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    Clinical Trial Results:
    A Randomized, Phase IIIB, Open-Label, Two-Arm, Multicenter, ComparatiVe Study on Efficacy and Safety of Lipegfilgrastim (LONQUEX®, TEVA) in Comparison to Pegfilgrastim (NEULASTA®, Amgen) in Elderly Patients With Aggressive B-Cell Non-HOdgkin Lymphomas at HIgh Risk for R-CHOP-21-InDuced Neutropenia – AVOID Neutropenia

    Summary
    EudraCT number
    		 2013-001284-23
    Trial protocol
    		 DE   ES   IT  
    Global end of trial date
    24 Apr 2018

    Results information
    Results version number
    		 v1(current)
    This version publication date
    12 May 2019
    First version publication date
    12 May 2019
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    XM22-ONC-305
    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
    Graf-Arco-Strasse 3, Ulm, Germany, 89079
    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)
    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
    24 Apr 2018
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    24 Apr 2018
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To demonstrate the non-inferiority of lipegfilgrastim (LONQUEX®) to pegfilgrastim (NEULASTA®) for the duration of severe neutropenia (DSN) in the first cycle of chemotherapy.
    Protection of trial subjects
    This study was conducted in full accordance with the International Conference for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH) Good Clinical Practice (GCP) Consolidated Guideline (E6), the principles of the Declaration of Helsinki, and any applicable national and local laws and regulations (for example, Title 21 Code of Federal Regulations [21CFR] Parts 11, 50, 54, 56, 312, and 314, European Union [EU] Directive 2001/20/EC and 2005/28/EC). Any episode of non-compliance was documented.
    Background therapy
    		 Chemotherapy (CTX) regimen were administered every 3 weeks up to 6 cycles (each cycle=21 days). CTX regimen included R-CHOP-21, which is comprised of the following drugs: rituximab 375 milligrams/square meter (mg/m^2) on Day 1 or on Day 2, cyclophosphamide 750 mg/m^2, doxorubicin 50 mg/m^2, vincristine 1.4 mg/m^2 (capped at 2.0 or 1.0 milligrams [mg]) intravenous (IV) on Day 2, and prednisone 100 mg orally on Days 2 to 6 (CHOP).
    Evidence for comparator
    		 -
    Actual start date of recruitment
    31 Mar 2014
    Long term follow-up planned
    Yes
    Long term follow-up rationale
    		 Safety
    Long term follow-up duration
    		 5 Months
    Independent data monitoring committee (IDMC) involvement?
    No
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Germany: 83
    Country: Number of subjects enrolled
    Italy: 3
    Country: Number of subjects enrolled
    Spain: 13
    Worldwide total number of subjects
    99
    EEA total number of subjects
    99
    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)
    0
    From 65 to 84 years
    99
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 A total of 115 participants were screened, of which 101 were randomized in 1:1 ratio to lipegfilgrastim or pegfilgrastim. 14 participants were screen failures mainly due to eligibility criteria not met. A total of 99 participants were included in intent-to-treat (ITT) analysis set.

    Pre-assignment
    Screening details
    		 2 participants randomized at early stages of study received CTX but not investigational medicinal product (IMP) (because 1 batch of lipegfilgrastim was put on hold due to failed acceptance criteria test for stability, and study recruitment halted) and were not included in ITT analysis set.

    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 lipegfilgrastim 6 mg subcutaneous (SC) injection on Day 3 of each treatment cycle for up to 6 treatment cycles. Additionally, participants received the CTX regimen for up to 6 treatment cycles (Each treatment cycle lasted=21 days).
    Arm type
    		 Experimental

    Investigational medicinal product name
    LONQUEX
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection in pre-filled syringe
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    Lipegfilgrastim 6 mg was administered on Day 3 of each cycle.

    Arm title
    		 Pegfilgrastim
    Arm description
    		 Participants received a single pegfilgrastim 6 mg SC injection on Day 3 of each treatment cycle for up to 6 treatment cycles. Additionally, participants received the CTX regimen for up to 6 treatment cycles (Each treatment cycle lasted=21 days).
    Arm type
    		 Active comparator

    Investigational medicinal product name
    NEULASTA®
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection in pre-filled syringe
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    Pegfilgrastim 6 mg was administered on Day 3 of each cycle.

    Number of subjects in period 1
    		Lipegfilgrastim Pegfilgrastim
    Started
    49
    50
    Received at least 1 dose of study drug
    46
    50
    Completed
    42
    40
    Not completed
    7
    10
         Consent withdrawn by subject
    2
    3
         Adverse Event
    -
    2
         Death
    3
    4
         Non-compliance
    1
    -
         Other than specified
    1
    1

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Lipegfilgrastim
    Reporting group description
    		 Participants received a single lipegfilgrastim 6 mg subcutaneous (SC) injection on Day 3 of each treatment cycle for up to 6 treatment cycles. Additionally, participants received the CTX regimen for up to 6 treatment cycles (Each treatment cycle lasted=21 days).

    Reporting group title
    Pegfilgrastim
    Reporting group description
    		 Participants received a single pegfilgrastim 6 mg SC injection on Day 3 of each treatment cycle for up to 6 treatment cycles. Additionally, participants received the CTX regimen for up to 6 treatment cycles (Each treatment cycle lasted=21 days).

