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    Clinical Trial Results:
    A Multicenter, Open-Label Study to Evaluate the Safety, Tolerability, Pharmacokinetics, Pharmacodynamics, Efficacy, and Immunogenicity of Daily Subcutaneous Administration of 5 μg/kg tbo-filgrastim in Infants, Children and Adolescents with Solid Tumors without Bone Marrow Involvement

    Summary
    EudraCT number
    		 2014-001772-55
    Trial protocol
    		 HU   BG   PL   RO   HR  
    Global end of trial date
    04 Apr 2017

    Results information
    Results version number
    		 v1(current)
    This version publication date
    06 Apr 2018
    First version publication date
    06 Apr 2018
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    XM02-ONC-201
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT02190721
    WHO universal trial number (UTN)
    		 -
    Other trial identifiers
    		 IND Number:: 103188
    Sponsors
    Sponsor organisation name
    Teva Pharmaceutical Industries Ltd
    Sponsor organisation address
    5 Basel Street, Petach Tiqva, Israel, 49131
    Public contact
    Director, Clinical Research, Teva Branded Pharmaceutical Products, R&D Inc., +01 215-591-3000, info.era-clinical@teva.de
    Scientific contact
    Director, Clinical Research, Teva Branded Pharmaceutical Products, R&D Inc., +01 215-591-3000, info.era-clinical@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
    25 Oct 2017
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    04 Apr 2017
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The primary objective of this study was to assess the safety and tolerability of 5 μg/kg tbo-filgrastim in the pediatric population with solid tumors without bone marrow involvement.
    Protection of trial subjects
    This study was conducted in full accordance with the International Conference on Harmonization (ICH) Good Clinical Practice (GCP) Consolidated Guideline (E6) and any applicable national and local laws and regulations (eg, Code of Federal Regulations [CFR] 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 good clinical practice in the conduct of clinical trials on medicinal products for human use. Written and/or oral information about the study was provided to all patients in a language understandable by the patient, parent, or other legally acceptable representative. The information included an adequate explanation of the aims, methods, anticipated benefits, potential hazards, and insurance arrangements in force. A signed and dated informed consent/assent form was obtained from each parent/guardian and a signed and dated assent form was obtained from each applicable minor patient before any study specific procedures or assessments are done and after the aims, methods, anticipated benefits, and potential hazards are explained; according to local IRB/IEC requirements. It was explained to the patients, parent, or other legally acceptable representative 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. Each patient’s willingness to participate in the study was documented in writing in assent/consent form(s) that was (were) signed by the patient and/or parent or other legally acceptable representative with the date of each signature indicated. Each investigator kept the original assent/consent forms, and copies were given to the patients, parents, or other legally acceptable representatives.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    12 May 2015
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Poland: 6
    Country: Number of subjects enrolled
    Romania: 15
    Country: Number of subjects enrolled
    Croatia: 9
    Country: Number of subjects enrolled
    Russian Federation: 12
    Country: Number of subjects enrolled
    Ukraine: 8
    Worldwide total number of subjects
    50
    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)
    2
    Children (2-11 years)
    30
    Adolescents (12-17 years)
    18
    Adults (18-64 years)
    0
    From 65 to 84 years
    0
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 A total of 55 patients were screened for this study. Of the 55 patients screened, 50 patients at 33 investigational centers in Central and Eastern Europe met inclusion/exclusion criteria and were considered to be eligible for enrollment into the study.

    Pre-assignment
    Screening details
    		 Of the 5 patients who were not enrolled, 2 patients were excluded due to inclusion criteria not met (baseline AST elevation, baseline ANC count was too low), 2 patients were excluded due to exclusion criteria not met (ongoing active infection or history of infectious disease within 2 weeks prior to screening), and 1 patient withdrew consent.

    Period 1
    Period 1 title
    Overall Trial (overall period)
    Is this the baseline period?
    		 Yes
    Allocation method
    Not applicable
    Blinding used
    		 Not blinded

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Infants (1 month to <2 years)
    Arm description
    		 Tbo-filgrastim administration was started at approximately 24 hours (±3 hours) after the end of the last chemotherapy (CTX) treatment in the first week of the CTX cycle. Daily dosing with tbo-filgrastim at a dose of 5 μg/kg/day of body weight continued until the expected neutrophil nadir was passed and the neutrophil count had recovered to 2.0 × 10^9/L but not longer than 14 consecutive days. An immunogenicity sample was collected 30 days and 3 months after the last tbo-filgrastim administration in the first cycle.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Tbo-filgrastim
    Investigational medicinal product code
    Other name
    GRANIX, TEVAGRASTIM, RATIOGRASTIM, human G-CSF Eschericia Coli (E-coli)-derived protein
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    Each daily dose was administered at the investigative site. The first dose of tbo-filgrastim was administered not earlier than 24 hours (±3 hours) following the end of myelosuppressive chemotherapy in week 1 of the cycle. Daily dosing with tbo-filgrastim continued until the expected neutrophil nadir was passed and the neutrophil count had recovered to 2.0 x 10^9/L but not longer than 14 consecutive days.

    Arm title
    		 Children (2 to <12 years)
    Arm description
    		 Tbo-filgrastim administration was started at approximately 24 hours (±3 hours) after the end of the last chemotherapy (CTX) treatment in the first week of the CTX cycle. Daily dosing with tbo-filgrastim at a dose of 5 μg/kg/day of body weight continued until the expected neutrophil nadir was passed and the neutrophil count had recovered to 2.0 × 10^9/L but not longer than 14 consecutive days. An immunogenicity sample was collected 30 days and 3 months after the last tbo-filgrastim administration in the first cycle.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Tbo-filgrastim
    Investigational medicinal product code
    Other name
    GRANIX, TEVAGRASTIM, RATIOGRASTIM, human G-CSF Eschericia Coli (E-coli)-derived protein
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    Each daily dose was administered at the investigative site. The first dose of tbo-filgrastim was administered not earlier than 24 hours (±3 hours) following the end of myelosuppressive chemotherapy in week 1 of the cycle. Daily dosing with tbo-filgrastim continued until the expected neutrophil nadir was passed and the neutrophil count had recovered to 2.0 × 10^9/L but not longer than 14 consecutive days.

    Arm title
    		 Adolescents (12 to <16 years)
    Arm description
    		 Tbo-filgrastim administration was started at approximately 24 hours (±3 hours) after the end of the last chemotherapy (CTX) treatment in the first week of the CTX cycle. Daily dosing with tbo-filgrastim at a dose of 5 μg/kg/day of body weight continued until the expected neutrophil nadir was passed and the neutrophil count had recovered to 2.0 × 10^9/L but not longer than 14 consecutive days. An immunogenicity sample was collected 30 days and 3 months after the last tbo-filgrastim administration in the first cycle.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Tbo-filgrastim
    Investigational medicinal product code
    Other name
    GRANIX, TEVAGRASTIM, RATIOGRASTIM, human G-CSF Eschericia Coli (E-coli)-derived protein
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    Each daily dose was administered at the investigative site. The first dose of tbo-filgrastim was administered not earlier than 24 hours (±3 hours) following the end of myelosuppressive chemotherapy in week 1 of the cycle. Daily dosing with tbo-filgrastim continued until the expected neutrophil nadir was passed and the neutrophil count had recovered to 2.0 × 10^9/L but not longer than 14 consecutive days.

    Number of subjects in period 1
    		Infants (1 month to <2 years) Children (2 to <12 years) Adolescents (12 to <16 years)
    Started
    2
    30
    18
    Completed treatment
    2
    30
    18
    Completed 30 day follow-up
    2
    29
    18
    Completed 90 day follow-up
    2
    29
    18
    Completed
    2
    29
    18
    Not completed
    0
    1
    0
         patient was out of the city
    -
    1
    -

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Infants (1 month to <2 years)
    Reporting group description
    		 Tbo-filgrastim administration was started at approximately 24 hours (±3 hours) after the end of the last chemotherapy (CTX) treatment in the first week of the CTX cycle. Daily dosing with tbo-filgrastim at a dose of 5 μg/kg/day of body weight continued until the expected neutrophil nadir was passed and the neutrophil count had recovered to 2.0 × 10^9/L but not longer than 14 consecutive days. An immunogenicity sample was collected 30 days and 3 months after the last tbo-filgrastim administration in the first cycle.

