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    Clinical Trial Results:
    An Open Label, Randomized, Active Controlled, Multicenter Study to Evaluate the Efficacy, Pharmacokinetics, Pharmacodynamics, Safety, Tolerability, and Immunogenicity of Lipegfilgrastim 100 mcg/kg Body Weight in Comparison to Filgrastim 5 mcg/kg Body Weight in Pediatric Patients Diagnosed With Ewing Family of Tumors or Rhabdomyosarcoma Receiving Chemotherapy

    Summary
    EudraCT number
    		 2015-000087-34
    Trial protocol
    		 HU   LT   SK   CZ   BG   DE   ES   RO   PL   BE   HR  
    Global end of trial date
    08 Jan 2019

    Results information
    Results version number
    		 v1(current)
    This version publication date
    19 Jul 2019
    First version publication date
    19 Jul 2019
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    XM22-08
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 -
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Merckle GmbH, Teva Pharmaceutical Industries
    Sponsor organisation address
    Ludwig-Merckle-Strasse 3, Blaubeuren, Germany, D-89143
    Public contact
    Director, Clinical Research, Teva Branded Pharmaceutical Products, R&D Inc, 001 2155913000, info.eraclinical@teva.de
    Scientific contact
    Director, Clinical Research, Teva Branded Pharmaceutical Products, R&D Inc, 001 2155913000, info.eraclinical@teva.de
    Paediatric regulatory details
    Is trial part of an agreed paediatric investigation plan (PIP)
    Yes
    EMA paediatric investigation plan number(s)
    		 EMEA-001019-PIP01-10
    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?
    Yes
    Results analysis stage
    Analysis stage
    Final
    Date of interim/final analysis
    08 Jan 2019
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    08 Jan 2019
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To assess the efficacy of a single subcutaneous (SC) dose of 100 micrograms per kilogram (mcg/kg) body weight (BW) of lipegfilgrastim per cycle compared to daily SC doses of 5 mcg/kg BW of filgrastim in children receiving cytotoxic chemotherapy (CTX).
    Protection of trial subjects
    This study was conducted in full accordance with the International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use (ICH) Good Clinical Practice (GCP) Consolidated Guideline (E6), and any applicable national and local laws and regulations (for example, Code of Federal Regulations Title 21, Parts 11, 50, 54, 56, 312, and 314; European Union Directive 2001/20/EC on the approximation of the laws, regulations and administrative provisions of the Member States relating to the implementation of GCP in the conduct of clinical trials on medicinal products for human use).
    Background therapy
    		 CTX regimens were administered intravenously (IV) every 3 weeks for 4 cycles. It comprised: • IVA (Used in Rhabdomyosarcoma): ifosfamide 3 grams per square meter (g/m^2) on Day 1,2 of each cycle + vincristine 1.5 mg/m^2 on Day 1,8,15 of each cycle + actinomycin D 1.5 mg/m^2 on Day 1 of each cycle; • VAC (Used in Ewing family of tumors rhabdomyosarcoma): vincristine 1.5 mg/m^2 on Day 1,8,15 of each cycle + actinomycin D 0.015 milligrams per kilogram per day (mg/kg/day) for 5 days or 1.5 mg/m^2 every 3 weeks + cyclophosphamide 1.2-2.2 g/m^2/day for 1 to 3 days starting on Day 1 of each cycle; • IVADo (Used in Rhabdomyosarcoma): ifosfamide 3.0 g/m^2 on Day 1,2 of each cycle + vincristine 1.5 mg/m^2 on Day 1, and weekly, for a total of 7 consecutive doses until Week 7, + actinomycin D 1.5 mg/ m^2 on Day 1 of each cycle + doxorubicin 30.0 mg/m^2 on Day 1,2 of each cycle; • VDC/IE (Used in Ewing family of tumors rhabdomyosarcoma): vincristine 2 mg/m^2 on Day 1,8,15 of Cycles 1 and 3 + doxorubicin 75.0 mg/m^2 on Day 1of Cycles 1 and 3 + cyclophosphamide 1200 mg/m^2 on Day 1, 2 of Cycles 1 and 3 alternating with ifosfamide 1800 mg/m^2/day for 5 days in Cycles 2 and 4 + etoposide 100 mg/m^2/day for 5 days in Cycles 2 and 4; • VIDE (Used in Ewing family of tumors): vincristine 1.5 mg/m^2 on Day 1 of each cycle + ifosfamide 3.0 g/m^2 on Day 1, 2, 3 of each cycle + doxorubicin 20 mg/m^2 on Day 1, 2, 3 of each cycle + etoposide 150 mg/m^2 on Day 1, 2, 3 of each cycle. Study Day 1 corresponding in different CTX regimens was calculated as: 1 day after end of CTX in week 1 of a cycle. Day 1 corresponds for VDC/IE CTX regimen: to CTX-day 2+1 during cycles 1 and 3, and to CTX day 5+1 during cycles 2 and 4; for VIDE CTX regimen: to CTX-day 3+1; for VAC CTX regimen: to CTX-day 1+1, CTX-day 2+1, CTX-day 3+1 or CTX-day 5+1 (depending on actinomycin schedule and number of days cyclophosphamide was given); for IVA CTX regimens: to CTX-day 2+1; for IVADo CTX regimen: to: CTX-day 2+1.
    Evidence for comparator
    		 Pegfilgrastim is not approved for children, therefore filgrastim is the comparator in this study.
    Actual start date of recruitment
    08 Sep 2015
    Long term follow-up planned
    Yes
    Long term follow-up rationale
    		 Safety
    Long term follow-up duration
    		 9 Months
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Russian Federation: 16
    Country: Number of subjects enrolled
    Ukraine: 12
    Country: Number of subjects enrolled
    Belarus: 3
    Country: Number of subjects enrolled
    Romania: 3
    Country: Number of subjects enrolled
    Czech Republic: 2
    Country: Number of subjects enrolled
    Slovakia: 2
    Country: Number of subjects enrolled
    Croatia: 1
    Country: Number of subjects enrolled
    Georgia: 1
    Country: Number of subjects enrolled
    Hungary: 1
    Country: Number of subjects enrolled
    Spain: 1
    Worldwide total number of subjects
    42
    EEA total number of subjects
    10
    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)
    28
    Adolescents (12-17 years)
    14
    Adults (18-64 years)
    0
    From 65 to 84 years
    0
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 -

