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    Clinical Trial Results:
    Safety and Efficacy of LONQUEX® (Lipegfilgrastim) in Comparison to Pegfilgrastim (NEULASTA®, Amgen Inc.) and Placebo in Patients with Non-Small-Cell Lung Cancer Receiving First-Line Chemotherapy

    Summary
    EudraCT number
    		 2014-005096-85
    Trial protocol
    		 SK   HU   LV   PL   GR   BG   ES   HR  
    Global end of trial date
    09 Feb 2018

    Results information
    Results version number
    		 v1(current)
    This version publication date
    14 Mar 2019
    First version publication date
    14 Mar 2019
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    XM22-ONC-40041
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 -
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Merckle GmbH
    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)
    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
    09 Feb 2018
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    09 Feb 2018
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The primary objective of this study was to collect comparative data for lipegfilgrastim, pegfilgrastim, and placebo in participants with advanced squamous or non-squamous non-small-cell lung cancer (NSCLC) Stage IIIB/IV, including full details of disease progression (whether or not leading to death) and mortality, for detailed clinical review.
    Protection of trial subjects
    This study was conducted in full accordance with the International Conference on Harmonisation (ICH) Good Clinical Practice (GCP) Consolidated Guideline (E6) and any applicable national and local laws and regulations (Code of Federal Regulations Title 21, Parts 50, 54, 56, 312, and 314; European Union [EU] 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). Written and/or oral information about the study was provided to all participants in a language understandable by the participants. The information included an adequate explanation of the aims, methods, anticipated benefits, potential hazards, and insurance arrangements in force. Written informed consent was obtained from each participant before any study procedures or assessments were done. It was explained to the participants that they were free to refuse entry into the study and free to withdraw from the study at any time without prejudice to future treatment.
    Background therapy
    		 Chemotherapy (CTX) regimens were administered intravenously (IV) every 3 weeks up to 6 cycles (each cycle=21 days). CTX regimen comprised: cisplatin 75 milligrams per square meter (mg/m^2) body surface and pemetrexed 500 mg/m^2 body surface on Day 1 of each cycle, or cisplatin 75 mg/m^2 body surface and docetaxel 75 mg/m^2 body surface on Day 1 of each cycle, or paclitaxel 135 mg/m^2 body surface on Day 0 and cisplatin 75 mg/m^2 body surface on Day 1 of each cycle. All participants treated with CTX were allowed to take dexamethasone as a prophylactic measure to reduce toxicity according to the local standard.
    Evidence for comparator
    		 -
    Actual start date of recruitment
    07 Aug 2015
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    No
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Belarus: 8
    Country: Number of subjects enrolled
    Bulgaria: 6
    Country: Number of subjects enrolled
    Hungary: 2
    Country: Number of subjects enrolled
    Latvia: 8
    Country: Number of subjects enrolled
    Romania: 13
    Country: Number of subjects enrolled
    Russian Federation: 93
    Country: Number of subjects enrolled
    Serbia: 5
    Country: Number of subjects enrolled
    Slovakia: 1
    Country: Number of subjects enrolled
    Turkey: 5
    Country: Number of subjects enrolled
    Ukraine: 162
    Worldwide total number of subjects
    303
    EEA total number of subjects
    30
    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)
    216
    From 65 to 84 years
    87
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 A total of 340 participants were screened, of which 303 were enrolled and randomized in 1:1:1 ratio to lipegfilgrastim, pegfilgrastim, or placebo. 37 participants were screen failures due to inclusion criteria not met or exclusion criteria met.

    Pre-assignment
    Screening details
    		 One participant was randomized to pegfilgrastim but was treated with lipegfilgrastim. This participant was in the lipegfilgrastim group for Safety Population and in the pegfilgrastim group for all other groups.

    Period 1
    Period 1 title
    Overall Study (overall period)
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Subject, Investigator

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Lipegfilgrastim
    Arm description
    		 Participants received lipegfilgrastim 6 milligrams (mg) subcutaneous (SC) injection on Day 2 and CTX regimen IV on Day 1 of each CTX cycle over 6 CTX cycles (each cycle=21 days).
    Arm type
    		 Experimental

    Investigational medicinal product name
    Lipegfilgrastim
    Investigational medicinal product code
    Other name
    LONQUEX®
    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 2 of each cycle.