    Reporting group title
    Children (2 to <12 years)
    Reporting group description
    		 Tbo-filgrastim administration was started at approximately 24 hours (±3 hours) after the end of the last chemotherapy (CTX) treatment in the first week of the CTX cycle. Daily dosing with tbo-filgrastim at a dose of 5 μg/kg/day of body weight continued until the expected neutrophil nadir was passed and the neutrophil count had recovered to 2.0 × 10^9/L but not longer than 14 consecutive days. An immunogenicity sample was collected 30 days and 3 months after the last tbo-filgrastim administration in the first cycle.

    Reporting group title
    Adolescents (12 to <16 years)
    Reporting group description
    		 Tbo-filgrastim administration was started at approximately 24 hours (±3 hours) after the end of the last chemotherapy (CTX) treatment in the first week of the CTX cycle. Daily dosing with tbo-filgrastim at a dose of 5 μg/kg/day of body weight continued until the expected neutrophil nadir was passed and the neutrophil count had recovered to 2.0 × 10^9/L but not longer than 14 consecutive days. An immunogenicity sample was collected 30 days and 3 months after the last tbo-filgrastim administration in the first cycle.

    Reporting group values
    		 Infants (1 month to <2 years) Children (2 to <12 years) Adolescents (12 to <16 years) Total
    Number of subjects
    		 2 30 18 50
    Age categorical
    Units: Subjects
    Age continuous
    Units: years
        median (full range (min-max))
    		 1.65 (1.4 to 1.9) 6.80 (2.4 to 11.5) 13.80 (12.0 to 15.9) -
    Gender categorical
    Units: Subjects
        Female
    		 1 13 6 20
        Male
    		 1 17 12 30
    Race
    Units: Subjects
        White
    		 2 30 18 50
        Other
    		 0 0 0 0
    Ethnicity
    Units: Subjects
        Not Hispanic or Latino
    		 2 30 18 50
        Hispanic or Latino
    		 0 0 0 0
    Chemotherapy Administration
    The chemotherapy (CTX) regimens administered included at least etoposide, doxorubicin, ifosfamide, or cyclophosphamide. The severity group (mild/moderate/severe) of myelotoxicity of the CTX regimens administered was assigned by a group of clinical experts, based on the scientific literature (Moreau et al 2009) and clinical experience.
    Units: Subjects
        Mild
    		 0 6 8 14
        Moderate
    		 2 16 7 25
        Severe
    		 0 8 3 11
    Weight
    Units: kg
        median (full range (min-max))
    		 9.90 (9.3 to 10.5) 20.25 (12.0 to 51.1) 53.90 (29.5 to 89.5) -
    Height
    Units: cm
        median (full range (min-max))
    		 78.00 (76.0 to 80.0) 121.00 (89.0 to 163.0) 161.00 (140.0 to 185.0) -
    Body Mass Index
    Units: kg/m^2
        median (full range (min-max))
    		 16.0 (16 to 16) 15.2 (12 to 20) 20.7 (15 to 28) -

    End points

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    End points reporting groups
    Reporting group title
    Infants (1 month to <2 years)
    Reporting group description
    		 Tbo-filgrastim administration was started at approximately 24 hours (±3 hours) after the end of the last chemotherapy (CTX) treatment in the first week of the CTX cycle. Daily dosing with tbo-filgrastim at a dose of 5 μg/kg/day of body weight continued until the expected neutrophil nadir was passed and the neutrophil count had recovered to 2.0 × 10^9/L but not longer than 14 consecutive days. An immunogenicity sample was collected 30 days and 3 months after the last tbo-filgrastim administration in the first cycle.

    Reporting group title
    Children (2 to <12 years)
    Reporting group description
    		 Tbo-filgrastim administration was started at approximately 24 hours (±3 hours) after the end of the last chemotherapy (CTX) treatment in the first week of the CTX cycle. Daily dosing with tbo-filgrastim at a dose of 5 μg/kg/day of body weight continued until the expected neutrophil nadir was passed and the neutrophil count had recovered to 2.0 × 10^9/L but not longer than 14 consecutive days. An immunogenicity sample was collected 30 days and 3 months after the last tbo-filgrastim administration in the first cycle.

    Reporting group title
    Adolescents (12 to <16 years)
    Reporting group description
    		 Tbo-filgrastim administration was started at approximately 24 hours (±3 hours) after the end of the last chemotherapy (CTX) treatment in the first week of the CTX cycle. Daily dosing with tbo-filgrastim at a dose of 5 μg/kg/day of body weight continued until the expected neutrophil nadir was passed and the neutrophil count had recovered to 2.0 × 10^9/L but not longer than 14 consecutive days. An immunogenicity sample was collected 30 days and 3 months after the last tbo-filgrastim administration in the first cycle.

    Primary: Participants with Adverse Events (AEs)

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    End point title
    		 Participants with Adverse Events (AEs) [1]
    End point description
    An adverse event was defined as any untoward medical occurrence that develops or worsens in severity during the conduct of a clinical study and does not necessarily have a causal relationship to the study drug. A treatment-emergent AE (TEAE) is an AE occurring during the timeframe. A non-TEAE is any AE not considered a TEAE. Severity was rated by the investigator using the NCI Common Terminology Criteria for Adverse Events (NCI-CTCAE) scale where 3=severe but not life-threatening, 4=life-threatening and 5=death. Relation of AE to treatment was determined by the investigator (related=reasonable possibility). Serious AEs include death, a life-threatening adverse event, inpatient hospitalization or prolongation of existing hospitalization, persistent or significant disability or incapacity, a congenital anomaly or birth defect, OR an important medical event that jeopardized the patient and required medical intervention to prevent the previously listed serious outcomes.
    End point type
    Primary
    End point timeframe
    Non-TEAE: signing of informed consent form to Day -1 (last day of chemotherapy in week 1). And > 30days after last dose of tbo-filgrastim. TEAE timeframe: Day 1 (start of tbo-filgrastim) to <= 30 days after the last dose of tbo-filgrastim
    Notes
    [1] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: This study is not powered for statistical analyses.
    End point values
    		 Infants (1 month to <2 years) Children (2 to <12 years) Adolescents (12 to <16 years)
    Number of subjects analysed
    2 [2]
    30 [3]
    18 [4]
    Units: participants
        Any adverse event
    2
    28
    16
        Any TEAE
    2
    28
    15
        Any non-TEAE
    2
    15
    9
        Any treatment-related TEAE
    0
    4
    5
        Any TEAE with NCI-CTCAE Toxicity Grade >=3
    2
    18
    8
        Any trt-related TEAE with Toxicity Grade >=3
    0
    1
    2
        Any serious TEAE
    0
    9
    3
        Any serious treatment-related TEAE
    0
    1
    1
        Any TEAE leading to discontinuation
    0
    0
    0
        Any treatment-related TEAE leading to discont
    0
    0
    0
        Any TEAE leading to death
    0
    0
    0
        Any treatment-related TEAE leading to death
    0
    0
    0
    Notes
    [2] - Safety analysis set
    [3] - Safety analysis set
    [4] - Safety analysis set
    No statistical analyses for this end point

    Primary: Participants with Potentially Clinically Significant Abnormal Serum Chemistry Results