    Reporting group values
    		 Lipegfilgrastim Pegfilgrastim Total
    Number of subjects
    		 49 50 99
    Age Categorical
    Units: Subjects
    Age Continuous
    Units: years
        arithmetic mean (standard deviation)
    		 72.3 ( 4.66 ) 75.2 ( 4.26 ) -
    Gender Categorical
    Units: Subjects
        Female
    		 23 23 46
        Male
    		 26 27 53

    End points

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    End points reporting groups
    Reporting group title
    Lipegfilgrastim
    Reporting group description
    		 Participants received a single lipegfilgrastim 6 mg subcutaneous (SC) injection on Day 3 of each treatment cycle for up to 6 treatment cycles. Additionally, participants received the CTX regimen for up to 6 treatment cycles (Each treatment cycle lasted=21 days).

    Reporting group title
    Pegfilgrastim
    Reporting group description
    		 Participants received a single pegfilgrastim 6 mg SC injection on Day 3 of each treatment cycle for up to 6 treatment cycles. Additionally, participants received the CTX regimen for up to 6 treatment cycles (Each treatment cycle lasted=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 Grade 4 neutropenia, (that is, the number of days with absolute neutrophil count [ANC] less than [<] 0.5 * 10^9/liter in Cycle 1). Duration of severe neutropenia was calculated as the sum of all days after first dose of chemotherapy with ANC <0.5 * 10^9/liter. If ANC did not drop to <0.5 * 10^9/liter, the DSN was set to 0. Per-protocol (PP) analysis set included all participants from intent-to-treat (ITT) analysis set (ITT analysis set: all randomized participants) for whom no protocol violations were reported that may have impacted the efficacy of the IMP.
    End point type
    Primary
    End point timeframe
    Cycle 1 (21 days)
    End point values
    		 Lipegfilgrastim Pegfilgrastim
    Number of subjects analysed
    41
    44
    Units: days
        arithmetic mean (standard deviation)
    0.8 ( 0.92 )
    0.9 ( 1.11 )
    Statistical analysis title
    		 Lipegfilgrastim versus Pegfilgrastim
    Statistical analysis description
    A Poisson regression with identity link was applied including treatment, body weight class (less than or equal to [<=] 60, greater than [>] 60 to <=75, and >75 kg), and country as fixed factors and with the last ANC value measured prior to start of the IMP (baseline ANC) as a covariate.
    Comparison groups
    Lipegfilgrastim v Pegfilgrastim
    Number of subjects included in analysis
    85
    Analysis specification
    Pre-specified
    Analysis type
    		 non-inferiority [1]
    Method
    Parameter type
    		 Treatment difference
    Point estimate
    -0.3
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.7
         upper limit
    		 0.19
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.22
    Notes
    [1] - 2-sided 95% confidence interval (CI) for difference in expected DSN for lipegfilgrastim and pegfilgrastim was used to test the non-inferiority hypothesis. If upper limit of 2-sided 95% CI for the treatment difference was <1, then the non-inferiority hypothesis was regarded as confirmed.

    Secondary: Number of Participants With Febrile Neutropenia (Strict Definition) in Cycles 1 Through 6

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    End point title
    		 Number of Participants With Febrile Neutropenia (Strict Definition) in Cycles 1 Through 6
    End point description
    Febrile neutropenia was defined as (per strict definition) body temperature of greater than (>)38.5 degrees centigrade for at least 1 hour, measured orally with a certified standard device, and ANC <0.5 * 10^9/liter, including cases of neutropenic sepsis or neutropenic serious or life-threatening infection. Participants with more than 1 incidence over all cycles are counted only once. PP analysis set included all participants from ITT analysis set for whom no protocol violations were reported that may have impacted the efficacy of the IMP. Here, 'n' signifies number of participants analysed for specified categories.
    End point type
    Secondary
    End point timeframe
    Cycles 1, 2, 3, 4, 5, and 6 (each cycle = 21 days)
    End point values
    		 Lipegfilgrastim Pegfilgrastim
    Number of subjects analysed
    41
    44
    Units: participants
        Cycle 1 (n=41,44)
    1
    0
        Cycle 2 (n=40,44)
    0
    0
        Cycle 3 (n=40,42)
    0
    0
        Cycle 4 (n=40,41)
    0
    0
        Cycle 5 (n=40,39)
    0
    0
        Cycle 6 (n=38,38)
    0
    1
        Overall Cycles (n=41,44)
    1
    1
    No statistical analyses for this end point

    Secondary: Number of Participants With Febrile Neutropenia (Non-Strict Definition) in Cycles 1 Through 6

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    End point title
    		 Number of Participants With Febrile Neutropenia (Non-Strict Definition) in Cycles 1 Through 6
    End point description
    Febrile neutropenia was defined (per non-strict definition) a single body temperature value of >=38.3 degrees centigrade or >=38.0 degrees centigrade for at least 1 hour, measured orally with a certified standard device, and ANC <1 x 10^9/liter, including cases of neutropenic sepsis or neutropenic serious or life-threatening infection. PP analysis set included all participants from ITT analysis set for whom no protocol violations were reported that may have impacted the efficacy of the IMP. Here, 'n' signifies number of participants analysed for specified categories.
    End point type
    Secondary
    End point timeframe
    Cycles 1, 2, 3, 4, 5, and 6 (each cycle = 21 days)
    End point values
    		 Lipegfilgrastim Pegfilgrastim
    Number of subjects analysed
    41
    44
    Units: participants
        Cycle 1 (n=41,44)
    3
    1
        Cycle 2 (n=40,44)
    1
    0
        Cycle 3 (n=40,42)
    0
    0
        Cycle 4 (n=40,41)
    1
    0
        Cycle 5 (n=40,39)
    0
    0
        Cycle 6 (n=38,38)
    0
    1
        Overall Cycles (n=41,44)
    5
    2
    No statistical analyses for this end point

    Secondary: Number of Participants With Severe Neutropenia and Very Severe Neutropenia in Cycle 1

