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Clinical Trial Details — Status: Completed

Administrative data

NCT number NCT01933971
Other study ID # CRO-PK-06-175
Secondary ID 2007DR1116
Status Completed
Phase Phase 1
First received August 29, 2013
Last updated September 6, 2013
Start date June 2007
Est. completion date April 2008

Study information

Verified date September 2013
Source Bio-ker S.r.l.
Contact n/a
Is FDA regulated No
Health authority Switzerland: Swissmedic • Swiss Agency for Therapeutic Products
Study type Interventional

Clinical Trial Summary

Study rationale: Bio-ker has developed the new formulation of filgrastim BK0023 with the same active content as Neupogen®. BK0023 is expected to have the same tolerability profile and clinical effects as Neupogen® in controlling myelo-toxicity induced by chemotherapy given for the treatment of solid and haematological tumours. It is worth noting that the production and manufacturing procedures allow to have a reduction of drug cost thus it is likely to have pharmacoeconomic advantages.

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.


Description:

In a first part of the study, 16 healthy male subjects will be included in each dose group and will receive test and reference product according to the cross-over design. After the end of the second period of each dose group (completion of both cross-over periods for each dose group) the pharmacodynamic and pharmacokinetic primary parameters will be calculated. The blinding will be temporarily broken by one statistician for the ad interim analysis of primary parameters that will be performed after conclusion of the treatment of 16 subjects for each dose group (results are not disclosed) with the aim to re-calculate the sample size and to conclude the study with the necessary and sufficient number of subjects for each dose regimen.

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.


Recruitment information / eligibility

Status Completed
Enrollment 102
Est. completion date April 2008
Est. primary completion date April 2008
Accepts healthy volunteers Accepts Healthy Volunteers
Gender Male
Age group 20 Years to 40 Years
Eligibility Inclusion Criteria:

- a body mass index (BMI) between 18 and 28 kg/m2,

- 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:

- intake of any concomitant medication,

- 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.

Study Design

Allocation: Randomized, Endpoint Classification: Bio-equivalence Study, Intervention Model: Crossover Assignment, Masking: Double Blind (Subject, Caregiver, Investigator), Primary Purpose: Treatment


Related Conditions & MeSH terms


Intervention

Drug:
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

Locations

Country Name City State
Switzerland CROSS Research SA Arzo Ticino

Sponsors (5)

Lead Sponsor Collaborator
Bio-ker S.r.l. AAI Deutschland GmbH & Co. KG, Cross Research S.A., Gife S.A., Nerviano Medical Sciences

Country where clinical trial is conducted

Switzerland, 

References & Publications (39)

Annex guideline on similar biological medicinal products containing biotechnology-derived proteins as active substance: non-clinical and clinical issues,

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Bönig H, Silbermann S, Weller S, Kirschke R, Körholz D, Janssen G, Göbel U, Nürnberger W. Glycosylated vs non-glycosylated granulocyte colony-stimulating factor (G-CSF)--results of a prospective randomised monocentre study. Bone Marrow Transplant. 2001 Aug;28(3):259-64. — View Citation

Borleffs JC, Bosschaert M, Vrehen HM, Schneider MM, van Strijp J, Small MK, Borkett KM. Effect of escalating doses of recombinant human granulocyte colony-stimulating factor (filgrastim) on circulating neutrophils in healthy subjects. Clin Ther. 1998 Jul-Aug;20(4):722-36. — View Citation

Bussolino F, Wang JM, Defilippi P, Turrini F, Sanavio F, Edgell CJ, Aglietta M, Arese P, Mantovani A. Granulocyte- and granulocyte-macrophage-colony stimulating factors induce human endothelial cells to migrate and proliferate. Nature. 1989 Feb 2;337(6206):471-3. — View Citation

Chow S and J Liu (2000), Design and analysis of bioavailability and bioequivalence studies, 2nd Edition, Revised and expanded, Marcel Dekker Inc., New York - Basel.

Crawford J, Ozer H, Stoller R, Johnson D, Lyman G, Tabbara I, Kris M, Grous J, Picozzi V, Rausch G, et al. Reduction by granulocyte colony-stimulating factor of fever and neutropenia induced by chemotherapy in patients with small-cell lung cancer. N Engl J Med. 1991 Jul 18;325(3):164-70. — View Citation

Fabian I, Kletter Y, Bleiberg I, Gadish M, Naparsteck E, Slavin S. Effect of exogenous recombinant human granulocyte and granulocyte-macrophage colony-stimulating factor on neutrophil function following allogeneic bone marrow transplantation. Exp Hematol. 1991 Oct;19(9):868-73. — View Citation

Fukunaga R, Ishizaka-Ikeda E, Nagata S. Purification and characterization of the receptor for murine granulocyte colony-stimulating factor. J Biol Chem. 1990 Aug 15;265(23):14008-15. — View Citation