    Pre-assignment
    Screening details
    		 A total of 45 participants were screened, of which 43 were enrolled and 42 were randomized in 1:1 ratio to lipegfilgrastim or filgrastim. 1 participant was enrolled but not randomized as the youngest age cohort (2 to less than [<] 6 years) was not started at time of enrollment. 2 participants were screen failure due to eligibility criteria not met.

    Period 1
    Period 1 title
    Overall Study (overall period)
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Not blinded

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Lipegfilgrastim
    Arm description
    		 Participants received a single SC dose of lipegfilgrastim (100 mcg/kg BW; maximum 6 milligrams [mg]) approximately 24 hours (+6 hours) after end of the last CTX in Week 1 of the specific regimen for a total of 4 CTX cycles; and CTX regimen IV every 3 weeks of each CTX cycle over 4 CTX cycles (each cycle=21 days).
    Arm type
    		 Experimental

    Investigational medicinal product name
    LONQUEX
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    Lipegfilgrastim 100 mcg/kg BW single dose was administered as per the schedule specified in the respective arm.

    Arm title
    		 Filgrastim
    Arm description
    		 Participants received filgrastim 5 mcg/kg BW SC injection once daily (approximately 24 hours [+6 hours] after end of the last CTX in Week 1 of the specific regimen) for at least 5 consecutive days or until absolute neutrophil count (ANC) had returned to greater than or equal to (>=) 2*10^9 per liter for each CTX cycle up to 4 cycles (maximum period of filgrastim administration was 14 days). Where ANC greater than (>) 2*10^9 per liter before the end of the expected nadir, dosing was continued until the expected nadir at the discretion of the Investigator. CTX regimen was administered IV every 3 weeks of each CTX cycle over 4 CTX cycles (each cycle=21 days).
    Arm type
    		 Active comparator

    Investigational medicinal product name
    NEUPOGEN
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    Filgrastim 5 mcg/kg BW was administered as per the schedule specified in the respective arm.

    Number of subjects in period 1
    		Lipegfilgrastim Filgrastim
    Started
    21
    21
    Received at least 1 dose of study drug
    21
    21
    Completed
    20
    17
    Not completed
    1
    4
         Death
    -
    2
         Adverse event
    -
    2
         Lost to follow-up
    1
    -

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Lipegfilgrastim
    Reporting group description
    		 Participants received a single SC dose of lipegfilgrastim (100 mcg/kg BW; maximum 6 milligrams [mg]) approximately 24 hours (+6 hours) after end of the last CTX in Week 1 of the specific regimen for a total of 4 CTX cycles; and CTX regimen IV every 3 weeks of each CTX cycle over 4 CTX cycles (each cycle=21 days).

    Reporting group title
    Filgrastim
    Reporting group description
    		 Participants received filgrastim 5 mcg/kg BW SC injection once daily (approximately 24 hours [+6 hours] after end of the last CTX in Week 1 of the specific regimen) for at least 5 consecutive days or until absolute neutrophil count (ANC) had returned to greater than or equal to (>=) 2*10^9 per liter for each CTX cycle up to 4 cycles (maximum period of filgrastim administration was 14 days). Where ANC greater than (>) 2*10^9 per liter before the end of the expected nadir, dosing was continued until the expected nadir at the discretion of the Investigator. CTX regimen was administered IV every 3 weeks of each CTX cycle over 4 CTX cycles (each cycle=21 days).

