Reticulocyte Count
Conditions
Brief summary
BCD-131-1 is an Open-Label Clinical Study of the Pharmacokinetics, Pharmacodynamics, Tolerability, Safety and Immunogenicity of Single Ascending Doses of BCD-131 in Healthy Volunteers
Detailed description
BCD-131 is novel drug product of pegylated darbepoetin alfa. Clinical trial BCD-131-1 will be conducted in two stages: Stage I is an open-label, non-randomized clinical study of pharmacokinetics, pharmacodynamics, tolerability, safety and immunogenicity of BCD-131 given to healthy volunteers at ascending doses (Phase 1, a traditional 3+3 design). Also, the PK and PD parameters of the closest analogues of BCD-131 (Mircera and Aranesp) given as subcutaneous injections at therapeutic doses will be evaluated. Stage II aims to further evaluate pharmacokinetics, pharmacodynamics and safety of subcutaneous and intravenous injections of BCD-131 at a dose which ensures PD effects similar to those of the closest analogues (Mircera, Aranesp) given as subcutaneous injections at therapeutic doses.
Sponsors
Biocad
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
OTHER
Masking
NONE
Eligibility
Sex/Gender
MALE
Age
18 Years to 45 Years
Healthy volunteers
Yes
Inclusion criteria
1. Signing of the Informed Consent Form; 2. Male sex; 3. Age of 18 to 45 years, inclusive; 4. BMI within normal limits (18.5-24.9 kg/m2); 5. Healthy patients, which is proved by their medical history, physical examination and laboratory findings: * No clinically significant abnormalities of circulatory, respiratory, nervous, hematopoietic, endocrine and digestive systems, liver and kidneys in the past medical history and at screening; * No history of cardiovascular disorders or thyroid disorders; * No history of hematologic disorders, including but not limited to any type of anemia, myelodysplastic syndrome, blood cancers, hemolytic syndrome, hemoglobinopathies, coagulopathies; * CBC results within normal limits, including: * Hemoglobin within 132-173 g/L; * Hematocrit (based on CBC results) within 39-49%; * Platelet count within 150-400\*109/L; * Absolute reticulocyte count within 30.4-93.5 \* 109/L; * Blood biochemistry and urinalysis results within normal limits; * Serum ferritin within 20-250 µg/L; * Serum endogenous erythropoietin within 4.3-29.0 MIU/mL; * Hemodynamic parameters within normal limits: systolic blood pressure within 100-139 mmHg; diastolic blood pressure within 60-90 mmHg; heart rate within 50-90 bpm; * No history of chronic infections (tuberculosis) or chronic inflammation; * No hepatitis B or C, HIV, or syphilis; * No acute infections within 4 weeks prior to inclusion in the study; * No psychiatric disorders and other conditions (including depression) that can interfere with the volunteer's ability to follow the study protocol; * Well-being (in the volunteer's opinion) within 30 days prior to inclusion in the study; 6. No history of or current (at baseline) alcohol or drug abuse; 7. Ability of the volunteer, in the investigator's opinion, to follow the study protocol procedures; 8. Willingness of volunteers and their sexual partners with preserved reproductive potential to use reliable contraception within 2 weeks before inclusion in the study and up to 7 weeks after the injection of the test product. This criterion is not applicable to subjects who underwent surgical sterilization. Reliable methods of contraception include one barrier method in combination with one of the following methods: spermicides, intrauterine device/oral contraceptives (for sexual partners). 9. Willingness of volunteers to avoid alcohol intake within 24 hours before and 8 days after each injection of the test drug;
Exclusion criteria
1. History of treatment with erythropoietins or any other ESAs; 2. Acute bleeding, blood/plasma donation or blood transfusion within 2 months before inclusion in the study; 3. History of chronic bleeding; 4. Standard laboratory and instrumental findings outside normal limits at screening; 5. History of allergies (anaphylactic shock or multiple drug allergy syndrome); 6. Known allergy or intolerance to any components of the investigational product; 7. Major surgery within 30 days prior to screening, or surgery being scheduled for any time during the study; 8. Impossibility to install a venous catheter for blood sampling (e.g. because of skin disorders at the sites of venipuncture); 9. Diseases or other conditions that can interfere with the pharmacokinetics of the investigational drug (e.g. chronic liver, kidney, blood, circulatory system, lung or neuroendocrine