Healthy
Conditions
Keywords
interferon beta-1a, pharmacokinetics, pharmacodynamics, volunteers
Brief summary
This is a randomized double-blind crossover study of pharmacokinetics, pharmacodynamics and tolerability of BCD-033 (interferon beta-1a manufactured by CJSC BIOCAD, Russia) and Rebif® (Merck Serono S.p.A.., Italy) in healthy volunteers. The purpose of the study is to demonstrate the non-inferiority of pharmacokinetics, pharmacodynamics and tolerability parameters after single subcutaneous injection. Each dtug will be administered to each volunteer at a dose of 44 µg as a single subcutaneous injection with an interval of at least 14 days.
Detailed description
Each dtug (BCD-033 and Rebif) will be administered to each volunteer at a dose of 44 µg as a single subcutaneous injection with an interval of at least 14 days.
Interventions
DRUGInterferon beta-1a
Each volunteer will receive 1 subcutaneous (sc) injection of the study drug BCD-033 (interferon beta-1a) and 1 sc injection of active comparator Rebif (interferon beta-1a) at a dose of 44 µg with an interval of at least 14 days.
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
* Written informed consent; * Male gender; * Age 18 - 45 years inclusive; * Body mass index (BMI) (18,5 - 24,99 kg/m2); * Healthy condition proven by the volunteer's history, global assessment and laboratory analysis results: * Absence in past medical history and at screening of clinically significant dysfunctions of circulatory, respiratory, nervous, hematopoietic, endocrine and digestive systems, liver and kidneys; * Haematology and biochemistry tests, urinalysis and thyroid hormone analysis results are within normal limits according to standards of the study site. Screening laboratory analyses should be performed not more than 14 days before volunteer's inclusion in the study; * Hemodynamic parameters are within normal limits: systolic blood pressure - from 100 to 139 mmHg, diastolic blood pressure - from 60 to 90 mmHg, heart rate - from 50 to 90 bpm; * Absence of history of chronic infection (tuberculosis) and chronic inflammation; * Absence of HIV, hepatitis B and C virus, syphilis; * Absence of acute infections within 4 weeks before inclusion in the study; * Absence of psychiatric disorders and other conditions that can interfere with volunteer's ability to follow the study protocol, including depression; * Well-being (in volunteer's opinion) within 30 days before participation in the study; * 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 8 days after each administration of the test or reference drugs; * Consent to avoid grapefruit juice (or other products containing grapefruit) intake within 72 hours before and 8 days after each administration of the study or reference drugs.
Exclusion criteria
* Previous use of IFN-β1-containing medications at any time before inclusion; * History of serious allergic reactions (anaphylaxis or multiple allergy); * Known allergy or intolerance to interferons or any other components of study or reference drugs; * Major surgery within 30 days before screening; * Impossibility to install 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 investigational drugs pharmacokinetics (e.g. chronic liver, kidney, blood, circulatory system, lung or neuroendocrine diseases, including diabetes mellitus and others); * History of epileptic seizures; * Regular oral or parenteral use of any medications including over-the-counter drugs, vitamins and nutritional additives within less than 2 weeks before inclusion in the study; * Intake of medications, including over-the-counter drugs and biologically active additives that can influence hemodynamics, liver function etc. (barbiturates, omeprazole, cimetidine etc.) within less than 30 days before inclusion in the study; * Intake of medications that influence immune status (cytokines and their inductors, glucocorticoids etc.) within less than 30 days before participation in the study; * Smoking more than 10 cigarettes per day; * Subjects who consume more than 10 units of alcohol per week or who have history of alcohol abuse or evidence of drug/chemical abuse (one unit of alcohol equals ½ l \[500 ml\] of beer, one glass \[200 ml\] of wine or l shot glass \[50 ml\] of spirits); * Donation of 450 ml and more of blood or plasma within 2 months before inclusion in the study; * Participation in other clinical studies within less than 1 month before inclusion in the study or simultaneous participation in another clinical study; * Previous participation in this study
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Area Under Concentration-time Curve (AUC) of Interferon (IFN) Beta-1a From the Moment of Drug Administration Until 48 Hours and to Infinity(AUC(0-48) and AUC(0-∞) Respectively) | 0 to 48 hours post-dose | Primary outcome measure for pharmacokinetics analysis. Blood samples were taken before the injection, then after 15 min, 30 min, 45 min, 1 hour, 2 hours, 3 hours, 4 hours, 6 hours, 8 hours, 12 hours, 24 hours and 48 hours. |