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    End point title
    		 Participants with Potentially Clinically Significant Abnormal Serum Chemistry Results [5]
    End point description
    Serum chemistry tests included alkaline phosphatase, alanine aminotransferase (ALT), aspartate aminotransferase (AST), direct bilirubin, indirect bilirubin, total bilirubin, calcium, creatinine, gammaglutamyl transpeptidase (GGT), glucose, potassium, lactate dehydrogenase (LDH), phosphate, sodium and uric acid. Only tests with potentially clinically significant abnormal results are reported. ULN = upper limit of normal
    End point type
    Primary
    End point timeframe
    Day 1 (start of tbo-filgrastim administration) up to Day 21
    Notes
    [5] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: This study is not powered for statistical analyses.
    End point values
    		 Infants (1 month to <2 years) Children (2 to <12 years) Adolescents (12 to <16 years)
    Number of subjects analysed
    2 [6]
    30 [7]
    18 [8]
    Units: participants
        Participants with >=1 abnormality
    0
    3
    1
        ALT: >20 * ULN
    0
    1
    1
        AST: >20 * ULN
    0
    1
    0
        AST: >5 * ULN and <= 20 * ULN
    0
    0
    1
        GGT: >5 * ULN and <=20 * ULN
    0
    3
    1
    Notes
    [6] - Safety analysis set
    [7] - Safety analysis set
    [8] - Safety analysis set
    No statistical analyses for this end point

    Primary: Participants with Potentially Clinically Significant Abnormal Hematology Results

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    End point title
    		 Participants with Potentially Clinically Significant Abnormal Hematology Results [9]
    End point description
    Hematology tests included Basophils ABS (x 10^9/L), Basophils (%), Eosinophils ABS (x 10^9/L), Eosinophils (%), Hematocrit (%), Hemoglobin (g/L), Lymphocytes ABS (x 10^9/L), Lymphocytes (%), Monocytes ABS (x 10^9/L), Monocytes (%), Neutrophils ABS (x 10^9/L), Neutrophils (%), Platelets (x 10^9/L), Red Blood Cell (RBC) (x 10^12/L), White Blood Cell (WBC) (x 10^9/L). Only tests with potentially clinically significant abnormal results are reported. ULN = upper limit of normal
    End point type
    Primary
    End point timeframe
    Day 1 (start of tbo-filgrastim administration) up to Day 21
    Notes
    [9] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: This study is not powered for statistical analyses.
    End point values
    		 Infants (1 month to <2 years) Children (2 to <12 years) Adolescents (12 to <16 years)
    Number of subjects analysed
    2 [10]
    30 [11]
    18 [12]
    Units: participants
        Participants with >=1 abnormality
    2
    6
    3
        Hemoglobin (g/L): <80
    1
    2
    0
        Hemoglobin (g/L): increase of >40 *ULN or baseline
    0
    0
    1
        Lymphocytes ABS (x 10^9/L): >=0.2 and <0.5
    0
    3
    0
        Neutrophils ABS (x 10^9/L): <0.5
    1
    1
    1
        Neutrophils ABS (x 10^9/L): >=0.5 and <1.0
    1
    1
    1
        Platelets (x 10^9/L): >=25 and <50
    0
    1
    0
        White Blood Cell (WBC) (x 10^9/L): <1.0
    0
    1
    0
        White Blood Cell (WBC) (x 10^9/L): >=1 and <2
    1
    3
    1
    Notes
    [10] - Safety analysis set
    [11] - Safety analysis set
    [12] - Safety analysis set
    No statistical analyses for this end point

    Primary: Participants with Potentially Clinically Significant Abnormal Vital Signs

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    End point title
    		 Participants with Potentially Clinically Significant Abnormal Vital Signs [13]
    End point description
    Vital sign tests included Pulse Rate (bpm), Systolic BP (mmHg), Diastolic BP (mmHg), Respiratory Rate (bpm), and Temperature (°C). Only tests with potentially clinically significant abnormal results are reported.
    End point type
    Primary
    End point timeframe
    Day 1 (start of tbo-filgrastim administration) up to Day 21
    Notes
    [13] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: This study is not powered for statistical analyses.
    End point values
    		 Infants (1 month to <2 years) Children (2 to <12 years) Adolescents (12 to <16 years)
    Number of subjects analysed
    2 [14]
    30 [15]
    18 [16]
    Units: participants
        Participants with >=1 abnormality
    1
    23
    11
        Pulse Rate (bpm): change of >=15 bpm
    0
    14
    9
        Systolic BP (mmHg): change of >=20 mmHg
    0
    5
    3
        Diastolic BP (mmHg): change of >=15 mmHg
    0
    5
    5
        Respiratory Rate (bpm): change of >=8 breaths/min
    0
    5
    0
        Temperature (°C): >=38.0 °C
    1
    14
    4
    Notes
    [14] - Safety analysis set
    [15] - Safety analysis set
    [16] - Safety analysis set
    No statistical analyses for this end point

    Primary: Participants with Potentially Clinically Significant Abnormal Electrocardiogram Results

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    End point title
    		 Participants with Potentially Clinically Significant Abnormal Electrocardiogram Results [17]
    End point description
    Triplicate 12-lead ECGs were conducted at screening, predose, 4 and 6 hours postdose on day 1 of tbo-filgrastim administration, and at the end-of-study visit. The ECGs were interpreted by both the investigator and a qualified physician at the central diagnostic center as normal, abnormal not clinically significant, or abnormal clinically significant. The following parameters were measured/derived for each ECG assessment: heart rate, PR interval, RR interval, QT interval, corrected QT interval according to Fridericia’s formula (QTcF), corrected QT interval according to Bazett’s formula (QTcB), QRS duration, and QRS axis. The count of participants with potentially clinically significant ECG findings is reported.
    End point type
    Primary
    End point timeframe
    Day 1 (start of tbo-filgrastim administration) pre-dose, 4 hours post dose and 6 hours post dose; Day 21 (end of study visit)
    Notes
    [17] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: This study is not powered for statistical analyses.
    End point values
    		 Infants (1 month to <2 years) Children (2 to <12 years) Adolescents (12 to <16 years)
    Number of subjects analysed
    2 [18]
    30 [19]
    18 [20]
    Units: participants
    0
    0
    0
    Notes
    [18] - Safety analysis set
    [19] - Safety analysis set
    [20] - Safety analysis set
    No statistical analyses for this end point

    Primary: Participants with Negative Shifts from Baseline to End of Study in Physical Exam Findings

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    End point title
    		 Participants with Negative Shifts from Baseline to End of Study in Physical Exam Findings [21]
    End point description
    Physical examination was performed at screening and at the end-of-study visit. The following body systems were marked as normal or abnormal and if abnormal, whether clinically significant: Head, ears, eyes, nose and throat (HEENT), chest and lungs, heart, abdomen, skin, lymph nodes and neurological. Any physical examination finding that is judged by the investigator as a clinically significant change (worsening) compared with a baseline value were considered as an adverse event. Counts of participants with a negative shift from baseline in any of the body systems (including shifts from normal to abnormal, not clinically significant) are presented.
    End point type
    Primary
    End point timeframe
    Day -21 (screening visit, about 21 days prior to start of tbo-filgrastim administration), Day 21 (end of study visit)
    Notes
    [21] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: This study is not powered for statistical analyses.
    End point values
    		 Infants (1 month to <2 years) Children (2 to <12 years) Adolescents (12 to <16 years)
    Number of subjects analysed
    2 [22]
    30 [23]
    18 [24]
    Units: participants
        HEENT
    0
    0
    0
        Chest and lungs
    0
    0
    0
        Heart
    0
    0
    0
        Abdomen
    0
    0
    0
        Skin
    0
    1
    0
        Lymph nodes
    0
    0
    0
        Neurological
    0
    0
    0
    Notes
    [22] - Safety analysis set
    [23] - Safety analysis set
    [24] - Safety analysis set
    No statistical analyses for this end point

    Primary: Injection Site Reactions to tbo-Filgrastim Administration

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    End point title
    		 Injection Site Reactions to tbo-Filgrastim Administration [25]
    End point description
    Local tolerability at the injection site was assessed at 1 hour following each tbo-filgrastim administration. Reported are counts of participants who exhibited each type of finding at some point during their treatment with tbo-filgrastim.
    End point type
    Primary
    End point timeframe
    Day 1 (start of tbo-filgrastim administration) up to Day 14
    Notes
    [25] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: This study is not powered for statistical analyses.
    End point values
    		 Infants (1 month to <2 years) Children (2 to <12 years) Adolescents (12 to <16 years)
    Number of subjects analysed
    2 [26]
    30 [27]
    18 [28]
    Units: participants
        Surface ecchymosis
    2
    7
    2
        Surface erythema/redness
    2
    2
    0
        Induration
    0
    1
    0
        Pain at the injection site
    0
    0
    0
    Notes
    [26] - Safety analysis set
    [27] - Safety analysis set
    [28] - Safety analysis set
    No statistical analyses for this end point

    Primary: Participants with Negative Shifts from Baseline to End of Study in Spleen Sonography Findings

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    End point title
    		 Participants with Negative Shifts from Baseline to End of Study in Spleen Sonography Findings [29]
    End point description
    The investigator assessed spleen sonography findings as normal, abnormal not clinically significant, or abnormal clinically significant. Data representing counts of participants with a negative shift from baseline in spleen sonography findings (including shifts from normal to abnormal, not clinically significant) are presented.
    End point type
    Primary
    End point timeframe
    Day -21 (screening visit, about 21 days prior to start of tbo-filgrastim administration), Day 21 (end of study visit)
    Notes
    [29] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: This study is not powered for statistical analyses.
    End point values
    		 Infants (1 month to <2 years) Children (2 to <12 years) Adolescents (12 to <16 years)
    Number of subjects analysed
    2 [30]
    30 [31]
    18 [32]
    Units: participants
    0
    0
    0
    Notes
    [30] - Safety analysis set
    [31] - Safety analysis set
    [32] - Safety analysis set
    No statistical analyses for this end point

    Primary: Participants Who Were Alive at the 90 Day Follow-Up

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    End point title
    		 Participants Who Were Alive at the 90 Day Follow-Up [33]
    End point description
    Summary of participant survival at 90 day follow-up.
    End point type
    Primary
    End point timeframe
    90 days post end of study visit (111 days from start of tbo-filgrastim administration)
    Notes
    [33] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: This study is not powered for statistical analyses.
    End point values
    		 Infants (1 month to <2 years) Children (2 to <12 years) Adolescents (12 to <16 years)
    Number of subjects analysed
    2 [34]
    30 [35]
    18 [36]
    Units: participants
    2
    30
    18
    Notes
    [34] - Safety analysis set
    [35] - Safety analysis set
    [36] - Safety analysis set
    No statistical analyses for this end point

    Secondary: Participants with Positive Immunogenicity Findings Tested at Four Study Timepoints

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    End point title
    		 Participants with Positive Immunogenicity Findings Tested at Four Study Timepoints
    End point description
    Blood was drawn for the assessment of ADA at screening, at the end-of-study visit, and at 30 and 90 days after the last administration of tbo-filgrastim in CTX cycle 1. The main endpoint from the assessment was the presence of antibodies in the sample, reported as positive or negative. Participants with positive results are summarized.
    End point type
    Secondary
    End point timeframe
    Day -21 (screening visit, about 21 days prior to start of tbo-filgrastim administration), Day 21 (end of study visit), Day 51 (30 Day follow-up) and Day 111 (90 Day follow-up)
    End point values
    		 Infants (1 month to <2 years) Children (2 to <12 years) Adolescents (12 to <16 years)
    Number of subjects analysed
    2 [37]
    30 [38]
    18 [39]
    Units: participants
        Screening
    0
    0
    0
        End of Study visit
    0
    0
    0
        30 Day Follow-up
    0
    0
    0
        90 Day Follow-up
    0
    0
    0
    Notes
    [37] - Safety analysis set
    [38] - Safety analysis set
    [39] - Safety analysis set
    No statistical analyses for this end point

    Secondary: Maximum Observed Serum Concentration (Cmax) of tbo-Filgrastim

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    End point title
    		 Maximum Observed Serum Concentration (Cmax) of tbo-Filgrastim
    End point description
    End point type
    Secondary
    End point timeframe
    Within 1 hour before the tbo-filgrastim dose and at 2, 4, 6, 8, and 12 hours after the tbo-filgrastim dose on Day 1
    End point values
    		 Infants (1 month to <2 years) Children (2 to <12 years) Adolescents (12 to <16 years)
    Number of subjects analysed
    2 [40]
    29 [41]
    18 [42]
    Units: pg/mL
        arithmetic mean (standard deviation)
    26087.95 ± 8647.562
    20048.27 ± 9232.446
    19032.60 ± 11086.273
    Notes
    [40] - PK analysis set
    [41] - PK analysis set
    [42] - PK analysis set
    No statistical analyses for this end point

    Secondary: Time to Maximum Observed Serum Concentration (tmax) of tbo-Filgrastim

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    End point title
    		 Time to Maximum Observed Serum Concentration (tmax) of tbo-Filgrastim
    End point description
    End point type
    Secondary
    End point timeframe
    Within 1 hour before the tbo-filgrastim dose and at 2, 4, 6, 8, and 12 hours after the tbo-filgrastim dose on Day 1
    End point values
    		 Infants (1 month to <2 years) Children (2 to <12 years) Adolescents (12 to <16 years)
    Number of subjects analysed
    2 [43]
    29 [44]
    18 [45]
    Units: hours
        median (full range (min-max))
    6.00 (6.0 to 6.0)
    4.07 (3.9 to 8.0)
    4.00 (3.9 to 8.0)
    Notes
    [43] - PK analysis set
    [44] - PK analysis set
    [45] - PK analysis set
    No statistical analyses for this end point

    Secondary: Area Under The Serum Concentration-Time Curve From Time 0 To Time Of Last Quantifiable Concentration (AUClast)

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    End point title
    		 Area Under The Serum Concentration-Time Curve From Time 0 To Time Of Last Quantifiable Concentration (AUClast)
    End point description
    End point type
    Secondary
    End point timeframe
    Within 1 hour before the tbo-filgrastim dose and at 2, 4, 6, 8, and 12 hours after the tbo-filgrastim dose on Day 1
    End point values
    		 Infants (1 month to <2 years) Children (2 to <12 years) Adolescents (12 to <16 years)
    Number of subjects analysed
    2 [46]
    29 [47]
    18 [48]
    Units: hr*pg/mL
        arithmetic mean (standard deviation)
    187889.69 ± 80122.148
    142124.91 ± 63127.420
    127447.08 ± 73894.137
    Notes
    [46] - PK analysis set
    [47] - PK analysis set
    [48] - PK analysis set
    No statistical analyses for this end point

    Secondary: Area Under The Serum Concentration-Time Curve From Time 0 To 12 Hours Postdose (AUC0-12)

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    End point title
    		 Area Under The Serum Concentration-Time Curve From Time 0 To 12 Hours Postdose (AUC0-12)
    End point description
    End point type
    Secondary
    End point timeframe
    Within 1 hour before the tbo-filgrastim dose and at 2, 4, 6, 8, and 12 hours after the tbo-filgrastim dose on Day 1
    End point values
    		 Infants (1 month to <2 years) Children (2 to <12 years) Adolescents (12 to <16 years)
    Number of subjects analysed
    2 [49]
    28 [50]
    15 [51]
    Units: hr*pg/mL
        arithmetic mean (standard deviation)
    187889.69 ± 80122.148
    144109.32 ± 63358.011
    140550.22 ± 73648.629
    Notes
    [49] - PK analysis set
    [50] - PK analysis set
    [51] - PK analysis set
    No statistical analyses for this end point

    Secondary: AUC from time 0 to infinity (AUC0-inf)

