		 In consideration of the global development of APO-Peg as a proposed biosimilar to Neulasta, EU-approved Neulasta and US-licensed Neulasta were selected as active reference products in this study to establish clinical biosimilarity of APO-Peg to Neulasta, thereby providing a scientific bridge for the APO-Peg and Neulasta US and Neulasta EU, which are the licensed reference products in the US and EU regions, respectively. Thus, the aim of this Phase III, randomized, active controlled, assessor-blinded safety and efficacy study was to confirm the absence of any clinically meaningful differences in efficacy and safety between APO-Peg and Neulasta US and Neulasta EU.
    Actual start date of recruitment
    28 Mar 2012
    Long term follow-up planned
    Yes
    Long term follow-up rationale
    		 Safety
    Long term follow-up duration
    		 7 Months
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Poland: 7
    Country: Number of subjects enrolled
    Slovakia: 1
    Country: Number of subjects enrolled
    Bulgaria: 66
    Country: Number of subjects enrolled
    Czech Republic: 3
    Country: Number of subjects enrolled
    Hungary: 85
    Country: Number of subjects enrolled
    Bosnia and Herzegovina: 23
    Country: Number of subjects enrolled
    Georgia: 228
    Country: Number of subjects enrolled
    Romania: 52
    Country: Number of subjects enrolled
    Russian Federation: 46
    Country: Number of subjects enrolled
    Serbia: 35
    Country: Number of subjects enrolled
    Ukraine: 43
    Worldwide total number of subjects
    589
    EEA total number of subjects
    214
    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)
    531
    From 65 to 84 years
    58
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 In this study, 58 centers from 12 countries contributed to screening but only 56 centers from 11 countries randomized and dosed subjects. Subjects were randomized (2:1:1) to either APO-Peg, Neulasta US or Neulasta EU. The first subject first visit occurred on March 29, 2012 and the last subject last visit occurred on May 30, 2014.

    Pre-assignment
    Screening details
    		 Screening period lasted up to 3 weeks prior to TAC administration (on Day 1) to collect clinical data and to perform all investigations required to establish a subject’s eligibility for the study. In total, 668 patients were screened, 595 patients were randomized of which 589 patients were dosed as 6 patients withdrew consent prior to dosing.

    Period 1
    Period 1 title
    Treatment
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Subject, Investigator, Monitor, Assessor
    Blinding implementation details
    The investigator performing the assessments (the assessor), the study subjects as well as all other sponsor/clinical research organization (CRO) personnel monitoring and analyzing the study had to remain blinded. Envelopes were provided to the centers in case emergency unblinding was needed.

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 APO-Peg
    Arm description
    		 APO-Peg was administered subcutaneously using prefilled syringes at a dose of 6 mg/0.6 mL once per chemotherapy cycle for 6 cycles. In total, 294 subjects from the FAS-As Randomized population were in the Apo-Peg arm. Out of the 294 subjects, 268 completed the treatment period and 246 subjects completed the safety follow-up period.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Pegylated Apo-Filgrastim
    Investigational medicinal product code
    Other name
    APO-Peg
    Pharmaceutical forms
    Injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    Sterile solution for injection was administered using a prefilled syringe containing a dose of 6 mg/0.6 mL once per chemotherapy cycle for 6 cycles.

    Arm title
    		 Neulasta US
    Arm description
    		 Neulasta US was administered subcutaneously using prefilled syringes at a dose of 6 mg/0.6 mL once per chemotherapy cycle for 6 cycles. In total, 148 subjects from the FAS-As Randomized population were in the Neulasta US arm. Out of the 148 subjects, 142 completed the treatment period and 131 subjects completed the safety follow-up period.
    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
    Sterile solution for injection was administered using a prefilled syringe containing a dose of 6 mg/0.6 mL once per chemotherapy cycle for 6 cycles.

