Multiple Sclerosis
Conditions
Brief summary
Study design is double-blind, randomized, placebo-controlled study in 3 parallel groups with the use of active comparator and placebo. Total duration of therapy of about 2 years. Study hypothesis is equivalence of efficacy and safety of the investigational drug BCD-033 original drug Rebif®.
Interventions
DRUGBCD-033 (interferon beta 1a)
Subcutaneous injection of BCD-033, 44 µg (0,5 ml) 3 times per week, every other day, for 92 weeks
DRUGRebif (interferon beta 1a)
Subcutaneous injection of Rebif, 44 µg (0,5 ml) 3 times per week, every other day, for 48 weeks
DRUGPlacebo
Subcutaneous injection of placebo, 0,5 ml 3 times per week, every other day, for12 weeks
Sponsors
Biocad
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
OTHER
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
18 Years to 55 Years
Healthy volunteers
No
Inclusion criteria
1. Age 18-55 2. Patients of both genders with Multiple Sclerosis (McDonald criteria 2010) 3. No relapses 28 days before randomisation 4. Expanded Disability Status Scale score 0-5,5
Exclusion criteria
1. Primary or secondary progression of Multiple Sclerosis 2. Expanded Disability Status Scale score more then 5,5 3. Severe depression, suicide ideas and/or attempts 4. Systemic corticosteroid application in 30 days before randomisation
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Number of Combined Unique Active Lesions | 52 weeks | Number of Combined Unique Active Lesions (CUA) -- the number of new MRI contrast uptake lesions on T1 images, and new or expanding lesions on T2 images (lesion identified on T1-and T2 images is not counted twice) after 52 weeks blinded application of interferon-β1а (BCD-033 and Rebif®) (44 mcg). |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Proportion of Subjects Without Confirmed Relapse | 16, 52 weeks | proportion of subjects without confirmed relapse in PP |
| Relapse Free Time | 96 weeks | Time to first relapse in per protocol population |
| Number of Combined Unique Active Lesions | 96 weeks | CUA (the number of new contrast-enhanced lesions on T1 images, and new or expanding lesions on T2 images (lesion identified on T1-and T2 images is not counted twice) |
| Annual Relapse Rate | 52 weeks | Annual relapse rate ARR for 52 weeks was evaluated in all three groups, after the application of IFN beta-1a |
Other
| Measure | Time frame | Description |
|---|---|---|
| Adverse Events/Serious Adverse Events | 96 weeks | quantity and grade of all AE/SAE is calculated in subjects, who received at least one dose of study drug |
| Serious Adverse Events | 52 week of study | quantity and grade of all SAE is calculated in subjects, who received at least one dose of study drug |
| Severe Adverse Events Frequency | 52 weeks | AE grade 3-4 (CTCAE 4.03) is calculated in subjects, who received at least one dose of study drug |
| Withdrawal | 16, 52 weeks | quantity of withdrawals due to AE/SAE is calculated in subjects, who received at least one dose of study drug |
| Immunogenicity | 16, 52 weeks | Count of Participants with Binding and Neutralizing Antibodies |
| Adverse Reaction/Serious Adverse Reactions | 16, 52 weeks | quantity and grade of all adverse reactions/serious adverse reactions is calculated in subjects, who received at least one dose of study drug |
Countries
Russia
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| BCD-033 interferon beta-1a (BCD-033) | 53 |
| Rebif / BCD-033 interferon beta-1a (Rebif / BCD-033) | 55 |
| Placebo / BCD-033 placebo / interferon beta-1a | 54 |
| Total | 162 |
Baseline characteristics
| Characteristic | BCD-033 | Rebif / BCD-033 | Placebo / BCD-033 | Total |
|---|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical Between 18 and 65 years | 53 Participants | 55 Participants | 54 Participants | 162 Participants |
| Age, Continuous | 28.00 years | 30.00 years | 29.5 years | 29.0 years |
| Sex: Female, Male Female | 38 Participants | 31 Participants | 34 Participants | 103 Participants |
| Sex: Female, Male Male | 15 Participants | 24 Participants | 20 Participants | 59 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 53 | 0 / 55 | 0 / 54 |
| other Total, other adverse events | 35 / 53 | 32 / 55 | 34 / 54 |
| serious Total, serious adverse events | 0 / 53 | 0 / 55 | 2 / 54 |
Outcome results
Primary
Number of Combined Unique Active Lesions
Number of Combined Unique Active Lesions (CUA) -- the number of new MRI contrast uptake lesions on T1 images, and new or expanding lesions on T2 images (lesion identified on T1-and T2 images is not counted twice) after 52 weeks blinded application of interferon-β1а (BCD-033 and Rebif®) (44 mcg).