    Arm title
    		 Pegfilgrastim
    Arm description
    		 Participants received pegfilgrastim 6 mg SC injection on Day 2 and CTX regimen IV on Day 1 of each CTX cycle over 6 CTX cycles (each cycle=21 days).
    Arm type
    		 Active comparator

    Investigational medicinal product name
    Pegfilgrastim
    Investigational medicinal product code
    Other name
    NEULASTA®
    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 2 of each cycle.

    Arm title
    		 Placebo
    Arm description
    		 Participants received placebo matched to lipegfilgrastim SC injection on Day 2 and CTX regimen IV on Day 1 of each CTX cycle over 6 CTX cycles (each cycle=21 days).
    Arm type
    		 Placebo

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection in pre-filled syringe
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    Placebo matched to lipegfilgrastim was administered on Day 2 of each cycle.

    Number of subjects in period 1
    		Lipegfilgrastim Pegfilgrastim Placebo
    Started
    101
    101
    101
    Treated
    95
    98
    98
    Completed
    14
    11
    14
    Not completed
    87
    90
    87
         Clinical progression
    -
    1
    -
         Consent withdrawn by subject
    8
    11
    11
         Death
    64
    71
    64
         Adverse event
    3
    1
    1
         Other than specified
    1
    -
    -
         Lost to follow-up
    10
    6
    11
         Protocol deviation
    1
    -
    -

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Lipegfilgrastim
    Reporting group description
    		 Participants received lipegfilgrastim 6 milligrams (mg) subcutaneous (SC) injection on Day 2 and CTX regimen IV on Day 1 of each CTX cycle over 6 CTX cycles (each cycle=21 days).

    Reporting group title
    Pegfilgrastim
    Reporting group description
    		 Participants received pegfilgrastim 6 mg SC injection on Day 2 and CTX regimen IV on Day 1 of each CTX cycle over 6 CTX cycles (each cycle=21 days).

    Reporting group title
    Placebo
    Reporting group description
    		 Participants received placebo matched to lipegfilgrastim SC injection on Day 2 and CTX regimen IV on Day 1 of each CTX cycle over 6 CTX cycles (each cycle=21 days).

    Reporting group values
    		 Lipegfilgrastim Pegfilgrastim Placebo Total
    Number of subjects
    		 101 101 101 303
    Age Categorical
    Units: Subjects
    Age Continuous
    Units: years
        arithmetic mean (standard deviation)
    		 60.5 ± 7.17 58.9 ± 7.55 59.5 ± 8.24 -
    Gender Categorical
    Units: Subjects
        Female
    		 15 18 25 58
        Male
    		 86 83 76 245
    Race
    Units: Subjects
        White
    		 101 101 101 303

    End points

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    End points reporting groups
    Reporting group title
    Lipegfilgrastim
    Reporting group description
    		 Participants received lipegfilgrastim 6 milligrams (mg) subcutaneous (SC) injection on Day 2 and CTX regimen IV on Day 1 of each CTX cycle over 6 CTX cycles (each cycle=21 days).

    Reporting group title
    Pegfilgrastim
    Reporting group description
    		 Participants received pegfilgrastim 6 mg SC injection on Day 2 and CTX regimen IV on Day 1 of each CTX cycle over 6 CTX cycles (each cycle=21 days).

    Reporting group title
    Placebo
    Reporting group description
    		 Participants received placebo matched to lipegfilgrastim SC injection on Day 2 and CTX regimen IV on Day 1 of each CTX cycle over 6 CTX cycles (each cycle=21 days).

    Primary: Progression-Free Survival (PFS) as Assessed by Central Reader According to Response Evaluation Criteria in Solid Tumors (RECIST) Version 1.1