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    End point title
    		 AUC from time 0 to infinity (AUC0-inf)
    End point description
    End point type
    Secondary
    End point timeframe
    Within 1 hour before the tbo-filgrastim dose and at 2, 4, 6, 8, and 12 hours after the tbo-filgrastim dose on Day 1
    End point values
    		 Infants (1 month to <2 years) Children (2 to <12 years) Adolescents (12 to <16 years)
    Number of subjects analysed
    0 [52]
    15 [53]
    8 [54]
    Units: hr*pg/mL
        arithmetic mean (standard deviation)
    ±
    161964.32 ± 87205.040
    198470.33 ± 80773.023
    Notes
    [52] - PK analysis set
    [53] - PK analysis set
    [54] - PK analysis set
    No statistical analyses for this end point

    Secondary: Elimination Half-life (t1/2)

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    End point title
    		 Elimination Half-life (t1/2)
    End point description
    End point type
    Secondary
    End point timeframe
    Within 1 hour before the tbo-filgrastim dose and at 2, 4, 6, 8, and 12 hours after the tbo-filgrastim dose on Day 1
    End point values
    		 Infants (1 month to <2 years) Children (2 to <12 years) Adolescents (12 to <16 years)
    Number of subjects analysed
    0 [55]
    15 [56]
    8 [57]
    Units: hours
        arithmetic mean (standard deviation)
    ±
    2.41 ± 0.549
    2.52 ± 0.561
    Notes
    [55] - PK analysis set
    [56] - PK analysis set
    [57] - PK analysis set
    No statistical analyses for this end point

    Secondary: Apparent Clearance (CL/F)

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    End point title
    		 Apparent Clearance (CL/F)
    End point description
    End point type
    Secondary
    End point timeframe
    Within 1 hour before the tbo-filgrastim dose and at 2, 4, 6, 8, and 12 hours after the tbo-filgrastim dose on Day 1
    End point values
    		 Infants (1 month to <2 years) Children (2 to <12 years) Adolescents (12 to <16 years)
    Number of subjects analysed
    0 [58]
    15 [59]
    8 [60]
    Units: L/hour
        arithmetic mean (standard deviation)
    ±
    0.98 ± 0.719
    1.68 ± 0.748
    Notes
    [58] - PK analysis set
    [59] - PK analysis set
    [60] - PK analysis set
    No statistical analyses for this end point

    Secondary: Apparent Volume of Distribution During the Terminal Phase (Vz/F)

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    End point title
    		 Apparent Volume of Distribution During the Terminal Phase (Vz/F)
    End point description
    End point type
    Secondary
    End point timeframe
    Within 1 hour before the tbo-filgrastim dose and at 2, 4, 6, 8, and 12 hours after the tbo-filgrastim dose on Day 1
    End point values
    		 Infants (1 month to <2 years) Children (2 to <12 years) Adolescents (12 to <16 years)
    Number of subjects analysed
    0 [61]
    15 [62]
    8 [63]
    Units: liters
        arithmetic mean (standard deviation)
    ±
    3.21 ± 1.963
    6.13 ± 3.094
    Notes
    [61] - PK analysis set
    [62] - PK analysis set
    [63] - PK analysis set
    No statistical analyses for this end point

    Secondary: Percentage of the AUC0–∞ that Is Due To the Extrapolation (%AUCext)

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    End point title
    		 Percentage of the AUC0–∞ that Is Due To the Extrapolation (%AUCext)
    End point description
    End point type
    Secondary
    End point timeframe
    Within 1 hour before the tbo-filgrastim dose and at 2, 4, 6, 8, and 12 hours after the tbo-filgrastim dose on Day 1
    End point values
    		 Infants (1 month to <2 years) Children (2 to <12 years) Adolescents (12 to <16 years)
    Number of subjects analysed
    0 [64]
    15 [65]
    8 [66]
    Units: percent of AUC0–∞
        arithmetic mean (standard deviation)
    ±
    7.97 ± 4.179
    8.19 ± 4.424
    Notes
    [64] - PK analysis set
    [65] - PK analysis set
    [66] - PK analysis set
    No statistical analyses for this end point

    Secondary: Terminal elimination rate (Lambda-z)

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    End point title
    		 Terminal elimination rate (Lambda-z)
    End point description
    End point type
    Secondary
    End point timeframe
    Within 1 hour before the tbo-filgrastim dose and at 2, 4, 6, 8, and 12 hours after the tbo-filgrastim dose on Day 1
    End point values
    		 Infants (1 month to <2 years) Children (2 to <12 years) Adolescents (12 to <16 years)
    Number of subjects analysed
    0 [67]
    15 [68]
    8 [69]
    Units: 1/hr
        arithmetic mean (standard deviation)
    ±
    0.30 ± 0.077
    0.29 ± 0.067
    Notes
    [67] - PK analysis set
    [68] - PK analysis set
    [69] - PK analysis set
    No statistical analyses for this end point

    Secondary: Incidence of Severe Neutropenia

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    End point title
    		 Incidence of Severe Neutropenia
    End point description
    Incidence of severe neutropenia = any value of absolute neutrophil count (ANC) <0.5 * 10^9/L at any time.
    End point type
    Secondary
    End point timeframe
    Blood samples (0.5 mL) for the assessment of ANC were collected within 1 hour before the tbo-filgrastim dose on Day 1, and on Days 5, 6, 7, 10, 12, and 15.
    End point values
    		 Infants (1 month to <2 years) Children (2 to <12 years) Adolescents (12 to <16 years)
    Number of subjects analysed
    2 [70]
    30 [71]
    18 [72]
    Units: participants
        Participants with event
    1
    19
    6
        Participants without event
    1
    11
    12
    Notes
    [70] - Full analysis set
    [71] - Full analysis set
    [72] - Full analysis set
    No statistical analyses for this end point

    Secondary: Duration of Severe Neutropenia

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    End point title
    		 Duration of Severe Neutropenia
    End point description
    The duration of severe neutropenia was derived by counting the number of days with absolute neutrophil count (ANC) values <0.5 * 10^9/L.
    End point type
    Secondary
    End point timeframe
    Blood samples (0.5 mL) for the assessment of ANC were collected within 1 hour before the tbo-filgrastim dose on Day 1, and on Days 5, 6, 7, 10, 12, and 15.
    End point values
    		 Infants (1 month to <2 years) Children (2 to <12 years) Adolescents (12 to <16 years)
    Number of subjects analysed
    2 [73]
    30 [74]
    18 [75]
    Units: days
        arithmetic mean (standard deviation)
    1.5 ± 2.12
    2.5 ± 2.46
    0.7 ± 1.14
    Notes
    [73] - Full analysis set
    [74] - Full analysis set
    [75] - Full analysis set
    No statistical analyses for this end point

    Secondary: Area Under The Serum Drug Concentration By Time Curve Of Absolute Neutrophil Count (AUC ANC)

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    End point title
    		 Area Under The Serum Drug Concentration By Time Curve Of Absolute Neutrophil Count (AUC ANC)
    End point description
    End point type
    Secondary
    End point timeframe
    Blood samples (0.5 mL) for the assessment of ANC were collected within 1 hour before the tbo-filgrastim dose on Day 1, and on Days 5, 6, 7, 10, 12, and 15.
    End point values
    		 Infants (1 month to <2 years) Children (2 to <12 years) Adolescents (12 to <16 years)
    Number of subjects analysed
    2 [76]
    30 [77]
    18 [78]
    Units: *10^9/L * days
        arithmetic mean (standard deviation)
    20.465 ± 6.1235
    53.931 ± 44.8741
    87.098 ± 61.1857
    Notes
    [76] - Full analysis set
    [77] - Full analysis set
    [78] - Full analysis set
    No statistical analyses for this end point