Time frame: 52 weeks
Population: The primary endpoint was assessed after 52 weeks of use of IFN-β1a (BCD-033 and Rebif) in a full dose (44 μg). In the analysis of the effeciency of MRI indicators included 100 patients
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| BCD-033 | Number of Combined Unique Active Lesions | 0.0 lesions |
| Rebif | Number of Combined Unique Active Lesions | 0.0 lesions |
Secondary
Annual Relapse Rate
Annual relapse rate ARR for 52 weeks was evaluated in all three groups, after the application of IFN beta-1a
Time frame: 52 weeks
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| BCD-033 | Annual Relapse Rate | 0.113 relapses | Standard Deviation 0.375 |
| Rebif | Annual Relapse Rate | 0.091 relapses | Standard Deviation 0.348 |
| Placebo / BCD-033 | Annual Relapse Rate | 0.109 relapses | Standard Deviation 0.369 |
Secondary
Annual Relapse Rate
Annual Relapse Rate ARR for 96 weeks was evaluated in two groups, after the administraion of IFN beta-1a in a full dose for 96 weeks.
Time frame: 96 week
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| BCD-033 | Annual Relapse Rate | 0.208 relapses | Standard Error 0.532 |
| Rebif | Annual Relapse Rate | 0.145 relapses | Standard Error 0.524 |
Secondary
Number of Combined Unique Active Lesions
CUA (the number of new contrast-enhanced lesions on T1 images, and new or expanding lesions on T2 images (lesion identified on T1-and T2 images is not counted twice)
Time frame: 96 weeks
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| BCD-033 | Number of Combined Unique Active Lesions | 0.0 lesions |
| Rebif | Number of Combined Unique Active Lesions | 0.0 lesions |
Secondary
Number of Combined Unique Active Lesions
CUA (the number of new contrast-enhanced lesions on T1 images, and new or expanding lesions on T2 images (lesion identified on T1-and T2 images is not counted twice).
Time frame: 16 weeks
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| BCD-033 | Number of Combined Unique Active Lesions | 0.0 lesions |
| Rebif | Number of Combined Unique Active Lesions | 0.0 lesions |
| Placebo / BCD-033 | Number of Combined Unique Active Lesions | 1.0 lesions |
Secondary
Proportion of Subjects Without Confirmed Relapse
proportion of subjects without confirmed relapse in PP
Time frame: 16, 52 weeks
Population: The analysis was performed in per protocol population at 16 and 52 weeks
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| BCD-033 | Proportion of Subjects Without Confirmed Relapse | week 16 | 49 Count of Participants |
| BCD-033 | Proportion of Subjects Without Confirmed Relapse | week 52 | 41 Count of Participants |
| Rebif | Proportion of Subjects Without Confirmed Relapse | week 16 | 46 Count of Participants |
| Rebif | Proportion of Subjects Without Confirmed Relapse | week 52 | 44 Count of Participants |
| Placebo / BCD-033 | Proportion of Subjects Without Confirmed Relapse | week 16 | 45 Count of Participants |
| Placebo / BCD-033 | Proportion of Subjects Without Confirmed Relapse | week 52 | 39 Count of Participants |
Secondary
Relapse Free Time
Time to first relapse in per protocol population
Time frame: 16, 52 weeks
Population: The analysis was performed in per protocol population at 16 and 52 weeks
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| BCD-033 | Relapse Free Time | week 52 | 193.0 days |
| BCD-033 | Relapse Free Time | week 16 | 33.5 days |
| Rebif | Relapse Free Time | week 16 | 14.0 days |
| Rebif | Relapse Free Time | week 52 | 123.5 days |
| Placebo / BCD-033 | Relapse Free Time | week 16 | 15.0 days |
| Placebo / BCD-033 | Relapse Free Time | week 52 | 74.0 days |
Secondary
Relapse Free Time
Time to first relapse in per protocol population
Time frame: 96 weeks
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| BCD-033 | Relapse Free Time | 207.0 days |
| Rebif | Relapse Free Time | 183.0 days |
Other Pre-specified
Adverse Events/Serious Adverse Events
quantity and grade of all AE/SAE is calculated in subjects, who received at least one dose of study drug
Time frame: 96 weeks
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| BCD-033 | Adverse Events/Serious Adverse Events | 124 adverse events |
| Rebif | Adverse Events/Serious Adverse Events | 110 adverse events |
Other Pre-specified
Adverse Reaction/Serious Adverse Reactions
