Comparative Study of the Efficacy and Safety of BCD-132 With Teriflunomide and Placebo in Multiple Sclerosis

Study Overview
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Brief Summary
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International multicenter, randomized, double-blind, double-masked, placebo-controlled study of efficacy and safety of BCD-132 (JSC BIOСAD, Russia) using an active reference drug (teriflunomide) for the treatment of patients with multiple sclerosis

Official Title
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International Multicenter, Randomized, Double-blind, Double-masked, Placebo-controlled Study of the Efficacy and Safety of BCD-132 Using an Active Reference Drug (Teriflunomide) for the Treatment of Patients With Multiple Sclerosis

Conditions
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Multiple Sclerosis

Intervention / Treatment
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* Biological: BCD-132, 125 mg
* Drug: Teriflunomide
* Drug: Placebo
* Biological: BCD-132, 500 mg


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Signed informed consent to participate in the study; Men and women aged from 18 to 60 years (inclusive) on the day of signing informed consent; Confirmed diagnosis of relapsing-remitting multiple sclerosis (according to McDonald criteria 2017 revision); Documentary evidence that within the last 12 months before signing informed consent the patient had: At least 1 relapse, or 2 relapses over the past 2 years, or At least 1 Gadolinium enhancing T1-weighted lesion and 1 relapse over the past 2 years (24 months) before signing informed consent; The patient should be neurologically stable during 30 days before signing informed consent (i.e. the patient should not have any new or aggravated neurological symptoms, as told by the patient); or the patient's condition should be completely stabilized since the last relapse, and the duration of stabilization should be at least 30 days); Total EDSS score of 0 to 5.5 inclusive; The presence of immunoglobulins G antibodies to the Varicella-Zoster virus according to the results of screening examination; The absence of suicidal ideation and suicidal behavior established in the screening, according to the C-SSRS score; The willingness of patients of both sexes and their partners with preserved reproductive function must implement reliable contraceptive methods starting from signing informed consent, throughout the study and within 48 weeks after the last dose of the drug in this study. This requirement does not apply to patients after operative sterilization. Reliable contraception methods include one barrier method in combination with one of the following: spermicides, intrauterine device/oral contraceptives; Exclusion Criteria: Primary or secondary progressive MS; The duration of the MS for more than 10 years with EDSS ≤ 2.0; Other conditions (except for multiple sclerosis) that can affect the assessment of MS symptoms: to mask, aggravate, change symptoms of multiple sclerosis, result in clinical signs or laboratory instrumental findings suggesting multiple sclerosis; A relapse during the screening period; Systemic corticosteroids used within 30 days before signing informed consent; Diseases requiring prolonged systemic therapy with corticosteroids and / or immunosuppressive drugs, with the exception of MS; Any acute infections, relapses of chronic infections or any other chronic diseases that are present on the day of signing informed consent and can, as judged by the Investigator, negatively affect the patient's safety during the study treatment; Congestive heart failure (Grade IV NYHA); A history of ischemic cerebrovascular disease or spinal cord ischemia, myelopathy, neuromyelitis optica, sarcoidosis; HIV, hepatitis B, hepatitis C, or syphilis; Metabolic abnormalities (disorders) manifesting as: baseline creatinine levels increased more than 2-fold vs. upper limit of normal; baseline urea levels increased more than 3-fold vs. upper limit of normal; baseline ALT (Alanine aminotransferase), AST (Aspartate Aminotransferase) or GGT (Gamma-glutamyltransferase) levels increased more than 2.5-fold vs. upper limit of normal; baseline bilirubin levels increased more than 1.5-fold vs. upper limit of normal; Baseline leukocyte counts