    Secondary: Absolute Neutrophil Count (ANC) Nadir

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    End point title
    		 Absolute Neutrophil Count (ANC) Nadir
    End point description
    ANC nadir (measured in 10^9/L) is the lowest ANC recorded.
    End point type
    Secondary
    End point timeframe
    Blood samples (0.5 mL) for the assessment of ANC were collected within 1 hour before the tbo-filgrastim dose on Day 1, and on Days 5, 6, 7, 10, 12, and 15.
    End point values
    		 Infants (1 month to <2 years) Children (2 to <12 years) Adolescents (12 to <16 years)
    Number of subjects analysed
    2 [79]
    30 [80]
    18 [81]
    Units: *10^9/L
        arithmetic mean (standard deviation)
    0.490 ± 0.4808
    0.851 ± 1.3633
    0.832 ± 0.6358
    Notes
    [79] - Full analysis set
    [80] - Full analysis set
    [81] - Full analysis set
    No statistical analyses for this end point

    Secondary: Time to Absolute Neutrophil Count (ANC) Nadir From Beginning of tbo-filgrastim Administration

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    End point title
    		 Time to Absolute Neutrophil Count (ANC) Nadir From Beginning of tbo-filgrastim Administration
    End point description
    End point type
    Secondary
    End point timeframe
    Blood samples (0.5 mL) for the assessment of ANC were collected within 1 hour before the tbo-filgrastim dose on Day 1, and on Days 5, 6, 7, 10, 12, and 15.
    End point values
    		 Infants (1 month to <2 years) Children (2 to <12 years) Adolescents (12 to <16 years)
    Number of subjects analysed
    2 [82]
    30 [83]
    18 [84]
    Units: days
        arithmetic mean (standard deviation)
    3.0 ± 4.24
    6.9 ± 2.55
    7.3 ± 2.72
    Notes
    [82] - Full analysis set
    [83] - Full analysis set
    [84] - Full analysis set
    No statistical analyses for this end point

    Secondary: Time to Absolute Neutrophil Count (ANC) Nadir From Beginning of Chemotherapy

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    End point title
    		 Time to Absolute Neutrophil Count (ANC) Nadir From Beginning of Chemotherapy
    End point description
    End point type
    Secondary
    End point timeframe
    Blood samples (0.5 mL) for the assessment of ANC were collected within 1 hour before the tbo-filgrastim dose on Day 1, and on Days 5, 6, 7, 10, 12, and 15.
    End point values
    		 Infants (1 month to <2 years) Children (2 to <12 years) Adolescents (12 to <16 years)
    Number of subjects analysed
    2 [85]
    30 [86]
    18 [87]
    Units: days
        arithmetic mean (standard deviation)
    6.5 ± 2.12
    10.3 ± 2.86
    11.2 ± 2.31
    Notes
    [85] - Full analysis set
    [86] - Full analysis set
    [87] - Full analysis set
    No statistical analyses for this end point

    Secondary: Time to ANC Recovery To ≥1.0 * 10^9/L From ANC Nadir

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    End point title
    		 Time to ANC Recovery To ≥1.0 * 10^9/L From ANC Nadir
    End point description
    End point type
    Secondary
    End point timeframe
    Blood samples (0.5 mL) for the assessment of ANC were collected within 1 hour before the tbo-filgrastim dose on Day 1, and on Days 5, 6, 7, 10, 12, and 15.
    End point values
    		 Infants (1 month to <2 years) Children (2 to <12 years) Adolescents (12 to <16 years)
    Number of subjects analysed
    2 [88]
    30 [89]
    18 [90]
    Units: days
        arithmetic mean (standard deviation)
    10.0 ± 7.07
    2.2 ± 2.02
    1.0 ± 1.19
    Notes
    [88] - Full analysis set
    [89] - Full analysis set
    [90] - Full analysis set
    No statistical analyses for this end point

    Secondary: Time to ANC Recovery To ≥2.0 * 10^9/L From ANC Nadir

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    End point title
    		 Time to ANC Recovery To ≥2.0 * 10^9/L From ANC Nadir
    End point description
    End point type
    Secondary
    End point timeframe
    Blood samples (0.5 mL) for the assessment of ANC were collected within 1 hour before the tbo-filgrastim dose on Day 1, and on Days 5, 6, 7, 10, 12, and 15
    End point values
    		 Infants (1 month to <2 years) Children (2 to <12 years) Adolescents (12 to <16 years)
    Number of subjects analysed
    2 [91]
    30 [92]
    18 [93]
    Units: days
        arithmetic mean (standard deviation)
    13.0 ± 2.83
    3.0 ± 3.09
    2.8 ± 2.09
    Notes
    [91] - Full analysis set
    [92] - Full analysis set
    [93] - Full analysis set
    No statistical analyses for this end point

    Secondary: Time to ANC Recovery To ≥1.0 * 10^9/L From Start of tbo-filgrastim Administration

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    End point title
    		 Time to ANC Recovery To ≥1.0 * 10^9/L From Start of tbo-filgrastim Administration
    End point description
    End point type
    Secondary
    End point timeframe
    Blood samples (0.5 mL) for the assessment of ANC were collected within 1 hour before the tbo-filgrastim dose on Day 1, and on Days 5, 6, 7, 10, 12, and 15
    End point values
    		 Infants (1 month to <2 years) Children (2 to <12 years) Adolescents (12 to <16 years)
    Number of subjects analysed
    2 [94]
    30 [95]
    18 [96]
    Units: days
        arithmetic mean (standard deviation)
    13.0 ± 2.83
    7.3 ± 4.43
    5.1 ± 5.30
    Notes
    [94] - Full analysis set
    [95] - Full analysis set
    [96] - Full analysis set
    No statistical analyses for this end point

    Secondary: Time to ANC Recovery To ≥2.0 * 10^9/L From Start of tbo-filgrastim Administration

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    End point title
    		 Time to ANC Recovery To ≥2.0 * 10^9/L From Start of tbo-filgrastim Administration
    End point description
    End point type
    Secondary
    End point timeframe
    Blood samples (0.5 mL) for the assessment of ANC were collected within 1 hour before the tbo-filgrastim dose on Day 1, and on Days 5, 6, 7, 10, 12, and 15
    End point values
    		 Infants (1 month to <2 years) Children (2 to <12 years) Adolescents (12 to <16 years)
    Number of subjects analysed
    2 [97]
    30 [98]
    18 [99]
    Units: days
        arithmetic mean (standard deviation)
    16.0 ± 1.41
    8.1 ± 5.20
    10.2 ± 4.22
    Notes
    [97] - Full analysis set
    [98] - Full analysis set
    [99] - Full analysis set
    No statistical analyses for this end point

    Secondary: Time to ANC Recovery To ≥1.0 * 10^9/L From Start of Chemotherapy

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    End point title
    		 Time to ANC Recovery To ≥1.0 * 10^9/L From Start of Chemotherapy
    End point description
    End point type
    Secondary
    End point timeframe
    Blood samples (0.5 mL) for the assessment of ANC were collected within 1 hour before the tbo-filgrastim dose on Day 1, and on Days 5, 6, 7, 10, 12, and 15
    End point values
    		 Infants (1 month to <2 years) Children (2 to <12 years) Adolescents (12 to <16 years)
    Number of subjects analysed
    2 [100]
    30 [101]
    18 [102]
    Units: days
        arithmetic mean (standard deviation)
    16.5 ± 4.95
    10.2 ± 5.98
    7.4 ± 7.09
    Notes
    [100] - Full analysis set
    [101] - Full analysis set
    [102] - Full analysis set
    No statistical analyses for this end point