    Reporting group values
    		 Lipegfilgrastim Filgrastim Total
    Number of subjects
    		 21 21 42
    Age Categorical
    Units: Subjects
        Children (2-11 years)
    		 15 13 28
        Adolescents (12-17 years)
    		 6 8 14
    Age Continuous
    Units: years
        arithmetic mean (standard deviation)
    		 9.11 ( 5.139 ) 9.37 ( 5.102 ) -
    Gender Categorical
    Units: Subjects
        Female
    		 7 9 16
        Male
    		 14 12 26

    End points

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    End points reporting groups
    Reporting group title
    Lipegfilgrastim
    Reporting group description
    		 Participants received a single SC dose of lipegfilgrastim (100 mcg/kg BW; maximum 6 milligrams [mg]) approximately 24 hours (+6 hours) after end of the last CTX in Week 1 of the specific regimen for a total of 4 CTX cycles; and CTX regimen IV every 3 weeks of each CTX cycle over 4 CTX cycles (each cycle=21 days).

    Reporting group title
    Filgrastim
    Reporting group description
    		 Participants received filgrastim 5 mcg/kg BW SC injection once daily (approximately 24 hours [+6 hours] after end of the last CTX in Week 1 of the specific regimen) for at least 5 consecutive days or until absolute neutrophil count (ANC) had returned to greater than or equal to (>=) 2*10^9 per liter for each CTX cycle up to 4 cycles (maximum period of filgrastim administration was 14 days). Where ANC greater than (>) 2*10^9 per liter before the end of the expected nadir, dosing was continued until the expected nadir at the discretion of the Investigator. CTX regimen was administered IV every 3 weeks of each CTX cycle over 4 CTX cycles (each cycle=21 days).

    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
    DSN was defined as the number of days with severe neutropenia in Cycle 1 (from start of CTX until Day 15). Severe neutropenia was defined as Grade 4 neutropenia with ANC less than (<) 0.5 * 10^9 per liter. If the ANC was >0.5 * 10^9 per liter, DSN was set to 0. Per-Protocol (PP) analysis set included all randomized participants for whom no protocol violations were reported that may have impacted the efficacy of the investigational medicinal product (IMP).
    End point type
    Primary
    End point timeframe
    From start of CTX until Day 15 of Cycle 1
    End point values
    		 Lipegfilgrastim Filgrastim
    Number of subjects analysed
    20
    19
    Units: days
        least squares mean (standard error)
    3.1 ( 0.46 )
    2.1 ( 0.39 )
    Statistical analysis title
    		 Lipegfilgrastim versus Filgrastim
    Statistical analysis description
    A Poisson regression with identity link was used with factors of treatment and age group, and baseline (before IMP administration) ANC value as covariate.
    Comparison groups
    Lipegfilgrastim v Filgrastim
    Number of subjects included in analysis
    39
    Analysis specification
    Pre-specified
    Analysis type
    		 other [1]
    P-value
    		 = 0.102 [2]
    Method
    		 Poisson analysis
    Parameter type
    		 Treatment difference
    Point estimate
    1
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.21
         upper limit
    		 2.26
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.61
    Notes
    [1] - There was no hypothesis testing as the study was not powered.
    [2] - p-value is reported for the treatment difference.

    Secondary: Number of Participants With Severe Neutropenia and Very Severe Neutropenia

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    End point title
    		 Number of Participants With Severe Neutropenia and Very Severe Neutropenia
    End point description
    Severe neutropenia was defined as Grade 4 neutropenia with ANC <0.5 * 10^9 per liter. Very severe neutropenia was defined as ANC <0.1 * 10^9 per liter. PP analysis set included all randomized participants for whom no protocol violations were reported that may have impacted the efficacy of the IMP. Here, 'n' signifies number of participants analyzed for specified categories.
    End point type
    Secondary
    End point timeframe
    Cycles 1, 2, 3, and 4 (each cycle=21 days)
    End point values
    		 Lipegfilgrastim Filgrastim
    Number of subjects analysed
    20
    19
    Units: participants
        Severe neutropenia: Cycle 1 (n=20,19)
    16
    14
        Severe neutropenia: Cycle 2 (n=20,17)
    13
    11
        Severe neutropenia: Cycle 3 (n=20,17)
    12
    10
        Severe neutropenia: Cycle 4 (n=19,16)
    12
    10
        Very severe neutropenia: Cycle 1 (n=20,19)
    10
    10
        Very severe neutropenia: Cycle 2 (n=20,17)
    9
    4
        Very severe neutropenia: Cycle 3 (n=20,17)
    9
    8
        Very severe neutropenia: Cycle 4 (n=19,16)
    8
    8
    No statistical analyses for this end point

    Secondary: Number of Participants With Febrile Neutropenia (FN)

