Safety and Efficacy Study of M2951 in Participants With Rheumatoid Arthritis

Phase IIa Randomized, Double-Blind, Placebo-Controlled Trial to Evaluate the Efficacy and Safety of M2951 in Subjects With Rheumatoid Arthritis on Stable Methotrexate Therapy

M2951 is an investigational drug under evaluation for treatment of autoimmune and inflammatory disorders. The purpose of the study is to assess the efficacy of M2951 in participants with rheumatoid arthritis (RA) currently treated with stable dose of methotrexate (MTX).

Inclusion Criteria:

• Men or women 18 to 75 years of age at the time of informed consent signature
• Confirmed diagnosis of RA according to 2010 American College of Rheumatology (ACR)/The European League Against Rheumatism (EULAR) RA classification criteria of at least 6 months duration
• Positive RF and/or anti-CCP (anti-cyclic citrullinated peptide)
• Persistently active disease defined as greater than equal to (>=) 6 swollen joints (of 66 counted) and >= 6 tender joints (of 68 counted)
• High-sensitivity C-reactive protein (hsCRP) >= 3.6 milligram per liter (mg/L)
• Treatment for >= 12 weeks with 10 to 25 mg/week MTX at a stable dose for at least 4 weeks prior to dosing with the investigational medicinal product (IMP) and maintained throughout the trial
• Women of childbearing potential must use acceptable methods of contraception for 4 weeks prior to randomization, throughout the trial, and for 90 days after the last dose of IMP. For the purposes of this trial
• Females who are postmenopausal (age-related amenorrhea >= 12 consecutive months and increased follicle-stimulating hormone [FSH] greater than (>) 40 milli international units per milliliter [mIU/mL]), or who have undergone hysterectomy or bilateral oophorectomy are exempt from pregnancy testing. If necessary to confirm postmenopausal status, an FSH will be drawn at Screening
• Acceptable contraception is defined as use of either 2 barrier methods (eg, female diaphragm and male condom), or 1 barrier method in conjunction with one of the following: spermicide, an intrauterine device, or hormonal contraceptives (implant or oral)
• Women of childbearing potential must have a negative serum pregnancy test at the Screening Visit and a negative urine pregnancy test at Day 1/randomization before dosing.

Exclusion Criteria:

• Use of oral corticosteroids > 10 mg daily prednisone equivalent, use of injectable corticosteroids, or change in dose of corticosteroids within 2 weeks prior to Screening or during Screening
• Initiation or change in dose for nonsteroidal anti-inflammatory drugs (NSAIDs) within 2 weeks prior to Screening
• Treatment with tofacitinib, other Bruton's Tyrosine Kinase (BTK) inhibitors, or a biologic disease-modifying antirheumatic drug (DMARD; eg, anti-tumor necrosis factor alpha [anti-TNF-α], tocilizumab [anti-interleukin-6 receptor], abatacept [CTLA4-Fc]), or other immunosuppressive drugs(sulfasalazine would be acceptable at a stable dose) other than methotrexate within 3 months prior to Screening or during Screening
• Treatment with anti-CD20 therapy (eg, rituximab) within 12 months prior to Screening or during Screening
• Immunologic disorder other than Rheumatoid Arthritis (RA), with the exception of secondary Sjogren's syndrome associated with RA, and well-controlled diabetes or thyroid disorder, or any other condition requiring oral, intravenous, intramuscular, or intra-articular corticosteroid therapy
• Vaccination with live or live-attenuated virus vaccine within 1 month prior to Screening
• Active, clinically significant, viral, bacterial, or fungal infection, or any major episode of infection requiring hospitalization or treatment with parenteral anti-infectives within 4 weeks of Screening or during Screening, or completion of oral anti-infectives within 2 weeks before or during Screening, or a history of recurrent infections (ie, 3 or more of the same type of infection in a 12-month rolling period). Vaginal candidiasis, onychomycosis, and genital or oral herpes simplex virus considered by the Investigator to be sufficiently controlled would not be exclusionary
• History of or positive testing for human immunodeficiency virus (HIV), hepatitis C antibody and/or polymerase chain reaction, hepatitis B surface antigen (HBsAg) (+) and/or hepatitis B core total, and/or IgM antibody (+) at Screening
• History of or current diagnosis of active tuberculosis (TB); undergoing treatment for latent TB infection (LTBI); untreated LTBI (as determined by documented results within 3 months of the Screening Visit of a positive TB skin test with purified protein derivative with induration >= 5 millimeter (mm), a positive QuantiFERON-TB test or positive or borderline T-SPOT [Elispot] test); or positive QuantiFERON-TB test at Screening. Participants with documented completed appropriate LTBI treatment would not be excluded and are not required to be tested
• Participants with current household contacts with active TB will also be excluded
• Indeterminate QuantiFERON-TB or T-SPOT tests may be repeated once, and will be considered positive if retest results are positive or indeterminate
• History of cancer, except adequately treated basal cell or squamous cell carcinomas of the skin (no more than 3 lesions requiring treatment in lifetime) or carcinoma in situ/cervical intraepithelial neoplasia of the uterine cervix, unless considered cured > 5 years
• Clinically significant abnormality on electrocardiogram (ECG), or an active infective process or any other clinically significant abnormality on Screening chest X-ray (CXR) taken within 4 weeks of the first dose, per Investigator opinion. If a CXR has been taken within the previous 3 months and results are available and normal, the CXR does not need to be carried out
• B cell (CD19) count less than (<) 50% of the lower limit of normal at Screening
• Significant cytopenia including absolute neutrophil count < 1,500/ mm^3, platelet count < 100,000/mm^3, or absolute lymphocyte count < 1,000/mm^3