    Arm title
    		 Neulasta EU
    Arm description
    		 Neulasta EU was administered subcutaneously using prefilled syringes at a dose of 6 mg/0.6 mL once per chemotherapy cycle for 6 cycles. In total, 147 subjects from the FAS-As Randomized population were in the Neulasta EU arm. Out of the 147 subjects, 137 completed the treatment period and 131 subjects completed the safety follow-up period.
    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
    Sterile solution for injection was administered using a prefilled syringe containing a dose of 6 mg/0.6 mL once per chemotherapy cycle for 6 cycles.

    Number of subjects in period 1
    		APO-Peg Neulasta US Neulasta EU
    Started
    294
    148
    147
    Completed
    268
    142
    137
    Not completed
    26
    6
    10
         Adverse event, not serious
    1
    -
    -
         Adverse event, serious fatal
    -
    1
    -
         Consent withdrawn by subject
    13
    1
    4
         Switched to safety follow-up
    6
    3
    5
         Non-compliance with study drug
    1
    -
    -
         Adverse event, serious non-fatal
    4
    -
    -
         Protocol deviation
    1
    1
    1
    Period 2
    Period 2 title
    Safety Follow-Up
    Is this the baseline period?
    		 No
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Subject, Investigator, Monitor, Assessor
    Blinding implementation details
    The investigator performing the assessments (the assessor), the study subjects as well as all other sponsor/clinical research organization (CRO) personnel monitoring and analyzing the study had to remain blinded. Envelopes were provided to the centers in case emergency unblinding was needed.

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 APO-Peg
    Arm description
    		 APO-Peg was administered subcutaneously using prefilled syringes at a dose of 6 mg/0.6 mL once per chemotherapy cycle for 6 cycles. In total, 294 subjects from the FAS-As Randomized population were in the Apo-Peg arm. Out of the 294 subjects, 268 completed the treatment period and 246 subjects completed the safety follow-up period.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Pegylated Apo-Filgrastim
    Investigational medicinal product code
    Other name
    APO-Peg
    Pharmaceutical forms
    Injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    Sterile solution for injection was administered using a prefilled syringe containing a dose of 6 mg/0.6 mL once per chemotherapy cycle for 6 cycles.

    Arm title
    		 Neulasta US
    Arm description
    		 Neulasta US was administered subcutaneously using prefilled syringes at a dose of 6 mg/0.6 mL once per chemotherapy cycle for 6 cycles. In total, 148 subjects from the FAS-As Randomized population were in the Neulasta US arm. Out of the 148 subjects, 142 completed the treatment period and 131 subjects completed the safety follow-up period.
    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
    Sterile solution for injection was administered using a prefilled syringe containing a dose of 6 mg/0.6 mL once per chemotherapy cycle for 6 cycles.

    Arm title
    		 Neulasta EU
    Arm description
    		 Neulasta EU was administered subcutaneously using prefilled syringes at a dose of 6 mg/0.6 mL once per chemotherapy cycle for 6 cycles. In total, 147 subjects from the FAS-As Randomized population were in the Neulasta EU arm. Out of the 147 subjects, 137 completed the treatment period and 131 subjects completed the safety follow-up period.
    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
    Sterile solution for injection was administered using a prefilled syringe containing a dose of 6 mg/0.6 mL once per chemotherapy cycle for 6 cycles.

    Number of subjects in period 2
    		APO-Peg Neulasta US Neulasta EU
    Started
    268
    142
    137
    Completed
    246
    131
    131
    Not completed
    28
    14
    11
         Adverse event, not serious
    2
    -
    2
         Adverse event, serious fatal
    1
    1
    -
         Consent withdrawn by subject
    18
    8
    4
         Physician decision
    -
    -
    1
         Adverse event, serious non-fatal
    1
    2
    -
         Lost to follow-up
    6
    3
    4
    Joined
    6
    3
    5
         Subjects not completing P1 and switching to P2
    6
    3
    5

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    APO-Peg
    Reporting group description
    		 APO-Peg was administered subcutaneously using prefilled syringes at a dose of 6 mg/0.6 mL once per chemotherapy cycle for 6 cycles. In total, 294 subjects from the FAS-As Randomized population were in the Apo-Peg arm. Out of the 294 subjects, 268 completed the treatment period and 246 subjects completed the safety follow-up period.