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    End point title
    		 Number of Participants With Febrile Neutropenia (FN)
    End point description
    FN was defined as an axillary or external ear temperature greater than (>) 38.3 degrees centigrade or 2 consecutive readings >37.8 degrees centigrade for 2 hours (2 consecutive readings at least 2 hours apart) and ANC<0.5 * 10^9 per liter or expected to be <0.5 * 10^9 per liter per cycle and across all cycles. PP analysis set included all randomized participants for whom no protocol violations were reported that may have impacted the efficacy of the IMP. Here, 'n' signifies number of participants analyzed for specified categories.
    End point type
    Secondary
    End point timeframe
    Cycles 1, 2, 3, and 4 (each cycle = 21 days)
    End point values
    		 Lipegfilgrastim Filgrastim
    Number of subjects analysed
    20
    19
    Units: participants
        Cycle 1 (n=20,19)
    5
    4
        Cycle 2 (n=20,17)
    3
    3
        Cycle 3 (n=20,17)
    4
    4
        Cycle 4 (n=19,16)
    1
    1
        Overall Cycle 1-4 (n=20,19)
    7
    8
    No statistical analyses for this end point

    Secondary: DSN in Cycles 2 to 4 Per Cycle

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    End point title
    		 DSN in Cycles 2 to 4 Per Cycle
    End point description
    DSN was defined as the number of days with severe neutropenia in Cycle 1 (from start of CTX until Day 15). Severe neutropenia was defined as Grade 4 neutropenia with ANC <0.5 * 10^9 per liter. If the ANC was >0.5 * 10^9 per liter, DSN was set to 0. PP analysis set included all randomized participants for whom no protocol violations were reported that may have impacted the efficacy of the IMP. Here, 'n' signifies number of participants analyzed for specified categories.
    End point type
    Secondary
    End point timeframe
    Cycles 2, 3, and 4
    End point values
    		 Lipegfilgrastim Filgrastim
    Number of subjects analysed
    20
    19
    Units: days
    arithmetic mean (standard deviation)
        Cycle 2 (n=20,17)
    2.1 ( 1.88 )
    2.5 ( 2.60 )
        Cycle 3 (n=20,17)
    2.2 ( 2.23 )
    2.2 ( 2.38 )
        Cycle 4 (n=19,16)
    2.1 ( 2.38 )
    2.0 ( 1.90 )
    No statistical analyses for this end point

    Secondary: Duration of Very Severe Neutropenia

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    End point title
    		 Duration of Very Severe Neutropenia
    End point description
    Very severe neutropenia was defined as ANC <0.1 * 10^9 per liter. It was set to 0, if ANC was <0.1 * 10^9 per liter. PP analysis set included all randomized participants for whom no protocol violations were reported that may have impacted the efficacy of the IMP. Here, 'n' signifies number of participants analyzed for specified categories.
    End point type
    Secondary
    End point timeframe
    Cycle 1, 2, 3, and 4 (each cycle =21 days)
    End point values
    		 Lipegfilgrastim Filgrastim
    Number of subjects analysed
    20
    19
    Units: days
    arithmetic mean (standard deviation)
        Cycle 1 (n=20,19)
    1.4 ( 1.88 )
    1.3 ( 1.83 )
        Cycle 2 (n=20,17)
    1.3 ( 1.65 )
    0.8 ( 1.82 )
        Cycle 3 (n=20,17)
    1.3 ( 1.62 )
    1.1 ( 1.43 )
        Cycle 4 (n=19,16)
    1.1 ( 1.56 )
    0.8 ( 0.93 )
    No statistical analyses for this end point

    Secondary: Area Under the Curve of ANC (AUCANC)

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    End point title
    		 Area Under the Curve of ANC (AUCANC)
    End point description
    Calculation of AUCANC was performed by linear trapezoid rule. Missing ANC values were not imputed. PP analysis set included all randomized participants for whom no protocol violations were reported that may have impacted the efficacy of the IMP.
    End point type
    Secondary
    End point timeframe
    Day 1 to Day 15 in Cycle 1 (Cycle length = 21 days)
    End point values
    		 Lipegfilgrastim Filgrastim
    Number of subjects analysed
    20
    19
    Units: * 10^9 per liter * days
        arithmetic mean (standard deviation)
    117.7773 ( 55.77054 )
    97.1271 ( 63.06220 )
    No statistical analyses for this end point

    Secondary: ANC Nadir: the Lowest ANC Value Recorded

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    End point title
    		 ANC Nadir: the Lowest ANC Value Recorded
    End point description
    PP analysis set included all randomized participants for whom no protocol violations were reported that may have impacted the efficacy of the IMP. Here, 'n' signifies number of participants analyzed for specified categories.
    End point type
    Secondary
    End point timeframe
    Cycle 1, 2, 3, and 4 (each cycle =21 days)
    End point values
    		 Lipegfilgrastim Filgrastim
    Number of subjects analysed
    20
    19
    Units: 10^9 per liter
    arithmetic mean (standard deviation)
        Cycle 1 (n= 20,19)
    0.316 ( 0.4968 )
    0.357 ( 0.5506 )
        Cycle 2 (n= 20,17)
    0.381 ( 0.4842 )
    0.549 ( 0.8320 )
        Cycle 3 (n= 20,17)
    0.500 ( 0.6853 )
    0.656 ( 0.7605 )
        Cycle 4 (n= 19,16)
    0.437 ( 0.4962 )
    0.546 ( 0.6975 )
    No statistical analyses for this end point