diseases, including diabetes mellitus and others); 10. History of fever of 40 °C or more; 11. History of elevated hepatic transaminases (above 2.5xULN); 12. Episodes of thrombosis and/or thromboembolia in past medical history (myocardial infarction, stroke, transient ischemic attacks, deep vein thrombosis, pulmonary embolism within 6 months prior to inclusion in the study) as well as an increased risk of deep vein thrombosis; 13. History of epileptic attacks or seizures; 14. History or current (at screening) depression, suicidal thoughts/ attempts; 15. Regular oral or parenteral use of any medications including over-the-counter drugs, vitamins and nutritional additives within 2 weeks before a scheduled injection of the test drug; 16. Use of drugs, including OTC products, that significantly affect the hemodynamics, hepatic function, etc. (barbiturates, omeprazole, cimetidine, etc.) within 30 days before a scheduled injection of the test drug; 17. Vaccination within 4 weeks before a scheduled injection of the test drug; 18. Smoking more than 10 cigarettes per day; 19. Consumption of more than 10 portions of alcohol per week (one portion equals to 0.5 L of beer, 200 mL of wine or 50 mL of ethanol) or a history of alcohol, drug or medication abuse; 20. Participation in other clinical studies within 1 month before screening or simultaneous participation in another clinical study; 21. Previous participation in this study.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| AUC (0-1176 Hours) | 0, 15 min, 30 min; 60 min; 2 h, 4 h; 8 h, 24 h, 48 h, 72 h, 96 h, 120 h, 168 h, 216 h, 288 h, 336 h, 504 h, 672 h, 840 h, 1008 h, 1176 h post dose | Area under curve (AUC) concentration - time from 0 hours to 1176 hours and to infinity |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Tmax | 0, 15 min, 30 min; 60 min; 2 h, 4 h; 8 h, 24 h, 48 h, 72 h, 96 h, 120 h, 168 h, 216 h, 288 h, 336 h, 504 h, 672 h, 840 h, 1008 h, 1176 hours post-dose | Time from 9 hours to time of maximal concentration of drug in blood after single injection |
| T1/2 | 0, 15 min, 30 min; 60 min; 2 h, 4 h; 8 h, 24 h, 48 h, 72 h, 96 h, 120 h, 168 h, 216 h, 288 h, 336 h, 504 h, 672 h, 840 h, 1008 h, 1176 hours post-dose | Half-life of drug in blood after single injection. In the coрort BCD-131 0,15 mcg/kg due to the absence of a linear terminal elimination phase in volunteers, the calculation of T1 / 2 was not possible |
| Kel | 0, 15 min, 30 min; 60 min; 2 h, 4 h; 8 h, 24 h, 48 h, 72 h, 96 h, 120 h, 168 h, 216 h, 288 h, 336 h, 504 h, 672 h, 840 h, 1008 h, 1176 hours post-dose | Elimination rate constant of drug in blood after single injection. In the cohort BCD-131 0,15 mcg/kg due to the absence of a linear terminal elimination phase in volunteers, the calculation of Kel was not possible |
| Clearance of BCD-131 | 0, 15 min, 30 min; 60 min; 2 h, 4 h; 8 h, 24 h, 48 h, 72 h, 96 h, 120 h, 168 h, 216 h, 288 h, 336 h, 504 h, 672 h, 840 h, 1008 h, 1176 hours post-dose | Clearance of BCD-131 in blood after single injection |
| AUEC (0-1176 Hours) - Reticulocytes | 0, 24 h, 48 h; 72 h; 96 h; 120 h; 168 h; 216 h; 288 h; 336 h, 504 h; 672 h; 840 h; 1008 h; 1176 h post-dose | Area under effect curve (AUEC) absolute reticulocyte count - time from 0 to 1176 hours post-dose after single injection of study drug |
| AUEC (0-1176 Hours) - Hemoglobin | 0, 24 h, 48 h; 72 h; 96 h; 120 h; 168 h; 216 h; 288 h; 336 h, 504 h; 672 h; 840 h; 1008 h; 1176 h post-dose | Area under effect curve (AUEC) hemoglobin - time from 0 to 1176 hours post-dose after single injection of study drug |
| AC-Emax - Reticulocytes | 0, 24 h, 48 h; 72 h; 96 h; 120 h; 168 h; 216 h; 288 h; 336 h, 504 h; 672 h; 840 h; 1008 h; 1176 h post-dose | Absolute maximum of reticulocyte count (AC-Emax - reticulocytes) after single injection of study drug |
| Cmax | 0, 15 min, 30 min; 60 min; 2 h, 4 h; 8 h, 24 h, 48 h, 72 h, 96 h, 120 h, 168 h, 216 h, 288 h, 336 h, 504 h, 672 h, 840 h, 1008 h, 1176 hours post-dose | Maximal concentration of drug in blood after single injection |
| Intensity of Pain After Subcutaneous Injection According to Visual Analog Scale | intraoperative | visual analog scale Minimum value - 0, Maximum value -10, Higher scores mean worse outcome |
| Number of Participants With Adverse Events and Serious Adverse Events | from the first administartion of the drug up to the end of follow up period (28 days after the last dose of the drug) | Total incidence of adverse events (AE)/ serious adverse events (SAE) |