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    End point title
    		 Progression-Free Survival (PFS) as Assessed by Central Reader According to Response Evaluation Criteria in Solid Tumors (RECIST) Version 1.1
    End point description
    PFS was defined as time from randomization to the first objectively documented progression per RECIST version 1.1 or death due to any cause, whichever occurred first, as documented by the central reader. Participants who did not have disease progression until the end of the study or discontinued the study early before disease progression was documented were censored at the time of their latest evaluable RECIST assessments. Disease progression: At least a 20 percent (%) increase in the sum of diameters of target lesions, taking as reference the smallest sum on study In addition to the relative increase of 20%, the sum also demonstrated an absolute increase of at least 5 millimeters (mm). Unequivocal progression of existing non-target lesions. The appearance of 1 or more new lesions was also considered progression. Safety population included all enrolled and randomized participants who received at least 1 injection of lipegfilgrastim, pegfilgrastim, or placebo.
    End point type
    Primary
    End point timeframe
    From randomization to the first objectively documented progression or death due to any cause, whichever occurred first (up to a maximum duration of 928 days)
    End point values
    		 Lipegfilgrastim Pegfilgrastim Placebo
    Number of subjects analysed
    95
    98
    98
    Units: months
        median (confidence interval 95%)
    5.9 (5.20 to 7.90)
    4.6 (4.10 to 5.80)
    5.8 (5.20 to 7.10)
    Statistical analysis title
    		 Lipegfilgrastim versus Pegfilgrastim
    Statistical analysis description
    Hazard ratio and corresponding 95% confidence interval (CI) were based on a Cox proportional hazard model fitting treatment as explanatory variable.
    Comparison groups
    Lipegfilgrastim v Pegfilgrastim
    Number of subjects included in analysis
    193
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.0865
    Method
    		 Logrank
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.77
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.569
         upper limit
    		 1.034
    Statistical analysis title
    		 Lipegfilgrastim versus Placebo
    Statistical analysis description
    Hazard ratio and corresponding 95% CI were based on a Cox proportional hazard model fitting treatment as explanatory variable.
    Comparison groups
    Lipegfilgrastim v Placebo
    Number of subjects included in analysis
    193
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.8114
    Method
    		 Logrank
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.96
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.713
         upper limit
    		 1.296
    Statistical analysis title
    		 Pegfilgrastim versus Placebo
    Statistical analysis description
    Hazard ratio and corresponding 95% CI were based on a Cox proportional hazard model fitting treatment as explanatory variable.
    Comparison groups
    Pegfilgrastim v Placebo
    Number of subjects included in analysis
    196
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.1429
    Method
    		 Logrank
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    1.25
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.932
         upper limit
    		 1.685

    Secondary: Duration of Severe Neutropenia (DSN)

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    End point title
    		 Duration of Severe Neutropenia (DSN)
    End point description
    DSN was defined as the number of days with Grade 4 neutropenia, i.e., the number of days with absolute neutrophil count (ANC) less than (<) 0.5 * 10^9 per liter in Cycle 1. Full analysis set (FAS) included all enrolled and randomized participants.
    End point type
    Secondary
    End point timeframe
    Cycle 1 (21 days)
    End point values
    		 Lipegfilgrastim Pegfilgrastim Placebo
    Number of subjects analysed
    0 [1]
    0 [2]
    9
    Units: days
        arithmetic mean (standard deviation)
    ±
    ±
    2.9 ± 1.36
    Notes
    [1] - There were no event of severe neutropenia in Cycle 1 in this arm.
    [2] - There were no event of severe neutropenia in Cycle 1 in this arm.
    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 occurrence of at least 1 of the following conditions: oral body temperature greater than (>) 38.5 degrees centigrade for at least 1 hour (2 consecutive measurements on the same day, at least 60 minutes apart) and an observed severe neutropenia (i.e., ANC value <0.5 * 10^9 per liter) on the day before, on the same day, or on the day after the elevated temperature readings; documentation of neutropenic sepsis, i.e., a sepsis in combination with an ANC value <0.5 × 10^9 per liter; documentation of serious or life-threatening neutropenic infection, i.e., a life-threatening infection in combination with an ANC value <0.5 × 10^9 per liter. FAS included all enrolled and randomized participants.
    End point type
    Secondary
    End point timeframe
    Cycle 1 (21 days)
    End point values
    		 Lipegfilgrastim Pegfilgrastim Placebo
    Number of subjects analysed
    101
    101
    101
    Units: participants
    0
    0
    0
    No statistical analyses for this end point

    Secondary: Number of Participants With Very Severe Neutropenia

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    End point title
    		 Number of Participants With Very Severe Neutropenia
    End point description
    Very severe neutropenia was defined as ANC <0.1 * 10^9 per liter. FAS included all enrolled and randomized participants.
    End point type
    Secondary
    End point timeframe
    Cycle 1 (21 days)
    End point values
    		 Lipegfilgrastim Pegfilgrastim Placebo
    Number of subjects analysed
    101
    101
    101
    Units: participants
    0
    0
    2
    No statistical analyses for this end point