    Secondary: Time to ANC Nadir From Start of CTX

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    End point title
    		 Time to ANC Nadir From Start of CTX
    End point description
    Time to ANC nadir was defined as the time from start of CTX until occurrence of the ANC nadir in the cycle. PP analysis set included all randomized participants for whom no protocol violations were reported that may have impacted the efficacy of the IMP. Here, 'n' signifies number of participants analyzed for specified categories.
    End point type
    Secondary
    End point timeframe
    Cycle 1, 2, 3, and 4 (each cycle =21 days)
    End point values
    		 Lipegfilgrastim Filgrastim
    Number of subjects analysed
    20
    19
    Units: days
    arithmetic mean (standard deviation)
        Cycle 1 (n= 20,19)
    9.1 ( 2.53 )
    9.7 ( 1.86 )
        Cycle 2 (n= 20,17)
    8.9 ( 2.83 )
    11.0 ( 2.76 )
        Cycle 3 (n= 20,17)
    9.3 ( 2.51 )
    8.8 ( 3.15 )
        Cycle 4 (n= 19,16)
    9.2 ( 3.32 )
    10.6 ( 1.21 )
    No statistical analyses for this end point

    Secondary: Time to ANC Nadir From First IMP Administration

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    End point title
    		 Time to ANC Nadir From First IMP Administration
    End point description
    Time to ANC nadir was defined as the time from first IMP administration in a cycle until occurrence of the ANC nadir in the cycle. PP analysis set included all randomized participants for whom no protocol violations were reported that may have impacted the efficacy of the IMP. Here, 'n' signifies number of participants analyzed for specified categories.
    End point type
    Secondary
    End point timeframe
    Cycle 1, 2, 3, and 4 (each cycle = 21 days)
    End point values
    		 Lipegfilgrastim Filgrastim
    Number of subjects analysed
    20
    19
    Units: days
    arithmetic mean (standard deviation)
        Cycle 1 (n=20,19)
    6.5 ( 2.42 )
    7.1 ( 1.81 )
        Cycle 2 (n=20,17)
    6.1 ( 2.78 )
    8.5 ( 2.81 )
        Cycle 3 (n=20,17)
    6.8 ( 2.40 )
    6.4 ( 2.91 )
        Cycle 4 (n=19,16)
    6.5 ( 3.01 )
    8.1 ( 1.41 )
    No statistical analyses for this end point

    Secondary: Time to ANC Recovery From First Day of CTX

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    End point title
    		 Time to ANC Recovery From First Day of CTX
    End point description
    Time to ANC recovery at threshold of ANC >1.0 * 10^9 per liter and >2.0 * 10^9 per liter are reported. PP analysis set included all randomized participants for whom no protocol violations were reported that may have impacted the efficacy of the IMP. Here, 'n' signifies number of participants analyzed for specified categories.
    End point type
    Secondary
    End point timeframe
    Cycle 1, 2, 3, and 4 (each cycle =21 days)
    End point values
    		 Lipegfilgrastim Filgrastim
    Number of subjects analysed
    20
    19
    Units: days
    arithmetic mean (standard deviation)
        ANC >1.0 * 10^9 per liter: Cycle 1 (n=20,19)
    10.3 ( 4.12 )
    11.9 ( 6.11 )
        ANC >1.0 * 10^9 per liter: Cycle 2 (n=20,17)
    10.1 ( 5.43 )
    11.2 ( 6.67 )
        ANC >1.0 * 10^9 per liter: Cycle 3 (n=20,17)
    10.0 ( 5.19 )
    8.2 ( 7.45 )
        ANC >1.0 * 10^9 per liter: Cycle 4 (n=19,16)
    10.6 ( 6.51 )
    9.4 ( 5.67 )
        ANC >2.0 * 10^9 per liter: Cycle 1 (n=20,19)
    14.2 ( 4.99 )
    15.3 ( 3.93 )
        ANC >2.0 * 10^9 per liter: Cycle 2 (n=20,17)
    15.1 ( 5.66 )
    14.6 ( 6.30 )
        ANC >2.0 * 10^9 per liter: Cycle 3 (n=20,17)
    12.3 ( 05.20 )
    13.8 ( 5.47 )
        ANC >2.0 * 10^9 per liter: Cycle 4 (n=19,16)
    13.8 ( 5.67 )
    15.2 ( 5.89 )
    No statistical analyses for this end point