| Number of Participants With Local Reactions | from the first administartion of the drug up to the end of follow up period (28 days after the last dose of the drug) | Incidence of administration site reactions |
| Number of Participants With AE/SAE 3-4 Grade CTCAE | from the first administartion of the drug up to the end of follow up period (28 days after the last dose of the drug) | Incidence of Grade 3-4 AEs and SAEs. |
| Number of Participants With Early Withdrawal Due to AE | from the first administartion of the drug up to the end of follow up period (28 days after the last dose of the drug) | Frequency of early withdrawals due to AEs and SAEs |
| Number of Participants With Binding Antibodies to BCD-131 | 0, day 50 post-dose | Incidence of Binding antibodies to BCD-131 on Day 50 after a single injection of BCD-131 |
| AC-Emax - Hemoglobin | 0, 24 h, 48 h; 72 h; 96 h; 120 h; 168 h; 216 h; 288 h; 336 h, 504 h; 672 h; 840 h; 1008 h; 1176 h post-dose | Absolute maximum of hemoglobin (AC-Emax - hemoglobin) after single injection of study drug |
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| BCD-131, 0.05 mcg/kg Subcutaneously Healthy volunteers received BCD-131 in a dose 0.05 mcg/kg subcutaneously
BCD-131 | 3 |
| BCD-131, 0.15 mcg/kg Subcutaneously Healthy volunteers received BCD-131 in a dose 0.15 mcg/kg subcutaneously
BCD-131 | 3 |
| BCD-131, 0.40 mcg/kg Subcutaneously Healthy volunteers received BCD-131 in a dose 0.40 mcg/kg subcutaneously
BCD-131 | 3 |
| BCD-131, 1.05 mcg/kg Subcutaneously Healthy volunteers received BCD-131 in a dose 1.05 mcg/kg subcutaneously
BCD-131 | 3 |
| BCD-131, 1.70 mcg/kg SC Healthy volunteers received BCD-131 in a dose 1.70 mcg/kg subcutaneously
BCD-131 | 3 |
| BCD-131, 2.25 mcg/kg SC Healthy volunteers received BCD-131 in a dose 2.25 mcg/kg subcutaneously
BCD-131 | 3 |
| BCD-131, 4.45 mcg/kg Subcutaneously Healthy volunteers received BCD-131 in a dose 4.45 mcg/kg subcutaneously
BCD-131 | 3 |
| Mircera®, 1.20 mcg/kg Subcutaneously Healthy volunteers received Mircera in a dose 1.20 mcg/kg subcutaneously
Mircera® | 6 |
| Aranesp®, 0.45 mcg/kg Subcutaneously Healthy volunteers received BCD-131 in a dose 0.45 mcg/kg subcutaneously
Aranesp® | 6 |
| BCD-131, Optimal Dose, Intravenously Healthy volunteers received BCD-131 in optimal dose - 2,75 mcg/kg determined on first stage of clinical trial intravenously
BCD-131 | 6 |
| BCD-131, Optimal Dose, Subcutaneously Healthy volunteers will receive BCD-131 in optimal dose - 2,75 mcg/kgdetermined on first stage of clinical trial subcutaneously
BCD-131 | 6 |
| Total | 45 |
Baseline characteristics
| Characteristic | BCD-131, 0.05 mcg/kg Subcutaneously | Total | BCD-131, Optimal Dose, Subcutaneously | BCD-131, Optimal Dose, Intravenously | Aranesp®, 0.45 mcg/kg Subcutaneously | Mircera®, 1.20 mcg/kg Subcutaneously | BCD-131, 4.45 mcg/kg Subcutaneously | BCD-131, 2.25 mcg/kg SC | BCD-131, 1.70 mcg/kg SC | BCD-131, 1.05 mcg/kg Subcutaneously | BCD-131, 0.40 mcg/kg Subcutaneously | BCD-131, 0.15 mcg/kg Subcutaneously |
|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Age, Continuous | 24 years | 26 years | 25 years | 24 years | 28 years | 28 years | 25 years | 25 years | 26 years | 32 years | 30 years | 26 years |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 3 Participants | 45 Participants | 6 Participants | 6 Participants | 6 Participants | 6 Participants | 3 Participants | 3 Participants | 3 Participants | 3 Participants | 3 Participants | 3 Participants |
| Sex: Female, Male Female | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Sex: Female, Male Male | 3 Participants | 45 Participants | 6 Participants | 6 Participants | 6 Participants | 6 Participants | 3 Participants | 3 Participants | 3 Participants | 3 Participants | 3 Participants | 3 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk | EG004 affected / at risk | EG005 affected / at risk | EG006 affected / at risk | EG007 affected / at risk | EG008 affected / at risk | EG009 affected / at risk | EG010 affected / at risk |
|---|---|---|---|---|---|---|---|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 3 | 0 / 3 | 0 / 3 | 0 / 3 | 0 / 3 | 0 / 3 | 0 / 3 | 0 / 6 | 0 / 6 | 0 / 6 | 0 / 6 |
| other Total, other adverse events | 0 / 3 | 1 / 3 | 2 / 3 | 2 / 3 | 0 / 3 | 0 / 3 | 2 / 3 | 4 / 6 | 4 / 6 | 4 / 6 | 5 / 6 |
| serious Total, serious adverse events | 0 / 3 | 0 / 3 | 0 / 3 | 0 / 3 | 0 / 3 | 0 / 3 | 0 / 3 | 0 / 6 | 0 / 6 | 0 / 6 | 0 / 6 |
Outcome results
Primary
AUC (0-1176 Hours)
Area under curve (AUC) concentration - time from 0 hours to 1176 hours and to infinity
