Efficacy and Safety of Divozilimab in Patients With Neuromyelitis Optica Spectrum Disorders (AQUARELLE)

Study Overview
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Brief Summary
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The goal of this clinical trial is to study the efficacy and safety of BCD-132 (divozilimab) in subjects with neuromyelitis optica spectrum disorders (NMOSD).

Detailed Description
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BCD-132-6/AQUARELLE is a randomized, double-blind, placebo-controlled phase 3 clinical study in subjects with NMOSD. Eligible subjects will be randomized at a 2:1 ratio to the divozilimab and placebo groups, respectively. At randomization, subjects will be stratified according to the presence of anti-AQP4 antibodies and number of relapses during the past 12 months. Approximately 105 subjects will be enrolled. The study consists of a screening period, a treatment period (Stage 1 and Stage 2), and a follow-up period.The maximum duration of Stage 1 will be about 24 weeks. During Stage 1, the subjects will receive one dose of the investigational product (divozilimab/placebo). During Stage 2, all subjects (both in the divozilimab and placebo groups) will receive therapy with divozilimab. The duration of participation for each subject will be approximately 56 weeks.

Official Title
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A Randomized, Double-Blind, Placebo-Controlled Study of the Efficacy and Safety of Divozilimab in Patients With Neuromyelitis Optica Spectrum Disorders

Conditions
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Neuromyelitis Optica Spectrum Disorders

Intervention / Treatment
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* Biological: divozilimab
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: NMOSD diagnosed based on the 2015 NMOSD International Consensus Diagnostic Criteria Documented evidence of at least 1 relapse within 12 months before signing the informed consent form, or 2 relapses within 24 months before signing the informed consent form A total EDSS score of ≤ 7 Presence of IgG antibodies to the Varicella Zoster virus at screening A CD19+ cell proportion of ≥ 1 % of the total lymphocyte count in patients exposed to other anti-B-cell therapies more than 6 months before signing the informed consent form Exclusion Criteria: A relapse occurring less than 30 days before signing the informed consent form or at screening (patients may be re-screened) Intrathecal oligoclonal or monoclonal IgG production (in patients who are anti-AQP4 seronegative) Other nervous system disorders (including multiple sclerosis) that can mask or affect the assessment of NMOSD symptoms History of other autoimmune diseases requiring immunosuppressive therapy Prior exposure to: alemtuzumab, total lymphatic irradiation, bone marrow transplantation; anti-B-cell therapy drugs, abatacept, satralizumab within 6 months prior to signing the informed consent form; mitoxantrone, cyclophosphamide, methotrexate, cyclosporine A, tacrolimus, eculizumab, tocilizumab, natalizumab, interferon beta, glatiramer acetate, fingolimod, teriflunomide, dimethyl fumarate within 3 months before signing the informed consent form; immunoglobulin products within 30 days before signing the informed consent form; transfusion of blood or blood components within 30 days before signing the informed consent form; systemic corticosteroids at the time of signing the informed consent form

Ages Eligible for Study
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Minimum Age: 18 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: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: BCD-132 (divozilimab)<br>Stage 1 and 2 - Intravenous infusion of BCD-132 every 24 weeks | Biological: divozilimab<br>* anti-CD20 monoclonal antibody<br>|
| Placebo Comparator: Placebo<br>Stage 1 - Intravenous infusion of Placebo; Stage 2 - Intravenous infusion of BCD-132 | Biological: divozilimab<br>* anti-CD20 monoclonal antibody<br>Drug: Placebo<br>* Placebo<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Time to the first adjudicated relapse within the first 24 weeks of the studу | Time to the first adjudicated relapse is defined as the time from the date of randomization in the study to the date of the onset of symptoms of the adjudicated relapse. Each relapse will be adjudicated by an independent neurological commission | Week 24 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Adjudicated annualized relapse rate | Adjudicated annualized relapse rate | Week 52 | 
| Proportion of subjects without adjudicated relapses | Proportion of subjects without adjudicated relapses at week 24 and 48 | Weeks 24, 48 | 
| Change in the Expanded Disability Status Scale (EDSS) score | Change in the Expanded Disability Status Scale (EDSS) at week 24 relative to baseline.The EDSS ranges from 0 to 10. An increase in EDSS values corresponds to a worsening disability. | Week 24 | 
| Proportion of subjects with confirmed increase in disability | Confirmed increase in disability is defined as an increase in the EDSS score (not related to a previous relapse and assuming there is no relapse at assessment) compared to Day 1 (baseline) by at least 1.5 in subjects with a baseline score of 0; by at least 1.0 in subjects with a baseline score of > 0 and ≤ 5.5; and by at least 0.5 in subjects with a baseline score of ≥ 6.0 persisting for ≥ 3 months | Weeks 24, 26, 48, 52 | 
| Vision acuity change | Vision acuity change at Week 24 relative to baseline | Week 24 | 
| Change in the Timed 25-Foot (7.62 m) Walk (T25-FW) test | Change in the Timed 25-Foot (7.62 m) Walk (T25-FW) test over time compared to baseline. T25-FW test is a way to quantify lower limb functions. The subject standing at one end of a clearly marked 25-foot (7.62-meter) course is asked to walk the distance as quickly but as safely as possible. After the first attempt, the subject is asked to walk the same distance again. The results (time in seconds) of both attempts are recorded. | Up to week 48 | 
| Changes in the severity of pain using a Numeric Rating Scale | Changes in the severity of pain at Week 4 and 24 relative to baseline. The Numerical Rating Scale (NRS) will be used to assess the intensity of the subject's pain. NRS consists of consecutive numbers from 0 to 10, where 0 is no pain and 10 is the most severe pain that can be imagined. | Week 4, 24 | 
| Change in the quality of life using a SF-36 | Change in the quality of life parameters using a SF-36 questionnaire at week 24 and 52 relative to baseline. SF-36 (Short Form-36) questionnaire includes a total of 36 questions. | Week 24, 52 | 
| CUA | CUA (Cumulative Total Active) - • Cumulative number of new Gd-enhancing T1-weighted lesions and new T2-weighted lesions or enlarging T2-weighted lesions without double counting | Week 24 |