    Reporting group title
    Neulasta US
    Reporting group description
    		 Neulasta US was administered subcutaneously using prefilled syringes at a dose of 6 mg/0.6 mL once per chemotherapy cycle for 6 cycles. In total, 148 subjects from the FAS-As Randomized population were in the Neulasta US arm. Out of the 148 subjects, 142 completed the treatment period and 131 subjects completed the safety follow-up period.

    Reporting group title
    Neulasta EU
    Reporting group description
    		 Neulasta EU was administered subcutaneously using prefilled syringes at a dose of 6 mg/0.6 mL once per chemotherapy cycle for 6 cycles. In total, 147 subjects from the FAS-As Randomized population were in the Neulasta EU arm. Out of the 147 subjects, 137 completed the treatment period and 131 subjects completed the safety follow-up period.

    Reporting group values
    		 APO-Peg Neulasta US Neulasta EU Total
    Number of subjects
    		 294 148 147 589
    Age categorical
    Units: Subjects
        In utero
    		 0 0 0 0
        Preterm newborn infants (gestational age < 37 wks)
    		 0 0 0 0
        Newborns (0-27 days)
    		 0 0 0 0
        Infants and toddlers (28 days-23 months)
    		 0 0 0 0
        Children (2-11 years)
    		 0 0 0 0
        Adolescents (12-17 years)
    		 0 0 0 0
        Adults (18-64 years)
    		 262 133 136 531
        From 65-84 years
    		 32 15 11 58
        85 years and over
    		 0 0 0 0
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    		 51.9 ± 10.00 51.4 ± 10.37 51.5 ± 10.22 -
    Gender categorical
    Units: Subjects
        Female
    		 294 148 147 589
        Male
    		 0 0 0 0

    End points

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    End points reporting groups
    Reporting group title
    APO-Peg
    Reporting group description
    		 APO-Peg was administered subcutaneously using prefilled syringes at a dose of 6 mg/0.6 mL once per chemotherapy cycle for 6 cycles. In total, 294 subjects from the FAS-As Randomized population were in the Apo-Peg arm. Out of the 294 subjects, 268 completed the treatment period and 246 subjects completed the safety follow-up period.

    Reporting group title
    Neulasta US
    Reporting group description
    		 Neulasta US was administered subcutaneously using prefilled syringes at a dose of 6 mg/0.6 mL once per chemotherapy cycle for 6 cycles. In total, 148 subjects from the FAS-As Randomized population were in the Neulasta US arm. Out of the 148 subjects, 142 completed the treatment period and 131 subjects completed the safety follow-up period.

    Reporting group title
    Neulasta EU
    Reporting group description
    		 Neulasta EU was administered subcutaneously using prefilled syringes at a dose of 6 mg/0.6 mL once per chemotherapy cycle for 6 cycles. In total, 147 subjects from the FAS-As Randomized population were in the Neulasta EU arm. Out of the 147 subjects, 137 completed the treatment period and 131 subjects completed the safety follow-up period.
    Reporting group title
    APO-Peg
    Reporting group description
    		 APO-Peg was administered subcutaneously using prefilled syringes at a dose of 6 mg/0.6 mL once per chemotherapy cycle for 6 cycles. In total, 294 subjects from the FAS-As Randomized population were in the Apo-Peg arm. Out of the 294 subjects, 268 completed the treatment period and 246 subjects completed the safety follow-up period.

    Reporting group title
    Neulasta US
    Reporting group description
    		 Neulasta US was administered subcutaneously using prefilled syringes at a dose of 6 mg/0.6 mL once per chemotherapy cycle for 6 cycles. In total, 148 subjects from the FAS-As Randomized population were in the Neulasta US arm. Out of the 148 subjects, 142 completed the treatment period and 131 subjects completed the safety follow-up period.