Time frame: 0, 15 min, 30 min; 60 min; 2 h, 4 h; 8 h, 24 h, 48 h, 72 h, 96 h, 120 h, 168 h, 216 h, 288 h, 336 h, 504 h, 672 h, 840 h, 1008 h, 1176 h post dose
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| BCD-131, 0.05 mcg/kg Subcutaneously | AUC (0-1176 Hours) | 206974.500 pg*hr/ml |
| BCD-131, 0.15 mcg/kg Subcutaneously | AUC (0-1176 Hours) | 657417.000 pg*hr/ml |
| BCD-131, 0.40 mcg/kg Subcutaneously | AUC (0-1176 Hours) | 827904.750 pg*hr/ml |
| BCD-131, 1.05 mcg/kg Subcutaneously | AUC (0-1176 Hours) | 1360020.000 pg*hr/ml |
| BCD-131, 1.70 mcg/kg SC | AUC (0-1176 Hours) | 1314197.750 pg*hr/ml |
| BCD-131, 2.25 mcg/kg SC | AUC (0-1176 Hours) | 3202606.500 pg*hr/ml |
| BCD-131, 4.45 mcg/kg Subcutaneously | AUC (0-1176 Hours) | 5220198.750 pg*hr/ml |
| Mircera®, 1.20 mcg/kg Subcutaneously | AUC (0-1176 Hours) | 688124.000 pg*hr/ml |
| Aranesp®, 0.45 mcg/kg Subcutaneously | AUC (0-1176 Hours) | 94628.375 pg*hr/ml |
| BCD-131, Optimal Dose, Intravenously | AUC (0-1176 Hours) | 6382389.188 pg*hr/ml |
| BCD-131, Optimal Dose, Subcutaneously | AUC (0-1176 Hours) | 2089193.125 pg*hr/ml |
Secondary
AC-Emax - Hemoglobin
Absolute maximum of hemoglobin (AC-Emax - hemoglobin) after single injection of study drug
Time frame: 0, 24 h, 48 h; 72 h; 96 h; 120 h; 168 h; 216 h; 288 h; 336 h, 504 h; 672 h; 840 h; 1008 h; 1176 h post-dose
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| BCD-131, 0.05 mcg/kg Subcutaneously | AC-Emax - Hemoglobin | 8.00 gramm per liter |
| BCD-131, 0.15 mcg/kg Subcutaneously | AC-Emax - Hemoglobin | 2.00 gramm per liter |
| BCD-131, 0.40 mcg/kg Subcutaneously | AC-Emax - Hemoglobin | 7.00 gramm per liter |
| BCD-131, 1.05 mcg/kg Subcutaneously | AC-Emax - Hemoglobin | 9.00 gramm per liter |
| BCD-131, 1.70 mcg/kg SC | AC-Emax - Hemoglobin | 9.00 gramm per liter |
| BCD-131, 2.25 mcg/kg SC | AC-Emax - Hemoglobin | 6.00 gramm per liter |
| BCD-131, 4.45 mcg/kg Subcutaneously | AC-Emax - Hemoglobin | 10.00 gramm per liter |
| Mircera®, 1.20 mcg/kg Subcutaneously | AC-Emax - Hemoglobin | 10.50 gramm per liter |
| Aranesp®, 0.45 mcg/kg Subcutaneously | AC-Emax - Hemoglobin | 9.00 gramm per liter |
| BCD-131, Optimal Dose, Intravenously | AC-Emax - Hemoglobin | 11.00 gramm per liter |
| BCD-131, Optimal Dose, Subcutaneously | AC-Emax - Hemoglobin | 10.5 gramm per liter |
Secondary
AC-Emax - Reticulocytes
Absolute maximum of reticulocyte count (AC-Emax - reticulocytes) after single injection of study drug
Time frame: 0, 24 h, 48 h; 72 h; 96 h; 120 h; 168 h; 216 h; 288 h; 336 h, 504 h; 672 h; 840 h; 1008 h; 1176 h post-dose
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| BCD-131, 0.05 mcg/kg Subcutaneously | AC-Emax - Reticulocytes | 23.65 10e9 reticulocytes per liter |
| BCD-131, 0.15 mcg/kg Subcutaneously | AC-Emax - Reticulocytes | 6.00 10e9 reticulocytes per liter |
| BCD-131, 0.40 mcg/kg Subcutaneously | AC-Emax - Reticulocytes | 13.00 10e9 reticulocytes per liter |
| BCD-131, 1.05 mcg/kg Subcutaneously | AC-Emax - Reticulocytes | 27.00 10e9 reticulocytes per liter |
| BCD-131, 1.70 mcg/kg SC | AC-Emax - Reticulocytes | 20.68 10e9 reticulocytes per liter |
| BCD-131, 2.25 mcg/kg SC | AC-Emax - Reticulocytes | 112.00 10e9 reticulocytes per liter |
| BCD-131, 4.45 mcg/kg Subcutaneously | AC-Emax - Reticulocytes | 110.00 10e9 reticulocytes per liter |
| Mircera®, 1.20 mcg/kg Subcutaneously | AC-Emax - Reticulocytes | 58.00 10e9 reticulocytes per liter |
| Aranesp®, 0.45 mcg/kg Subcutaneously | AC-Emax - Reticulocytes | 62.22 10e9 reticulocytes per liter |
| BCD-131, Optimal Dose, Intravenously | AC-Emax - Reticulocytes | 70.18 10e9 reticulocytes per liter |
| BCD-131, Optimal Dose, Subcutaneously | AC-Emax - Reticulocytes | 57.5 10e9 reticulocytes per liter |
Secondary
AUEC (0-1176 Hours) - Hemoglobin
Area under effect curve (AUEC) hemoglobin - time from 0 to 1176 hours post-dose after single injection of study drug
Time frame: 0, 24 h, 48 h; 72 h; 96 h; 120 h; 168 h; 216 h; 288 h; 336 h, 504 h; 672 h; 840 h; 1008 h; 1176 h post-dose
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| BCD-131, 0.05 mcg/kg Subcutaneously | AUEC (0-1176 Hours) - Hemoglobin | 864.00 gr*hr/l |
| BCD-131, 0.15 mcg/kg Subcutaneously | AUEC (0-1176 Hours) - Hemoglobin | 216.00 gr*hr/l |
| BCD-131, 0.40 mcg/kg Subcutaneously | AUEC (0-1176 Hours) - Hemoglobin | 1992.00 gr*hr/l |
| BCD-131, 1.05 mcg/kg Subcutaneously | AUEC (0-1176 Hours) - Hemoglobin | 4752.00 gr*hr/l |
| BCD-131, 1.70 mcg/kg SC | AUEC (0-1176 Hours) - Hemoglobin | 1548.00 gr*hr/l |
| BCD-131, 2.25 mcg/kg SC | AUEC (0-1176 Hours) - Hemoglobin | 1392.00 gr*hr/l |