    Secondary: Time to ANC Recovery To ≥2.0 * 10^9/L From Start of Chemotherapy

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    End point title
    		 Time to ANC Recovery To ≥2.0 * 10^9/L From Start of Chemotherapy
    End point description
    End point type
    Secondary
    End point timeframe
    Blood samples (0.5 mL) for the assessment of ANC were collected within 1 hour before the tbo-filgrastim dose on Day 1, and on Days 5, 6, 7, 10, 12, and 15
    End point values
    		 Infants (1 month to <2 years) Children (2 to <12 years) Adolescents (12 to <16 years)
    Number of subjects analysed
    2 [103]
    30 [104]
    18 [105]
    Units: days
        arithmetic mean (standard deviation)
    19.5 ± 0.71
    11.0 ± 6.52
    14.0 ± 3.73
    Notes
    [103] - Full analysis set
    [104] - Full analysis set
    [105] - Full analysis set
    No statistical analyses for this end point

    Secondary: Incidence of Febrile Neutropenia

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    End point title
    		 Incidence of Febrile Neutropenia
    End point description
    The efficacy variable was evaluated for up to 21 days from the start of the first cycle of chemotherapy. Febrile neutropenia was defined as an axillary or external ear temperature >38.3°C (100.94°F) or 2 consecutive readings >37.8°C (100.04°F) at least 2 hours apart and an ANC <0.5 * 10^9/L.
    End point type
    Secondary
    End point timeframe
    (relative to tbo-filgrastim therapy) Days -7 to Day 14
    End point values
    		 Infants (1 month to <2 years) Children (2 to <12 years) Adolescents (12 to <16 years)
    Number of subjects analysed
    2 [106]
    30 [107]
    18 [108]
    Units: participants
        Participants with event
    1
    9
    3
        Participants without event
    1
    21
    15
    Notes
    [106] - Full analysis set
    [107] - Full analysis set
    [108] - Full analysis set
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Day 1 (start of tbo-filgrastim administration) to <= 30 days after the last dose (up to Day 45)
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    17.0
    Reporting groups
    Reporting group title
    Infants (1 month to <2 years)
    Reporting group description
    		 Tbo-filgrastim administration was started at approximately 24 hours (±3 hours) after the end of the last chemotherapy (CTX) treatment in the first week of the CTX cycle. Daily dosing with tbo-filgrastim at a dose of 5 μg/kg/day of body weight continued until the expected neutrophil nadir was passed and the neutrophil count had recovered to 2.0 × 10^9/L but not longer than 14 consecutive days. An immunogenicity sample was collected 30 days and 3 months after the last tbo-filgrastim administration in the first cycle.

    Reporting group title
    Children (2 to <12 years)
    Reporting group description
    		 Tbo-filgrastim administration was started at approximately 24 hours (±3 hours) after the end of the last chemotherapy (CTX) treatment in the first week of the CTX cycle. Daily dosing with tbo-filgrastim at a dose of 5 μg/kg/day of body weight continued until the expected neutrophil nadir was passed and the neutrophil count had recovered to 2.0 × 10^9/L but not longer than 14 consecutive days. An immunogenicity sample was collected 30 days and 3 months after the last tbo-filgrastim administration in the first cycle.

    Reporting group title
    Adolescents (12 to <16 years)
    Reporting group description
    		 Tbo-filgrastim administration was started at approximately 24 hours (±3 hours) after the end of the last chemotherapy (CTX) treatment in the first week of the CTX cycle. Daily dosing with tbo-filgrastim at a dose of 5 μg/kg/day of body weight continued until the expected neutrophil nadir was passed and the neutrophil count had recovered to 2.0 × 10^9/L but not longer than 14 consecutive days. An immunogenicity sample was collected 30 days and 3 months after the last tbo-filgrastim administration in the first cycle.