quantity and grade of all adverse reactions/serious adverse reactions is calculated in subjects, who received at least one dose of study drug
Time frame: 16, 52 weeks
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| BCD-033 | Adverse Reaction/Serious Adverse Reactions | week 16 | 67 adverse events |
| BCD-033 | Adverse Reaction/Serious Adverse Reactions | week 52 | 92 adverse events |
| Rebif | Adverse Reaction/Serious Adverse Reactions | week 16 | 59 adverse events |
| Rebif | Adverse Reaction/Serious Adverse Reactions | week 52 | 80 adverse events |
| Placebo / BCD-033 | Adverse Reaction/Serious Adverse Reactions | week 16 | 33 adverse events |
| Placebo / BCD-033 | Adverse Reaction/Serious Adverse Reactions | week 52 | 92 adverse events |
Other Pre-specified
Immunogenicity
Count of Participants with Binding and Neutralizing Antibodies
Time frame: 96 weeks
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| BCD-033 | Immunogenicity | Binding Antibodies | 19 participants |
| BCD-033 | Immunogenicity | Neutralizing Antibodies | 16 participants |
| Rebif | Immunogenicity | Binding Antibodies | 14 participants |
| Rebif | Immunogenicity | Neutralizing Antibodies | 13 participants |
Other Pre-specified
Immunogenicity
Count of Participants with Binding and Neutralizing Antibodies
Time frame: 16, 52 weeks
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| BCD-033 | Immunogenicity | week 52 : Neutralizing Antibodies | 9 participants |
| BCD-033 | Immunogenicity | week 52 : Binding Antibodies | 10 participants |
| BCD-033 | Immunogenicity | week 16 : Neutralizing Antibodies | 5 participants |
| BCD-033 | Immunogenicity | week 16 : Binding Antibodies | 6 participants |
| Rebif | Immunogenicity | week 52 : Binding Antibodies | 9 participants |
| Rebif | Immunogenicity | week 16 : Neutralizing Antibodies | 5 participants |
| Rebif | Immunogenicity | week 16 : Binding Antibodies | 5 participants |
| Rebif | Immunogenicity | week 52 : Neutralizing Antibodies | 8 participants |
| Placebo / BCD-033 | Immunogenicity | week 16 : Neutralizing Antibodies | 2 participants |
| Placebo / BCD-033 | Immunogenicity | week 16 : Binding Antibodies | 2 participants |
| Placebo / BCD-033 | Immunogenicity | week 52 : Neutralizing Antibodies | 7 participants |
| Placebo / BCD-033 | Immunogenicity | week 52 : Binding Antibodies | 7 participants |
Other Pre-specified
Serious Adverse Events
quantity and grade of all SAE is calculated in subjects, who received at least one dose of study drug
Time frame: 52 week of study
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| BCD-033 | Serious Adverse Events | 0 adverse events |
| Rebif | Serious Adverse Events | 0 adverse events |
| Placebo / BCD-033 | Serious Adverse Events | 3 adverse events |
Other Pre-specified
Severe Adverse Events Frequency
AE grade 3-4 (CTCAE 4.03)is calculated in subjects, who received at least one dose of study drug
Time frame: 96 weeks
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| BCD-033 | Severe Adverse Events Frequency | 2 adverse events |
| Rebif | Severe Adverse Events Frequency | 3 adverse events |
Other Pre-specified
Severe Adverse Events Frequency
AE grade 3-4 (CTCAE 4.03) is calculated in subjects, who received at least one dose of study drug
Time frame: 52 weeks
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| BCD-033 | Severe Adverse Events Frequency | 5 adverse events |
| Rebif | Severe Adverse Events Frequency | 4 adverse events |
| Placebo / BCD-033 | Severe Adverse Events Frequency | 7 adverse events |
Other Pre-specified
Withdrawal
quantity of withdrawals due to AE/SAE is calculated in subjects, who received at least one dose of study drug
Time frame: 96 weeks
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| BCD-033 | Withdrawal | 1 Participants |
| Rebif | Withdrawal | 1 Participants |
Other Pre-specified
Withdrawal
quantity of withdrawals due to AE/SAE is calculated in subjects, who received at least one dose of study drug
Time frame: 16, 52 weeks
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| BCD-033 | Withdrawal | week 16 | 0 Participants |
| BCD-033 | Withdrawal | week 52 | 1 Participants |
| Rebif | Withdrawal | week 16 | 1 Participants |
| Rebif | Withdrawal | week 52 | 1 Participants |
| Placebo / BCD-033 | Withdrawal | week 16 | 1 Participants |
| Placebo / BCD-033 | Withdrawal | week 52 | 2 Participants |