| BCD-131, 4.45 mcg/kg Subcutaneously | AUEC (0-1176 Hours) - Hemoglobin | 3516.00 gr*hr/l |
| Mircera®, 1.20 mcg/kg Subcutaneously | AUEC (0-1176 Hours) - Hemoglobin | 3492.00 gr*hr/l |
| Aranesp®, 0.45 mcg/kg Subcutaneously | AUEC (0-1176 Hours) - Hemoglobin | 3120.00 gr*hr/l |
| BCD-131, Optimal Dose, Intravenously | AUEC (0-1176 Hours) - Hemoglobin | 4008 gr*hr/l |
| BCD-131, Optimal Dose, Subcutaneously | AUEC (0-1176 Hours) - Hemoglobin | 4632 gr*hr/l |
Secondary
AUEC (0-1176 Hours) - Reticulocytes
Area under effect curve (AUEC) absolute reticulocyte count - time from 0 to 1176 hours post-dose after single injection of study drug
Time frame: 0, 24 h, 48 h; 72 h; 96 h; 120 h; 168 h; 216 h; 288 h; 336 h, 504 h; 672 h; 840 h; 1008 h; 1176 h post-dose
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| BCD-131, 0.05 mcg/kg Subcutaneously | AUEC (0-1176 Hours) - Reticulocytes | 10568.04 cells (10^9) * hr/l |
| BCD-131, 0.15 mcg/kg Subcutaneously | AUEC (0-1176 Hours) - Reticulocytes | 348.000 cells (10^9) * hr/l |
| BCD-131, 0.40 mcg/kg Subcutaneously | AUEC (0-1176 Hours) - Reticulocytes | 2868.000 cells (10^9) * hr/l |
| BCD-131, 1.05 mcg/kg Subcutaneously | AUEC (0-1176 Hours) - Reticulocytes | 11004.00 cells (10^9) * hr/l |
| BCD-131, 1.70 mcg/kg SC | AUEC (0-1176 Hours) - Reticulocytes | 14481.60 cells (10^9) * hr/l |
| BCD-131, 2.25 mcg/kg SC | AUEC (0-1176 Hours) - Reticulocytes | 25512.00 cells (10^9) * hr/l |
| BCD-131, 4.45 mcg/kg Subcutaneously | AUEC (0-1176 Hours) - Reticulocytes | 69120.00 cells (10^9) * hr/l |
| Mircera®, 1.20 mcg/kg Subcutaneously | AUEC (0-1176 Hours) - Reticulocytes | 10269.72 cells (10^9) * hr/l |
| Aranesp®, 0.45 mcg/kg Subcutaneously | AUEC (0-1176 Hours) - Reticulocytes | 14223.60 cells (10^9) * hr/l |
| BCD-131, Optimal Dose, Intravenously | AUEC (0-1176 Hours) - Reticulocytes | 21370.44 cells (10^9) * hr/l |
| BCD-131, Optimal Dose, Subcutaneously | AUEC (0-1176 Hours) - Reticulocytes | 13129.2 cells (10^9) * hr/l |
Secondary
Clearance of BCD-131
Clearance of BCD-131 in blood after single injection
Time frame: 0, 15 min, 30 min; 60 min; 2 h, 4 h; 8 h, 24 h, 48 h, 72 h, 96 h, 120 h, 168 h, 216 h, 288 h, 336 h, 504 h, 672 h, 840 h, 1008 h, 1176 hours post-dose
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| BCD-131, 0.05 mcg/kg Subcutaneously | Clearance of BCD-131 | 17.393 ml per hour |
| BCD-131, 0.15 mcg/kg Subcutaneously | Clearance of BCD-131 | 16.200 ml per hour |
| BCD-131, 0.40 mcg/kg Subcutaneously | Clearance of BCD-131 | 33.337 ml per hour |
| BCD-131, 1.05 mcg/kg Subcutaneously | Clearance of BCD-131 | 54.043 ml per hour |
| BCD-131, 1.70 mcg/kg SC | Clearance of BCD-131 | 92.812 ml per hour |
| BCD-131, 2.25 mcg/kg SC | Clearance of BCD-131 | 65.259 ml per hour |
| BCD-131, 4.45 mcg/kg Subcutaneously | Clearance of BCD-131 | 51.774 ml per hour |
| Mircera®, 1.20 mcg/kg Subcutaneously | Clearance of BCD-131 | 108.993 ml per hour |
| Aranesp®, 0.45 mcg/kg Subcutaneously | Clearance of BCD-131 | 332.263 ml per hour |
| BCD-131, Optimal Dose, Intravenously | Clearance of BCD-131 | 29.84 ml per hour |
| BCD-131, Optimal Dose, Subcutaneously | Clearance of BCD-131 | 136.391 ml per hour |
Secondary
Cmax
Maximal concentration of drug in blood after single injection
Time frame: 0, 15 min, 30 min; 60 min; 2 h, 4 h; 8 h, 24 h, 48 h, 72 h, 96 h, 120 h, 168 h, 216 h, 288 h, 336 h, 504 h, 672 h, 840 h, 1008 h, 1176 hours post-dose
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| BCD-131, 0.05 mcg/kg Subcutaneously | Cmax | 585.000 picogram per ml |
| BCD-131, 0.15 mcg/kg Subcutaneously | Cmax | 1035.000 picogram per ml |
| BCD-131, 0.40 mcg/kg Subcutaneously | Cmax | 2248.000 picogram per ml |
| BCD-131, 1.05 mcg/kg Subcutaneously | Cmax | 3634.000 picogram per ml |
| BCD-131, 1.70 mcg/kg SC | Cmax | 3541.000 picogram per ml |
| BCD-131, 2.25 mcg/kg SC | Cmax | 12023.000 picogram per ml |
| BCD-131, 4.45 mcg/kg Subcutaneously | Cmax | 15433.000 picogram per ml |
| Mircera®, 1.20 mcg/kg Subcutaneously | Cmax | 2298.000 picogram per ml |
| Aranesp®, 0.45 mcg/kg Subcutaneously | Cmax | 964.500 picogram per ml |
| BCD-131, Optimal Dose, Intravenously | Cmax | 87526.5 picogram per ml |
| BCD-131, Optimal Dose, Subcutaneously | Cmax | 10588 picogram per ml |
Secondary
Intensity of Pain After Subcutaneous Injection According to Visual Analog Scale
visual analog scale Minimum value - 0, Maximum value -10, Higher scores mean worse outcome
Time frame: intraoperative