    Secondary: Number of Participants With Severe Neutropenia

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    End point title
    		 Number of Participants With Severe Neutropenia
    End point description
    Severe neutropenia was defined as Grade 4 neutropenia, i.e., ANC <0.5 * 10^9 per liter. FAS included all enrolled and randomized participants.
    End point type
    Secondary
    End point timeframe
    Cycle 1 (21 days)
    End point values
    		 Lipegfilgrastim Pegfilgrastim Placebo
    Number of subjects analysed
    101
    101
    101
    Units: participants
    0
    0
    9
    No statistical analyses for this end point

    Secondary: PFS as Assessed by Investigator According to RECIST Version 1.1

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    End point title
    		 PFS as Assessed by Investigator According to RECIST Version 1.1
    End point description
    PFS was defined as time from randomization to the first objectively documented progression per RECIST version 1.1 or death due to any cause, whichever occurred first, as documented by the central reader. Participants who did not have disease progression until the end of the study or discontinued the study early before disease progression was documented were censored at the time of their latest evaluable RECIST assessments. Disease progression: At least a 20% increase in the sum of diameters of target lesions, taking as reference the smallest sum on study In addition to the relative increase of 20%, the sum also demonstrated an absolute increase of at least 5 mm. Unequivocal progression of existing non-target lesions. The appearance of 1 or more new lesions was also considered progression. Safety population included all enrolled and randomized participants who received at least 1 injection of lipegfilgrastim, pegfilgrastim, or placebo.
    End point type
    Secondary
    End point timeframe
    From randomization to the first objectively documented progression or death due to any cause, whichever occurred first (up to a maximum duration of 928 days)
    End point values
    		 Lipegfilgrastim Pegfilgrastim Placebo
    Number of subjects analysed
    95
    98
    98
    Units: months
        median (confidence interval 95%)
    5.9 (5.60 to 7.50)
    5.3 (4.20 to 6.00)
    6.2 (5.60 to 7.10)
    No statistical analyses for this end point

    Secondary: Percentage of Participants With Objective Response, as Assessed by Central Reader According to RECIST Version 1.1

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    End point title
    		 Percentage of Participants With Objective Response, as Assessed by Central Reader According to RECIST Version 1.1
    End point description
    Objective response was defined as achieving a best overall response of complete response (CR) or partial response (PR), as defined by RECIST version 1.1. The best overall response was the best response recorded from the start of the investigational medicinal product (IMP) until the end of the study. CR: Disappearance of all target and non-target lesions. Any pathological lymph nodes (whether target or non-target) with a reduction in short axis to <10 mm. PR: At least a 30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum diameters. Safety population included all enrolled and randomized participants who received at least 1 injection of lipegfilgrastim, pegfilgrastim, or placebo.
    End point type
    Secondary
    End point timeframe
    From randomization until first appearance of CR or PR (up to a maximum duration of 928 days)
    End point values
    		 Lipegfilgrastim Pegfilgrastim Placebo
    Number of subjects analysed
    95
    98
    98
    Units: percentage of participants
        number (not applicable)
    43
    37
    40
    No statistical analyses for this end point

    Secondary: Percentage of Participants With Objective Response, as Assessed by Investigator According to RECIST Version 1.1

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    End point title
    		 Percentage of Participants With Objective Response, as Assessed by Investigator According to RECIST Version 1.1
    End point description
    Objective response was defined as achieving a best overall response of CR or PR, as defined by RECIST version 1.1. The best overall response was the best response recorded from the start of the IMP until the end of the study. CR: Disappearance of all target and non-target lesions. Any pathological lymph nodes (whether target or non-target) with a reduction in short axis to <10 mm. PR: At least a 30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum diameters. Safety population included all enrolled and randomized participants who received at least 1 injection of lipegfilgrastim, pegfilgrastim, or placebo.
    End point type
    Secondary
    End point timeframe
    From randomization until first appearance of CR or PR (up to a maximum duration of 928 days)
    End point values
    		 Lipegfilgrastim Pegfilgrastim Placebo
    Number of subjects analysed
    95
    98
    98
    Units: percentage of participants
        number (not applicable)
    45
    39
    40
    No statistical analyses for this end point

    Secondary: Overall Survival

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    End point title
    		 Overall Survival
    End point description
    Overall survival was defined as time from randomization to the date of death from any cause. Safety population included all enrolled and randomized participants who received at least 1 injection of lipegfilgrastim, pegfilgrastim, or placebo.
    End point type
    Secondary
    End point timeframe
    From randomization to the date of death from any cause (up to maximum duration of 928 days)
    End point values
    		 Lipegfilgrastim Pegfilgrastim Placebo
    Number of subjects analysed
    95
    98
    98
    Units: months
        median (confidence interval 95%)
    11.7 (9.60 to 14.50)
    10.7 (9.10 to 14.80)
    11.9 (10.00 to 14.80)
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    From randomization until end of study (up to a maximum duration of 928 days)
    Adverse event reporting additional description
    Safety population included all enrolled and randomized participants who received at least 1 injection of lipegfilgrastim, pegfilgrastim, or placebo.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    20.0
    Reporting groups
    Reporting group title
    Lipegfilgrastim 6mg
    Reporting group description
    		 Lipegfilgrastim 6mg

    Reporting group title
    Pegfilgrastim 6mg
    Reporting group description
    		 Pegfilgrastim 6mg

    Reporting group title
    Placebo
    Reporting group description
    		 Placebo

    Serious adverse events
    		 Lipegfilgrastim 6mg Pegfilgrastim 6mg Placebo
    Total subjects affected by serious adverse events
         subjects affected / exposed
    81 / 95 (85.26%)
    86 / 98 (87.76%)
    80 / 98 (81.63%)
         number of deaths (all causes)
    75
    81
    76
         number of deaths resulting from adverse events
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Brain neoplasm
         subjects affected / exposed
    0 / 95 (0.00%)
    0 / 98 (0.00%)
    1 / 98 (1.02%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Lung adenocarcinoma
         subjects affected / exposed
    0 / 95 (0.00%)
    1 / 98 (1.02%)
    0 / 98 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Metastases to central nervous system
         subjects affected / exposed
    0 / 95 (0.00%)
    1 / 98 (1.02%)
    3 / 98 (3.06%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    Non-small cell lung cancer
         subjects affected / exposed
    71 / 95 (74.74%)
    72 / 98 (73.47%)
    71 / 98 (72.45%)
         occurrences causally related to treatment / all
    0 / 107
    0 / 107
    0 / 103
         deaths causally related to treatment / all
    0 / 66
    0 / 67
    0 / 67
    Squamous cell carcinoma of lung
         subjects affected / exposed
    1 / 95 (1.05%)
    1 / 98 (1.02%)
    1 / 98 (1.02%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 2
    0 / 2
         deaths causally related to treatment / all
    0 / 1
    0 / 1
    0 / 1
    Vascular disorders
    Embolism
         subjects affected / exposed
    0 / 95 (0.00%)
    0 / 98 (0.00%)
    1 / 98 (1.02%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    Internal haemorrhage
         subjects affected / exposed
    1 / 95 (1.05%)
    0 / 98 (0.00%)
    0 / 98 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Peripheral artery thrombosis
         subjects affected / exposed
    1 / 95 (1.05%)
    0 / 98 (0.00%)
    0 / 98 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Shock haemorrhagic
         subjects affected / exposed
    2 / 95 (2.11%)
    0 / 98 (0.00%)
    0 / 98 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 2
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Death
         subjects affected / exposed
    3 / 95 (3.16%)
    2 / 98 (2.04%)
    1 / 98 (1.02%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 3
    0 / 2
    0 / 1
    General physical health deterioration
         subjects affected / exposed
    0 / 95 (0.00%)
    0 / 98 (0.00%)
    1 / 98 (1.02%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    Pyrexia
         subjects affected / exposed
    0 / 95 (0.00%)
    0 / 98 (0.00%)
    1 / 98 (1.02%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Immune system disorders
    Anaphylactic shock
         subjects affected / exposed
    0 / 95 (0.00%)
    1 / 98 (1.02%)
    0 / 98 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Bronchial haemorrhage
         subjects affected / exposed
    0 / 95 (0.00%)
    1 / 98 (1.02%)
    0 / 98 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    Dyspnoea
         subjects affected / exposed
    0 / 95 (0.00%)
    1 / 98 (1.02%)
    0 / 98 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    Oesophagobronchial fistula
         subjects affected / exposed
    1 / 95 (1.05%)
    0 / 98 (0.00%)
    0 / 98 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pneumothorax
         subjects affected / exposed
    1 / 95 (1.05%)
    0 / 98 (0.00%)
    0 / 98 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pneumothorax spontaneous
         subjects affected / exposed
    1 / 95 (1.05%)
    0 / 98 (0.00%)
    0 / 98 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pulmonary embolism
         subjects affected / exposed
    0 / 95 (0.00%)
    2 / 98 (2.04%)
    2 / 98 (2.04%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 2
    0 / 2
    Pulmonary haemorrhage
         subjects affected / exposed
    3 / 95 (3.16%)
    3 / 98 (3.06%)
    0 / 98 (0.00%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 3
    0 / 0
    Psychiatric disorders
    Abnormal behaviour
         subjects affected / exposed
    1 / 95 (1.05%)
    0 / 98 (0.00%)
    0 / 98 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Delirium tremens
         subjects affected / exposed
    1 / 95 (1.05%)
    0 / 98 (0.00%)
    0 / 98 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Investigations
    Blood potassium decreased
         subjects affected / exposed
    1 / 95 (1.05%)
    0 / 98 (0.00%)
    0 / 98 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Neutrophil count decreased
         subjects affected / exposed
    0 / 95 (0.00%)
    1 / 98 (1.02%)
    0 / 98 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    White blood cell count decreased
         subjects affected / exposed
    0 / 95 (0.00%)
    1 / 98 (1.02%)
    0 / 98 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Alcohol poisoning
         subjects affected / exposed
    1 / 95 (1.05%)
    0 / 98 (0.00%)
    0 / 98 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    Brain contusion
         subjects affected / exposed
    1 / 95 (1.05%)
    0 / 98 (0.00%)
    0 / 98 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cardiac disorders
    Acute coronary syndrome
         subjects affected / exposed
    1 / 95 (1.05%)
    1 / 98 (1.02%)
    0 / 98 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
    Atrial fibrillation
         subjects affected / exposed
    0 / 95 (0.00%)
    1 / 98 (1.02%)
    0 / 98 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cardiac failure acute
         subjects affected / exposed
    0 / 95 (0.00%)
    0 / 98 (0.00%)
    2 / 98 (2.04%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    Cardio-respiratory arrest
         subjects affected / exposed
    0 / 95 (0.00%)
    2 / 98 (2.04%)
    0 / 98 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 2
    0 / 0
    Supraventricular tachycardia
         subjects affected / exposed
    0 / 95 (0.00%)
    0 / 98 (0.00%)
    1 / 98 (1.02%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Nervous system disorders
    Cerebrovascular accident
         subjects affected / exposed
    1 / 95 (1.05%)
    0 / 98 (0.00%)
    0 / 98 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cerebrovascular disorder
         subjects affected / exposed
    0 / 95 (0.00%)
    0 / 98 (0.00%)
    1 / 98 (1.02%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Syncope
         subjects affected / exposed
    1 / 95 (1.05%)
    0 / 98 (0.00%)
    0 / 98 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    3 / 95 (3.16%)
    2 / 98 (2.04%)
    2 / 98 (2.04%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 4
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Neutropenia
         subjects affected / exposed
    0 / 95 (0.00%)
    0 / 98 (0.00%)
    1 / 98 (1.02%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pancytopenia
         subjects affected / exposed
    0 / 95 (0.00%)
    1 / 98 (1.02%)
    0 / 98 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    Thrombocytopenia
         subjects affected / exposed
    1 / 95 (1.05%)
    1 / 98 (1.02%)
    0 / 98 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Gastric ulcer
         subjects affected / exposed
    0 / 95 (0.00%)
    1 / 98 (1.02%)