lower than <3.0 × 109/L, platelet counts lower than <125 × 109/L or hemoglobin levels <100 g/L; TSH (thyroid stimulating hormone) level increased more than 2-fold vs. upper limit of normal; A history of severe depression, suicidal thoughts or suicide attempts ; Pregnancy, lactation or planned pregnancy over the entire study period; A history of use: any time before signing informed consent: anti-B cell therapy drugs (rituximab, oсrelizumab, abatacept, belimumab, ofatumumab and others); any time before signing informed consent: alemtuzumab, daclizumab, teriflunomide, mitoxantrone, cladribine, as well as total lymphatic irradiation (TLI), bone marrow transplantation; within 2 years (24 months) before signing informed consent: cyclophosphamide, cyclosporine, azathioprine; mycophenolate mofetil, fingolimod and sphingosine-1-phosphate (S1P) receptor modulator, natalizumab; immunoglobulin therapy within 30 days before signing informed consent. Intolerance, including hypersensitivity to any of the components of BCD-132 / teriflunomide, premedication, as well as conditions that, as judged by the Investigator, are a contraindication to the appointment of the above drugs; The history of severe allergic or anaphylactic reactions; Progressive multifocal leukoencephalopathy (PML); Known alcoholic or drug dependency or signs of present alcoholic/drug dependence that, in the Investigator's opinion, can be contraindications for study therapy of MS with anti-CD20 Mab or limit treatment compliance; Inability to follow the Protocol procedures (in the Investigator's opinion); Contraindications to MRI or use of gadolinium-containing contrast agents: Metal foreign objects in the body: magnetic implants, ferromagnetic clips for cerebral vessels, artificial heart valves, electronic middle ear implants, pacemakers; A history of allergy to gadolinium or gadolinium-containing contrast agents; Fear of cramped spaces; d) Kidney function impairment with a risk of delayed gadolinium elimination (creatinine level increased to more than 2 x upper limit of normal); d) Documented diagnosis of sickle cell or hemolytic anemia, hemoglobinopathy; Any malignancies or a history of malignancies, except for cured basal cell carcinoma or cervical cancer in situ; Vaccination within 4 weeks before signing informed consent (as told by the patient); Participation in other clinical studies within 90 months before signing informed consent.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 60 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: BCD-132, 125 mg<br>72 patients | Biological: BCD-132, 125 mg<br>* IV infusion every 24 weeks in combination with placebo tablet daily. The total duration of blinded therapy is 100 weeks (a total of 5 cycles of therapy BCD-132 in combination with a daily placebo)<br>|
| Experimental: BCD-132, 500 mg<br>72 patients | Biological: BCD-132, 500 mg<br>* IV infusion every 24 weeks in combination with placebo tablet daily. The total duration of blinded therapy is 100 weeks (a total of 5 cycles of therapy BCD-132 in combination with a daily placebo)<br>|
| Active Comparator: Teriflunomide<br>72 patients | Drug: Teriflunomide<br>* 14 mg teriflunomide tablet. Per os. Daily in combination with IV placebo. The total duration of blinded therapy is 100 weeks (a total of 5 cycles of placebo IV therapy in combination with daily administration of teriflunomide)<br>|
| Placebo Comparator: Placebo<br>54 patients | Drug: Placebo<br>* intravenous infusion in combination with placebo tablet daily. The total duration of blinded therapy is 100 weeks<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of T1 Gd+ Lesions (per scan) | The number of T1 gadolinium enhancing (T1 Gd+) lesions | week 24 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| CUA | The number of combined unique active (CUA) lesions. Changes in MRI (magnetic resonance imaging) markers | week 24, week 100 | 
| Proportion of Patients Without Contrast-enhancing Lesions | Changes in MRI markers | week 24, week 100 | 
| Number of New or Enlarging T2-weighted Lesions | Changes in MRI markers | week 24, week 100 | 
| Number of Patients Without New or Enlarging T2-weighted Lesions | Changes in MRI markers | week 24, week 100 | 
| Changes in T2-weighted Lesion Volume | Changes in MRI markers | week 24, week 100 | 