Population: In second period of study, when healthy volunteers received BCD-131 in optimal dose, visual analoge scale was not applied (by protocol)
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| BCD-131, 0.05 mcg/kg Subcutaneously | Intensity of Pain After Subcutaneous Injection According to Visual Analog Scale | 0 score on a scale |
| BCD-131, 0.15 mcg/kg Subcutaneously | Intensity of Pain After Subcutaneous Injection According to Visual Analog Scale | 0 score on a scale |
| BCD-131, 0.40 mcg/kg Subcutaneously | Intensity of Pain After Subcutaneous Injection According to Visual Analog Scale | 0 score on a scale |
| BCD-131, 1.05 mcg/kg Subcutaneously | Intensity of Pain After Subcutaneous Injection According to Visual Analog Scale | 2 score on a scale |
| BCD-131, 1.70 mcg/kg SC | Intensity of Pain After Subcutaneous Injection According to Visual Analog Scale | 2 score on a scale |
| BCD-131, 2.25 mcg/kg SC | Intensity of Pain After Subcutaneous Injection According to Visual Analog Scale | 0 score on a scale |
| BCD-131, 4.45 mcg/kg Subcutaneously | Intensity of Pain After Subcutaneous Injection According to Visual Analog Scale | 2 score on a scale |
| Mircera®, 1.20 mcg/kg Subcutaneously | Intensity of Pain After Subcutaneous Injection According to Visual Analog Scale | 0 score on a scale |
| Aranesp®, 0.45 mcg/kg Subcutaneously | Intensity of Pain After Subcutaneous Injection According to Visual Analog Scale | 2 score on a scale |
Secondary
Kel
Elimination rate constant of drug in blood after single injection. In the cohort BCD-131 0,15 mcg/kg due to the absence of a linear terminal elimination phase in volunteers, the calculation of Kel was not possible
Time frame: 0, 15 min, 30 min; 60 min; 2 h, 4 h; 8 h, 24 h, 48 h, 72 h, 96 h, 120 h, 168 h, 216 h, 288 h, 336 h, 504 h, 672 h, 840 h, 1008 h, 1176 hours post-dose
Population: the calculation of the Kel in group 0,15 mcg/kg was not carried out, due to the lack of a linear terminal phase of elimination in volunteers
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| BCD-131, 0.05 mcg/kg Subcutaneously | Kel | 0.002152 fraction per hour |
| BCD-131, 0.40 mcg/kg Subcutaneously | Kel | 0.001965 fraction per hour |
| BCD-131, 1.05 mcg/kg Subcutaneously | Kel | 0.003266 fraction per hour |
| BCD-131, 1.70 mcg/kg SC | Kel | 0.001746 fraction per hour |
| BCD-131, 2.25 mcg/kg SC | Kel | 0.003620 fraction per hour |
| BCD-131, 4.45 mcg/kg Subcutaneously | Kel | 0.003823 fraction per hour |
| Mircera®, 1.20 mcg/kg Subcutaneously | Kel | 0.006057 fraction per hour |
| Aranesp®, 0.45 mcg/kg Subcutaneously | Kel | 0.009019 fraction per hour |
| BCD-131, Optimal Dose, Intravenously | Kel | 0.005977 fraction per hour |
| BCD-131, Optimal Dose, Subcutaneously | Kel | 0.003828 fraction per hour |
Secondary
Number of Participants With Adverse Events and Serious Adverse Events
Total incidence of adverse events (AE)/ serious adverse events (SAE)
Time frame: from the first administartion of the drug up to the end of follow up period (28 days after the last dose of the drug)
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| BCD-131, 0.05 mcg/kg Subcutaneously | Number of Participants With Adverse Events and Serious Adverse Events | 0 Participants |
| BCD-131, 0.15 mcg/kg Subcutaneously | Number of Participants With Adverse Events and Serious Adverse Events | 1 Participants |
| BCD-131, 0.40 mcg/kg Subcutaneously | Number of Participants With Adverse Events and Serious Adverse Events | 2 Participants |
| BCD-131, 1.05 mcg/kg Subcutaneously | Number of Participants With Adverse Events and Serious Adverse Events | 2 Participants |
| BCD-131, 1.70 mcg/kg SC | Number of Participants With Adverse Events and Serious Adverse Events | 0 Participants |
| BCD-131, 2.25 mcg/kg SC | Number of Participants With Adverse Events and Serious Adverse Events | 0 Participants |
| BCD-131, 4.45 mcg/kg Subcutaneously | Number of Participants With Adverse Events and Serious Adverse Events | 2 Participants |
| Mircera®, 1.20 mcg/kg Subcutaneously | Number of Participants With Adverse Events and Serious Adverse Events | 4 Participants |
| Aranesp®, 0.45 mcg/kg Subcutaneously | Number of Participants With Adverse Events and Serious Adverse Events | 4 Participants |
| BCD-131, Optimal Dose, Intravenously | Number of Participants With Adverse Events and Serious Adverse Events | 4 Participants |
| BCD-131, Optimal Dose, Subcutaneously | Number of Participants With Adverse Events and Serious Adverse Events | 5 Participants |
Secondary
Number of Participants With AE/SAE 3-4 Grade CTCAE
Incidence of Grade 3-4 AEs and SAEs.