    0 / 98 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Intervertebral disc protrusion
         subjects affected / exposed
    0 / 95 (0.00%)
    0 / 98 (0.00%)
    1 / 98 (1.02%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Infections and infestations
    Chronic hepatitis C
         subjects affected / exposed
    0 / 95 (0.00%)
    1 / 98 (1.02%)
    0 / 98 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pneumonia
         subjects affected / exposed
    0 / 95 (0.00%)
    1 / 98 (1.02%)
    1 / 98 (1.02%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    Pneumonia bacterial
         subjects affected / exposed
    1 / 95 (1.05%)
    0 / 98 (0.00%)
    0 / 98 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Lipegfilgrastim 6mg Pegfilgrastim 6mg Placebo
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    77 / 95 (81.05%)
    84 / 98 (85.71%)
    84 / 98 (85.71%)
    Investigations
    Alanine aminotransferase increased
         subjects affected / exposed
    11 / 95 (11.58%)
    6 / 98 (6.12%)
    7 / 98 (7.14%)
         occurrences all number
    15
    12
    8
    Aspartate aminotransferase increased
         subjects affected / exposed
    8 / 95 (8.42%)
    5 / 98 (5.10%)
    7 / 98 (7.14%)
         occurrences all number
    12
    15
    8
    Blood alkaline phosphatase increased
         subjects affected / exposed
    11 / 95 (11.58%)
    10 / 98 (10.20%)
    7 / 98 (7.14%)
         occurrences all number
    15
    12
    10
    Blood creatine phosphokinase increased
         subjects affected / exposed
    1 / 95 (1.05%)
    4 / 98 (4.08%)
    5 / 98 (5.10%)
         occurrences all number
    1
    5
    7
    Blood creatinine increased
         subjects affected / exposed
    8 / 95 (8.42%)
    7 / 98 (7.14%)
    12 / 98 (12.24%)
         occurrences all number
    12
    8
    21
    Blood lactate dehydrogenase increased
         subjects affected / exposed
    5 / 95 (5.26%)
    5 / 98 (5.10%)
    6 / 98 (6.12%)
         occurrences all number
    6
    9
    9
    Blood urea increased
         subjects affected / exposed
    7 / 95 (7.37%)
    5 / 98 (5.10%)
    5 / 98 (5.10%)
         occurrences all number
    11
    5
    8
    Creatinine renal clearance decreased
         subjects affected / exposed
    6 / 95 (6.32%)
    0 / 98 (0.00%)
    3 / 98 (3.06%)
         occurrences all number
    8
    0
    3
    Gamma-glutamyltransferase increased
         subjects affected / exposed
    15 / 95 (15.79%)
    9 / 98 (9.18%)
    10 / 98 (10.20%)
         occurrences all number
    25
    13
    18
    Lymphocyte count decreased
         subjects affected / exposed
    7 / 95 (7.37%)
    4 / 98 (4.08%)
    4 / 98 (4.08%)
         occurrences all number
    12
    8
    6
    Weight decreased
         subjects affected / exposed
    6 / 95 (6.32%)
    9 / 98 (9.18%)
    4 / 98 (4.08%)
         occurrences all number
    8
    12
    4
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Non-small cell lung cancer
         subjects affected / exposed
    27 / 95 (28.42%)
    27 / 98 (27.55%)
    35 / 98 (35.71%)
         occurrences all number
    27
    27
    35
    Nervous system disorders
    Headache
         subjects affected / exposed
    8 / 95 (8.42%)
    2 / 98 (2.04%)
    8 / 98 (8.16%)
         occurrences all number
    10
    3
    8
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    38 / 95 (40.00%)
    40 / 98 (40.82%)
    37 / 98 (37.76%)
         occurrences all number
    93
    98
    103
    Leukopenia
         subjects affected / exposed
    5 / 95 (5.26%)
    6 / 98 (6.12%)
    18 / 98 (18.37%)
         occurrences all number
    8
    7
    54
    Neutropenia
         subjects affected / exposed
    11 / 95 (11.58%)
    13 / 98 (13.27%)
    41 / 98 (41.84%)
         occurrences all number
    16
    15
    111
    Thrombocytopenia
         subjects affected / exposed
    15 / 95 (15.79%)
    11 / 98 (11.22%)
    10 / 98 (10.20%)
         occurrences all number
    39
    16
    23
    General disorders and administration site conditions
    Asthenia
         subjects affected / exposed
    11 / 95 (11.58%)
    6 / 98 (6.12%)
    11 / 98 (11.22%)
         occurrences all number
    16
    8
    20
    Fatigue
         subjects affected / exposed
    8 / 95 (8.42%)
    13 / 98 (13.27%)
    13 / 98 (13.27%)
         occurrences all number
    10
    23
    23
    Non-cardiac chest pain
         subjects affected / exposed
    5 / 95 (5.26%)