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    End point title
    		 Number of Participants With Severe Neutropenia and Very Severe Neutropenia in Cycle 1
    End point description
    Severe neutropenia was defined as Grade 4 neutropenia with ANC <0.5 * 10^9/liter. Very severe neutropenia was defined as ANC <0.1 * 10^9/liter. PP analysis set included all participants from ITT analysis set for whom no protocol violations were reported that may have impacted the efficacy of the IMP.
    End point type
    Secondary
    End point timeframe
    Cycle 1 (21 days)
    End point values
    		 Lipegfilgrastim Pegfilgrastim
    Number of subjects analysed
    41
    44
    Units: participants
        Severe Neutropenia
    21
    23
        Very Severe Neutropenia
    5
    8
    No statistical analyses for this end point

    Secondary: Depth of ANC Nadir in Cycle 1

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    End point title
    		 Depth of ANC Nadir in Cycle 1
    End point description
    Depth of ANC nadir in was defined as the smallest value collected following the start of CTX. PP analysis set included all participants from ITT analysis set for whom no protocol violations were reported that may have impacted the efficacy of the IMP.
    End point type
    Secondary
    End point timeframe
    Cycle 1 (21 days)
    End point values
    		 Lipegfilgrastim Pegfilgrastim
    Number of subjects analysed
    41
    44
    Units: * 10^9/liter
        arithmetic mean (standard deviation)
    1.0012 ( 1.35637 )
    1.1937 ( 1.92099 )
    No statistical analyses for this end point

    Secondary: Percentage of Participants With Severe Neutropenia in Cycle 1 lasting <1 day, <2 days, <3 days, or >=3 days

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    End point title
    		 Percentage of Participants With Severe Neutropenia in Cycle 1 lasting <1 day, <2 days, <3 days, or >=3 days
    End point description
    Severe neutropenia was defined as Grade 4 neutropenia with ANC <0.5 * 10^9/liter. The denominator for calculating percentage is the respective number of participants who participated in Cycle 1. PP analysis set included all participants from ITT analysis set for whom no protocol violations were reported that may have impacted the efficacy of the IMP.
    End point type
    Secondary
    End point timeframe
    Cycle 1 (21 days)
    End point values
    		 Lipegfilgrastim Pegfilgrastim
    Number of subjects analysed
    41
    44
    Units: percentage of participants
    number (not applicable)
        <1 day
    20
    21
        <2 days
    34
    32
        <3 days
    38
    39
        >=3 days
    3
    5
    No statistical analyses for this end point

    Secondary: Time to ANC Recovery in Cycle 1

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    End point title
    		 Time to ANC Recovery in Cycle 1
    End point description
    Time to ANC recovery in Cycle 1 was defined as the time in days from start of chemotherapy administration until the ANC increased to >=1.0 * 10^9/liter, >=1.5 * 10^9/liter, or >=2.0 * 10^9/liter after the expected nadir. If the ANC nadir value was >=1.0 * 10^9/liter, >=1.5 * 10^9/liter, or >=2.0 * 10^9/liter, as applicable, time to ANC recovery was set to 0 days. If ANC does not recover to >=1.0 * 10^9/liter, >=1.5 * 10^9/liter, or >=2.0 * 10^9/liter, time to ANC recovery was set to 22 days. PP analysis set included all participants from ITT analysis set for whom no protocol violations were reported that may have impacted the efficacy of the IMP.
    End point type
    Secondary
    End point timeframe
    Cycle 1 (21 days)
    End point values
    		 Lipegfilgrastim Pegfilgrastim
    Number of subjects analysed
    41
    44
    Units: days
    arithmetic mean (standard deviation)
        >= 1.0 * 10^9/liter
    6.2 ( 4.34 )
    6.8 ( 5.41 )
        >= 1.5 * 10^9/liter
    7.7 ( 3.69 )
    8.2 ( 4.98 )
        >= 2.0 * 10^9/liter
    8.3 ( 3.30 )
    9.4 ( 4.92 )
    No statistical analyses for this end point

    Secondary: Number of Participants With Infections in Cycles 1 Through 6

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    End point title
    		 Number of Participants With Infections in Cycles 1 Through 6
    End point description
    Infection was recorded on a separate case report form (CRF). Participants with more than 1 incidence over all cycles are counted only once. PP analysis set included all participants from ITT analysis set for whom no protocol violations were reported that may have impacted the efficacy of the IMP. Here, 'n' signifies number of participants analysed for specified categories.
    End point type
    Secondary
    End point timeframe
    Cycles 1, 2, 3, 4, 5, and 6 (each cycle = 21 days)
    End point values
    		 Lipegfilgrastim Pegfilgrastim
    Number of subjects analysed
    41
    44
    Units: participants
        Cycle 1 (n=41,44)
    6
    4
        Cycle 2 (n=40,44)
    3
    3
        Cycle 3 (n=40,42)
    3
    0
        Cycle 4 (n=40,41)
    4
    0
        Cycle 5 (n=40,39)
    1
    1
        Cycle 6 (n=38,38)
    4
    3
        Overall Cycles (n=41,44)
    16
    6
    No statistical analyses for this end point

    Secondary: Number of Participants who Were Hospitalized due to Febrile Neutropenia During Cycles 1 Through 6