    Reporting group title
    Neulasta EU
    Reporting group description
    		 Neulasta EU was administered subcutaneously using prefilled syringes at a dose of 6 mg/0.6 mL once per chemotherapy cycle for 6 cycles. In total, 147 subjects from the FAS-As Randomized population were in the Neulasta EU arm. Out of the 147 subjects, 137 completed the treatment period and 131 subjects completed the safety follow-up period.

    Primary: Duration of Severe Neutropenia (DSN) in Cycle 1

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    End point title
    		 Duration of Severe Neutropenia (DSN) in Cycle 1
    End point description
    Severe neutropenia was defined as ANC below 0.5 x 10^9/L.
    End point type
    Primary
    End point timeframe
    End of Cycle 1
    End point values
    		 APO-Peg Neulasta US Neulasta EU
    Number of subjects analysed
    294
    148
    147
    Units: Days
        arithmetic mean (standard deviation)
    1.6 ± 1.48
    1.4 ± 1.17
    1.6 ± 1.34
    Statistical analysis title
    		 Analysis of Efficacy
    Statistical analysis description
    The DSN in Cycle 1 was the primary efficacy endpoint in this study. For the assessment and the demonstration of similar efficacy of APO-Peg as compared to commercially available Neulasta US and Neulasta EU, the 95% Confidence Interval (CI) of the difference (APO-Peg minus Neulasta US or EU) in mean DSN in Cycle 1 was calculated. For declaring equivalence, the 95% CI should lie within the range of -0.5 to +0.5 day.
    Comparison groups
    APO-Peg v Neulasta US
    Number of subjects included in analysis
    442
    Analysis specification
    Pre-specified
    Analysis type
    		 equivalence
    Method
    Parameter type
    		 LS Mean Difference
    Point estimate
    0.24
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.03
         upper limit
    		 0.51
    Statistical analysis title
    		 Analysis of Efficacy
    Statistical analysis description
    The DSN in Cycle 1 was the primary efficacy endpoint in this study. For the assessment and the demonstration of similar efficacy of APO-Peg as compared to commercially available Neulasta US and Neulasta EU, the 95% Confidence Interval (CI) of the difference (APO-Peg minus Neulasta US or EU) in mean DSN in Cycle 1 was calculated. For declaring equivalence, the 95% CI should lie within the range of -0.5 to +0.5 day.
    Comparison groups
    APO-Peg v Neulasta EU
    Number of subjects included in analysis
    441
    Analysis specification
    Pre-specified
    Analysis type
    		 equivalence
    Method
    Parameter type
    		 LS Mean Difference
    Point estimate
    0.02
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.25
         upper limit
    		 0.3
    Statistical analysis title
    		 Analysis of Efficacy
    Statistical analysis description
    The DSN in Cycle 1 was the primary efficacy endpoint in this study. For the assessment and the demonstration of similar efficacy of APO-Peg as compared to commercially available Neulasta US and Neulasta EU, the 95% Confidence Interval (CI) of the difference (APO-Peg minus Neulasta US or EU) in mean DSN in Cycle 1 was calculated. For declaring equivalence, the 95% CI should lie within the range of -0.5 to +0.5 day.
    Comparison groups
    Neulasta EU v Neulasta US
    Number of subjects included in analysis
    295
    Analysis specification
    Pre-specified
    Analysis type
    		 equivalence
    Method
    Parameter type
    		 LS Mean Difference
    Point estimate
    0.21
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.1
         upper limit
    		 0.53

