NCT01933971

Brief 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.

Trial Health

87
On Track

Trial Health Score

Automated assessment based on enrollment pace, timeline, and geographic reach

Enrollment
102

participants targeted

Target at P75+ for phase_1

Timeline
Completed

Started Jun 2007

Geographic Reach
1 country

1 active site

Status
completed

Health score is calculated from publicly available data and should be used for screening purposes only.

Trial Relationships

Click on a node to explore related trials.

Study Timeline

Key milestones and dates

Study Start

First participant enrolled

June 1, 2007

Completed
10 months until next milestone

Primary Completion

Last participant's last visit for primary outcome

April 1, 2008

Completed
Same day until next milestone

Study Completion

Last participant's last visit for all outcomes

April 1, 2008

Completed
5.4 years until next milestone

First Submitted

Initial submission to the registry

August 29, 2013

Completed
6 days until next milestone

First Posted

Study publicly available on registry

September 4, 2013

Completed
Last Updated

September 9, 2013

Status Verified

September 1, 2013

Enrollment Period

10 months

First QC Date

August 29, 2013

Last Update Submit

September 6, 2013

Conditions

Healthy Male Subjects

Outcome Measures

Primary Outcomes (1)

  • 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)

Secondary Outcomes (1)

  • 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

    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)

Other Outcomes (1)

  • 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)

Study Arms (3)

Group 1: filgrastim 2.5 µg/kg/day for 7 consecutive days

OTHER

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.

Drug: Filgrastim testDrug: Filgrastim reference

Group 2: filgrastim 5 µg/kg/day for 7 consecutive days

OTHER

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.

Drug: Filgrastim testDrug: Filgrastim reference

Group 3: filgrastim 10 µg/kg/day for 5 consecutive days

OTHER

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.

Drug: Filgrastim testDrug: Filgrastim reference

Interventions

Filgrastim testDRUG

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

Also known as: r-metHuG-CSF, BK0023
Group 1: filgrastim 2.5 µg/kg/day for 7 consecutive daysGroup 2: filgrastim 5 µg/kg/day for 7 consecutive daysGroup 3: filgrastim 10 µg/kg/day for 5 consecutive days
Filgrastim referenceDRUG

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

Also known as: r-metHuG-CSF, Neupogen®
Group 1: filgrastim 2.5 µg/kg/day for 7 consecutive daysGroup 2: filgrastim 5 µg/kg/day for 7 consecutive daysGroup 3: filgrastim 10 µg/kg/day for 5 consecutive days

Eligibility Criteria

Age20 Years - 40 Years
Sexmale
Healthy VolunteersYes
Age GroupsAdult (18-64)

You may qualify if:

  • 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.

You may not qualify if:

  • 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.

Contact the study team to confirm eligibility.

Sponsors & Collaborators

Study Sites (1)

CROSS Research SA

Arzo, Canton Ticino, 6864, Switzerland

Location

Related Publications (40)

  • Hryniuk W, Bush H. The importance of dose intensity in chemotherapy of metastatic breast cancer. J Clin Oncol. 1984 Nov;2(11):1281-8. doi: 10.1200/JCO.1984.2.11.1281. No abstract available.

    PMID: 6387060BACKGROUND

  • 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.

    PMID: 10728708BACKGROUND

  • Skipper HE. Kinetics of mammary tumor cell growth and implications for therapy. Cancer. 1971 Dec;28(6):1479-99. doi: 10.1002/1097-0142(197112)28:63.0.co;2-m. No abstract available.

    PMID: 5127796BACKGROUND

  • Skipper HE, Schabel FM, Lloyd HH. Dose-response and tumour cell repopulation rate in chemotherapeutic trials. Adv Cancer Chemother 1: 205-253, 1979

    BACKGROUND

  • 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. doi: 10.1073/pnas.82.5.1526.

    PMID: 3871951BACKGROUND

  • 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. doi: 10.1002/j.1460-2075.1986.tb04297.x.

    PMID: 3487449BACKGROUND

  • 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.

    PMID: 2439153BACKGROUND

  • Nicola NA. Hemopoietic cell growth factors and their receptors. Annu Rev Biochem. 1989;58:45-77. doi: 10.1146/annurev.bi.58.070189.000401. No abstract available.

    PMID: 2549855BACKGROUND

  • 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.

    PMID: 6190815BACKGROUND

  • 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. doi: 10.1038/314625a0.

    PMID: 2986009BACKGROUND

  • 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.

    PMID: 1696260BACKGROUND

  • 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. doi: 10.1074/jbc.M104787200. Epub 2001 Jul 23.

    PMID: 11468284BACKGROUND

  • Shimoda K, Okamura S, Harada N, Kondo S, Okamura T, Niho Y. Identification of a functional receptor for granulocyte colony-stimulating factor on platelets. J Clin Invest. 1993 Apr;91(4):1310-3. doi: 10.1172/JCI116330.

    PMID: 7682568BACKGROUND

  • Boneberg EM, Hareng L, Gantner F, Wendel A, Hartung T. Human monocytes express functional receptors for granulocyte colony-stimulating factor that mediate suppression of monokines and interferon-gamma. Blood. 2000 Jan 1;95(1):270-6.

