Healthy
Conditions
Keywords
darbepoetin alfa, pharmacokinetics, pharmacodynamics, healthy volunteers
Brief summary
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.
Interventions
DRUGDarbepoetin alfa
Sponsors
Biocad
Study design
Allocation
RANDOMIZED
Intervention model
CROSSOVER
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
MALE
Age
18 Years to 45 Years
Healthy volunteers
Yes
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| AUC | 336 hours (sc) / 72 hours (iv) | 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. |
| Cmax | 336 hours (sc) / 72 hours (iv) | 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. |
| AUEC | 504 hours | 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. |
| AC-Emax | 504 hours | 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. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Tmax | 336 hours (sc) / 72 hours (iv) | Time to achieve maximum serum concentration of darbepoetin alfa after single sc of iv administration |
| Cl | 336 hours (sc) / 72 hours (iv) | 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. |
| T1/2 | 336 hours (sc) / 72 hours (iv) | 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. |
Countries
Russia
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| BCD-066 → Aranesp - Subcutaneous 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. | 13 |
| Aranesp → BCD-066 - Subcutaneous 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. | 12 |
| BCD-066 → Aranesp - Intravenous 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. | 25 |
| Aranesp → BCD-066 - Intravenous 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. | 24 |
| Total | 74 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 |
|---|---|---|---|---|---|
| First Intervention (Day 1) | Protocol Violation | 0 | 0 | 1 | 0 |
| First Intervention (Day 1) | Violation of blood storage conditions | 0 | 0 | 12 | 12 |
| First Intervention (Day 1) | Withdrawal by Subject | 1 | 0 | 0 | 0 |
Baseline characteristics
| Characteristic | BCD-066 → Aranesp - Subcutaneous | Aranesp → BCD-066 - Subcutaneous | BCD-066 → Aranesp - Intravenous | Aranesp → BCD-066 - Intravenous | Total |
|---|---|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical Between 18 and 65 years | 13 Participants | 12 Participants | 25 Participants | 24 Participants | 74 Participants |
| Age, Continuous | 23 years | 22 years | 24 years | 24.5 years | 24 years |
| Sex: Female, Male Female | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Sex: Female, Male Male | 13 Participants | 12 Participants | 25 Participants | 24 Participants | 74 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk |
|---|---|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — | — / — | — / — |
| other Total, other adverse events | 23 / 25 | 22 / 25 | 44 / 49 | 42 / 49 |
| serious Total, serious adverse events | 0 / 25 | 0 / 25 | 0 / 49 | 0 / 49 |
Outcome results
Primary
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.
Time frame: 504 hours
Population: Population for analysis of pharmacodynamics included patients who received at least one study drug injection.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| BCD-066 Subcutaneous | AC-Emax | 44.8 reticulocytes * 10^9/l |
| Aranesp® Subcutaneous | AC-Emax | 54.55 reticulocytes * 10^9/l |
| BCD-066 - Intravenous | AC-Emax | 71.3 reticulocytes * 10^9/l |
| Aranesp® - Intravenous | AC-Emax | 72.1 reticulocytes * 10^9/l |
Primary
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.
Time frame: 336 hours (sc) / 72 hours (iv)
Population: Population for pharmacokinetics analysis: patients who received at least one study drug injection.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| BCD-066 Subcutaneous | AUC | 150607 (pg/ml)*hour |
| Aranesp® Subcutaneous | AUC | 152208 (pg/ml)*hour |
| BCD-066 - Intravenous | AUC | 504584 (pg/ml)*hour |
| Aranesp® - Intravenous | AUC | 544818 (pg/ml)*hour |
Primary
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.
Time frame: 504 hours
Population: Population for pharmacokinetics analysis included patients who received at least one study drug injection.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| BCD-066 Subcutaneous | AUEC | 28248 (reticulocytes * 10^9/l)*hour |
| Aranesp® Subcutaneous | AUEC | 27916 (reticulocytes * 10^9/l)*hour |
| BCD-066 - Intravenous | AUEC | 35610 (reticulocytes * 10^9/l)*hour |
| Aranesp® - Intravenous | AUEC | 36928 (reticulocytes * 10^9/l)*hour |
Primary
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.
Time frame: 336 hours (sc) / 72 hours (iv)
Population: Population for pharmacokinetics analysis included patients who received at least one study drug injection.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| BCD-066 Subcutaneous | Cmax | 984 pg/ml |
| Aranesp® Subcutaneous | Cmax | 885 pg/ml |
| BCD-066 - Intravenous | Cmax | 23908 pg/ml |
| Aranesp® - Intravenous | Cmax | 24478 pg/ml |
Secondary
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.
Time frame: 336 hours (sc) / 72 hours (iv)
Population: Population for pharmacokinetics analysis: patients who received at least one study drug injection.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| BCD-066 Subcutaneous | Cl | 0.433 hours*kg |
| Aranesp® Subcutaneous | Cl | 0.375 hours*kg |
| BCD-066 - Intravenous | Cl | 139.0 hours*kg |
| Aranesp® - Intravenous | Cl | 134.2 hours*kg |
Secondary
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.
Time frame: 336 hours (sc) / 72 hours (iv)
Population: Population for pharmacokinetics analysis: patients who received at least one study drug injection.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| BCD-066 Subcutaneous | T1/2 | 74.8 hours |
| Aranesp® Subcutaneous | T1/2 | 80.6 hours |
| BCD-066 - Intravenous | T1/2 | 13.1 hours |
| Aranesp® - Intravenous | T1/2 | 12.7 hours |
Secondary
Tmax
Time to achieve maximum serum concentration of darbepoetin alfa after single sc of iv administration
Time frame: 336 hours (sc) / 72 hours (iv)
Population: Population for pharmacokinetics analysis: patients who received at least one study drug injection.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| BCD-066 Subcutaneous | Tmax | 36 hours |
| Aranesp® Subcutaneous | Tmax | 36 hours |
| BCD-066 - Intravenous | Tmax | 0.25 hours |
| Aranesp® - Intravenous | Tmax | 0.25 hours |