    Secondary: Time to ANC Recovery From Nadir

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    End point title
    		 Time to ANC Recovery From Nadir
    End point description
    Time to ANC recovery at threshold of ANC >1.0 * 10^9 per liter and >2.0 * 10^9 per liter are reported. PP analysis set included all randomized participants for whom no protocol violations were reported that may have impacted the efficacy of the IMP. Here, 'n' signifies number of participants analyzed for specified categories.
    End point type
    Secondary
    End point timeframe
    Cycle 1, 2, 3, and 4 (each cycle = 21 days)
    End point values
    		 Lipegfilgrastim Filgrastim
    Number of subjects analysed
    20
    19
    Units: days
    arithmetic mean (standard deviation)
        ANC >1.0 * 10^9 per liter: Cycle 1 (n=20,19)
    3.1 ( 1.76 )
    5.3 ( 6.18 )
        ANC >1.0 * 10^9 per liter: Cycle 2 (n=20,17)
    3.9 ( 4.61 )
    4.6 ( 6.70 )
        ANC >1.0 * 10^9 per liter: Cycle 3 (n=20,17)
    3.3 ( 2.27 )
    3.1 ( 5.25 )
        ANC >1.0 * 10^9 per liter: Cycle 4 (n=19,16)
    4.9 ( 6.31 )
    2.4 ( 1.63 )
        ANC >2.0 * 10^9 per liter: Cycle 1 (n=20,19)
    8.2 ( 8.30 )
    8.5 ( 7.54 )
        ANC >2.0 * 10^9 per liter: Cycle 2 (n=20,17)
    10.1 ( 9.04 )
    8.5 ( 9.11 )
        ANC >2.0 * 10^9 per liter: Cycle 3 (n=20,17)
    5.7 ( 5.91 )
    8.2 ( 8.13 )
        ANC >2.0 * 10^9 per liter: Cycle 4 (n=19,16)
    8.1 ( 7.70 )
    9.1 ( 9.10 )
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    From start of study drug administration (Day 1) up to end of follow-up (Day 365)
    Adverse event reporting additional description
    Safety analysis set included all randomized participants who received at least 1 dose of IMP.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    20.0
    Reporting groups
    Reporting group title
    Filgrastim
    Reporting group description
    		 Participants received filgrastim 5 mcg/kg BW SC injection once daily (approximately 24 hours [+6 hours] after end of the last CTX in Week 1 of the specific regimen) for at least 5 consecutive days or until ANC had returned to >=2*10^9 per liter for each CTX cycle up to 4 cycles (maximum period of filgrastim administration was 14 days). Where ANC >2*10^9 per liter before the end of the expected nadir, dosing was continued until the expected nadir at the discretion of the Investigator. CTX regimen was administered IV every 3 weeks of each CTX cycle over 4 CTX cycles (each cycle=21 days).

    Reporting group title
    Lipegfilgrastim
    Reporting group description
    		 Participants received a single SC dose of lipegfilgrastim (100 mcg/kg BW; maximum 6 mg) approximately 24 hours (+6 hours) after end of the last CTX in Week 1 of the specific regimen for a total of 4 CTX cycles; and CTX regimen IV every 3 weeks of each CTX cycle over 4 CTX cycles (each cycle=21 days).