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    All adverse events were reported during the Treatment Phase (18 weeks). Only suspected adverse reactions and serious adverse events were reported during the Safety Follow-Up Phase (up to 30 weeks following the completion of TAC regimen)
    Adverse event reporting additional description
    Adverse event reporting was summarized using the Safety Analysis Set (SAS) which included all subjects who received at least one dose of active treatment. Treatment assignment for subjects in the SAS was based on their randomized treatment. The FAS-As Randomized and the SAS are identical in this study.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    14.1
    Reporting groups
    Reporting group title
    APO-Peg
    Reporting group description
    		 APO-Peg was administered subcutaneously using prefilled syringes at a dose of 6 mg/0.6 mL once per chemotherapy cycle for 6 cycles. In total, 294 subjects from the FAS-As Randomized population were in the Apo-Peg arm. Out of the 294 subjects, 268 completed the treatment period and 246 subjects completed the safety follow-up period.

    Reporting group title
    Neulasta US
    Reporting group description
    		 Neulasta US was administered subcutaneously using prefilled syringes at a dose of 6 mg/0.6 mL once per chemotherapy cycle for 6 cycles. In total, 148 subjects from the FAS-As Randomized population were in the Neulasta US arm. Out of the 148 subjects, 142 completed the treatment period and 131 subjects completed the safety follow-up period.

    Reporting group title
    Neulasta EU
    Reporting group description
    		 Neulasta EU was administered subcutaneously using prefilled syringes at a dose of 6 mg/0.6 mL once per chemotherapy cycle for 6 cycles. In total, 147 subjects from the FAS-As Randomized population were in the Neulasta EU arm. Out of the 147 subjects, 137 completed the treatment period and 131 subjects completed the safety follow-up period.