    PMID: 10607712BACKGROUND

  • 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. doi: 10.1038/337471a0.

    PMID: 2464767BACKGROUND

  • Souza LM, Boone TC, Gabrilove J, Lai PH, Zsebo KM, Murdock DC, Chazin VR, Bruszewski J, Lu H, Chen KK, Barendt J, Platzer E, Moore MAS, Mertelsmann R, Welte K. Recombinant human granulocyte colony-stimulating factor: effects on normal and leukemic myeloid cells. Science. 1986 Apr 4;232(4746):61-5. doi: 10.1126/science.2420009.

    PMID: 2420009BACKGROUND

  • 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. doi: 10.1016/S0171-2985(86)80097-3.

    PMID: 3492428BACKGROUND

  • Bonig H, Silbermann S, Weller S, Kirschke R, Korholz D, Janssen G, Gobel U, Nurnberger 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. doi: 10.1038/sj.bmt.1703136.

    PMID: 11535993BACKGROUND

  • Gabrilove JL, Jakubowski A, Scher H, Sternberg C, Wong G, Grous J, Yagoda A, Fain K, Moore MA, Clarkson B, Oettgen HF, Alton K, Welte K, Souza L. 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. doi: 10.1056/NEJM198806023182202.

    PMID: 2452983BACKGROUND

  • 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. doi: 10.7326/0003-4819-109-10-789.

    PMID: 2461131BACKGROUND

  • 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.

    PMID: 1716591BACKGROUND

  • 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. No abstract available.

    PMID: 8822908BACKGROUND

  • 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. doi: 10.1016/s0140-6736(88)91475-4.

    PMID: 2895212BACKGROUND

  • 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. doi: 10.1056/NEJM199107183250305.

    PMID: 1711156BACKGROUND

  • 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.

    PMID: 1381626BACKGROUND

  • 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. doi: 10.1016/0959-8049(93)90376-q.

    PMID: 7691119BACKGROUND

  • 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. doi: 10.7326/0003-4819-121-7-199410010-00004.

    PMID: 7520676BACKGROUND

  • Vial T, Descotes J. Clinical toxicity of cytokines used as haemopoietic growth factors. Drug Saf. 1995 Dec;13(6):371-406. doi: 10.2165/00002018-199513060-00006.

    PMID: 8652081BACKGROUND

  • 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.

    PMID: 2479425BACKGROUND

  • Sakamaki S, Matsunaga T, Hirayama Y, Kuga T, Niitsu Y. Haematological study of healthy volunteers 5 years after G-CSF. Lancet. 1995 Nov 25;346(8987):1432-3. doi: 10.1016/s0140-6736(95)92450-7. No abstract available.

    PMID: 7475852BACKGROUND

  • 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. doi: 10.1016/s0149-2918(98)80135-5.

    PMID: 9737832BACKGROUND

  • 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

    BACKGROUND

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

    BACKGROUND

  • 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. doi: 10.1046/j.1365-2141.1996.412949.x.

    PMID: 8616069BACKGROUND

  • 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.

    BACKGROUND

  • 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. doi: 10.1002/ajh.1052.

    PMID: 11279634BACKGROUND

  • 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. doi: 10.1046/j.1365-2125.1999.00888.x.

    PMID: 10215752BACKGROUND

  • Hoglund M, Smedmyr B, Bengtsson M, Totterman 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. doi: 10.1111/j.1600-0609.1997.tb00972.x.

    PMID: 9310126BACKGROUND

  • U.S. Department of Health and Human Services and U.S. Department of Agriculture, Nutrition and your health: Dietary Guidelines for Americans, 2005

    BACKGROUND

  • Crobu D, Spinetti G, Schrepfer R, Tonon G, Jotti GS, Onali P, Dedoni S, Orsini G, Di Stefano A. Preclinical and clinical phase I studies of a new recombinant Filgrastim (BK0023) in comparison with Neupogen(R). BMC Pharmacol Toxicol. 2014 Feb 21;15:7. doi: 10.1186/2050-6511-15-7.

    PMID: 24555723DERIVED

MeSH Terms

Interventions

Filgrastim

Intervention Hierarchy (Ancestors)

Granulocyte Colony-Stimulating FactorColony-Stimulating FactorsGlycoproteinsGlycoconjugatesCarbohydratesHematopoietic Cell Growth FactorsCytokinesIntercellular Signaling Peptides and ProteinsPeptidesAmino Acids, Peptides, and ProteinsProteinsBiological Factors

Study Officials

  • Antonio Rusca, MD

    CROSS Research SA

    PRINCIPAL INVESTIGATOR

Study Design

Study Type
interventional
Phase
phase 1
Allocation
RANDOMIZED
Masking
TRIPLE
Who Masked
PARTICIPANT, CARE PROVIDER, INVESTIGATOR
Purpose
TREATMENT
Intervention Model
CROSSOVER
Sponsor Type
INDUSTRY
Responsible Party
SPONSOR

Study Record Dates

First Submitted

August 29, 2013

First Posted

September 4, 2013

Study Start

June 1, 2007

Primary Completion

April 1, 2008

Study Completion

April 1, 2008

Last Updated

September 9, 2013

Record last verified: 2013-09

Locations

CH(1)