Pharmacokinetics and Pharmacodynamics Study of BCD-066 Compared to Aranesp® in Healthy Volunteers

Study Overview
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Brief Summary
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This is a randomized double-blind crossover study of pharmacokinetics, pharmacodynamics and safety of BCD-066 (darbepoetin alfa manufactured by CJSC BIOCAD, Russia) and Aranesp® (Amgen Europe B.V., Netherlands) in healthy volunteers. The purpose of the study is to demonstrate the equivalence of pharmacokinetics, pharmacodynamics and safety parameters after single subcutaneous or intravenous injection. Each drug will be administered to each volunteer at a dose of 1 µg per kilogram as a single subcutaneous or intravenous injection with an interval of at least 25 days.

Official Title
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International Multicenter Comparative Randomized Double-blind Crossover Study of Pharmacokinetics, Pharmacodynamics and Safety of BCD-066 and Aranesp® After Single Subcutaneous and Intravenous Injection in Healthy Volunteers.

Conditions
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Healthy

Intervention / Treatment
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* Drug: Darbepoetin alfa


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Signed written informed consent Male gender Age 18 - 45 years inclusively Body mass index (BMI) 19 - 29 kg/m2 inclusively Hemoglobin level 120-160 g/l (12 - 16 g/dL) inclusively during 14 days prior to first study drugs administration White blood cells count ≥3,0×109/L, Platelet count ≥140×109/L during 14 days prior to first study drugs administration Subjects must be in good health as determined by a medical history, medical examination, electrocardiogram, serum biochemistry, haematology, serology and urinalysis Absence of history of systematic alcohol and drug abuse Ability of the volunteer, in investigator's opinion, to follow the study protocol procedures and requirements Willingness of volunteers and their sexual partners of childbearing potential to use reliable contraception methods starting from 2 weeks before inclusion into the study and until 4 weeks after receiving the last dose of the investigational products. This criterion is not applicable to patients who underwent surgical sterilization. Reliable contraceptive measures include one barrier method in combination with one of the following methods: spermicides, intrauterine device or oral contraceptives used by participant's partner Consent to avoid alcohol intake within 24 hours before and 48 hours after each administration of the test or reference drugs Exclusion Criteria: Clinically significant abnormalities on ECG or in laboratory tests, which could interfere with the objective of the study or the safety of the volunteer. Clinically significant illness within 4 weeks prior to the screening visit Subjects with past or present history of liver disease, angina, renal disease, hypertension, epilepsy, cardiovascular, cerebrovascular, peripheral vascular disease or thrombocytosis History of any oncological disease Prior exposure to any erythropoietins, darbepoetin Prior exposure to IV iron supplementation (within 2 years before randomisation) Subjects who have used any medication, including over-the-counter drugs, herbal medications, and nutritional supplements within 14 days prior to IDs administration with the exception of paracetamol (acetaminophen) up to 3g per day or ibuprofen up to 1g per day Subjects who smoke more than 10 cigarettes per day Subjects who have donated more than 450 ml of blood within the 1 month prior to ID injection Epileptic seizures within the 6 months prior to ID injection Major surgery within 1 month prior to the enrollment into the study Inability to install intravenous catheter (e.g., due to skin disease) Subjects who have received any experimental drug within 3 months preceding the 1st ID administration Subjects who have a clinically significant history of drug hypersensitivity or allergic disease Possibility that the subject will not cooperate with the requirements of the protocol as set out in the volunteer information Subjects who consume excessive amounts of caffeine (more than 5 cups of coffee per day) Participation in any other clinical study or any preceding participation in other studies within 3 months prior to the 1st ID administration

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 45 Years

Sexes Eligible for Study
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Male