    9 / 98 (9.18%)
    7 / 98 (7.14%)
         occurrences all number
    7
    11
    8
    Pyrexia
         subjects affected / exposed
    7 / 95 (7.37%)
    6 / 98 (6.12%)
    4 / 98 (4.08%)
         occurrences all number
    11
    7
    4
    Gastrointestinal disorders
    Abdominal pain upper
         subjects affected / exposed
    3 / 95 (3.16%)
    3 / 98 (3.06%)
    5 / 98 (5.10%)
         occurrences all number
    4
    4
    5
    Diarrhoea
         subjects affected / exposed
    4 / 95 (4.21%)
    7 / 98 (7.14%)
    8 / 98 (8.16%)
         occurrences all number
    4
    8
    10
    Nausea
         subjects affected / exposed
    38 / 95 (40.00%)
    29 / 98 (29.59%)
    33 / 98 (33.67%)
         occurrences all number
    68
    57
    86
    Vomiting
         subjects affected / exposed
    10 / 95 (10.53%)
    7 / 98 (7.14%)
    11 / 98 (11.22%)
         occurrences all number
    14
    9
    19
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    3 / 95 (3.16%)
    3 / 98 (3.06%)
    6 / 98 (6.12%)
         occurrences all number
    3
    6
    7
    Dyspnoea
         subjects affected / exposed
    7 / 95 (7.37%)
    7 / 98 (7.14%)
    12 / 98 (12.24%)
         occurrences all number
    7
    8
    17
    Haemoptysis
         subjects affected / exposed
    8 / 95 (8.42%)
    4 / 98 (4.08%)
    3 / 98 (3.06%)
         occurrences all number
    10
    5
    4
    Skin and subcutaneous tissue disorders
    Alopecia
         subjects affected / exposed
    26 / 95 (27.37%)
    35 / 98 (35.71%)
    33 / 98 (33.67%)
         occurrences all number
    38
    54
    46
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    6 / 95 (6.32%)
    4 / 98 (4.08%)
    2 / 98 (2.04%)
         occurrences all number
    11
    10
    2
    Bone pain
         subjects affected / exposed
    7 / 95 (7.37%)
    1 / 98 (1.02%)
    1 / 98 (1.02%)
         occurrences all number
    12
    5
    2
    Myalgia
         subjects affected / exposed
    7 / 95 (7.37%)
    3 / 98 (3.06%)
    4 / 98 (4.08%)
         occurrences all number
    15
    10
    11
    Pain in extremity
         subjects affected / exposed
    2 / 95 (2.11%)
    2 / 98 (2.04%)
    7 / 98 (7.14%)
         occurrences all number
    4
    2
    8
    Metabolism and nutrition disorders
    Decreased appetite
         subjects affected / exposed
    8 / 95 (8.42%)
    12 / 98 (12.24%)
    7 / 98 (7.14%)
         occurrences all number
    15
    17
    15
    Hyperglycaemia
         subjects affected / exposed
    5 / 95 (5.26%)
    8 / 98 (8.16%)
    10 / 98 (10.20%)
         occurrences all number
    7
    14
    17
    Hyperkalaemia
         subjects affected / exposed
    5 / 95 (5.26%)
    5 / 98 (5.10%)
    5 / 98 (5.10%)
         occurrences all number
    10
    7
    6

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    03 Mar 2015
    The following major procedural changes (not all-inclusive) were made to the protocol: In response to a request from the authorities, the study exclusion criteria related to participation in a clinical study within 30 days has been updated to incorporate “5 half-lives of the investigational product before randomization, whichever is longer.”
    23 May 2016
    The following major procedural changes (not all-inclusive) were made to the protocol: - Urinalysis monitoring conducted by dipstick at the investigational center, including protein, glucose, blood, leucocytes and pH, has been added to the clinical laboratory tests required. - Clarification that the follow-up visits that were performed every 6 weeks can be conducted within a time window of +/-1 week.

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

    Limitations and caveats
    Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.
    None reported
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    The status and protocol content of GB trials is no longer updated since 1 January 2021. For the UK, as of 31 January 2021, EU Law applies only to the territory of Northern Ireland (NI) to the extent foreseen in the Protocol on Ireland/NI. Legal notice
    As of 31 January 2023, all EU/EEA initial clinical trial applications must be submitted through CTIS . Updated EudraCT trials information and information on PIP/Art 46 trials conducted exclusively in third countries continues to be submitted through EudraCT and published on this website.

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