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    End point title
    		 Number of Participants who Were Hospitalized due to Febrile Neutropenia During Cycles 1 Through 6
    End point description
    PP analysis set included all participants from ITT analysis set for whom no protocol violations were reported that may have impacted the efficacy of the IMP. Here, 'n' signifies number of participants analysed for specified categories.
    End point type
    Secondary
    End point timeframe
    Cycles 1, 2, 3, 4, 5, and 6 (each cycle = 21 days)
    End point values
    		 Lipegfilgrastim Pegfilgrastim
    Number of subjects analysed
    41
    44
    Units: participants
        Cycle 1 (n=41,44)
    5
    1
        Cycle 2 (n=40,44)
    0
    0
        Cycle 3 (n=40,42)
    0
    0
        Cycle 4 (n=40,41)
    0
    0
        Cycle 5 (n=40,39)
    0
    0
        Cycle 6 (n=38,38)
    0
    0
    No statistical analyses for this end point

    Secondary: Duration of Hospitalization Due to Febrile Neutropenia and All Causes During Cycles 1 Through 6

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    End point title
    		 Duration of Hospitalization Due to Febrile Neutropenia and All Causes During Cycles 1 Through 6
    End point description
    PP analysis set included all participants from ITT analysis set for whom no protocol violations were reported that may have impacted the efficacy of the IMP. Here, 'n' signifies number of participants who were hospitalized. Here; '99999' signifies 'due to single participant, SD could not be calculated'.
    End point type
    Secondary
    End point timeframe
    Cycles 1, 2, 3, 4, 5, and 6 (each cycle = 21 days)
    End point values
    		 Lipegfilgrastim Pegfilgrastim
    Number of subjects analysed
    41
    44
    Units: days
    arithmetic mean (standard deviation)
        Due to Febrile Neutropenia (n=5,1)
    8.6 ( 4.28 )
    5.0 ( 99999 )
        Due to All Causes (n=13,17)
    9.4 ( 4.21 )
    10.2 ( 8.15 )
    No statistical analyses for this end point

    Secondary: Duration of Intensive Care Unit (ICU) Stay Due to Febrile Neutropenia and All Causes During Cycles 1 Through 6

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    End point title
    		 Duration of Intensive Care Unit (ICU) Stay Due to Febrile Neutropenia and All Causes During Cycles 1 Through 6
    End point description
    PP analysis set included all participants from ITT analysis set for whom no protocol violations were reported that may have impacted the efficacy of the IMP. Here, 'n' signifies number of participants who stayed in ICU. Here, 99999 signifies data not available as none of the participants stayed in ICU due to febrile neutropenia. Here; '9999' signifies 'due to single participant, SD could not be calculated'.
    End point type
    Secondary
    End point timeframe
    Cycles 1, 2, 3, 4, 5, and 6 (each cycle = 21 days)
    End point values
    		 Lipegfilgrastim Pegfilgrastim
    Number of subjects analysed
    41
    44
    Units: days
    arithmetic mean (standard deviation)
        Due to Febrile Neutropenia (n=0,0)
    99999 ( 99999 )
    99999 ( 99999 )
        Due to All Causes (n=0,1)
    99999 ( 99999 )
    2.0 ( 9999 )
    No statistical analyses for this end point

    Secondary: Number of Participants who Were Treated With IV and Oral Antibiotics due to Febrile Neutropenia in Cycles 1 Through 6

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    End point title
    		 Number of Participants who Were Treated With IV and Oral Antibiotics due to Febrile Neutropenia in Cycles 1 Through 6
    End point description
    The incidence of use of antibiotics (either iv or oral) as treatment or prophylaxis for febrile neutropenia is presented. Prophylaxis with systemically (iv, intramuscular, or oral) active antibiotics was defined as prohibited concomitant medication in the study (except for participants with an individual high risk of infection as assessed by the investigator). Participants with more than 1 incidence over all cycles are counted only once. PP analysis set included all participants from ITT analysis set for whom no protocol violations were reported that may have impacted the efficacy of the IMP.
    End point type
    Secondary
    End point timeframe
    Cycles 1, 2, 3, 4, 5, and 6 (each cycle = 21 days)
    End point values
    		 Lipegfilgrastim Pegfilgrastim
    Number of subjects analysed
    41
    44
    Units: participants
    16
    4
    No statistical analyses for this end point

    Secondary: Cumulative Percentage of Actually Delivered Versus Scheduled Cumulative Chemotherapy Dose in Cycles 1 Through 6

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    End point title
    		 Cumulative Percentage of Actually Delivered Versus Scheduled Cumulative Chemotherapy Dose in Cycles 1 Through 6
    End point description
    The chemotherapy regimen administered consisted of R-CHOP every 21 days for up to 6 cycles according to local standards. Cumulative percentage was defined as: 100*(total dose taken) / (scheduled dose per cycle according to protocol * number of cycles the participant participated in). PP analysis set included all participants from ITT analysis set for whom no protocol violations were reported that may have impacted the efficacy of the IMP. Here, 'n' signifies number of participants analysed for specified categories.
    End point type
    Secondary
    End point timeframe
    Cycles 1, 2, 3, 4, 5, and 6 (each cycle = 21 days)
    End point values
    		 Lipegfilgrastim Pegfilgrastim
    Number of subjects analysed
    41
    44
    Units: percentage of dose
    arithmetic mean (standard deviation)
        Rituximab (n=41,44)
    105.2 ( 25.40 )
    102.8 ( 15.21 )
        Cyclophosphamide (n=41,44)
    104.3 ( 19.80 )
    106.3 ( 20.24 )
        Doxorubicin (n=41,44)
    107.8 ( 29.86 )
    106.0 ( 21.22 )
        Vincristine (n=41,44)
    297.7 ( 1397.91 )
    75.1 ( 30.22 )
        Prednisone (n=31,38)
    96.2 ( 10.85 )
    98.2 ( 6.45 )
    No statistical analyses for this end point

    Secondary: Percentage of Participants With Protocol Deviations of Prescribed Administration of Chemotherapy in Cycles 1 Through 6

