Study of Safety and Efficacy of BCD-020 Comparing to MabThera in Patients With Rheumatoid Arthritis

This is an international multicenter double-blind randomized clinical study of the efficacy and safety (Phase III) with an active comparator; the study provides the additional evaluation of the interchangeability of rituximab biosimilar and original product MabThera.

The study will include 308 subjects with active seropositive rheumatoid arthritis who had intolerance or inadequate response to current therapy regimens including one or more TNF inhibitors, or who had contraindications to TNF inhibitors.

The first 24-week stage includes one course of rituximab therapy. The first study stage proposes central randomization into 2 large groups (1:1): patients from the first group will recieve BCD-020 (rituximab manufactured by CJSC BIOCAD) at a dose 1000 mg in a drop-wise manner on day 1 and day 15; patients from the second group will recieve MabThera at a same regimen.

On the final visit of Stage 1 (visit 11 at week 24) all efficacy parameters must be evaluated. If the disease activity remains (DAS28 score ≥2.6 or increased by 0.6 points or more compared to the last measurement) the patient will recieve another course of rituximab treatment. In this case a partial crossover (Stage 2) will take place (by means of the second randomization): one half of patients with active RA, previously treated with BCD-020, will receive MabThera at a dose 1000 mg on day 1 and day 15; and one half of patients with active RA, previously treated with MabThera, will receive BCD-020 at a dose 1000 mg ion day 1 and day 15. After the first rituximab infusion performed for retreatment, the patient will undergo 24-week follow-up (counted starting from the date of retreatment initiation). Thus, effects of the switch from BCD-020 to MabThera and vice versa will be assessed in 24 weeks after the crossover (Stage 2 of the study).

Patients in whom remission of RA (DAS28 < 2.6) is reported on week 24 counting from the initial randomization will undergo the follow up for the next 24 weeks. During this period they will attend 3 visits (weeks 32, 40 and 48) in order to monitor the disease. If the exacerbation occurs within the time period not corresponding to week 32 or week 40, the patient will be invited to the study site for an out-of-schedule visit. If disease exacerbation is confirmed, he/she undergoes the second randomization, second rituximab treatment course and further follow up for 6 months (as described above).

Inclusion criteria

• Having signed a written informed consent form.
• Patients must be from 18 to 80 years of age (both ages inclusive)
• Rheumatoid arthritis confirmed according to ACR 1987 criteria.
• Seropositive rheumatoid arthritis.
• Active rheumatoid arthritis during the last 3 months.
• Disease score according to DAS28 of 3.2 or more, TJC≥8 (68), SJC≥8 (66), hsCRP≥6 mg/l, ESR≥28 mm/hr (by Westergren) at the moment of screening.
• Patient's functional status - class I-III according to ACR classification
• Inadequate response to DMARDs that include one or more TNF inhibitors, intolerance or contraindications to TNF inhibitors.
• Necessity of methotrexate treatment during the last 4 weeks prior to screening period with stable/consistent dosage of 7.5 - 20 mg per week.
• Patient's ability (in Investigator's opinion) to follow the protocol procedures;
• Willingness to use contraception during all study period.

Exclusion criteria

• Patients with Felty's syndrome (irrespectively to clinical form).
• Patient's functional status - class IV according to ACR classification .
• Rheumatoid arthritis low activity (less than 3.2 according to DAS28).
• Concomitant therapy:

• Previous treatment with any biological drug products causing CD20+ lymphocyte depletion, including biological investigational drugs.
• Treatment with azathioprine within 28 days before the study initiation and with leflunomide within 8 weeks before the study's principal phase (treatment with rituximab).
• Intra-articular glucocorticosteroids within 4 weeks before the study's principal phase (treatment with rituximab).
• Necessity for prednisone or its equivalent administration at dose more than 10 mg per day.
• Necessity for prednisone or its equivalent administration at dose ≤10 mg per day in cases when this dose wasn't stable/consistent during last 4 weeks.
• Necessity for administration of non-steroidal anti-inflammatory drugs for arthritis treatment in cases when its doses were not stable/consistent during last 4 weeks.
• Pregnancy and breast-feeding.
• Changes of laboratory values:

• Hemoglobin level is less than 100 g/l;
• Leucocyte level is less than 3,0×10e9/l;
• Absolute neutrophil count is less than 1,5×10e9/l;
• Thrombocyte level is less than 100×10e9/l.
• Confirmed chicken pox within 30 days before inclusion to the screening.
• Confirmed herpes zoster infection.
• Acute forms of any infectious diseases, history of chronic infections with severe clinical manifestations.
• Active tuberculosis, history of latent tuberculosis.
• Inflammatory disease of the joints (present or in anamnesis) not related to rheumatoid arthritis (including gout, reactive arthritis, psoriatic arthritis, seronegative spondyloarthropathy, Lyme disease and others) or other systemic autoimmune disease (including systemic lupus erythematosus, Crohn's disease, ulcerative colitis, systemic scleroderma, inflammatory myopathy, mixed forms of connective tissue inflammatory diseases, cross-syndrome and others).
• Juvenile idiopathic arthritis or juvenile rheumatoid arthritis and/or rheumatoid arthritis developed before the age of 16.
• Any determined immunodeficiency.
• Pernicious anemia.
• Confirmed cobalamine deficiency.
• Other somatic diseases (apart from rheumatoid arthritis) that can increase the probability of adverse events during the study or can influence the estimation of symptom manifestation of RA ; mask, enhance or alter the symptoms of RA or cause clinical or laboratory symptoms similar to that of RA;
• Positive results of serological test of Hepatitis B surface antigen (HbsAg) or presence of Hbc IgM together with positive results of HBV PCR test, presence of antibodies to Hepatitis C virus, syphilis or HIV.
• Major surgery within 28 days prior to the trial principal phase (treatment with rituximab).
• Any mental disorder, including major depression and/or suicidal thoughts in anamnesis that can, in Investigator's opinion, create a risk for the patient or influence the patient's ability to follow the study protocol.
• Unstable angina pectoris.
• Myocardial infarction within less than 1 year prior to participation in the study.
• Severe central or peripheral nervous system diseases.
• Drug addiction, alcoholism.
• Known hypersensitivity to murine proteins or any other components of the medications used in the treatment, methotrexate, folic acid and any drugs used in premedication.
• Presence of malignant neoplasm, with the exception of adequately treated basal cell carcinoma and cervical carcinoma in situ and any malignancy with complete remission of more than 5 years;
• Simultaneous participation in any other clinical trial, as well as former participation in other clinical trials within 3 months before this study initiation; previous participation in this study.