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Crossover Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: BCD-066 → Aranesp - subcutaneous<br>Volunteers in this group initially will receive a single sc injection of the study drug BCD-066 (darbepoetin alfa) at a dose of 1 µg/kg (on Day 1) and then, after at least 25 days, a single sc injection of the reference drug Aranesp® (darbepoetin alfa) at a dose of 1 µg/kg. | Drug: Darbepoetin alfa<br> <br> * Other names: BCD-066;|
| Experimental: Aranesp → BCD-066 - subcutaneous<br>Volunteers in this group initially will receive a single sc injection of the reference drug Aranesp® (darbepoetin alfa) at a dose of 1 µg/kg (on Day 1) and then, after at least 25 days, a single sc injection of the study drug BCD-066 (darbepoetin alfa) at a dose of 1 µg/kg. | Drug: Darbepoetin alfa<br> <br> * Other names: BCD-066;|
| Experimental: BCD-066 → Aranesp - intravenous<br>Volunteers in this group initially will receive a single iv injection of the study drug BCD-066 (darbepoetin alfa) at a dose of 1 µg/kg (on Day 1) and then, after at least 25 days, a single iv injection of the reference drug Aranesp® (darbepoetin alfa) at a dose of 1 µg/kg. | Drug: Darbepoetin alfa<br> <br> * Other names: BCD-066;|
| Experimental: Aranesp → BCD-066 - intravenous<br>Volunteers in this group initially will receive a single iv injection of the reference drug Aranesp® (darbepoetin alfa) at a dose of 1 µg/kg (on Day 1) and then, after at least 25 days, a single iv injection of the study drug BCD-066 (darbepoetin alfa) at a dose of 1 µg/kg. | Drug: Darbepoetin alfa<br> <br> * Other names: BCD-066;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| AUC | Area Under Concentration-time Curve (AUC) of Darbepoetin Alfa From the Moment of Drug Administration Until 336 (sc administration) or 72 (iv administration) Hours and to Infinity(AUC(0-336)/AUC(0-72) and AUC(0-∞) Respectively Blood samples were taken 30, 20, 10, 0 minutes before injection of study drug and then after 12, 24, 36, 72, 96, 144, 336 and 504 hours post-dose. | 336 hours (sc) / 72 hours (iv) | 
| Cmax | Maximal concentration of darbepoetin alfa From the Moment of Drug Administration Until 336 (sc administration) or 72 (iv administration) hours. Blood samples were taken 30, 20, 10, 0 minutes before injection of study drug and then after 12, 24, 36, 72, 96, 144, 336 and 504 hours post-dose. | 336 hours (sc) / 72 hours (iv) | 
| AUEC | Area Under Effect Curve (AUEC) of reticulocytes count from the Moment of Drug Administration Until 504 hours. Blood samples were taken 30, 20, 10, 0 minutes before injection of study drug and then after 12, 24, 36, 72, 96, 144, 336 and 504 hours post-dose. | 504 hours | 
| AC-Emax | Maximum elevation of absolute reticulocyte count from the baseline from the Moment of Drug Administration Until 504 hours. Blood samples were taken 30, 20, 10, 0 minutes before injection of study drug and then after 12, 24, 36, 72, 96, 144, 336 and 504 hours post-dose. | 504 hours | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| T1/2 | Serum half-life of darbepoetin alfa after single sc of iv administration. Blood samples were taken 30, 20, 10, 0 minutes before injection of study drug and then after 12, 24, 36, 72, 96, 144, 336 and 504 hours post-dose. | 336 hours (sc) / 72 hours (iv) | 
| Tmax | Time to achieve maximum serum concentration of darbepoetin alfa after single sc of iv administration | 336 hours (sc) / 72 hours (iv) | 
| Cl | Serum clearance of of darbepoetin alfa after single sc of iv administration. Blood samples were taken 30, 20, 10, 0 minutes before injection of study drug and then after 12, 24, 36, 72, 96, 144, 336 and 504 hours post-dose. | 336 hours (sc) / 72 hours (iv) | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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darbepoetin alfa, pharmacokinetics, pharmacodynamics, healthy volunteers