Evaluation of Dose-response, Pharmacodynamic and Pharmacokinetic Bioequivalence of Filgrastim in Healthy Male Volunteers After Single and Multiple-dose Subcutaneous Administration of the Test Injectable Formulation BK0023 vs. Neupogen®
NCT ID: NCT01933971
Last Updated: 2013-09-09
Study Results
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Basic Information
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COMPLETED
PHASE1
102 participants
INTERVENTIONAL
2007-06-30
2008-04-30
Brief Summary
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The study is aimed at investigating the pharmacodynamic equivalence and the pharmacokinetic bioequivalence of the new BK0023 injectable formulation of filgrastim 0.3 mg/mL by Bio-Ker S.r.l. vs. the comparator (Neupogen® 0.3 mg/mL, Dompé Biotec S.p.A., Italy). Healthy male subjects will receive test and reference at the doses of 2.5 and 5 µg/kg/day for 7 consecutive days and at the dose of 10 µg/kg/day for 5 consecutive days according to a randomised cross-over design. Pharmacodynamics, pharmacokinetics and safety of BK0023 injectable formulation 0.3 mg/mL and of Neupogen® 0.3 mg/mL, administered in 2 consecutive periods with a wash-out of at least 28 days elapsing between the last injection of period I and the first of period II, are compared.
Study design: Single and multiple escalating dose, double-blind, randomised, two-way cross-over, pharmacodynamic and pharmacokinetic bioequivalence study.
Detailed Description
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The study design was chosen according to the internationally recognised guideline for pharmacokinetics studies and in accordance with the EMEA guidance on similar medicinal products containing recombinant granulocyte-colony stimulating factor (G-CSF), which is annexed to the guideline on similar biological medicinal products containing biotechnology-derived proteins as active substance: non-clinical and clinical issues. A clinical development plan including the study outline was also submitted to EMEA, which examined the documentation and gave advice about the present study design .
A multiple-dose design was chosen instead of a single-dose design, since G-CSF pharmacokinetics is non linear due to 2 reasons: non-proportional increase with dose and time dependent non-linearity. However, pharmacodynamic equivalence and pharmacokinetic bioequivalence will be both tested after the 1st and the last dose of the multiple dose treatment.
Since the effects of r-h-met-G-CSF can be directly measured as pharmacodynamic responses, i.e. the increase in the absolute neutrophil count (ANC) and the development of peripheral blood cells (CD34+ cells), both parameters will be evaluated for the equivalence testing.
Dose levels of 2.5 and 5 μg/kg/day were chosen for the pharmacodynamic equivalence, since literature data show a clear dose-response relationship in terms of the pharmacodynamic parameters over this range. The 10 μg/kg/day dose was chosen to make the investigated range relevant with respect to the clinical indications and the usual praxis for Neupogen®. Moreover, the subcutaneous administration was chosen, since this administration route is the most commonly used in the clinical setting.
Conditions
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Study Design
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RANDOMIZED
CROSSOVER
TREATMENT
TRIPLE
Study Groups
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Group 1: filgrastim 2.5 µg/kg/day for 7 consecutive days
The test investigational product is BK0023. The reference product is Neupogen® 30, by Dompé Biotec S.p.A., Italy.
Both study treatments were administered according to a cross-over design in 2 subsequent periods separated by wash-out periods of at least 28 days.
The sites, where the injections are to be performed, are planned as follows:
1. st injection: upper part of the upper arm, posterior surface
2. nd injection: upper part of the thigh
3. rd injection: abdomen with the exception of the umbilical area
4. th injection: upper part of the contra-lateral upper arm, posterior surface
5. th injection: upper part of the contra-lateral thigh
6. th injection: abdomen with the exception of the umbilical area
7. th injection: upper part of the same upper arm, posterior surface as for the 1st injection.
Filgrastim test
0.3 mg/mL injectable solution in 1 mL vials Manufacturer (Drug Substance): Eurogenetec S.A., B-4102 Seraing, Belgium Manufacturer (Drug Product): Areta International S.r.l., I-21040 Gerenzano, Italy Batch release: Areta International S.r.l., I-21040 Gerenzano, Italy Route of administration: subcutaneous
Filgrastim reference
0.3 mg/mL injectable solution in 1 mL vials Licensed owner: Dompé farmaceutici S.p.A., Milan, Italy Manufacturer (Drug Product): Hoffmann - La Roche Ltd., Basel, Switzerland and Amgen Manufacturing Limited, Puertorico.
Batch release: Amgen Europe B.V., Breda, Netherlands Route of administration: subcutaneous
Group 2: filgrastim 5 µg/kg/day for 7 consecutive days
The test investigational product is BK0023. The reference product is Neupogen® 30, by Dompé Biotec S.p.A., Italy.
Both study treatments were administered according to a cross-over design in 2 subsequent periods separated by wash-out periods of at least 28 days.