    Serious adverse events
    		 Filgrastim Lipegfilgrastim
    Total subjects affected by serious adverse events
         subjects affected / exposed
    15 / 21 (71.43%)
    18 / 21 (85.71%)
         number of deaths (all causes)
    2
    0
         number of deaths resulting from adverse events
    Investigations
    Lymphocyte count decreased
         subjects affected / exposed
    2 / 21 (9.52%)
    2 / 21 (9.52%)
         occurrences causally related to treatment / all
    0 / 18
    0 / 12
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Platelet count decreased
         subjects affected / exposed
    2 / 21 (9.52%)
    3 / 21 (14.29%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 5
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Alveolar rhabdomyosarcoma
         subjects affected / exposed
    1 / 21 (4.76%)
    0 / 21 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Ewing's sarcoma
         subjects affected / exposed
    1 / 21 (4.76%)
    0 / 21 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Peripheral primitive neuroectodermal bone tumour
         subjects affected / exposed
    0 / 21 (0.00%)
    1 / 21 (4.76%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Rhabdomyosarcoma
         subjects affected / exposed
    0 / 21 (0.00%)
    1 / 21 (4.76%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac disorders
    Cardio-respiratory arrest
         subjects affected / exposed
    1 / 21 (4.76%)
    0 / 21 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    2 / 21 (9.52%)
    3 / 21 (14.29%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 8
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Febrile neutropenia
         subjects affected / exposed
    5 / 21 (23.81%)
    1 / 21 (4.76%)
         occurrences causally related to treatment / all
    0 / 6
    0 / 6
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Leukopenia
         subjects affected / exposed
    5 / 21 (23.81%)
    2 / 21 (9.52%)
         occurrences causally related to treatment / all
    0 / 11
    0 / 7
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lymphopenia
         subjects affected / exposed
    5 / 21 (23.81%)
    9 / 21 (42.86%)
         occurrences causally related to treatment / all
    0 / 10
    0 / 34
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Neutropenia
         subjects affected / exposed
    2 / 21 (9.52%)
    3 / 21 (14.29%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 18
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Thrombocytopenia
         subjects affected / exposed
    3 / 21 (14.29%)
    10 / 21 (47.62%)
         occurrences causally related to treatment / all
    0 / 14
    0 / 48
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pancytopenia
         subjects affected / exposed
    0 / 21 (0.00%)
    1 / 21 (4.76%)
         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
    Pyrexia
         subjects affected / exposed
    1 / 21 (4.76%)
    0 / 21 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Nausea
         subjects affected / exposed
    0 / 21 (0.00%)
    1 / 21 (4.76%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Stomatitis
         subjects affected / exposed
    1 / 21 (4.76%)
    0 / 21 (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
    0 / 21 (0.00%)
    1 / 21 (4.76%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatobiliary disorders
    Drug-induced liver injury
         subjects affected / exposed
    1 / 21 (4.76%)
    0 / 21 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Joint contracture
         subjects affected / exposed
    1 / 21 (4.76%)
    0 / 21 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infections and infestations
    Device related infection
         subjects affected / exposed
    1 / 21 (4.76%)
    0 / 21 (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
    Hypernatraemia
         subjects affected / exposed
    1 / 21 (4.76%)
    0 / 21 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypocalcaemia
         subjects affected / exposed
    1 / 21 (4.76%)
    0 / 21 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Filgrastim Lipegfilgrastim
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    21 / 21 (100.00%)
    21 / 21 (100.00%)
    Investigations
    Alanine aminotransferase increased
         subjects affected / exposed
    1 / 21 (4.76%)
    5 / 21 (23.81%)
         occurrences all number
    1
    11
    Aspartate aminotransferase increased
         subjects affected / exposed
    1 / 21 (4.76%)
    5 / 21 (23.81%)
         occurrences all number
    1
    7
    Gamma-glutamyltransferase increased
         subjects affected / exposed
    1 / 21 (4.76%)
    3 / 21 (14.29%)
         occurrences all number
    1
    3
    Neutrophil count decreased
         subjects affected / exposed
    1 / 21 (4.76%)
    3 / 21 (14.29%)
         occurrences all number
    3
    16
    Platelet count decreased
         subjects affected / exposed
    3 / 21 (14.29%)
    5 / 21 (23.81%)
         occurrences all number
    19
    25
    Weight decreased
         subjects affected / exposed
    0 / 21 (0.00%)
    3 / 21 (14.29%)
         occurrences all number
    0
    9
    Cardiac disorders
    Sinus tachycardia
         subjects affected / exposed
    2 / 21 (9.52%)
    0 / 21 (0.00%)
         occurrences all number
    2
    0
    Nervous system disorders
    Headache
         subjects affected / exposed
    5 / 21 (23.81%)
    1 / 21 (4.76%)
         occurrences all number
    14
    3
    Polyneuropathy
         subjects affected / exposed
    1 / 21 (4.76%)
    3 / 21 (14.29%)
         occurrences all number
    1
    3
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    15 / 21 (71.43%)
    16 / 21 (76.19%)
         occurrences all number
    42
    71
    Febrile neutropenia
         subjects affected / exposed
    2 / 21 (9.52%)
    2 / 21 (9.52%)
         occurrences all number
    3
    3
    Leukocytosis
         subjects affected / exposed
    1 / 21 (4.76%)
    2 / 21 (9.52%)
         occurrences all number
    4
    6
    Leukopenia
         subjects affected / exposed
    9 / 21 (42.86%)
    2 / 21 (9.52%)
         occurrences all number
    25
    5
    Lymphopenia
         subjects affected / exposed
    4 / 21 (19.05%)
    7 / 21 (33.33%)
         occurrences all number
    7
    24
    Neutropenia
         subjects affected / exposed
    8 / 21 (38.10%)
    11 / 21 (52.38%)
         occurrences all number
    30
    30
    Thrombocytopenia
         subjects affected / exposed
    14 / 21 (66.67%)
    12 / 21 (57.14%)
         occurrences all number
    32
    66
    General disorders and administration site conditions
    Fatigue
         subjects affected / exposed
    0 / 21 (0.00%)
    2 / 21 (9.52%)
         occurrences all number
    0
    2
    Hyperthermia
         subjects affected / exposed
    0 / 21 (0.00%)
    4 / 21 (19.05%)
         occurrences all number
    0
    7
    Mucosal inflammation
         subjects affected / exposed
    1 / 21 (4.76%)
    3 / 21 (14.29%)
         occurrences all number
    4
    4
    Pyrexia
         subjects affected / exposed
    6 / 21 (28.57%)
    5 / 21 (23.81%)
         occurrences all number
    13
    9
    Gastrointestinal disorders
    Constipation
         subjects affected / exposed
    2 / 21 (9.52%)
    1 / 21 (4.76%)
         occurrences all number
    2
    1
    Diarrhoea
         subjects affected / exposed
    3 / 21 (14.29%)
    3 / 21 (14.29%)
         occurrences all number
    3
    3
    Enterocolitis
         subjects affected / exposed
    0 / 21 (0.00%)
    2 / 21 (9.52%)
         occurrences all number
    0
    3
    Nausea
         subjects affected / exposed
    7 / 21 (33.33%)
    8 / 21 (38.10%)
         occurrences all number
    15
    17
    Stomatitis
         subjects affected / exposed
    4 / 21 (19.05%)
    3 / 21 (14.29%)
         occurrences all number
    5
    4
    Toothache
         subjects affected / exposed
    0 / 21 (0.00%)
    2 / 21 (9.52%)
         occurrences all number
    0
    3
    Vomiting
         subjects affected / exposed
    8 / 21 (38.10%)
    11 / 21 (52.38%)
         occurrences all number
    19
    47
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    1 / 21 (4.76%)
    2 / 21 (9.52%)
         occurrences all number
    1
    2
    Epistaxis
         subjects affected / exposed
    2 / 21 (9.52%)
    1 / 21 (4.76%)
         occurrences all number
    3
    3
    Skin and subcutaneous tissue disorders
    Alopecia
         subjects affected / exposed
    2 / 21 (9.52%)
    6 / 21 (28.57%)
         occurrences all number
    2
    6
    Renal and urinary disorders
    Proteinuria
         subjects affected / exposed
    1 / 21 (4.76%)
    2 / 21 (9.52%)
         occurrences all number
    1
    2
    Musculoskeletal and connective tissue disorders
    Back pain
         subjects affected / exposed
    2 / 21 (9.52%)
    1 / 21 (4.76%)
         occurrences all number
    3
    1
    Infections and infestations
    Bronchitis
         subjects affected / exposed
    2 / 21 (9.52%)
    1 / 21 (4.76%)
         occurrences all number
    2
    1
    Rhinitis
         subjects affected / exposed
    1 / 21 (4.76%)
    3 / 21 (14.29%)
         occurrences all number
    1
    5
    Metabolism and nutrition disorders
    Decreased appetite
         subjects affected / exposed
    0 / 21 (0.00%)
    3 / 21 (14.29%)
         occurrences all number
    0
    4
    Fluid retention
         subjects affected / exposed
    0 / 21 (0.00%)
    2 / 21 (9.52%)
         occurrences all number
    0
    5
    Hypoglycaemia
         subjects affected / exposed
    0 / 21 (0.00%)
    2 / 21 (9.52%)
         occurrences all number
    0
    2
    Hypokalaemia
         subjects affected / exposed
    0 / 21 (0.00%)
    4 / 21 (19.05%)
         occurrences all number
    0
    15

