Study of Pharmacokinetics, Pharmacodynamics, Safety of BCD-131 Compared to Mircera and Aranesp in Healthy Volunteers

Study Overview
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Brief Summary
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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
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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.

Official Title
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Clinical Study of the Pharmacokinetics, Pharmacodynamics, Tolerability, Safety and Immunogenicity of BCD-131 Compared to Mircera and Aranesp in Healthy Volunteers

Conditions
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Reticulocyte Count

Intervention / Treatment
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* Biological: BCD-131
* Biological: Mircera®
* Biological: Aranesp®


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Signing of the Informed Consent Form; Male sex; Age of 18 to 45 years, inclusive; BMI within normal limits (18.5-24.9 kg/m2); 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; No history of or current (at baseline) alcohol or drug abuse; Ability of the volunteer, in the investigator's opinion, to follow the study protocol procedures; 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). Willingness of volunteers to avoid alcohol intake within 24 hours before and 8 days after each injection of the test drug; Exclusion Criteria: History of treatment with erythropoietins or any other ESAs; Acute bleeding, blood/plasma donation or blood transfusion within 2 months before inclusion in the study; History of chronic bleeding; Standard laboratory and instrumental findings outside normal limits at screening; History of allergies (anaphylactic shock or multiple drug allergy syndrome); Known allergy or intolerance to any components of the investigational product; Major surgery within 30 days prior to screening, or surgery being scheduled for any time during the study; Impossibility to install a venous catheter for blood sampling (e.g. because of skin disorders at the sites of venipuncture); 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); History of fever of 40 °C or more; History of elevated hepatic transaminases (above 2.5xULN); 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; History of epileptic attacks or seizures; History or current (at screening) depression, suicidal thoughts/ attempts; 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; 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; Vaccination within 4 weeks before a scheduled injection of the test drug; Smoking more than 10 cigarettes per day; 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; Participation in other clinical studies within 1 month before screening or simultaneous participation in another clinical study; Previous participation in this study.

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: Other
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: BCD-131, 0.05 mcg/kg subcutaneously<br>Healthy volunteers will receive BCD-131 in a dose 0.05 mcg/kg subcutaneously | Biological: BCD-131<br> <br> * Other names: pegylated darbepoetin alfa;|
| Experimental: BCD-131, 0.15 mcg/kg subcutaneously<br>Healthy volunteers will receive BCD-131 in a dose 0.15 mcg/kg subcutaneously | Biological: BCD-131<br> <br> * Other names: pegylated darbepoetin alfa;|
| Experimental: BCD-131, 0.40 mcg/kg subcutaneously<br>Healthy volunteers will receive BCD-131 in a dose 0.40 mcg/kg subcutaneously | Biological: BCD-131<br> <br> * Other names: pegylated darbepoetin alfa;|
| Experimental: BCD-131, 1.05 mcg/kg subcutaneously<br>Healthy volunteers will receive BCD-131 in a dose 1.05 mcg/kg subcutaneously | Biological: BCD-131<br> <br> * Other names: pegylated darbepoetin alfa;|
| Experimental: BCD-131, 1.70 mcg/kg SC<br>Healthy volunteers will receive BCD-131 in a dose 1.70 mcg/kg subcutaneously | Biological: BCD-131<br> <br> * Other names: pegylated darbepoetin alfa;|
| Experimental: BCD-131, 2.25 mcg/kg SC<br>Healthy volunteers will receive BCD-131 in a dose 2.25 mcg/kg subcutaneously | Biological: BCD-131<br> <br> * Other names: pegylated darbepoetin alfa;|
| Experimental: BCD-131, 4.45 mcg/kg subcutaneously<br>Healthy volunteers will receive BCD-131 in a dose 4.45 mcg/kg subcutaneously | Biological: BCD-131<br> <br> * Other names: pegylated darbepoetin alfa;|
| Active Comparator: Mircera®, 1.20 mcg/kg subcutaneously<br>Healthy volunteers will receive Mircera in a dose 1.20 mcg/kg subcutaneously | Biological: Mircera®<br> <br> * Other names: Methoxy polyethylene glycol-epoetin beta;|
| Active Comparator: Aranesp®, 0.45 mcg/kg subcutaneously<br>Healthy volunteers will receive BCD-131 in a dose 0.45 mcg/kg subcutaneously | Biological: Aranesp®<br> <br> * Other names: darbepoetin alfa;|
| Experimental: BCD-131, optimal dose, intravenously<br>Healthy volunteers will receive BCD-131 in optimal dose determined on first stage of clinical trial intravenously | Biological: BCD-131<br> <br> * Other names: pegylated darbepoetin alfa;|
| Experimental: BCD-131, optimal dose, subcutaneously<br>Healthy volunteers will receive BCD-131 in optimal dose determined on first stage of clinical trial subcutaneously | Biological: BCD-131<br> <br> * Other names: pegylated darbepoetin alfa;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| AUC (0-1176 Hours) | Area under curve (AUC) concentration - time from 0 hours to 1176 hours and to infinity | 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 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Cmax | Maximal concentration of drug in blood after single injection | 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 | 
| Tmax | Time from 9 hours to time of maximal concentration of drug in blood after single injection | 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 | 
| 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 | 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 | 
| 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 | 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 | Clearance of BCD-131 in blood after single injection | 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 | 
| 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 | 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 | 
| 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 | 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 | 
| AC-Emax - Reticulocytes | Absolute maximum of reticulocyte count (AC-Emax - reticulocytes) after single injection of study drug | 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 | 
| AC-Emax - Hemoglobin | Absolute maximum of hemoglobin (AC-Emax - hemoglobin) after single injection of study drug | 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 | 
| 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 | intraoperative | 
| Number of Participants With Adverse Events and Serious Adverse Events | Total incidence of adverse events (AE)/ serious adverse events (SAE) | from the first administartion of the drug up to the end of follow up period (28 days after the last dose of the drug) | 
| Number of Participants With Local Reactions | Incidence of administration site 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) | 
| Number of Participants With AE/SAE 3-4 Grade CTCAE | Incidence of Grade 3-4 AEs and SAEs. | from the first administartion of the drug up to the end of follow up period (28 days after the last dose of the drug) | 
| Number of Participants With Early Withdrawal Due to AE | Frequency of early withdrawals due to AEs and SAEs | from the first administartion of the drug up to the end of follow up period (28 days after the last dose of the drug) | 
| 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 | 0, day 50 post-dose |