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    End point title
    		 Percentage of Participants With Protocol Deviations of Prescribed Administration of Chemotherapy in Cycles 1 Through 6
    End point description
    Insufficient or wrong CTX administered in Cycle 1, and delayed or omitted CTX over Cycles 2 to 6 were protocol deviations of prescribed CTX and are presented. For summary by cycle, the denominator for calculating percentages is number of participants who participated in that cycle. Starting from Cycle 2, delayed dose was defined as number of days from date of dose to the previous dose larger than 21 days. If number of days from the dose to previous dose was > 5 weeks (35 days), omitted dose was identified. In case a delayed or omitted dose in 1 cycle occurred, the schedule for subsequent treatment was adjusted (so that redundancies in delays from original schedule would not impact subsequent reporting). PP analysis set included all participants from ITT analysis set for whom no protocol violations were reported that may have impacted the efficacy of the IMP. Here, 'n' signifies number of participants analysed for specified categories.
    End point type
    Secondary
    End point timeframe
    Cycles 1, 2, 3, 4, 5, and 6 (each cycle = 21 days)
    End point values
    		 Lipegfilgrastim Pegfilgrastim
    Number of subjects analysed
    41
    44
    Units: percentage of participants
    number (not applicable)
        Cycle 1 Insufficient (n=41,44)
    1
    1
        Cycle 1 Wrong (n=41,44)
    0
    0
        Cycles 2-6 Delayed (n=40,44)
    32
    33
        Cycles 2-6 Omitted (n=40,44)
    0
    2
    No statistical analyses for this end point

    Secondary: Percentage of Participants With Chemotherapy Doses Reduced in Cycles 1 Through 6

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    End point title
    		 Percentage of Participants With Chemotherapy Doses Reduced in Cycles 1 Through 6
    End point description
    For summary by cycle, the denominator for calculating percentages is the number of participants who participated in that cycle. PP analysis set included all participants from ITT analysis set for whom no protocol violations were reported that may have impacted the efficacy of the IMP. Here, 'n' signifies number of participants analysed for specified categories.
    End point type
    Secondary
    End point timeframe
    Cycles 1, 2, 3, 4, 5, and 6 (each cycle = 21 days)
    End point values
    		 Lipegfilgrastim Pegfilgrastim
    Number of subjects analysed
    41
    44
    Units: percentage of participants
    number (not applicable)
        Rituximab (n=40,44)
    0
    1
        Cyclophosphamide (n=40,44)
    5
    3
        Doxorubicin (n=40,44)
    5
    4
        Vincristine (n=40,42)
    23
    15
        Prednisone (n=30,38)
    7
    4
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    All adverse events that occurred after IMP administration in Cycle 1 through the end of treatment visit (Day 126), and deaths that occurred up to end of follow-up visit (Day 270) are reported.
    Adverse event reporting additional description
    Safety analysis set included all randomized participants who received at least 1 dose or partial dose of the IMP.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    20.0
    Reporting groups
    Reporting group title
    Pegfilgrastim
    Reporting group description
    		 Participants received a single pegfilgrastim 6 mg SC injection on Day 3 of each treatment cycle for up to 6 treatment cycles. Additionally, participants received the CTX regimen for up to 6 treatment cycles (Each treatment cycle lasted=21 days).

    Reporting group title
    Lipegfilgrastim
    Reporting group description
    		 Participants received a single lipegfilgrastim 6 mg SC injection on Day 3 of each treatment cycle for up to 6 treatment cycles. Additionally, participants received the CTX regimen for up to 6 treatment cycles (Each treatment cycle lasted=21 days).