| Changes in Hypointense T1-weighted Lesion Volume | Changes in MRI markers | week 24, week 100 | 
| Whole-brain Volume Change according MRI | Changes in MRI markers | week 24, week 100 | 
| Annual Average Frequency of Relapses | Number of relapses during the year | week 24, week 100 | 
| Time to First Relapse | Relapse-related variables | week 24, week 100 | 
| Number of Relapse-free Patients | Relapse-related variables | week 24, week 100 | 
| Number of Patients With Sustained Disability Progression | Relapse-related variables | week 24, week 100 | 
| Expanded Disability Status Scale (EDSS) | EDSS is a scale for assessing neurologic impairment in MS. It consists of eight functional systems (FS) which are used to derive the EDSS steps (score) ranging from 0 (normal) to 10 (death due to MS). The functional systems are Visual, Brain Stem, Pyramidal, Cerebellar, Sensory, Bowel and Bladder, Cerebral and Other functions. Based on the assessment of each FS, the participant's score is determined between 0 to 10. A positive change from baseline indicates improvement | week 24, week 100 | 
| Timed 25-Foot Walk | Quantitative mobility and leg function performance test based on a timed 25-walk. | week 24, week 100 | 
| 9-Hole Peg Test (9 HPT) | 9HPT is a brief, standardized, quantitative test of upper extremity function | week 24, week 100 | 
| Symbol Digit Modalities Test (SDMT) | SDMT it is neuropsychological test detecting not only the presence of brain damage, but also changes in cognitive functioning over time and in response to treatment. | week 24, week 100 | 
| 36-Item Short Form Survey (SF-36) | SF-36 it is a 36-item, patient-reported survey of patient health.The SF-36 consists of eight scaled scores, which are the weighted sums of the questions in their section. Each scale is directly transformed into a 0-100 scale on the assumption that each question carries equal weight. The lower the score the more disability. The higher the score the less disability i.e., a score of zero is equivalent to maximum disability and a score of 100 is equivalent to no disability | week 24, week 100 | 
| EQ-5D Questionnaire | EQ-5D - European Quality of Life Questionnaire. It has two components: health state description and evaluation. Rated level can be coded as a number 1, 2, or 3, which indicates having no problems for 1, having some problems for 2, and having extreme problems for 3. | week 24, week 100 | 
| MSQOL-54 Questionnaire | MSQOL - Multiple Sclerosis Quality of Life-54. Two summary scores - physical health and mental health - can be derived from a weighted combination of scale scores. MSQoL-54 has 0-100 scales. Higher values indicate better quality of life. | week 24, week 100 | 
| Number of Patients Who Developed AEs That, in the Investigator's Opinion, Are Related to Treatment | The Proportion of Patients Who Developed AEs That, in the Investigator's Opinion, Are Related to Treatment | week 24, week 100 | 
| The Number of Patients Who Developed SAEs That, in the Investigator's Opinion, Are Related to Treatment | SAE- Serious adverse event | week 24, week 100 | 
| Number of participants with treatment-related adverse events as assessed by CTCAE v5.0 | The Proportion of Patients, in Each Group, Who Developed СТСАЕ v. 5.0 Grade 3-4 AEs That, in the Investigator's Opinion, Are Related to Treatment CTCAE - Common Terminology Criteria for Adverse Events | week 24, week 100 | 
| The Number of Patients, in Each Group, Who Discontinued the Study Due to AEs/SAEs | AE- adverse event, SAE - serious adverse event | week 24, week 100 | 
| Number of patients with binding and neutralizing antibodies | The Proportion of binding and neutralizing positive patients | week 24, week 100 | 
| Beck Depression Inventory | Beck Depression Inventory is a 21-item self-reporting questionnaire for evaluating the severity of depression. Minimum score -0, maximum score - 63. Higher total scores indicate more severe depressive symptoms. | week 24, week 100 | 
| C-SSRS | The Columbia Suicide Severity Rating Scale, or C-SSRS, is a suicidal ideation and behavior rating scale. C-SSRS - Columbia-Suicide Severity Rating Scale. Suicidal Ideation Score: The maximum suicidal ideation category (1-5 on the CSSRS) present at the assessment. Assign a score of 0 if no ideation is present. | week 24, week 100 |