Time frame: from the first administartion of the drug up to the end of follow up period (28 days after the last dose of the drug)
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| BCD-131, 0.05 mcg/kg Subcutaneously | Number of Participants With AE/SAE 3-4 Grade CTCAE | 0 Participants |
| BCD-131, 0.15 mcg/kg Subcutaneously | Number of Participants With AE/SAE 3-4 Grade CTCAE | 0 Participants |
| BCD-131, 0.40 mcg/kg Subcutaneously | Number of Participants With AE/SAE 3-4 Grade CTCAE | 0 Participants |
| BCD-131, 1.05 mcg/kg Subcutaneously | Number of Participants With AE/SAE 3-4 Grade CTCAE | 0 Participants |
| BCD-131, 1.70 mcg/kg SC | Number of Participants With AE/SAE 3-4 Grade CTCAE | 0 Participants |
| BCD-131, 2.25 mcg/kg SC | Number of Participants With AE/SAE 3-4 Grade CTCAE | 0 Participants |
| BCD-131, 4.45 mcg/kg Subcutaneously | Number of Participants With AE/SAE 3-4 Grade CTCAE | 0 Participants |
| Mircera®, 1.20 mcg/kg Subcutaneously | Number of Participants With AE/SAE 3-4 Grade CTCAE | 0 Participants |
| Aranesp®, 0.45 mcg/kg Subcutaneously | Number of Participants With AE/SAE 3-4 Grade CTCAE | 1 Participants |
| BCD-131, Optimal Dose, Intravenously | Number of Participants With AE/SAE 3-4 Grade CTCAE | 0 Participants |
| BCD-131, Optimal Dose, Subcutaneously | Number of Participants With AE/SAE 3-4 Grade CTCAE | 0 Participants |
Secondary
Number of Participants With Binding Antibodies to BCD-131
Incidence of Binding antibodies to BCD-131 on Day 50 after a single injection of BCD-131
Time frame: 0, day 50 post-dose
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| BCD-131, 0.05 mcg/kg Subcutaneously | Number of Participants With Binding Antibodies to BCD-131 | 0 Participants |
| BCD-131, 0.15 mcg/kg Subcutaneously | Number of Participants With Binding Antibodies to BCD-131 | 0 Participants |
| BCD-131, 0.40 mcg/kg Subcutaneously | Number of Participants With Binding Antibodies to BCD-131 | 0 Participants |
| BCD-131, 1.05 mcg/kg Subcutaneously | Number of Participants With Binding Antibodies to BCD-131 | 0 Participants |
| BCD-131, 1.70 mcg/kg SC | Number of Participants With Binding Antibodies to BCD-131 | 0 Participants |
| BCD-131, 2.25 mcg/kg SC | Number of Participants With Binding Antibodies to BCD-131 | 0 Participants |
| BCD-131, 4.45 mcg/kg Subcutaneously | Number of Participants With Binding Antibodies to BCD-131 | 0 Participants |
| Mircera®, 1.20 mcg/kg Subcutaneously | Number of Participants With Binding Antibodies to BCD-131 | 0 Participants |
| Aranesp®, 0.45 mcg/kg Subcutaneously | Number of Participants With Binding Antibodies to BCD-131 | 0 Participants |
| BCD-131, Optimal Dose, Intravenously | Number of Participants With Binding Antibodies to BCD-131 | 0 Participants |
| BCD-131, Optimal Dose, Subcutaneously | Number of Participants With Binding Antibodies to BCD-131 | 0 Participants |
Secondary
Number of Participants With Early Withdrawal Due to AE
Frequency of early withdrawals due to AEs and SAEs
Time frame: from the first administartion of the drug up to the end of follow up period (28 days after the last dose of the drug)
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| BCD-131, 0.05 mcg/kg Subcutaneously | Number of Participants With Early Withdrawal Due to AE | 0 Participants |
| BCD-131, 0.15 mcg/kg Subcutaneously | Number of Participants With Early Withdrawal Due to AE | 0 Participants |
| BCD-131, 0.40 mcg/kg Subcutaneously | Number of Participants With Early Withdrawal Due to AE | 0 Participants |
| BCD-131, 1.05 mcg/kg Subcutaneously | Number of Participants With Early Withdrawal Due to AE | 0 Participants |
| BCD-131, 1.70 mcg/kg SC | Number of Participants With Early Withdrawal Due to AE | 0 Participants |
| BCD-131, 2.25 mcg/kg SC | Number of Participants With Early Withdrawal Due to AE | 0 Participants |
| BCD-131, 4.45 mcg/kg Subcutaneously | Number of Participants With Early Withdrawal Due to AE | 0 Participants |