    Serious adverse events
    		 Infants (1 month to <2 years) Children (2 to <12 years) Adolescents (12 to <16 years)
    Total subjects affected by serious adverse events
         subjects affected / exposed
    0 / 2 (0.00%)
    9 / 30 (30.00%)
    3 / 18 (16.67%)
         number of deaths (all causes)
    0
    0
    0
         number of deaths resulting from adverse events
    Investigations
    Aspartate aminotransferase increased
         subjects affected / exposed
    0 / 2 (0.00%)
    2 / 30 (6.67%)
    1 / 18 (5.56%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 2
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Alanine aminotransferase increased
         subjects affected / exposed
    0 / 2 (0.00%)
    2 / 30 (6.67%)
    1 / 18 (5.56%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 2
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Gamma-glutamyltransferase increased
         subjects affected / exposed
    0 / 2 (0.00%)
    0 / 30 (0.00%)
    1 / 18 (5.56%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    0 / 2 (0.00%)
    4 / 30 (13.33%)
    0 / 18 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 5
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pancytopenia
         subjects affected / exposed
    0 / 2 (0.00%)
    1 / 30 (3.33%)
    0 / 18 (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
    Febrile neutropenia
         subjects affected / exposed
    0 / 2 (0.00%)
    4 / 30 (13.33%)
    2 / 18 (11.11%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 6
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Thrombocytopenia
         subjects affected / exposed
    0 / 2 (0.00%)
    2 / 30 (6.67%)
    2 / 18 (11.11%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Haematemesis
         subjects affected / exposed
    0 / 2 (0.00%)
    1 / 30 (3.33%)
    0 / 18 (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
    Skin and subcutaneous tissue disorders
    Hangnail
         subjects affected / exposed
    0 / 2 (0.00%)
    1 / 30 (3.33%)
    0 / 18 (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
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Infants (1 month to <2 years) Children (2 to <12 years) Adolescents (12 to <16 years)
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    2 / 2 (100.00%)
    27 / 30 (90.00%)
    15 / 18 (83.33%)
    Investigations
    Neutrophil count decreased
         subjects affected / exposed
    0 / 2 (0.00%)
    2 / 30 (6.67%)
    0 / 18 (0.00%)
         occurrences all number
    0
    3
    0
    White blood cell count decreased
         subjects affected / exposed
    0 / 2 (0.00%)
    2 / 30 (6.67%)
    0 / 18 (0.00%)
         occurrences all number
    0
    3
    0
    Gamma-glutamyltransferase increased
         subjects affected / exposed
    0 / 2 (0.00%)
    2 / 30 (6.67%)
    0 / 18 (0.00%)
         occurrences all number
    0
    2
    0
    Aspartate aminotransferase increased
         subjects affected / exposed
    0 / 2 (0.00%)
    2 / 30 (6.67%)
    0 / 18 (0.00%)
         occurrences all number
    0
    2
    0
    Alanine aminotransferase increased
         subjects affected / exposed
    0 / 2 (0.00%)
    2 / 30 (6.67%)
    0 / 18 (0.00%)
         occurrences all number
    0
    2
    0
    Blood lactate dehydrogenase increased
         subjects affected / exposed
    0 / 2 (0.00%)
    0 / 30 (0.00%)
    1 / 18 (5.56%)
         occurrences all number
    0
    0
    1
    Cardiac disorders
    Sinus tachycardia
         subjects affected / exposed
    0 / 2 (0.00%)
    0 / 30 (0.00%)
    1 / 18 (5.56%)
         occurrences all number
    0
    0
    1
    Nervous system disorders
    Headache
         subjects affected / exposed
    0 / 2 (0.00%)
    1 / 30 (3.33%)
    2 / 18 (11.11%)
         occurrences all number
    0
    1
    2
    Neurotoxicity
         subjects affected / exposed
    0 / 2 (0.00%)
    0 / 30 (0.00%)
    1 / 18 (5.56%)
         occurrences all number
    0
    0
    1
    Blood and lymphatic system disorders
    Neutropenia
         subjects affected / exposed
    2 / 2 (100.00%)
    16 / 30 (53.33%)
    9 / 18 (50.00%)
         occurrences all number
    6
    34
    16
    Febrile neutropenia
         subjects affected / exposed
    1 / 2 (50.00%)
    5 / 30 (16.67%)
    0 / 18 (0.00%)
         occurrences all number
    1
    5
    0
    Thrombocytopenia
         subjects affected / exposed
    2 / 2 (100.00%)
    8 / 30 (26.67%)
    4 / 18 (22.22%)
         occurrences all number
    5
    16
    5
    Leukopenia
         subjects affected / exposed
    2 / 2 (100.00%)
    6 / 30 (20.00%)
    3 / 18 (16.67%)
         occurrences all number
    2
    11
    3
    Anaemia
         subjects affected / exposed
    1 / 2 (50.00%)
    12 / 30 (40.00%)
    3 / 18 (16.67%)
         occurrences all number
    1
    20
    3
    Lymphopenia
         subjects affected / exposed
    0 / 2 (0.00%)
    0 / 30 (0.00%)
    1 / 18 (5.56%)
         occurrences all number
    0
    0
    3
    General disorders and administration site conditions
    Mucosal inflammation
         subjects affected / exposed
    0 / 2 (0.00%)
    3 / 30 (10.00%)
    3 / 18 (16.67%)
         occurrences all number
    0
    3
    3
    Pyrexia
         subjects affected / exposed
    0 / 2 (0.00%)
    2 / 30 (6.67%)
    2 / 18 (11.11%)
         occurrences all number
    0
    2
    10
    Hyperthermia
         subjects affected / exposed
    0 / 2 (0.00%)
    0 / 30 (0.00%)
    1 / 18 (5.56%)
         occurrences all number
    0
    0
    1
    Immune system disorders
    Hypogammaglobulinaemia
         subjects affected / exposed
    0 / 2 (0.00%)
    0 / 30 (0.00%)
    3 / 18 (16.67%)
         occurrences all number
    0
    0
    6
    Gastrointestinal disorders
    Enterocolitis
         subjects affected / exposed
    1 / 2 (50.00%)
    0 / 30 (0.00%)
    0 / 18 (0.00%)
         occurrences all number
    1
    0
    0
    Colitis
         subjects affected / exposed
    1 / 2 (50.00%)
    1 / 30 (3.33%)
    0 / 18 (0.00%)
         occurrences all number
    1
    1
    0
    Stomatitis
         subjects affected / exposed
    1 / 2 (50.00%)
    3 / 30 (10.00%)
    2 / 18 (11.11%)
         occurrences all number
    1
    3
    2
    Vomiting
         subjects affected / exposed
    0 / 2 (0.00%)
    5 / 30 (16.67%)
    3 / 18 (16.67%)
         occurrences all number
    0
    6
    6
    Nausea
         subjects affected / exposed
    0 / 2 (0.00%)
    2 / 30 (6.67%)
    2 / 18 (11.11%)
         occurrences all number
    0
    2
    2
    Diarrhoea
         subjects affected / exposed
    0 / 2 (0.00%)
    2 / 30 (6.67%)
    1 / 18 (5.56%)
         occurrences all number
    0
    2
    2
    Abdominal rigidity
         subjects affected / exposed
    0 / 2 (0.00%)
    0 / 30 (0.00%)
    1 / 18 (5.56%)
         occurrences all number
    0
    0
    1
    Abdominal pain upper
         subjects affected / exposed
    0 / 2 (0.00%)
    0 / 30 (0.00%)
    1 / 18 (5.56%)
         occurrences all number
    0
    0
    2
    Constipation
         subjects affected / exposed
    0 / 2 (0.00%)
    0 / 30 (0.00%)
    1 / 18 (5.56%)
         occurrences all number
    0
    0
    1
    Skin and subcutaneous tissue disorders
    Skin necrosis
         subjects affected / exposed
    0 / 2 (0.00%)
    0 / 30 (0.00%)
    1 / 18 (5.56%)
         occurrences all number
    0
    0
    1
    Rash vesicular
         subjects affected / exposed
    0 / 2 (0.00%)
    0 / 30 (0.00%)
    1 / 18 (5.56%)
         occurrences all number
    0
    0
    1
    Musculoskeletal and connective tissue disorders
    Pain in extremity
         subjects affected / exposed
    0 / 2 (0.00%)
    2 / 30 (6.67%)
    1 / 18 (5.56%)
         occurrences all number
    0
    2
    4
    Back pain
         subjects affected / exposed
    0 / 2 (0.00%)
    1 / 30 (3.33%)
    1 / 18 (5.56%)
         occurrences all number
    0
    1
    1
    Infections and infestations
    Clostridium difficile colitis
         subjects affected / exposed
    0 / 2 (0.00%)
    1 / 30 (3.33%)
    1 / 18 (5.56%)
         occurrences all number
    0
    1
    2
    Oral candidiasis
         subjects affected / exposed
    0 / 2 (0.00%)
    0 / 30 (0.00%)
    1 / 18 (5.56%)
         occurrences all number
    0
    0
    1
    Cellulitis staphylococcal
         subjects affected / exposed
    0 / 2 (0.00%)
    0 / 30 (0.00%)
    1 / 18 (5.56%)
         occurrences all number
    0
    0
    1
    Metabolism and nutrition disorders
    Decreased appetite
         subjects affected / exposed
    0 / 2 (0.00%)
    2 / 30 (6.67%)
    0 / 18 (0.00%)
         occurrences all number
    0
    2
    0
    Hypoalbuminaemia
         subjects affected / exposed
    0 / 2 (0.00%)
    0 / 30 (0.00%)
    2 / 18 (11.11%)
         occurrences all number
    0
    0
    4
    Hypokalaemia
         subjects affected / exposed
    0 / 2 (0.00%)
    1 / 30 (3.33%)
    1 / 18 (5.56%)
         occurrences all number
    0
    1
    1

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    11 Jan 2016
    Amendment 1 (dated 11 January 2016) to the original protocol (dated 12 May 2014), was issued when 20 patients were enrolled in the study. The primary reason for this amendment was to clarify the minimum number of 5 daily doses of tbo-filgrastim in the CTX cycle. This change was implemented to prevent premature discontinuation of tbo-filgrastim, which was observed in practice, since a transient increase in neutrophil counts typically seen 1 to 2 days after initiation of tbo-filgrastim therapy, but this does not imply that the nadir had passed. The revisions were considered substantial by the Teva Authorized Representative. The following major procedural changes (not all-inclusive) were made to the protocol: - The confidentiality statement had been updated to reflect Sicor Biotech UAB as the applicant for the BLA - The identity of the clinical laboratory, the laboratory used for immunogenicity analysis, pharmacokinetic analysis, and the identity of the central IRB, and central ECG evaluation was added. - An additional physician at the contract research organization was added as a contact for medical issues. - The study design was updated to clarify that the minimum duration of daily dosing of tbo-filgrastim was clarified since it is not expected that the neutrophil nadir were passed before 5 days. - Recording times for concomitant therapy or medications and adverse events were specified. With the procedures for screening and enrollment, permission to use local lab results to facilitate timely beginning of CTX for treatment of the children was added. - Clarification that tbo-filgrastim should not be administered for longer than 14 days. - An exclusion criterion of patient participation in an interventional clinical study within 30 days or 5 half-lives of the investigational product before enrollment, whichever was longer, was added. - other
    24 Feb 2016
    Amendment 2 (dated 24 February 2016) to the protocol was issued approximately 1 month after Amendment 01 was issued, after 20 patients in total were enrolled into the study. The primary reason for Amendment 02 was to delete the requirement of administering at least 5 daily doses of tbo-filgrastim in the CTX cycle. This change was implemented in response to the FDA response to Amendment 01 that the instruction to administer at least 5 days of tbo-filgrastim was not consistent with the prescribing information or the current standard of care. The following major procedural changes (not all-inclusive) were made to the protocol: -The requirement to administer at least 5 daily doses of tbo-filgrastim was deleted. The tbo-filgrastim dosing schedule was amended to clarify that a transient increase in neutrophil counts is typically seen 1 to 2 days after initiation of tbo-filgrastim therapy followed by the CTX-induced nadir.

    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.
    The overall sample size of 50 was not the result of a formal sample size calculation but chosen due to the difficulty of recruiting subjects in the requested age classes, and is considered sufficient to allow exploratory analysis.
    For support, Contact us.
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    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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