Dose Finding Study of Namilumab in Combination With Methotrexate in Participants With Moderate to Severe Rheumatoid Arthritis (RA)

1. Participants \<18 years of age (\<20 years in Japan) or less than the legal adult age in the country of the study site, whichever is higher. Participants \>65 years of age in Czech Republic.

2. Has received any investigational compound within 30 days, or within 5 half lives (whichever is longer) prior to the Screening Visit, or is participating or plans to participate in any other clinical study during this study.

3. Has a history of or currently has any inflammatory joint disease other than RA (eg, gout, reactive arthritis, psoriatic arthritis, seronegative spondyloarthropathy or Lyme disease) or other systemic autoimmune disorder (eg, systemic lupus erythematosus \[SLE\], inflammatory bowel disease, scleroderma, inflammatory myopathy, mixed connective tissue disease or other overlap syndrome).

4. Has any major systemic features of RA, eg, Felty's syndrome, vasculitis or interstitial fibrosis of the lungs.

5. Has a diagnosis of primary fibromyalgia that would make it difficult to appropriately assess RA activity for the purposes of this study.

6. History of juvenile idiopathic arthritis or arthritis onset prior to age 16.

7. Is required to take or has taken excluded medications.

Has any of the following laboratory abnormalities at the screening visit (identified by the central laboratory):

1. Hemoglobin \<8.5 g/dL;

2. Neutrophils \<1500/mm\^3;

3. Platelet count \<75000 cells/mm\^3;

4. Aspartate aminotransferase (AST) or alanine aminotransferase (ALT) \>1.5 x upper limit of normal (ULN);

5. Bilirubin (total) \>ULN, unless Gilbert's disease has been determined by genetic testing and has been documented.

9\. Has a history of hypersensitivity or allergies to any of the contents of the formulation.

10\. Has any clinically significant illness, including infection requiring antibiotics, within 4 weeks prior to the first dose of study medication, which may influence the outcome of the study.

11\. Has an underlying condition that predisposes to infections (eg, immunodeficiency, poorly controlled diabetes history, splenectomy).

12\. Evidence of clinically significant respiratory disease, on the basis of review the data from participants' respiratory assessments, including chest x-ray, lung function tests (forced expiratory volume in one second \[FEV1\] and forced vital capacity \[FVC\]) by spirometry performed at screening). The participants must have Saturation of peripheral oxygen (SpO2) ≥94%, FEV1 and FVC ≥60 % of predicted values and a Medical Research Council (MRC) Breathlessness Scale score of less than 4 at Screening and at Baseline and no uncontrolled lung disease. A participant's treatment which has been modified to control lung disease within 24 weeks prior to screening is exclusionary.

13\. History of clinically significant interstitial lung disease (ILD) eg, history of chronic or recurrent pulmonary infection where macrophages are important for the clearance of the infection eg, pneumocystis jiroveci pneumonia (PJP) formerly known as pneumocystis carinii pneumonia (PCP), allergic bronchopulmonary aspergillosis (ABPA), nocardia infections, Actinomyces infection, Japanese and Korean participants will be tested using Beta glucans test and participants will be excluded unless the Beta-Glucans test is negative.

14\. Presence or history of active tuberculosis (TB) or latent TB infection, where no anti-TB treatment has been given or where successful completion of an appropriate course of anti-TB therapy cannot be documented.

15\. A positive QuantiFERON-TB Gold test and/or evidence of active or latent TB by chest X-ray, not accompanied by initiation of an approved regimen of anti-TB therapy at least 12 months prior to the Baseline visit.

16\. Has a known history of infection with hepatitis B virus, hepatitis C virus, or human immunodeficiency virus, or has serological findings at the Screening Visit which indicate active or latent hepatitis B, hepatitis C or human immunodeficiency virus (HIV) infection.

(Japan only) Participant has a positive result for hepatitis B virus surface antigen (HBsAg), hepatitis B virus antibody \[hepatitis B surface antibody (HBs antibody) / hepatitis B virus core antibody (HBc antibody)\], hepatitis C virus (HCV) antibody, and human immunodeficiency virus (HIV) antibody. However, participants who are HBs antibody solely positive (but HBsAg and HBc antibody negative), resulting from hepatitis B virus (HBV) vaccination, are not to be excluded from the study.

17\. Has a history of severe chronic obstructive pulmonary disease (COPD) and/or history of severe COPD exacerbation(s), or a history of asthma with exacerbations requiring hospitalization (including emergency or acute care treatments), within the last 12 months prior to the Screening visit.

18\. History of MTX-associated lung toxicity. 19. Has a history or evidence of a clinically significant disorder (including but not limited to cardiopulmonary, oncologic, renal, metabolic, hematologic or psychiatric), condition or disease that, in the opinion of the investigator and/or Medical Monitor would pose a risk to participant safety or interfere with the study evaluation, procedures or completion.

20\. Any significant cardiac disease (eg, coronary artery disease with unstable angina, coronary heart failure New York Heart Association \[NYHA\] Class III and IV, familial long QT syndrome).

21\. Has a history of treatment with anti-chemotherapy (eg, alkylating agents, anti-metabolites \[except MTX and Azathioprine\], and purine analogues) and/or anti-cancer monoclonal antibodies within the last 5 years with the exception of topical anticancer drugs used in the treatment of basal or squamous cell carcinoma of the skin or pre-cancerous skin lesions.

22\. Has a history of cancer within the last 10 years except for basal cell or squamous cell carcinomas of the skin or in situ carcinoma of the cervix treated and considered cured.

23\. Has a history of drug abuse (defined as any illicit drug use), or a history of alcohol abuse within 2 years prior to the Screening visit.

24\. Has a severe psychiatric or neurological disorder. 25. If female, the participant is pregnant or lactating or intends to become pregnant before, during, or within 18 weeks after the last treatment visit; or intends to donate ova during such time periods.

26\. If male, the participant intends to donate sperm during or within 18 weeks after the last treatment visit.

27\. Has plans to donate germ cells, organs or bone marrow during the course of the study and within 6 months after the last injection of investigational medicinal product (IMP).

28\. Elective surgical procedure, including bone or joint surgery/ synovectomy (including joint fusion or replacement) within 12 weeks prior to baseline visit, or if the participant plans to have elective surgical procedure during the study, or within 18 weeks after the last treatment visit.

29\. Is an immediate family member, study site employee, or is in a dependent relationship with a study site employee involved in conduct of this study (eg, spouse, parent, child, sibling), or may consent under duress.

30\. Is suspected to be unable or unwilling to adequately comply with study procedures eg, language problems.

What this study is about