Clinical trial NCT04056897: Comparative Study of the Efficacy and Safety of BCD-132 With Teriflunomide and Placebo in Multiple Sclerosis
Official title: 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
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: Multiple Sclerosis
Lead sponsor: Biocad
Sponsor class: INDUSTRY
First posted: 2019-08-14
Enrollment: 271
Sex: ALL
Minimum age (years): 18
Maximum age (years): 60
Standard ages: ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: 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


Eligibility criteria: Inclusion Criteria:

1. Signed informed consent to participate in the study;
2. Men and women aged from 18 to 60 years (inclusive) on the day of signing informed consent;
3. Confirmed diagnosis of relapsing-remitting multiple sclerosis (according to McDonald criteria 2017 revision);
4. Documentary evidence that within the last 12 months before signing informed consent the patient had:

   1. At least 1 relapse, or
   2. 2 relapses over the past 2 years, or
   3. At least 1 Gadolinium enhancing T1-weighted lesion and 1 relapse over the past 2 years (24 months) before signing informed consent;
5. 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);
6. Total EDSS score of 0 to 5.5 inclusive;
7. The presence of immunoglobulins G antibodies to the Varicella-Zoster virus according to the results of screening examination;
8. The absence of suicidal ideation and suicidal behavior established in the screening, according to the C-SSRS score;
9. 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:

1. Primary or secondary progressive MS;
2. The duration of the MS for more than 10 years with EDSS ≤ 2.0;
3. 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;
4. A relapse during the screening period;
5. Systemic corticosteroids used within 30 days before signing informed consent;
6. Diseases requiring prolonged systemic therapy with corticosteroids and / or immunosuppressive drugs, with the exception of MS;
7. 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;
8. Congestive heart failure (Grade IV NYHA);
9. A history of ischemic cerebrovascular disease or spinal cord ischemia, myelopathy, neuromyelitis optica, sarcoidosis;
10. HIV, hepatitis B, hepatitis C, or syphilis;
11. Metabolic abnormalities (disorders) manifesting as:

    1. baseline creatinine levels increased more than 2-fold vs. upper limit of normal;
    2. baseline urea levels increased more than 3-fold vs. upper limit of normal;
    3. baseline ALT (Alanine aminotransferase), AST (Aspartate Aminotransferase) or GGT (Gamma-glutamyltransferase) levels increased more than 2.5-fold vs. upper limit of normal;
    4. baseline bilirubin levels increased more than 1.5-fold vs. upper limit of normal;
12. Baseline leukocyte counts lower than \<3.0 × 109/L, platelet counts lower than \<125 × 109/L or hemoglobin levels \<100 g/L;
13. TSH (thyroid stimulating hormone) level increased more than 2-fold vs. upper limit of normal;
14. A history of severe depression, suicidal thoughts or suicide attempts ;
15. Pregnancy, lactation or planned pregnancy over the entire study period;
16. 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.
17. 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;
18. The history of severe allergic or anaphylactic reactions;
19. Progressive multifocal leukoencephalopathy (PML);
20. 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;
21. Inability to follow the Protocol procedures (in the Investigator's opinion);
22. Contraindications to MRI or use of gadolinium-containing contrast agents:

    1. Metal foreign objects in the body: magnetic implants, ferromagnetic clips for cerebral vessels, artificial heart valves, electronic middle ear implants, pacemakers;
    2. A history of allergy to gadolinium or gadolinium-containing contrast agents;
    3. 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;
23. Any malignancies or a history of malignancies, except for cured basal cell carcinoma or cervical cancer in situ;
24. Vaccination within 4 weeks before signing informed consent (as told by the patient);
25. Participation in other clinical studies within 90 months before signing informed consent.

Primary outcomes:
measure: Number of T1 Gd+ Lesions (per scan)
timeFrame: week 24
Secondary outcomes:
measure: CUA
timeFrame: week 24, week 100
measure: Proportion of Patients Without Contrast-enhancing Lesions
timeFrame: week 24, week 100
measure: Number of New or Enlarging T2-weighted Lesions
timeFrame: week 24, week 100
measure: Number of Patients Without New or Enlarging T2-weighted Lesions
timeFrame: week 24, week 100
measure: Changes in T2-weighted Lesion Volume
timeFrame: week 24, week 100
measure: Changes in Hypointense T1-weighted Lesion Volume
timeFrame: week 24, week 100
measure: Whole-brain Volume Change according MRI
timeFrame: week 24, week 100
measure: Annual Average Frequency of Relapses
timeFrame: week 24, week 100
measure: Time to First Relapse
timeFrame: week 24, week 100
measure: Number of Relapse-free Patients
timeFrame: week 24, week 100
measure: Number of Patients With Sustained Disability Progression
timeFrame: week 24, week 100
measure: Expanded Disability Status Scale (EDSS)
timeFrame: week 24, week 100
measure: Timed 25-Foot Walk
timeFrame: week 24, week 100
measure: 9-Hole Peg Test (9 HPT)
timeFrame: week 24, week 100
measure: Symbol Digit Modalities Test (SDMT)
timeFrame: week 24, week 100
measure: 36-Item Short Form Survey (SF-36)
timeFrame: week 24, week 100
measure: EQ-5D Questionnaire
timeFrame: week 24, week 100
measure: MSQOL-54 Questionnaire
timeFrame: week 24, week 100
measure: Number of Patients Who Developed AEs That, in the Investigator's Opinion, Are Related to Treatment
timeFrame: week 24, week 100
measure: The Number of Patients Who Developed SAEs That, in the Investigator's Opinion, Are Related to Treatment
timeFrame: week 24, week 100
measure: Number of participants with treatment-related adverse events as assessed by CTCAE v5.0
timeFrame: week 24, week 100
measure: The Number of Patients, in Each Group, Who Discontinued the Study Due to AEs/SAEs
timeFrame: week 24, week 100
measure: Number of patients with binding and neutralizing antibodies
timeFrame: week 24, week 100
measure: Beck Depression Inventory
timeFrame: week 24, week 100
measure: C-SSRS
timeFrame: week 24, week 100
Other outcomes:
Locations:
city: Nizhny Novgorod
country: Russian Federation
facility: State Budgetary Healthcare Institution of Nizhny Novgorod region "Regional Clinical Hospital N.A. Semashko, Nizhny Novgorod"
Study officials:
affiliation: JSC BIOCAD
name: Roman Ivanov, PhD
role: STUDY_CHAIR
References: