Dose Escalation Study of the Pharmacodynamics, Pharmacokinetics, Safety, and Immunogenicity of BCD-132 in Patients With Relapsing-Remitting Multiple Sclerosis

Study Overview
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Brief Summary
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BCD-132 is a humanized monoclonal antibody against CD20. BCD-132-1 is a Multicenter Open-Label Non-Comparative Dose Escalation Study (Phase 1) of the Pharmacodynamics, Pharmacokinetics, Safety, and Immunogenicity of BCD-132 (JSC BIOCAD, Russia) in Patients with Relapsing-Remitting Multiple Sclerosis.

Official Title
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A Multicenter Open-Label Non-Comparative Dose Escalation Study (Phase 1) of the Pharmacodynamics, Pharmacokinetics, Safety, and Immunogenicity of BCD-132 (JSC BIOCAD, Russia) in Patients With Relapsing-Remitting Multiple Sclerosis

Conditions
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Multiple Sclerosis

Intervention / Treatment
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* Biological: BCD-132


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Signed written 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 2010); Documentary evidence that within the last 12 months before signing informed consent the patient had: At least one relapse, or At least one gadolinium enhancing T1-weighted lesion or one new T2-weighted lesion in dynamics. 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 during this period, 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); A total EDSS score of 0 to 5.5 inclusive (assessed by the Assessing Neurologist); Presence of IgG antibodies to varicella zoster virus according to screening results; Patients of childbearing potential and their partners with preserved reproductive function must implement reliable contraceptive methods starting from signing informed consent and throughout the 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. Body weight ≥65 kg at the screening The absence of suicidal ideation and suicidal behavior, as assessed by the C-SSRC scale, for the period of the 1st month preceding the signing of the informed consent by the patient (0 score in the evaluation of suicidal ideation and the lack of positive responses in the section of suicidal behavior) established in the screening. Exclusion Criteria: Primary and secondary progressive multiple sclerosis; Multiple sclerosis duration of more than 10 years with EDSS score ≤2.0 according to screening results; Other conditions (except for multiple sclerosis) that can affect the assessment of multiple sclerosis 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; 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; 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, AST or GGT 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 × 10 9/L, platelet counts lower than <125 × 10 9/L or hemoglobin levels <100 g/L; A history of severe depression, suicidal thoughts or suicide attempts; Signs of clinical significant depression (baseline Beck's score of more than 15); A history of hypothyroidism/hyperthyroidism and/or baseline abnormalities of TSH levels vs. lower or upper limits of normal; Epilepsy; Pregnancy, lactation or planned pregnancy over the entire study period; A history of use any time before signing informed consent: anti-B-cell agents (e.g., rituximab, ocrelizumab, abatacept, belimumab, ofatumumab, etc.); any time before signing informed consent: alemtuzumab, anti-CD4 agents, daclizumab, teriflunomide, laquinimod, mitoxantrone, cladribine, total lymphatic irradiation, bone marrow transplant; within 2 years (24 months) before signing informed consent: cyclophosphamide, cyclosporin, azathioprine; mycophenolate mofetil, fingolimod and other sphingosine-1-phosphate (S1P) receptor-modulating agents, natalizumab ; therapy with immunoglobulin drug products within 12 weeks before signing informed consent. Systemic corticosteroids used within 30 days before signing informed consent; Hypersensitivity to any of BCD-132 ingredients; 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 multiple sclerosis with anti-CD20 monoclonal antibodies 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; с) 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); e) 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 6 weeks before signing informed consent (as told by the patient); Participation in other clinical studies within 90 days 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: Other
Allocation: Non-Randomized
Intervention Model: Factorial Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Cohort no. 1, BCD-132, 100 mg, IV<br>Cohort no. 1, Group #1 includes 3 (+3) subjects who will receive the single intravenous infusion of BCD-132 at the dose of 100 mg. Cohort no. 1, Group #2 includes 3 (+3) subjects who will receive the single intravenous infusion of BCD-132 at the dose of 50 mg and second dose of 50 mg IV after 14 days period after first infusion. If there is no DLT within the first 14 days after infusion then Cohort no.2 is included. | Biological: BCD-132<br>* Dose Escalation Study<br>* Other names: humanized monoclonal antibody against CD20;|
| Experimental: Cohort no. 2, BCD-132, 250 mg, IV<br>Cohort no. 2, Group #3 includes 3 (+3) subjects who will receive the single intravenous infusion of BCD-132 at the dose of 250 mg. Cohort no. 2, Group #4 includes 3 (+3) subjects who will receive the single intravenous infusion of BCD-132 at the dose of 125 mg and second dose of 125 mg IV after 14 days period after first infusion. If there is no DLT within the first 14 days after infusion then Cohort no.3 is included. | Biological: BCD-132<br>* Dose Escalation Study<br>* Other names: humanized monoclonal antibody against CD20;|
| Experimental: Cohort no. 3, BCD-132, 500 mg, IV<br>Cohort no. 3, Group #5 includes 3 (+3) subjects who will receive the single intravenous infusion of BCD-132 at the dose of 500 mg. Cohort no. 3, Group #6 includes 3 (+3) subjects who will receive the single intravenous infusion of BCD-132 at the dose of 250 mg and second dose of 250 mg IV after 14 days period after first infusion. If there is no DLT within the first 14 days after infusion then Cohort no.4 is included. | Biological: BCD-132<br>* Dose Escalation Study<br>* Other names: humanized monoclonal antibody against CD20;|
| Experimental: Cohort no. 4, BCD-132, 1000 mg, IV<br>Cohort no. 4, Group #7 includes 3 (+3) subjects who will receive the single intravenous infusion of BCD-132 at the dose of 1000 mg. Cohort no. 4, Group #8 includes 3 (+3) subjects who will receive the single intravenous infusion of BCD-132 at the dose of 500 mg and second dose of 500 mg IV after 14 days period after first infusion. | Biological: BCD-132<br>* Dose Escalation Study<br>* Other names: humanized monoclonal antibody against CD20;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| The proportion of patients who developed AEs/SAEs that, in the Investigator's opinion, are related to BCD-132 |  | day 169 | 
| The proportion of patients, in each group, who developed СТСАЕ v. 4.03 Grade 3-4 AEs that, in the Investigator's opinion, are related to BCD-132 |  | day 169 | 
| The proportion of patients, in each group, who discontinued the study due to AEs/SAEs |  | day 169 | 
| The proportion of BAb- and NAb-positive patients |  | day 169 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| AUC (0-2016 hours) |  | day 85, day 169 | 
| AUC (0-∞) |  | day 85, day 169 | 
| AUEC (0-2016 hours) |  | day 85, day 169 | 
| AUEC (0-∞) |  | day 85, day 169 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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BCD-132, Multiple Sclerosis, anti-CD20