The sites, where the injections are to be performed, are planned as follows:
1. st injection: upper part of the upper arm, posterior surface
2. nd injection: upper part of the thigh
3. rd injection: abdomen with the exception of the umbilical area
4. th injection: upper part of the contra-lateral upper arm, posterior surface
5. th injection: upper part of the contra-lateral thigh
6. th injection: abdomen with the exception of the umbilical area
7. th injection: upper part of the same upper arm, posterior surface as for the 1st injection.
Filgrastim test
0.3 mg/mL injectable solution in 1 mL vials Manufacturer (Drug Substance): Eurogenetec S.A., B-4102 Seraing, Belgium Manufacturer (Drug Product): Areta International S.r.l., I-21040 Gerenzano, Italy Batch release: Areta International S.r.l., I-21040 Gerenzano, Italy Route of administration: subcutaneous
Filgrastim reference
0.3 mg/mL injectable solution in 1 mL vials Licensed owner: Dompé farmaceutici S.p.A., Milan, Italy Manufacturer (Drug Product): Hoffmann - La Roche Ltd., Basel, Switzerland and Amgen Manufacturing Limited, Puertorico.
Batch release: Amgen Europe B.V., Breda, Netherlands Route of administration: subcutaneous
Group 3: filgrastim 10 µg/kg/day for 5 consecutive days
The test investigational product is BK0023. The reference product is Neupogen® 30, by Dompé Biotec S.p.A., Italy.
Both study treatments were administered according to a cross-over design in 2 subsequent periods separated by wash-out periods of at least 28 days.
The sites, where the injections are to be performed, are planned as follows:
1. st injection: upper part of the upper arm, posterior surface
2. nd injection: upper part of the thigh
3. rd injection: abdomen with the exception of the umbilical area
4. th injection: upper part of the contra-lateral upper arm, posterior surface
5. th injection: upper part of the contra-lateral thigh.
Filgrastim test
0.3 mg/mL injectable solution in 1 mL vials Manufacturer (Drug Substance): Eurogenetec S.A., B-4102 Seraing, Belgium Manufacturer (Drug Product): Areta International S.r.l., I-21040 Gerenzano, Italy Batch release: Areta International S.r.l., I-21040 Gerenzano, Italy Route of administration: subcutaneous
Filgrastim reference
0.3 mg/mL injectable solution in 1 mL vials Licensed owner: Dompé farmaceutici S.p.A., Milan, Italy Manufacturer (Drug Product): Hoffmann - La Roche Ltd., Basel, Switzerland and Amgen Manufacturing Limited, Puertorico.
Batch release: Amgen Europe B.V., Breda, Netherlands Route of administration: subcutaneous
Interventions
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Filgrastim test
0.3 mg/mL injectable solution in 1 mL vials Manufacturer (Drug Substance): Eurogenetec S.A., B-4102 Seraing, Belgium Manufacturer (Drug Product): Areta International S.r.l., I-21040 Gerenzano, Italy Batch release: Areta International S.r.l., I-21040 Gerenzano, Italy Route of administration: subcutaneous
Filgrastim reference
0.3 mg/mL injectable solution in 1 mL vials Licensed owner: Dompé farmaceutici S.p.A., Milan, Italy Manufacturer (Drug Product): Hoffmann - La Roche Ltd., Basel, Switzerland and Amgen Manufacturing Limited, Puertorico.
Batch release: Amgen Europe B.V., Breda, Netherlands Route of administration: subcutaneous
Other Intervention Names
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Eligibility Criteria
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Inclusion Criteria
* a body weight between 60 and 90 kg,
* good health based on medical history, physical examination, a 12-lead electrocardiogram (ECG) and routine haematology and blood chemistry tests,
* willingness to provide written informed consent
* values of leukocytes and thrombocytes had to be inside the normality range at the screening.
Exclusion Criteria
* a history of drug, caffeine (\>5 cups coffee/tea/day) or tobacco (\>/=10 cigarettes/day) abuse, or alcohol consumption in excess of two drinks per day, as defined by the U.S.D.A. dietary guidelines,
* ascertained or presumptive hypersensitivity to the active compound or history of anaphylaxis to drugs.
20 Years
40 Years
MALE
Yes
Sponsors
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Cross Research S.A.
INDUSTRY
Nerviano Medical Sciences
INDUSTRY
AAI Deutschland GmbH & Co. KG
OTHER
Gife S.A.
OTHER
Bio-ker S.r.l.
INDUSTRY
Responsible Party
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Principal Investigators
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Antonio Rusca, MD
Role: PRINCIPAL_INVESTIGATOR
CROSS Research SA
Locations
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CROSS Research SA
Arzo, Canton Ticino, Switzerland
Countries
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References
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Other Identifiers
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2007DR1116
Identifier Type: OTHER
Identifier Source: secondary_id
CRO-PK-06-175
Identifier Type: -
Identifier Source: org_study_id