Gabrilove JL, Jakubowski A, Scher H, Sternberg C, Wong G, Grous J, Yagoda A, Fain K, Moore MA, Clarkson B, et al. Effect of granulocyte colony-stimulating factor on neutropenia and associated morbidity due to chemotherapy for transitional-cell carcinoma of the urothelium. N Engl J Med. 1988 Jun 2;318(22):1414-22. — View Citation

Gardner SN. A mechanistic, predictive model of dose-response curves for cell cycle phase-specific and -nonspecific drugs. Cancer Res. 2000 Mar 1;60(5):1417-25. — View Citation

Glaspy JA, Baldwin GC, Robertson PA, Souza L, Vincent M, Ambersley J, Golde DW. Therapy for neutropenia in hairy cell leukemia with recombinant human granulocyte colony-stimulating factor. Ann Intern Med. 1988 Nov 15;109(10):789-95. — View Citation

Höglund M, Smedmyr B, Bengtsson M, Tötterman TH, Cour-Chabernaud V, Yver A, Simonsson B. Mobilization of CD34+ cells by glycosylated and nonglycosylated G-CSF in healthy volunteers--a comparative study. Eur J Haematol. 1997 Sep;59(3):177-83. — View Citation

Houston AC, Stevens LA, Cour V. Pharmacokinetics of glycosylated recombinant human granulocyte colony-stimulating factor (lenograstim) in healthy male volunteers. Br J Clin Pharmacol. 1999 Mar;47(3):279-84. — View Citation

Hryniuk W, Bush H. The importance of dose intensity in chemotherapy of metastatic breast cancer. J Clin Oncol. 1984 Nov;2(11):1281-8. Review. — View Citation

Layton JE, Hall NE, Connell F, Venhorst J, Treutlein HR. Identification of ligand-binding site III on the immunoglobulin-like domain of the granulocyte colony-stimulating factor receptor. J Biol Chem. 2001 Sep 28;276(39):36779-87. Epub 2001 Jul 23. — View Citation

Lindemann A, Herrmann F, Oster W, Haffner G, Meyenburg W, Souza LM, Mertelsmann R. Hematologic effects of recombinant human granulocyte colony-stimulating factor in patients with malignancy. Blood. 1989 Dec;74(8):2644-51. — View Citation

Maher DW, Lieschke GJ, Green M, Bishop J, Stuart-Harris R, Wolf M, Sheridan WP, Kefford RF, Cebon J, Olver I, McKendrick J, Toner G, Bradstock K, Lieschke M, Cruickshank S, Tomita DK, Hoffman EW, Fox RM, Morstyn G. Filgrastim in patients with chemotherapy-induced febrile neutropenia. A double-blind, placebo-controlled trial. Ann Intern Med. 1994 Oct 1;121(7):492-501. — View Citation

Morstyn G, Campbell L, Souza LM, Alton NK, Keech J, Green M, Sheridan W, Metcalf D, Fox R. Effect of granulocyte colony stimulating factor on neutropenia induced by cytotoxic chemotherapy. Lancet. 1988 Mar 26;1(8587):667-72. — View Citation

Nicola NA, Begley CG, Metcalf D. Identification of the human analogue of a regulator that induces differentiation in murine leukaemic cells. Nature. 1985 Apr 18-24;314(6012):625-8. — View Citation

Nicola NA, Metcalf D, Matsumoto M, Johnson GR. Purification of a factor inducing differentiation in murine myelomonocytic leukemia cells. Identification as granulocyte colony-stimulating factor. J Biol Chem. 1983 Jul 25;258(14):9017-23. — View Citation

Nicola NA. Hemopoietic cell growth factors and their receptors. Annu Rev Biochem. 1989;58:45-77. Review. — View Citation

Nomura H, Imazeki I, Oheda M, Kubota N, Tamura M, Ono M, Ueyama Y, Asano S. Purification and characterization of human granulocyte colony-stimulating factor (G-CSF). EMBO J. 1986 May;5(5):871-6. — View Citation

Note for Guidance on the Investigation of Bioavailability and Bioequivalence, The European Agency for the Evaluation of Medicinal Products (EMEA), guideline CPMP/EWP/QWP/1401/98, London, 26 July 2001

Pettengell R, Gurney H, Radford JA, Deakin DP, James R, Wilkinson PM, Kane K, Bentley J, Crowther D. Granulocyte colony-stimulating factor to prevent dose-limiting neutropenia in non-Hodgkin's lymphoma: a randomized controlled trial. Blood. 1992 Sep 15;80(6):1430-6. — View Citation

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Simmers RN, Webber LM, Shannon MF, Garson OM, Wong G, Vadas MA, Sutherland GR. Localization of the G-CSF gene on chromosome 17 proximal to the breakpoint in the t(15;17) in acute promyelocytic leukemia. Blood. 1987 Jul;70(1):330-2. — View Citation

