Study, Evaluating Pharmacokinetics, Pharmacodynamics, Immunogenicity and Safety Profiles of Rituximab Compared to MabThera® in Patients With Rheumatoid Arthritis

Study Overview
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Brief Summary
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A randomised, double blind, parallel group, multicentre study to compare the pharmacokinetics, pharmacodynamics, immunogenicity and safety of Rituximab (Mabscale LLC, Russia) versus MabThera® in patients with rheumatoid arthritis.

Detailed Description
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RIT-1/01092021 is a double-blind randomized, parallel group, multicenter clinical trial comparing pharmacokinetics, pharmacodynamics, immunogenicity and safety of Rituximab (Mabscale LLC, Russia) and MabThera® in adult patients with moderate or severe rheumatoid arthritis with insufficient response to treatment tumor necrosis factor (TNF-α) inhibitors receiving background treatment with methotrexate. The purpose of the study is to demonstrate equivalence of pharmacokinetics, pharmacodynamics, immunogenicity and safety of Rituximab (Mabscale LLC, Russia) and MabThera®. The study will take place across approximately 30 study sites in Russia in order to randomize 208 patients. Rituximab is a monoclonal antibody currently being developed by Mabscale LLC, as a proposed biosimilar to MabThera®, which is approved as treatment in case of insufficient response or toxicity to treatment tumor necrosis factor (TNF-α) inhibitors receiving background treatment with methotrexate. This randomized equivalence study is designed to meet the regulatory requirement for approval of a biosimilar product.

Official Title
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Randomized Double Blind Phase I Trial Comparing Pharmacokinetics, Pharmacodynamics, Immunogenicity and Safety of Rituximab (Mabscale LLC, Russia)+ Methotrexate+ Folic Acid and MabThera® Methotrexate+ Folic Acid in Adult Patients With Moderate or Severe Rheumatoid Arthritis With Insufficient Response to Treatment Tumor Necrosis Factor (TNF-α)

Conditions
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Rheumatoid Arthritis

Intervention / Treatment
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* Drug: Rituximab
* Drug: MabThera®


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Male and Female 18-65 y.o. with body weight 50-120 kg Patients with active rheumatoid arthritis with disease duration minimum 6 months prior to screening visit per ACR/EULAR 2019 criteria classification. Moderate or severe active course of rheumatoid arthritis, which is defined as the fulfillment of all of the following conditions: ≥6 tender joints (based on a score of 68 joints) at screening and baseline; And ≥6 swollen joints (based on a score of 66 joints) at screening and at baseline; And level of C-reactive protein is not less than 10 mg/l or ESR is not less than 28 mm/hour at screening. Positive result of the analysis for antibodies to cyclic citrullinated peptide (≥10 units/ml) and / or the presence of rheumatoid factor (≥ 20 units/ml) at screening (see section). Received treatment for RA and experienced an inadequate response or intolerance to treatment with at least 1 anti-TNF alpha therapy; Must have received MTX for a minimum of 12 weeks, with the last 4 weeks, prior to screening at a stable dose 10-25 mg/week; Exclusion Criteria: Contraindications according to the MabThera SmPC and every serious coexisting diseases which, in the Investigator's opinion, would preclude subject participation History of current rheumatic autoimmune disease other than RA and current inflammatory joint disease other than RA Positive tests for HIV, hepatitis B surface antigen (HBsAg) Anti-HBc antibody, hepatitis C antibody Prior treatment with rituximab, other anti-CD20 mAb Pregnancy or lactation or women planning to get pregnant during the course of the study and/or within 12 months post last study drug infusion COVID prior 8 weeks prior to Screening visit or other acute systemic infection within 4 weeks prior to Day 1 Allergic reaction or intolerance to rituximab, MabionCD20 or any of their components Severe allergic or anaphylactic reactions to humanized or murine monoclonal antibodies or previous treatment of any lymphocyte-depleting therapies Confirmed current active tuberculosis (TB). Any significant cardiac disease History of a severe allergic reaction or anaphylactic reaction to a biological agent or history of hypersensitivity to any component of the study drug including known hypersensitivity or allergy to a murine product.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 65 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: Randomized
Intervention Model: Parallel Assignment
Masking: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Rituximab (manufactured by Mabscale, LLC)<br>Eligible subjects (104 patients) will receive Rituximab 1000 mg in 150 ml 0,9 % NaCl (total volume of infusion 250 ml) twice: on Visit 1 and 5. The following visits are the visits of safety and PK, PD and immunogenicity and also preliminary effectiveness). Patients will also receive background treatment Methotrexate+ Folic acid. | Drug: Rituximab<br>* Rituximab 1000 mg in 150 ml 0,9 % NaCl (total volume of infusion 250 ml)<br>|
| Active Comparator: MabThera®<br>Eligible subjects (104 patients) will receive MabThera® 1000 mg in 150 ml 0,9 % NaCl (total volume of infusion 250 ml) twice: on Visit 1 and 5. The following visits are the visits of safety and PK, PD and immunogenicity and also preliminary effectiveness). Patients will also receive background treatment Methotrexate+ Folic acid. | Drug: MabThera®<br>* MabThera® 1000 mg in 150 ml 0,9 % NaCl (total volume of infusion 250 ml)<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| AUC(w2-24) | Area Under the Concentration Time Curve predose Day 1 to Week 24 (AUC(w2-24). | Day 1 to Week 24 | 
| AUC0-inf | Area Under the Concentration Time Curve extrapolated from 0 to infinity (AUC0-inf) | Day 1 to Week 24 | 
| Cmax | Maximum Plasma Concentration (Cmax) after Dose 2 | Dose 2 to the end of the study | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Ctrough | Residual concentration (Ctrough) before the second infusion on Day 15 | Day 1 to Day 15 | 
| AUC0-d15 | Area under the concentration-time curve from 0 (directly pre-infusion on Day 1) before pre-infusion measurement on Day 15 (AUC0-d15) | Day 1 - Day 15 (before infusion) | 
| AUC0-w12 | Area under the concentration-time curve from 0 and before measurement at Week 12 (AUC0-w12) | Day 1 - Week 12 (before infusion) | 
| AUCd15-n24 | Area under the concentration-time curve from measurement immediately before the second infusion (Day 15) before measuring in point Week 24 (AUCd15-n24) | Day 15 - Week 24 |