| Cmax of Interferon Beta-1a | 0 to 48 hours post-dose | Primary outcome measure for pharmacokinetics analysis Blood samples were taken before the injection, then after 15 min, 30 min, 45 min, 1 hour, 2 hours, 3 hours, 4 hours, 6 hours, 8 hours, 12 hours, 24 hours and 48 hours. |
| AUC(0-168) and AUC(0-∞) of Neopterin and MxA Protein | 0 to 168 hours post-dose | Primary outcome measure for pharmacodynamics analysis. Blood samples were taken before the injection, then after 1, 2, 3, 4, 6, 8, 12, 24, 48, 72, 96, 120, 144 and 168 hours. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Cl of Interferon Beta-1a Blood Samples Were Taken Before the Injection, Then After 15 Min, 30 Min, 45 Min, 1 Hour, 2 Hours, 3 Hours, 4 Hours, 6 Hours, 8 Hours, 12 Hours, 24 Hours and 48 Hours. | 0 to 48 hours post-dose | Secondary outcome measure for pharmacokinetics analysis |
| Cmax of Neopterin and MxA Protein Blood Samples Were Taken Before the Injection, Then After 1, 2, 3, 4, 6, 8, 12, 24, 48, 72, 96, 120, 144 and 168 Hours. | 0 to 168 hours post-dose | Secondary outcome measure for pharmacodynamics analysis |
| Tmax of Neopterin and MxA Protein | 0 to 168 hours post-dose | Secondary outcome measure for pharmacodynamics analysis |
| Тmax of Interferon Beta-1a Blood Samples Were Taken Before the Injection, Then After 15 Min, 30 Min, 45 Min, 1 Hour, 2 Hours, 3 Hours, 4 Hours, 6 Hours, 8 Hours, 12 Hours, 24 Hours and 48 Hours. | 0 to 48 hours post-dose | Secondary outcome measure for pharmacokinetics analysis |
| AE of Garde 3-4 Incidence | up to Day 43 | Secondary outcome measure for safety assessment |
| Local Reaction Incidence | up to Day 43 | Secondary outcome measure for tolerability assessment |
| Study Withdrawal Rate Due to AE | up to Day 43 | Secondary outcome measure for safety assessment |
| Adverse Event (AE) and Serious Adverse Event (SAE) Incidence | up to Day 43 | Secondary outcome measure for safety assessment |
| Т½ of Interferon Beta-1a Blood Samples Were Taken Before the Injection, Then After 15 Min, 30 Min, 45 Min, 1 Hour, 2 Hours, 3 Hours, 4 Hours, 6 Hours, 8 Hours, 12 Hours, 24 Hours and 48 Hours. | 0 to 48 hours post-dose | Secondary outcome measure for pharmacokinetics analysis |
| Кel of Interferon Beta-1a Blood Samples Were Taken Before the Injection, Then After 15 Min, 30 Min, 45 Min, 1 Hour, 2 Hours, 3 Hours, 4 Hours, 6 Hours, 8 Hours, 12 Hours, 24 Hours and 48 Hours. | 0 to 48 hours post-dose | Secondary outcome measure for pharmacokinetics analysis |
Countries
Russia
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| BCD-033 → Rebif Volunteers in this group initially will receive a single sc injection of the study drug BCD-033 (interferon beta-1a) at a dose of 44 µg (on Day 1) and then, after at least 14 days, a single sc injection of the reference drug Rebif® (interferon beta-1a) at a dose of 44 µg.
Interferon beta-1a: Each volunteer will receive 1 subcutaneous (sc) injection of the study drug BCD-033 (interferon beta-1a) and 1 sc injection of active comparator Rebif (interferon beta-1a) at a dose of 44 µg with an interval of at least 14 days. | 16 |
| Rebif → BCD-033 Volunteers in this group initially will receive a single sc injection of active comparator Rebif (interferon beta-1a) at a dose of 44 µg (on Day 1) and then, after at least 14 days, a single sc injection of the study drug BCD-033 (interferon beta-1a) at a dose of 44 µg.
Interferon beta-1a: Each volunteer will receive 1 subcutaneous (sc) injection of the study drug BCD-033 (interferon beta-1a) and 1 sc injection of active comparator Rebif (interferon beta-1a) at a dose of 44 µg with an interval of at least 14 days. | 16 |
| Total | 32 |
Baseline characteristics
| Characteristic | BCD-033 → Rebif | Rebif → BCD-033 | Total |
|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical Between 18 and 65 years | 16 Participants | 16 Participants | 32 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 16 Participants | 16 Participants | 32 Participants |
| Region of Enrollment Russian Federation | 16 participants | 16 participants | 32 participants |
| Sex: Female, Male Female | 0 Participants | 0 Participants | 0 Participants |
| Sex: Female, Male Male | 16 Participants | 16 Participants | 32 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 32 / 32 | 32 / 32 |
| serious Total, serious adverse events | 0 / 32 | 0 / 32 |
Outcome results
Primary
Area Under Concentration-time Curve (AUC) of Interferon (IFN) Beta-1a From the Moment of Drug Administration Until 48 Hours and to Infinity(AUC(0-48) and AUC(0-∞) Respectively)
Primary outcome measure for pharmacokinetics analysis. Blood samples were taken before the injection, then after 15 min, 30 min, 45 min, 1 hour, 2 hours, 3 hours, 4 hours, 6 hours, 8 hours, 12 hours, 24 hours and 48 hours.
