This is a randomized double-blind comparative parallel group study of the efficacy and safety of tocilizumab biosimilar Complarate® and Actemra® in the treatment of patients with rheumatoid arthritis with moderate to high disease activity. Participants received an intravenous dose of tocilizumab 8 mg/kg once 4 weeks. The time on study treatment was 24 weeks.

Complarate® (INN: tocilizumab) is being developed as a biosimilar to the drug Actemra®, a concentrate for the preparation of a solution for infusion.

Tocilizumab is a recombinant humanized monoclonal antibody to the human interleukin-6 (IL-6) receptor from the immunoglobulin G1 (IgG1) subclass of immunoglobulins. Tocilizumab binds to and inhibits both soluble and membrane IL-6 receptors.

This III phase study is aimed to compare the effectiveness, safety and immunogenicity of Complarate® and Actemra®. The study included patients aged 18-75 years at the time of signing the informed consent form with a documented diagnosis of rheumatoid artritis, established according to the 2010 ACR/EULAR classification criteria, at least 6 months before screening, with moderate or high degree of disease activity and insufficient response to methotrexate monotherapy (preservation of moderate/high disease activity for at least 3 months) and/or poor tolerability of methotrexate (including the subcutaneous form of the drug) and/or insufficient response to or intolerance to other synthetic disease-modifying anti-inflammatory drugs (sDMARDs) with or without methotrexate inclusive, who meet all criteria for participation in the study. The study included a screening period and a treatment period. Allocation of patients to treatment groups was carried out by randomization in a ratio of 2:1 to the study drug (Complarate®) and comparator drug (Actemra®). 465 patients (310 to the study drug group and 155 to the comparator drug group) were randomized.

Inclusion Criteria:

• Availability of written informed consent obtained from the patient before the start of any procedures related to the study.
• Men and women 18-75 years of age, inclusive, at the time of signing the informed consent form.
• Patients with a documented diagnosis of rheumatoid artritis (RA), established according to the 2010 ACR/EULAR classification criteria at least 6 months before screening, with moderate to high disease activity and an insufficient response to methotrexate monotherapy (maintaining moderate/high disease activity for at least 3 months) and/or poor tolerability of methotrexate (including the subcutaneous form of the drug) and/or insufficient response to or intolerance to other synthetic disease-modifying anti-inflammatory drugs (sDMARDs) in combination with methotrexate or without methotrexate.
• The number of swollen and/or painful joints is 6 or more.
• No changes in the dosage regimen of standard RA therapy with oral glucocorticosteroids and NSAIDs for ≥ 4 weeks before screening.
• No changes in the dosing regimen of standard RA sDMARD therapy for ≥ 4 weeks before screening.
• Agreement to adhere to adequate methods of contraception throughout the study and for 3 months after the end of tocilizumab therapy.

Exclusion Criteria:

• A history of rheumatic autoimmune disease other than rheumatoid arthritis.
• Functional Class IV according to the ACR Functional Status Classification or wheelchair/bedridden.
• Development of pronounced extra-articular (systemic) manifestations of the disease and complications (rheumatoid vasculitis, amyloidosis, Felty's syndrome, neuropathy, damage to the organ of vision).
• Use of oral corticosteroids in doses greater than >10 mg daily prednisolone equivalent, or change in oral corticosteroid dose within 4 weeks before or during screening.
• Use of injectable corticosteroids (including intra-articular corticosteroids) or intra-articular hyaluronic acid injections within 4 weeks before or during screening.
• Therapy with tumor necrosis factor-alfa (TNF-alpha) inhibitors or any other genetically engineered biological drugs within 1 month before screening.
• History of tocilizumab therapy.
• Major surgery (including joint surgery) within 8 weeks before the start of the study or elective surgery within 6 months after the start of the study.
• A history of an adverse drug reaction to any of the components of the study drug or a reference drug.
• Immunization with any live or live attenuated vaccine within 1 month before the first dose of the study or comparator drug.
• A history of a disease associated with the accumulation of immune complexes (including serum sickness).
• Concomitant diseases and conditions that, in the opinion of the Investigator and/or Sponsor, jeopardize the safety of the patient during participation in the study, or which will influence the analysis of safety data.
• Active systemic infection (bacterial, viral or fungal) within 14 days before signing the informed consent form or at the time of screening.
• Blood donation or blood loss (450 ml of blood or more) less than 2 months before the start of the study.
• Pregnancy or breastfeeding.
• History of demyelinating disease of the central nervous system.
• History of diverticulosis/intestinal diverticulitis or chronic ulcerative diseases of the lower gastrointestinal tract, such as Crohn's disease, ulcerative colitis.
• History of tuberculosis.
• Positive/doubtful test with tuberculosis allergen.
• Participation in clinical trials of drugs less than 3 months before signing the informed consent form.
• Positive tests for hepatitis B or C, HIV or syphilis.
• Unwillingness or inability to comply with the recommendations prescribed by this protocol.
• Identification during screening of other diseases/conditions not listed above that, in the opinion of the physician-researcher, prevent the inclusion of the patient in the study.

Throughout the study neither the investigators nor the patients knew which drug was being administered until the end of the comparative treatment study period