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Souza LM, Boone TC, Gabrilove J, Lai PH, Zsebo KM, Murdock DC, Chazin VR, Bruszewski J, Lu H, Chen KK, et al. Recombinant human granulocyte colony-stimulating factor: effects on normal and leukemic myeloid cells. Science. 1986 Apr 4;232(4746):61-5. — View Citation

Tanaka R, Matsudaira T, Aizawa J, Ebihara Y, Muraoka K, Tsuji K, Ikebuchi K, Kodama K, Takaku F, Nakahata T. Characterization of peripheral blood progenitor cells (PBPC) mobilized by filgrastim (rHuG-CSF) in normal volunteers: dose-effect relationship for filgrastim with the character of mobilized PBPC. Br J Haematol. 1996 Mar;92(4):795-803. — View Citation

Trillet-Lenoir V, Green J, Manegold C, Von Pawel J, Gatzemeier U, Lebeau B, Depierre A, Johnson P, Decoster G, Tomita D, et al. Recombinant granulocyte colony stimulating factor reduces the infectious complications of cytotoxic chemotherapy. Eur J Cancer. 1993;29A(3):319-24. — View Citation

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van Der Auwera P, Platzer E, Xu ZX, Schulz R, Feugeas O, Capdeville R, Edwards DJ. Pharmacodynamics and pharmacokinetics of single doses of subcutaneous pegylated human G-CSF mutant (Ro 25-8315) in healthy volunteers: comparison with single and multiple daily doses of filgrastim. Am J Hematol. 2001 Apr;66(4):245-51. — View Citation

Vial T, Descotes J. Clinical toxicity of cytokines used as haemopoietic growth factors. Drug Saf. 1995 Dec;13(6):371-406. Review. — View Citation

Welte K, Gabrilove J, Bronchud MH, Platzer E, Morstyn G. Filgrastim (r-metHuG-CSF): the first 10 years. Blood. 1996 Sep 15;88(6):1907-29. Review. — View Citation

Welte K, Platzer E, Lu L, Gabrilove JL, Levi E, Mertelsmann R, Moore MA. Purification and biochemical characterization of human pluripotent hematopoietic colony-stimulating factor. Proc Natl Acad Sci U S A. 1985 Mar;82(5):1526-30. — View Citation

Zsebo KM, Cohen AM, Murdock DC, Boone TC, Inoue H, Chazin VR, Hines D, Souza LM. Recombinant human granulocyte colony stimulating factor: molecular and biological characterization. Immunobiology. 1986 Sep;172(3-5):175-84. — View Citation

* Note: There are 39 references in allClick here to view all references

Outcome

Type Measure Description Time frame Safety issue
Other adverse events, blood pressure, heart rate, body temperature, body weight, ECGs, clinical laboratory assays From day 1 to 10 (dose groups of 2.5 and 5 µg/kg/day) or from day 1 to 8 (dose group of 10 µg/kg/day) Yes
Primary Area under the curve of absolute neutrophil count (AUCANCday1) and maximum absolute neutrophil count (ANCday1max); AUCANCday1-10 and AUCANCday1-8; ANCday1-10max and ANCday1-8max; AUCday1 and AUCss of filgrastim in serum. Baseline adjusted AUC of ANC on day 1 after single dose (AUCANCday1) and from day 1 to 10 (dose groups of 2.5 and 5 µg/kg/day) or from day 1 to 8 (dose group of 10 µg/kg/day) including the elimination period (AUCANCday1-10 and AUCANCday1-8) and ANCday1max, ANCday1-10max and ANCday1-8max after treatment with filgrastim 0.3 mg/mL by Bio-ker and Neupogen® AUC of serum filgrastim after both single (AUCday1) and multiple dose (AUCss) of filgrastim 0.3 mg/mL by Bio-ker and Neupogen® Day 1 after single dose and from day 1 to 10 (dose groups of 2.5 and 5 µg/kg/day) or from day 1 to 8 (dose group of 10 µg/kg/day) No
Secondary Area under the curve of CD34+ cell count (AUCCD34+) and maximum CD34+ cell count (CD34+max); maximum concentrations at steady state (Cssmax), Cmaxday1, time to achieve Cmax (Tmax), t1/2 and clearance of serum filgrastim Baseline adjusted AUCCD34+ from day 1 to 10 (dose groups of 2.5 and 5 µg/kg/day) or from day 1 to 8 (dose group of 10 µg/kg/day) including the elimination period and CD34+max after treatment with filgrastim 0.3 mg/mL by Bio-ker and Neupogen® Cmax, Tmax t1/2 and clearance of serum filgrastim after both single (Cmaxday1, Tmaxday1, t1/2day1 and Clday1) and multiple dose (Cssmax, Tssmax, tss1/2, Clss) of filgrastim 0.3 mg/mL by Bio-ker and Neupogen® On day 1 after single dose and from day 1 to 10 (dose groups of 2.5 and 5 µg/kg/day) or from day 1 to 8 (dose group of 10 µg/kg/day) No
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