    Serious adverse events
    		 Pegfilgrastim Lipegfilgrastim
    Total subjects affected by serious adverse events
         subjects affected / exposed
    23 / 50 (46.00%)
    21 / 46 (45.65%)
         number of deaths (all causes)
    5
    2
         number of deaths resulting from adverse events
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Burkitt's lymphoma
         subjects affected / exposed
    1 / 50 (2.00%)
    0 / 46 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Diffuse large B-cell lymphoma
         subjects affected / exposed
    1 / 50 (2.00%)
    0 / 46 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Metastases to central nervous system
         subjects affected / exposed
    1 / 50 (2.00%)
    1 / 46 (2.17%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Non-Hodgkin's lymphoma
         subjects affected / exposed
    3 / 50 (6.00%)
    2 / 46 (4.35%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 2
         deaths causally related to treatment / all
    0 / 3
    0 / 1
    Pancreatic carcinoma
         subjects affected / exposed
    0 / 50 (0.00%)
    1 / 46 (2.17%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vascular disorders
    Embolism
         subjects affected / exposed
    0 / 50 (0.00%)
    1 / 46 (2.17%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lymphocele
         subjects affected / exposed
    1 / 50 (2.00%)
    0 / 46 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Asthenia
         subjects affected / exposed
    1 / 50 (2.00%)
    0 / 46 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gait disturbance
         subjects affected / exposed
    1 / 50 (2.00%)
    0 / 46 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    General physical health deterioration
         subjects affected / exposed
    1 / 50 (2.00%)
    3 / 46 (6.52%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Malaise
         subjects affected / exposed
    0 / 50 (0.00%)
    1 / 46 (2.17%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Non-cardiac chest pain
         subjects affected / exposed
    0 / 50 (0.00%)
    1 / 46 (2.17%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Oedema peripheral
         subjects affected / exposed
    1 / 50 (2.00%)
    0 / 46 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Performance status decreased
         subjects affected / exposed
    1 / 50 (2.00%)
    0 / 46 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Peripheral swelling
         subjects affected / exposed
    1 / 50 (2.00%)
    0 / 46 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pyrexia
         subjects affected / exposed
    1 / 50 (2.00%)
    1 / 46 (2.17%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Dyspnoea
         subjects affected / exposed
    1 / 50 (2.00%)
    1 / 46 (2.17%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Idiopathic pulmonary fibrosis
         subjects affected / exposed
    0 / 50 (0.00%)
    1 / 46 (2.17%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pleural effusion
         subjects affected / exposed
    0 / 50 (0.00%)
    1 / 46 (2.17%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonitis
         subjects affected / exposed
    1 / 50 (2.00%)
    0 / 46 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Psychiatric disorders
    Confusional state
         subjects affected / exposed
    1 / 50 (2.00%)
    1 / 46 (2.17%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Product issues
    Device dislocation
         subjects affected / exposed
    0 / 50 (0.00%)
    1 / 46 (2.17%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Fall
         subjects affected / exposed
    0 / 50 (0.00%)
    1 / 46 (2.17%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Femur fracture
         subjects affected / exposed
    1 / 50 (2.00%)
    0 / 46 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Spinal compression fracture
         subjects affected / exposed
    0 / 50 (0.00%)
    1 / 46 (2.17%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Suture rupture
         subjects affected / exposed
    1 / 50 (2.00%)
    0 / 46 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac disorders
    Acute myocardial infarction
         subjects affected / exposed
    1 / 50 (2.00%)
    1 / 46 (2.17%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Arrhythmia
         subjects affected / exposed
    0 / 50 (0.00%)
    1 / 46 (2.17%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Atrial fibrillation
         subjects affected / exposed
    2 / 50 (4.00%)
    1 / 46 (2.17%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac failure congestive
         subjects affected / exposed
    0 / 50 (0.00%)
    1 / 46 (2.17%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Stress cardiomyopathy
         subjects affected / exposed
    0 / 50 (0.00%)
    1 / 46 (2.17%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nervous system disorders
    Cerebrovascular accident
         subjects affected / exposed
    1 / 50 (2.00%)
    0 / 46 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Coma
         subjects affected / exposed
    1 / 50 (2.00%)
    0 / 46 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Epilepsy
         subjects affected / exposed
    1 / 50 (2.00%)
    0 / 46 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Monoparesis
         subjects affected / exposed
    0 / 50 (0.00%)
    1 / 46 (2.17%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Orthostatic intolerance
         subjects affected / exposed
    1 / 50 (2.00%)
    0 / 46 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Syncope
         subjects affected / exposed
    1 / 50 (2.00%)
    2 / 46 (4.35%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    0 / 50 (0.00%)
    1 / 46 (2.17%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Febrile neutropenia
         subjects affected / exposed
    1 / 50 (2.00%)
    4 / 46 (8.70%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Neutropenia
         subjects affected / exposed
    1 / 50 (2.00%)
    0 / 46 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Colitis ischaemic
         subjects affected / exposed
    1 / 50 (2.00%)
    0 / 46 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Constipation
         subjects affected / exposed
    0 / 50 (0.00%)
    1 / 46 (2.17%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ileus
         subjects affected / exposed
    1 / 50 (2.00%)
    0 / 46 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nausea
         subjects affected / exposed
    1 / 50 (2.00%)
    0 / 46 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Oesophagitis
         subjects affected / exposed
    0 / 50 (0.00%)
    1 / 46 (2.17%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vomiting
         subjects affected / exposed
    1 / 50 (2.00%)
    0 / 46 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Skin and subcutaneous tissue disorders
    Diabetic foot
         subjects affected / exposed
    0 / 50 (0.00%)
    1 / 46 (2.17%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal and urinary disorders
    Acute kidney injury
         subjects affected / exposed
    0 / 50 (0.00%)
    1 / 46 (2.17%)
         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
    Back pain
         subjects affected / exposed
    0 / 50 (0.00%)
    1 / 46 (2.17%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bone pain
         subjects affected / exposed
    1 / 50 (2.00%)
    0 / 46 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bursitis
         subjects affected / exposed
    1 / 50 (2.00%)
    0 / 46 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Osteoporotic fracture
         subjects affected / exposed
    1 / 50 (2.00%)
    0 / 46 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Systemic lupus erythematosus
         subjects affected / exposed
    0 / 50 (0.00%)
    1 / 46 (2.17%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infections and infestations
    Abscess neck
         subjects affected / exposed
    1 / 50 (2.00%)
    0 / 46 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bronchitis
         subjects affected / exposed
    0 / 50 (0.00%)
    1 / 46 (2.17%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infection
         subjects affected / exposed
    0 / 50 (0.00%)
    1 / 46 (2.17%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infectious pleural effusion
         subjects affected / exposed
    0 / 50 (0.00%)
    1 / 46 (2.17%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nail bed infection
         subjects affected / exposed
    0 / 50 (0.00%)
    1 / 46 (2.17%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Neutropenic infection
         subjects affected / exposed
    0 / 50 (0.00%)
    1 / 46 (2.17%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonia
         subjects affected / exposed
    1 / 50 (2.00%)
    1 / 46 (2.17%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonia influenzal
         subjects affected / exposed
    0 / 50 (0.00%)
    1 / 46 (2.17%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Sepsis
         subjects affected / exposed
    1 / 50 (2.00%)
    0 / 46 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Tooth abscess
         subjects affected / exposed
    1 / 50 (2.00%)
    0 / 46 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Upper respiratory tract infection
         subjects affected / exposed
    1 / 50 (2.00%)
    0 / 46 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Urinary tract infection
         subjects affected / exposed
    1 / 50 (2.00%)
    0 / 46 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vaginal infection
         subjects affected / exposed
    0 / 50 (0.00%)
    1 / 46 (2.17%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Dehydration
         subjects affected / exposed
    2 / 50 (4.00%)
    1 / 46 (2.17%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypokalaemia
         subjects affected / exposed
    2 / 50 (4.00%)
    0 / 46 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hyponatraemia
         subjects affected / exposed
    1 / 50 (2.00%)
    0 / 46 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Metabolic acidosis
         subjects affected / exposed
    1 / 50 (2.00%)
    0 / 46 (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
    		 Pegfilgrastim Lipegfilgrastim
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    48 / 50 (96.00%)
    44 / 46 (95.65%)
    Investigations
    C-reactive protein increased
         subjects affected / exposed
    1 / 50 (2.00%)
    4 / 46 (8.70%)
         occurrences all number
    1
    4
    Neutrophil count decreased
         subjects affected / exposed
    3 / 50 (6.00%)
    3 / 46 (6.52%)
         occurrences all number
    14
    11
    Weight decreased
         subjects affected / exposed
    10 / 50 (20.00%)
    3 / 46 (6.52%)
         occurrences all number
    13
    3
    White blood cell count decreased
         subjects affected / exposed
    2 / 50 (4.00%)
    5 / 46 (10.87%)
         occurrences all number
    16
    17
    Vascular disorders
    Hypotension
         subjects affected / exposed
    4 / 50 (8.00%)
    3 / 46 (6.52%)
         occurrences all number
    5
    3
    Nervous system disorders
    Dizziness
         subjects affected / exposed
    6 / 50 (12.00%)
    8 / 46 (17.39%)
         occurrences all number
    8
    8
    Dysgeusia
         subjects affected / exposed
    5 / 50 (10.00%)
    4 / 46 (8.70%)
         occurrences all number
    5
    6
    Headache
         subjects affected / exposed
    7 / 50 (14.00%)
    4 / 46 (8.70%)
         occurrences all number
    9
    5
    Neuropathy peripheral
         subjects affected / exposed
    2 / 50 (4.00%)
    3 / 46 (6.52%)
         occurrences all number
    2
    4
    Paraesthesia
         subjects affected / exposed
    2 / 50 (4.00%)
    4 / 46 (8.70%)
         occurrences all number
    4
    7
    Peripheral sensory neuropathy
         subjects affected / exposed
    2 / 50 (4.00%)
    6 / 46 (13.04%)
         occurrences all number
    5
    6
    Polyneuropathy
         subjects affected / exposed
    10 / 50 (20.00%)
    9 / 46 (19.57%)
         occurrences all number
    10
    10
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    20 / 50 (40.00%)
    12 / 46 (26.09%)
         occurrences all number
    31
    19
    Leukocytosis
         subjects affected / exposed
    3 / 50 (6.00%)
    2 / 46 (4.35%)
         occurrences all number
    4
    6
    Leukopenia
         subjects affected / exposed
    9 / 50 (18.00%)
    7 / 46 (15.22%)
         occurrences all number
    17
    8
    Neutropenia
         subjects affected / exposed
    15 / 50 (30.00%)
    17 / 46 (36.96%)
         occurrences all number
    28
    44
    Thrombocytopenia
         subjects affected / exposed
    5 / 50 (10.00%)
    5 / 46 (10.87%)
         occurrences all number
    5
    9
    General disorders and administration site conditions
    Asthenia
         subjects affected / exposed
    6 / 50 (12.00%)
    7 / 46 (15.22%)
         occurrences all number
    6
    14
    Fatigue
         subjects affected / exposed
    16 / 50 (32.00%)
    12 / 46 (26.09%)
         occurrences all number
    24
    17
    Mucosal inflammation
         subjects affected / exposed
    6 / 50 (12.00%)
    5 / 46 (10.87%)
         occurrences all number
    8
    6
    Oedema peripheral
         subjects affected / exposed
    5 / 50 (10.00%)
    9 / 46 (19.57%)
         occurrences all number
    6
    18
    Pyrexia
         subjects affected / exposed
    3 / 50 (6.00%)
    7 / 46 (15.22%)
         occurrences all number
    4
    9
    Gastrointestinal disorders
    Abdominal pain
         subjects affected / exposed
    5 / 50 (10.00%)
    2 / 46 (4.35%)
         occurrences all number
    5
    2
    Abdominal pain upper
         subjects affected / exposed
    3 / 50 (6.00%)
    6 / 46 (13.04%)
         occurrences all number
    5
    6
    Aphthous ulcer
         subjects affected / exposed
    0 / 50 (0.00%)
    3 / 46 (6.52%)
         occurrences all number
    0
    3
    Constipation
         subjects affected / exposed
    16 / 50 (32.00%)
    18 / 46 (39.13%)
         occurrences all number
    17
    18
    Diarrhoea
         subjects affected / exposed
    16 / 50 (32.00%)
    9 / 46 (19.57%)
         occurrences all number
    22
    10
    Dry mouth
         subjects affected / exposed
    3 / 50 (6.00%)
    3 / 46 (6.52%)
         occurrences all number
    3
    3
    Nausea
         subjects affected / exposed
    18 / 50 (36.00%)
    10 / 46 (21.74%)
         occurrences all number
    21
    19
    Stomatitis
         subjects affected / exposed
    4 / 50 (8.00%)
    6 / 46 (13.04%)
         occurrences all number
    4
    8
    Vomiting
         subjects affected / exposed
    6 / 50 (12.00%)
    6 / 46 (13.04%)
         occurrences all number
    7
    9
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    4 / 50 (8.00%)
    9 / 46 (19.57%)
         occurrences all number
    4
    9
    Dyspnoea
         subjects affected / exposed
    4 / 50 (8.00%)
    7 / 46 (15.22%)
         occurrences all number
    4
    9
    Oropharyngeal pain
         subjects affected / exposed
    1 / 50 (2.00%)
    3 / 46 (6.52%)
         occurrences all number
    1
    3
    Skin and subcutaneous tissue disorders
    Alopecia
         subjects affected / exposed
    13 / 50 (26.00%)
    16 / 46 (34.78%)
         occurrences all number
    17
    19
    Erythema
         subjects affected / exposed
    0 / 50 (0.00%)
    3 / 46 (6.52%)
         occurrences all number
    0
    3
    Rash
         subjects affected / exposed
    3 / 50 (6.00%)
    1 / 46 (2.17%)
         occurrences all number
    3
    1
    Psychiatric disorders
    Insomnia
         subjects affected / exposed
    3 / 50 (6.00%)
    4 / 46 (8.70%)
         occurrences all number
    4
    6
    Restlessness
         subjects affected / exposed
    3 / 50 (6.00%)
    3 / 46 (6.52%)
         occurrences all number
    3
    3
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    1 / 50 (2.00%)
    4 / 46 (8.70%)
         occurrences all number
    1
    5
    Back pain
         subjects affected / exposed
    4 / 50 (8.00%)
    4 / 46 (8.70%)
         occurrences all number
    4
    11
    Flank pain
         subjects affected / exposed
    3 / 50 (6.00%)
    0 / 46 (0.00%)
         occurrences all number
    3
    0
    Infections and infestations
    Bronchitis
         subjects affected / exposed
    0 / 50 (0.00%)
    3 / 46 (6.52%)
         occurrences all number
    0
    3
    Conjunctivitis
         subjects affected / exposed
    3 / 50 (6.00%)
    1 / 46 (2.17%)
         occurrences all number
    3
    1
    Herpes zoster
         subjects affected / exposed
    3 / 50 (6.00%)
    2 / 46 (4.35%)
         occurrences all number
    4
    2
    Oral candidiasis
         subjects affected / exposed
    3 / 50 (6.00%)
    1 / 46 (2.17%)
         occurrences all number
    3
    2
    Urinary tract infection
         subjects affected / exposed
    0 / 50 (0.00%)
    3 / 46 (6.52%)
         occurrences all number
    0
    3
    Viral upper respiratory tract infection
         subjects affected / exposed
    3 / 50 (6.00%)
    4 / 46 (8.70%)
         occurrences all number
    5
    4
    Metabolism and nutrition disorders
    Decreased appetite
         subjects affected / exposed
    5 / 50 (10.00%)
    5 / 46 (10.87%)
         occurrences all number
    6
    5
    Hypokalaemia
         subjects affected / exposed
    6 / 50 (12.00%)
    5 / 46 (10.87%)
         occurrences all number
    10
    9

