Study of the Efficacy and Safety of BCD-089 in Combination With Methotrexate in Patients With Active Rheumatoid Arthritis

An International, Multicenter, Randomized, Double-blind, Placebo-controlled Clinical Study of the Efficacy and Safety of BCD-089 (JSC BIOCAD, Russia) in Combination With Methotrexate in Patients With Active Rheumatoid Arthritis

BCD-089 is the original therapeutic monoclonal antibody binding the alpha subunit of the IL-6 receptor.

The aim of the study is to demonstrate the efficacy and safety of BCD-089 in combination with methotrexate in patients with active rheumatoid arthritis resistant to monotherapy with methotrexate.

BCD-089-3/SOLAR is the international, multicenter, double blind, placebo-controlled phase III clinical study.

The main period of the study (Weeks 0-24) is blinded; study subjects will receive BCD-089/placebo.

At Week 24 the study will become open-label and all patients will receive BCD-089 once a week for 4 weeks. At week 28 patients who achieved the RA remission at week 24 will be switched to BCD-089 Q2W dosing regimen and will receive it through Week 51. Patients who failed to achieve remission at week 24 will receive BCD-089 once a week through Week 51.

Inclusion Criteria:

1. Signed informed consent form (ICF).
2. Men and women aged 18 years or older on the day of signing the ICF.
3. Verified rheumatoid arthritis according to the ACR 2010 criteria diagnosed at least 24 weeks before signing the ICF .
4. Use of methotrexate for the last 12 weeks before signing the ICF.
5. Use of a stable dose of methotrexate for the last 4 weeks before signing the ICF (the dose of methotrexate should be 15 to 25 mg per week). Methotrexate can be used at a dose of 10 mg in the case of intolerability/toxicity of higher doses.
6. Inefficacy of methotrexate used for the last 12 weeks before signing the ICF (in the opinion of the Investigator).
7. Active rheumatoid arthritis at randomization in the study.
8. The ability of the patient (in the Investigator's opinion) to follow the Protocol procedures.
9. Patients and their sexual partners of childbearing potential agree to use reliable contraceptive methods starting from signing the ICF, during the study and for 8 weeks from the last injection of the investigational product. This requirement does not apply to patients and their partners who underwent surgical sterilization and to women who are post-menopausal for at least 2 years. Reliable contraceptive methods include one barrier method in combination with one of the following: spermicides, intrauterine device/oral contraceptives.

Exclusion Criteria:

1. Previous exposure to tocilizumab or other anti-IL6 or anti-IL-6R monoclonal antibodies.

2. Previous exposure to JAK inhibitors.

3. Previous exposure to rituximab or other B-cell depleting/suppressing agents.

4. Felty's syndrome (regardless of clinical form).

5. Patient's functional status: class IV according to the ACR 1991 classification.

6. Known allergy to or intolerance of any ingredients of BCD-089 or placebo.

7. Use of any of the following concomitant therapies:

   • Oral prednisolone or its equivalent in a dose more than 10 mg/day;
   • Need in oral prednisolone (or its equivalent) ≤ 10 mg if its dose was not stable during the last 4 weeks before signing the ICF (patients who used topical glucocorticoids are allowed to participate in the study);
   • Need in NSAIDs if the dose was not stable during the last 4 weeks before signing the ICF (patients who have occasionally used NSAIDs for fever or allergy syndrome associated with an intercurrent disease can be included in the study);
   • Use of alkylating agents any time within 12 months before signing the ICF.
   • Intra-articular use of corticosteroids within 4 weeks before signing the ICF.
   • Vaccination with live or attenuated vaccines any time within 8 weeks before signing the ICF.
   • Use of leflunomide within 8 weeks before signing the ICF.
   • Use of TNFα inhibitors or T-cell costimulation blockers within 8 weeks before signing the ICF.

8. Any of the following laboratory values at screening:

   • Hemoglobin level < 80 g/L;
   • Leukocyte count < 3.0 × 109/L;
   • Platelet count < 100 × 109/L;
   • Neutrophil count < 2 × 109/L;
   • AST and ALT ≥ 1.5×ULN (based on the reference limits used by the laboratory);
   • Serum creatinine ≥ 1.7 × ULN (based on the reference limits used by the laboratory).

9. Positive pregnancy urine test in female subjects at screening (no test is required in women who are post-menopausal for at least 2 years and in surgically sterile women).

10. Current diagnosis or a history of a severe immunodeficiency of any other origin.

11. Diagnosed HIV, hepatitis B, hepatitis C, or syphilis ;

12. Tuberculosis now or in the past.

13. Latent TB forms (positive Diaskintest®, QuantiFERON®-TB Gold or T-SPOT.TB test with no radiographic signs of pulmonary TB).

14. Herpes zoster infection now or in the past .

15. Documented chickenpox within 30 days before signing the ICF.

16. Definite diagnosis of any other chronic infection (e.g. sepsis, invasive mycoses, histoplasmosis, etc.) that, in the Investigator's opinion, can increase the risk of infectious complications.

17. Any acute infection or aggravation of a chronic infection within 30 days before signing the ICF if this condition may, in the Investigator's opinion, increase the risk of infectious complications.

18. Severe infections (including those that required hospitalization or parenteral antibacterial/antimycotic/antiprotozoal treatment) within 6 months before signing the ICF.

19. Systemic antibacterial/antimycotic/antiprotozoal treatments used within 8 weeks before the signing the ICF.

20. More than 4 episodes of respiratory infections within 6 months before signing the ICF.

21. A major surgery within 30 days before signing the ICF or a major surgery scheduled at any time during the study.

22. History of epileptic attacks or seizures.

23. History of severe depression, suicidal thoughts or suicide attempts .

24. Diverticulosis and/or diverticulitis .

25. Alcohol, drug or psychoactive substance dependence or medication abuse now or in the past, signs of alcohol/drug dependence.

26. Other documented medical conditions that can increase a risk of adverse events during the study treatment, affect the assessment of the main disease severity, mask, aggravate, affect symptoms of the main disease, or result in the same clinical and laboratory instrumental symptoms as those of rheumatoid arthritis:

    • Diabetes mellitus with inadequate glycemic control ;
    • Severe treatment-resistant hypertension ;
    • Current or a history of inflammatory joint diseases other than rheumatoid arthritis (including ankylosing spondylitis, gout, psoriatic arthritis, Lyme disease etc. ) or other systemic autoimmune diseases (including systemic lupus erythematosus, Crohn's disease, non-specific ulcerative colitis, systemic scleroderma, inflammatory myopathy, mixed connective tissue disease, overlap syndrome, fibromyalgia etc.);
    • Malignant neoplasms except for cured basal-cell carcinoma and cancer of the cervix in situ (complete remission ≥ 5 years); cured basal-cell carcinoma of the skin (complete remission ≥ 5 years); cured ductal breast cancer (complete remission ≥ 5 years);
    • Decompensated liver or kidney diseases;
    • Unstable angina;
    • Chronic heart failure of NYHA class III-IV;
    • Myocardial infarction within 1 year before signing the ICF;
    • History of organ transplantation;
    • History of angioedema;
    • Respiratory system disorders with decompensated respiratory insufficiency;
    • Definite diagnosis of multiple sclerosis, Devic's disease, or Guillain-Barre syndrome;
    • Nervous system disorders with motor and/or sensitivity abnormalities.

27. Pregnancy , planned pregnancy less than 8 weeks after the last injection of the investigational product; lactation.

28. Current participation in other clinical studies; previous participation in other clinical studies within 3 calendar months before signing the ICF (except for screenouts); previous participation in this study (except for screenouts).