| Mircera®, 1.20 mcg/kg Subcutaneously | Number of Participants With Early Withdrawal Due to AE | 0 Participants |
| Aranesp®, 0.45 mcg/kg Subcutaneously | Number of Participants With Early Withdrawal Due to AE | 0 Participants |
| BCD-131, Optimal Dose, Intravenously | Number of Participants With Early Withdrawal Due to AE | 0 Participants |
| BCD-131, Optimal Dose, Subcutaneously | Number of Participants With Early Withdrawal Due to AE | 0 Participants |
Secondary
Number of Participants With Local Reactions
Incidence of administration site reactions
Time frame: from the first administartion of the drug up to the end of follow up period (28 days after the last dose of the drug)
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| BCD-131, 0.05 mcg/kg Subcutaneously | Number of Participants With Local Reactions | 0 Participants |
| BCD-131, 0.15 mcg/kg Subcutaneously | Number of Participants With Local Reactions | 0 Participants |
| BCD-131, 0.40 mcg/kg Subcutaneously | Number of Participants With Local Reactions | 0 Participants |
| BCD-131, 1.05 mcg/kg Subcutaneously | Number of Participants With Local Reactions | 0 Participants |
| BCD-131, 1.70 mcg/kg SC | Number of Participants With Local Reactions | 0 Participants |
| BCD-131, 2.25 mcg/kg SC | Number of Participants With Local Reactions | 0 Participants |
| BCD-131, 4.45 mcg/kg Subcutaneously | Number of Participants With Local Reactions | 0 Participants |
| Mircera®, 1.20 mcg/kg Subcutaneously | Number of Participants With Local Reactions | 0 Participants |
| Aranesp®, 0.45 mcg/kg Subcutaneously | Number of Participants With Local Reactions | 0 Participants |
| BCD-131, Optimal Dose, Intravenously | Number of Participants With Local Reactions | 0 Participants |
| BCD-131, Optimal Dose, Subcutaneously | Number of Participants With Local Reactions | 0 Participants |
Secondary
T1/2
Half-life of drug in blood after single injection. In the coрort BCD-131 0,15 mcg/kg due to the absence of a linear terminal elimination phase in volunteers, the calculation of T1 / 2 was not possible
Time frame: 0, 15 min, 30 min; 60 min; 2 h, 4 h; 8 h, 24 h, 48 h, 72 h, 96 h, 120 h, 168 h, 216 h, 288 h, 336 h, 504 h, 672 h, 840 h, 1008 h, 1176 hours post-dose
Population: the calculation of the half-life in group 0,15 mcg/kg was not carried out, due to the lack of a linear terminal phase of elimination in volunteers
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| BCD-131, 0.05 mcg/kg Subcutaneously | T1/2 | 322.094 hours |
| BCD-131, 0.40 mcg/kg Subcutaneously | T1/2 | 377.272 hours |
| BCD-131, 1.05 mcg/kg Subcutaneously | T1/2 | 212.231 hours |
| BCD-131, 1.70 mcg/kg SC | T1/2 | 416.482 hours |
| BCD-131, 2.25 mcg/kg SC | T1/2 | 191.477 hours |
| BCD-131, 4.45 mcg/kg Subcutaneously | T1/2 | 181.310 hours |
| Mircera®, 1.20 mcg/kg Subcutaneously | T1/2 | 114.855 hours |
| Aranesp®, 0.45 mcg/kg Subcutaneously | T1/2 | 79.473 hours |
| BCD-131, Optimal Dose, Intravenously | T1/2 | 116.125 hours |
| BCD-131, Optimal Dose, Subcutaneously | T1/2 | 182.392 hours |
Secondary
Tmax
Time from 9 hours to time of maximal concentration of drug in blood after single injection
Time frame: 0, 15 min, 30 min; 60 min; 2 h, 4 h; 8 h, 24 h, 48 h, 72 h, 96 h, 120 h, 168 h, 216 h, 288 h, 336 h, 504 h, 672 h, 840 h, 1008 h, 1176 hours post-dose
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| BCD-131, 0.05 mcg/kg Subcutaneously | Tmax | 216.000 hours |
| BCD-131, 0.15 mcg/kg Subcutaneously | Tmax | 168.000 hours |
| BCD-131, 0.40 mcg/kg Subcutaneously | Tmax | 96.000 hours |
| BCD-131, 1.05 mcg/kg Subcutaneously | Tmax | 72.000 hours |
| BCD-131, 1.70 mcg/kg SC | Tmax | 72.000 hours |
| BCD-131, 2.25 mcg/kg SC | Tmax | 120.000 hours |
| BCD-131, 4.45 mcg/kg Subcutaneously | Tmax | 96.000 hours |
| Mircera®, 1.20 mcg/kg Subcutaneously | Tmax | 48.000 hours |
| Aranesp®, 0.45 mcg/kg Subcutaneously | Tmax | 36.000 hours |
| BCD-131, Optimal Dose, Intravenously | Tmax | 0.75 hours |
| BCD-131, Optimal Dose, Subcutaneously | Tmax | 84 hours |