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    13 Aug 2014
    There were 5 amendments after start of recruitment. The following major procedural changes (not all-inclusive) were made to the protocol via amendment 1: 1. Organizational changes to the clinical study personnel were made. 2. A study objective to further characterize exposure-response relationship for lipegfilgrastim was deleted. 3. The planned study period was changed to “March 2014 to March 2016”, with duration of 24 months excluding the follow-up period. 4. Procedures for Screening and Enrollment were clarified to specify that laboratory tests may be only used if performed within 8 days prior to screening in the local laboratory qualified for the study.
    02 Feb 2015
    The following major procedural changes (not all-inclusive) were made to the protocol: 1. The statistical considerations were revised. The sample size was recalculated to 100 participants (from 150 participants), as part of an internal review process, to confirm sufficient power with a smaller sample size. This resulted in a decrease in the number of investigational centers to 60 (from 70), decrease in countries planned to 3 (from 4), and a change in the planned study period to “March 2014 to September 2016”. 2. A secondary objective of the study was clarified to indicate that the characterization of the immunogenicity of lipegfilgrastim was “in comparison to pegfilgrastim”. 3. It was clarified that anti-drug antibodies (ADA) samples were taken both from participants treated with lipegfilgrastim and pegfilgrastim. 4. It was clarified that the end of the study would occur after the last participant has had his/her End-of-Treatment Visit (EOV).
    25 Jun 2015
    The following major procedural changes (not all-inclusive) were made to the protocol: 1. The planned study period was extended to March 2017. 2. A cap of 1.0 mg on the dose of vincristine 1.4 mg/m^2 on Day 2 was added for safety of participants older than 65 years. 3. A section was added to define a clinical product complaint and to detail reporting and documenting procedures.
    27 Apr 2016
    The following major procedural changes (not all-inclusive) were made to the protocol: 1. The Study Procedures and Assessments section was modified to include urinalysis monitoring, which has been added to align with the update to the Special Warnings and Precautions for Use section of the NEULASTA (pegfilgrastim) (NEULASTA SmPC). Urinalysis could be performed at the investigational center. 2. Details that urinalysis tests could be performed according to local standards and included at least protein, glucose, blood, leucocytes, and pH were added.
    22 Nov 2017
    The following changes (not all-inclusive) were made to the protocol. 1. The definition of the end of the study was modified to “as after the last participant has had his/her last follow-up visit”. 2. Due to a delay in recruitment, the date of the Last Participant List Visit was postponed to May 2018 (including follow-up) for a duration of 50 months. 3. It was clarified that body weight and height (screening only) was to be conducted at screening, at baseline and at end of study visit (or early termination).

    Interruptions (globally)
    Were there any global interruptions to the trial? Yes
    Date
    Interruption
    Restart date
    01 Apr 2014
    The study recruitment halted because 1 batch of lipegfilgrastim was put on hold due to failed acceptance criteria test for stability.
    -

    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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