Time frame: 0 to 48 hours post-dose
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| BCD-033 | Area Under Concentration-time Curve (AUC) of Interferon (IFN) Beta-1a From the Moment of Drug Administration Until 48 Hours and to Infinity(AUC(0-48) and AUC(0-∞) Respectively) | 6318.3 (pg/ml)•h |
| Rebif | Area Under Concentration-time Curve (AUC) of Interferon (IFN) Beta-1a From the Moment of Drug Administration Until 48 Hours and to Infinity(AUC(0-48) and AUC(0-∞) Respectively) | 6807.9 (pg/ml)•h |
Primary
AUC(0-168) and AUC(0-∞) of Neopterin and MxA Protein
Primary outcome measure for pharmacodynamics analysis. Blood samples were taken before the injection, then after 1, 2, 3, 4, 6, 8, 12, 24, 48, 72, 96, 120, 144 and 168 hours.
Time frame: 0 to 168 hours post-dose
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| BCD-033 | AUC(0-168) and AUC(0-∞) of Neopterin and MxA Protein | neopterin | 552.7 (ng/ml)*h |
| BCD-033 | AUC(0-168) and AUC(0-∞) of Neopterin and MxA Protein | MxA protein | 2444.2 (ng/ml)*h |
| Rebif | AUC(0-168) and AUC(0-∞) of Neopterin and MxA Protein | neopterin | 537.6 (ng/ml)*h |
| Rebif | AUC(0-168) and AUC(0-∞) of Neopterin and MxA Protein | MxA protein | 2131.2 (ng/ml)*h |
Primary
Cmax of Interferon Beta-1a
Primary outcome measure for pharmacokinetics analysis Blood samples were taken before the injection, then after 15 min, 30 min, 45 min, 1 hour, 2 hours, 3 hours, 4 hours, 6 hours, 8 hours, 12 hours, 24 hours and 48 hours.
Time frame: 0 to 48 hours post-dose
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| BCD-033 | Cmax of Interferon Beta-1a | 104.9 pg/ml |
| Rebif | Cmax of Interferon Beta-1a | 102.4 pg/ml |
Secondary
Adverse Event (AE) and Serious Adverse Event (SAE) Incidence
Secondary outcome measure for safety assessment
Time frame: up to Day 43
Secondary
AE of Garde 3-4 Incidence
Secondary outcome measure for safety assessment
Time frame: up to Day 43
Secondary
Cl of Interferon Beta-1a Blood Samples Were Taken Before the Injection, Then After 15 Min, 30 Min, 45 Min, 1 Hour, 2 Hours, 3 Hours, 4 Hours, 6 Hours, 8 Hours, 12 Hours, 24 Hours and 48 Hours.
Secondary outcome measure for pharmacokinetics analysis
Time frame: 0 to 48 hours post-dose
Secondary
Cmax of Neopterin and MxA Protein Blood Samples Were Taken Before the Injection, Then After 1, 2, 3, 4, 6, 8, 12, 24, 48, 72, 96, 120, 144 and 168 Hours.
Secondary outcome measure for pharmacodynamics analysis
Time frame: 0 to 168 hours post-dose
Secondary
Local Reaction Incidence
Secondary outcome measure for tolerability assessment
Time frame: up to Day 43
Secondary
Study Withdrawal Rate Due to AE
Secondary outcome measure for safety assessment
Time frame: up to Day 43
Secondary
Tmax of Neopterin and MxA Protein
Secondary outcome measure for pharmacodynamics analysis
Time frame: 0 to 168 hours post-dose
Secondary
Кel of Interferon Beta-1a Blood Samples Were Taken Before the Injection, Then After 15 Min, 30 Min, 45 Min, 1 Hour, 2 Hours, 3 Hours, 4 Hours, 6 Hours, 8 Hours, 12 Hours, 24 Hours and 48 Hours.
Secondary outcome measure for pharmacokinetics analysis
Time frame: 0 to 48 hours post-dose
Secondary
Т½ of Interferon Beta-1a Blood Samples Were Taken Before the Injection, Then After 15 Min, 30 Min, 45 Min, 1 Hour, 2 Hours, 3 Hours, 4 Hours, 6 Hours, 8 Hours, 12 Hours, 24 Hours and 48 Hours.
Secondary outcome measure for pharmacokinetics analysis
Time frame: 0 to 48 hours post-dose
Secondary
Тmax of Interferon Beta-1a Blood Samples Were Taken Before the Injection, Then After 15 Min, 30 Min, 45 Min, 1 Hour, 2 Hours, 3 Hours, 4 Hours, 6 Hours, 8 Hours, 12 Hours, 24 Hours and 48 Hours.
Secondary outcome measure for pharmacokinetics analysis
Time frame: 0 to 48 hours post-dose