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    02 Feb 2016
    The following major procedural changes (not all-inclusive) were made to the protocol: a) Introduce additional permitted on-study CTX regimens, VAC, for participants with Ewing family of tumors, and IVADo (ifosfamide plus vincristine plus actinomycin plus doxorubicin) for participants with rhabdomyosarcoma. These changes are aligned with the European Medicine Agency decision (EMA/773335/2015, dated 21 December 2015) on the acceptance of modification of the agreed upon pediatric investigational plan for lipegfilgrastim (EMEA-001019-PIP01-10_M03). - Indicate that lipegfilgrastim will be administered on CTX-Day 2+1 for the IVADo regimen. - Indicate that CTX Dn, the last day of the CTX in week 1 of a cycle for the IVADo regimen is Day 2. - Indicate that study Day 1, which is the day after end of CTX in Week 1 of a cycle for IVADo regimen is CTX-Day 2+1. b) Indicate that the maximum allowable dose of vincristine is per local standards for VIDE, VDC/IE, and VAC regimens. Specify CTX regimen by cancer type. Indicate that the maximum allowable dose of actinomycin is per local standards for IVA. c) Modify the description of the IMP to comply with the product specification. d) Modify the adverse drug reaction profile with respect to the incidence of splenomegaly to align with forthcoming changes to the Summary of Product Characteristics. e) Clarify that the Investigator may use test results from local laboratories (as part of routine medical care) at screening to initiate CTX and check inclusion and exclusion criteria only in exceptional medical situations, should the results from the central laboratory for the clinical study not be available. f) Clarify exclusion criteria to indicate participation in a clinical study “with an IMP” within 30 days or “5 half-lives” before randomization, whichever is longer.

    Interruptions (globally)
    Were there any global interruptions to the trial? Yes
    Date
    Interruption
    Restart date
    13 Apr 2017
    The recruitment to this study was interrupted due to non-availability of IMP.
    07 Sep 2017

    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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