    Serious adverse events
    		 APO-Peg Neulasta US Neulasta EU
    Total subjects affected by serious adverse events
         subjects affected / exposed
    16 / 294 (5.44%)
    9 / 148 (6.08%)
    6 / 147 (4.08%)
         number of deaths (all causes)
    1
    2
    0
         number of deaths resulting from adverse events
    1
    2
    0
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Metastases to bone
         subjects affected / exposed
    0 / 294 (0.00%)
    1 / 148 (0.68%)
    0 / 147 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Metastases to CNS
         subjects affected / exposed
    0 / 294 (0.00%)
    1 / 148 (0.68%)
    0 / 147 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Metastatic breast cancer
         subjects affected / exposed
    0 / 294 (0.00%)
    1 / 148 (0.68%)
    0 / 147 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    Injury, poisoning and procedural complications
    Spinal fracture
         subjects affected / exposed
    1 / 294 (0.34%)
    0 / 148 (0.00%)
    0 / 147 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    Febrile neutropenia
         subjects affected / exposed
    9 / 294 (3.06%)
    3 / 148 (2.03%)
    2 / 147 (1.36%)
         occurrences causally related to treatment / all
    0 / 9
    0 / 3
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Neutropenia
         subjects affected / exposed
    1 / 294 (0.34%)
    0 / 148 (0.00%)
    2 / 147 (1.36%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Anaemia
         subjects affected / exposed
    1 / 294 (0.34%)
    0 / 148 (0.00%)
    0 / 147 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pancytopenia
         subjects affected / exposed
    1 / 294 (0.34%)
    0 / 148 (0.00%)
    0 / 147 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Thrombocytopenia
         subjects affected / exposed
    1 / 294 (0.34%)
    0 / 148 (0.00%)
    0 / 147 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Disease progression
         subjects affected / exposed
    0 / 294 (0.00%)
    1 / 148 (0.68%)
    0 / 147 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    Effusion
         subjects affected / exposed
    0 / 294 (0.00%)
    1 / 148 (0.68%)
    0 / 147 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Death
         subjects affected / exposed
    1 / 294 (0.34%)
    0 / 148 (0.00%)
    0 / 147 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Duodenal ulcer
         subjects affected / exposed
    1 / 294 (0.34%)
    0 / 148 (0.00%)
    0 / 147 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pancreatitis acute
         subjects affected / exposed
    0 / 294 (0.00%)
    0 / 148 (0.00%)
    1 / 147 (0.68%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Large intestine perforation
         subjects affected / exposed
    1 / 294 (0.34%)
    0 / 148 (0.00%)
    0 / 147 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Reproductive system and breast disorders
    Ovarian cyst
         subjects affected / exposed
    1 / 294 (0.34%)
    0 / 148 (0.00%)
    0 / 147 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hepatobiliary disorders
    Cholecystitis
         subjects affected / exposed
    0 / 294 (0.00%)
    0 / 148 (0.00%)
    1 / 147 (0.68%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Pulmonary embolism
         subjects affected / exposed
    1 / 294 (0.34%)
    0 / 148 (0.00%)
    0 / 147 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Skin and subcutaneous tissue disorders
    Toxic skin eruption
         subjects affected / exposed
    0 / 294 (0.00%)
    1 / 148 (0.68%)
    0 / 147 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Infections and infestations
    Pneumonia
         subjects affected / exposed
    0 / 294 (0.00%)
    1 / 148 (0.68%)
    1 / 147 (0.68%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Acute sinusitis
         subjects affected / exposed
    1 / 294 (0.34%)
    0 / 148 (0.00%)
    0 / 147 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 APO-Peg Neulasta US Neulasta EU
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    263 / 294 (89.46%)
    138 / 148 (93.24%)
    136 / 147 (92.52%)
    Nervous system disorders
    Dizziness
         subjects affected / exposed
    58 / 294 (19.73%)
    27 / 148 (18.24%)
    28 / 147 (19.05%)
         occurrences all number
    121
    71
    71
    Headache
         subjects affected / exposed
    66 / 294 (22.45%)
    38 / 148 (25.68%)
    32 / 147 (21.77%)
         occurrences all number
    163
    110
    92
    Hypoaesthesia
         subjects affected / exposed
    9 / 294 (3.06%)
    9 / 148 (6.08%)
    6 / 147 (4.08%)
         occurrences all number
    15
    15
    8
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    14 / 294 (4.76%)
    8 / 148 (5.41%)
    8 / 147 (5.44%)
         occurrences all number
    27
    11
    10
    Febrile neutropenia
         subjects affected / exposed
    6 / 294 (2.04%)
    4 / 148 (2.70%)
    2 / 147 (1.36%)
         occurrences all number
    6
    4
    3
    Leukocytosis
         subjects affected / exposed
    20 / 294 (6.80%)
    18 / 148 (12.16%)
    14 / 147 (9.52%)
         occurrences all number
    50
    34
    34
    Leukopenia
         subjects affected / exposed
    62 / 294 (21.09%)
    41 / 148 (27.70%)
    41 / 147 (27.89%)
         occurrences all number
    98
    67
    71
    Neutropenia
         subjects affected / exposed
    148 / 294 (50.34%)
    85 / 148 (57.43%)
    75 / 147 (51.02%)
         occurrences all number
    291
    177
    182
    Neutrophilia
         subjects affected / exposed
    13 / 294 (4.42%)
    14 / 148 (9.46%)
    11 / 147 (7.48%)
         occurrences all number
    18
    15
    19
    Thrombocytopenia
         subjects affected / exposed
    11 / 294 (3.74%)
    5 / 148 (3.38%)
    16 / 147 (10.88%)
         occurrences all number
    25
    17
    23
    General disorders and administration site conditions
    Asthenia
         subjects affected / exposed
    72 / 294 (24.49%)
    44 / 148 (29.73%)
    37 / 147 (25.17%)
         occurrences all number
    194
    116
    102
    Fatigue
         subjects affected / exposed
    43 / 294 (14.63%)
    18 / 148 (12.16%)
    32 / 147 (21.77%)
         occurrences all number
    80
    44
    68
    Malaise
         subjects affected / exposed
    9 / 294 (3.06%)
    8 / 148 (5.41%)
    5 / 147 (3.40%)
         occurrences all number
    14
    20
    8
    Oedema peripheral
         subjects affected / exposed
    15 / 294 (5.10%)
    10 / 148 (6.76%)
    9 / 147 (6.12%)
         occurrences all number
    24
    21
    14
    Pyrexia
         subjects affected / exposed
    21 / 294 (7.14%)
    10 / 148 (6.76%)
    21 / 147 (14.29%)
         occurrences all number
    55
    15
    41
    Ear and labyrinth disorders
    Vertigo
         subjects affected / exposed
    17 / 294 (5.78%)
    9 / 148 (6.08%)
    14 / 147 (9.52%)
         occurrences all number
    38
    19
    40
    Gastrointestinal disorders
    Abdominal pain
         subjects affected / exposed
    19 / 294 (6.46%)
    9 / 148 (6.08%)
    10 / 147 (6.80%)
         occurrences all number
    26
    16
    18
    Abdominal pain upper
         subjects affected / exposed
    18 / 294 (6.12%)
    13 / 148 (8.78%)
    18 / 147 (12.24%)
         occurrences all number
    27
    60
    40
    Diarrhoea
         subjects affected / exposed
    51 / 294 (17.35%)
    32 / 148 (21.62%)
    37 / 147 (25.17%)
         occurrences all number
    84
    77
    93
    Dyspepsia
         subjects affected / exposed
    10 / 294 (3.40%)
    7 / 148 (4.73%)
    11 / 147 (7.48%)
         occurrences all number
    11
    13
    22
    Nausea
         subjects affected / exposed
    138 / 294 (46.94%)
    67 / 148 (45.27%)
    72 / 147 (48.98%)
         occurrences all number
    479
    293
    265
    Stomatitis
         subjects affected / exposed
    20 / 294 (6.80%)
    10 / 148 (6.76%)
    5 / 147 (3.40%)
         occurrences all number
    38
    22
    14
    Vomiting
         subjects affected / exposed
    43 / 294 (14.63%)
    18 / 148 (12.16%)
    28 / 147 (19.05%)
         occurrences all number
    69
    32
    49
    Respiratory, thoracic and mediastinal disorders
    Oropharyngeal pain
         subjects affected / exposed
    14 / 294 (4.76%)
    8 / 148 (5.41%)
    6 / 147 (4.08%)
         occurrences all number
    17
    11
    9
    Skin and subcutaneous tissue disorders
    Alopecia
         subjects affected / exposed
    75 / 294 (25.51%)
    37 / 148 (25.00%)
    39 / 147 (26.53%)
         occurrences all number
    83
    39
    43
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    13 / 294 (4.42%)
    8 / 148 (5.41%)
    10 / 147 (6.80%)
         occurrences all number
    34
    23
    27
    Bone pain
         subjects affected / exposed
    139 / 294 (47.28%)
    73 / 148 (49.32%)
    78 / 147 (53.06%)
         occurrences all number
    1095
    534
    545
    Myalgia
         subjects affected / exposed
    28 / 294 (9.52%)
    19 / 148 (12.84%)
    15 / 147 (10.20%)
         occurrences all number
    47
    39
    36
    Metabolism and nutrition disorders
    Decreased appetite
         subjects affected / exposed
    12 / 294 (4.08%)
    9 / 148 (6.08%)
    17 / 147 (11.56%)
         occurrences all number
    29
    25
    36

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    07 Oct 2011
    APO-Peg-03 Protocol Final Version 1.1
    13 Jan 2012
    APO-Peg-03 Protocol Amendment 1 Final Version 2.0
    25 Jun 2012
    APO-Peg-03 Protocol Amendment 2 Final Version 3.0
    21 Nov 2012
    APO-Peg-03 Protocol Amendment 3 Final Version 4.0

    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
    As of 31 January 2023, all EU/EEA initial clinical trial applications must be submitted through CTIS . Updated EudraCT trials information and information on PIP/Art 46 trials conducted exclusively in third countries continues to be submitted through EudraCT and published on this website.

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