Dose Finding Study of Namilumab in Combination With Methotrexate in Participants With Moderate to Severe Rheumatoid Arthritis (RA)
Condition: Rheumatoid Arthritis
MeSH terms: Arthritis; Arthritis, Rheumatoid
Intervention: Namilumab; Placebo; Methotrexate; Folic/folinic acid
Intervention description: Namilumab subcutaneous injection; Namilumab placebo-matching subcutaneous injection; Methotrexate tablets; Folic/folinic acid tablets
Intervention MeSH terms: Leucovorin; Folic Acid; Methotrexate; Levoleucovorin
Phase: Phase 2
Study type: Interventional
Primary purpose: Treatment
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Enrollment: 108.0
Sex: All
Minimum age: 18 Years
Healthy volunteers: No
Keywords: Drug therapy

Summary:

      The purpose of this study is to establish proof of concept and identify the optimal
      efficacious dose for namilumab in RA in patients with an inadequate response to methotrexate
      (MTX-IR) and in patients with an inadequate response to one tumor necrosis factor
      (TNF)-inhibitor (TNF-IR).
    

Eligibility criteria:

        Inclusion Criteria:

          1. In the opinion of the investigator, the participant is capable of understanding and
             complying with protocol requirements.

          2. The participant or, when applicable, the participant's legally acceptable
             representative signs and dates a written, informed consent form and any required
             privacy authorization prior to the initiation of any study procedures.

          3. Is male or female and aged 18 years (20 years in Japan) or older (65 years maximum in
             Czech Republic) at time of signing the informed consent form.

          4. Must have adult onset rheumatoid arthritis (RA) as defined by the 2010 American
             College of Rheumatology (ACR)/ European League against Rheumatism (EULAR) criteria for
             the classification of RA for at least 6 months prior to Screening Visit.

          5. Must have active disease defined as:

             a. At least moderately active disease defined by Disease Activity Score 28 based on
             C-reactive protein [DAS28(CRP)] ≥3.2 at screening and Disease Activity Score 28 based
             on Erythrocyte Sedimentation Rate [DAS28(ESR)] ≥3.2 at baseline visit [Day 1] and
             Swollen joint count (SJC) ≥4 (within the 28 joints from DAS28) at both the Screening
             and baseline [Day 1] Visits.

          6. Visual analog scale (VAS) pain >40 mm as measured using the 100 mm study site
             electronic VAS scale at the Screening Visit and baseline [Day 1] Visits.

          7. Currently receiving treatment for Rheumatoid Arthritis (RA) with methotrexate (MTX),
             and:

               -  Has received MTX on a weekly basis for at least 3 months prior to the Baseline
                  (Day 1) Visit AND;

               -  Has received treatment with 15 mg/week ≤MTX ≤25 mg/week (6 mg/week ≤MTX ≤16
                  mg/week in Japan) at a stable dose via the same route of administration and
                  formulation for at least 8 weeks prior to Baseline [Day 1] Visit

             OR:

             For participants outside Japan, a stable dose for at least 8 weeks of MTX of ≥7.5
             mg/week is acceptable, if the MTX dose has been reduced for reasons of documented
             intolerance to MTX, e.g. hepatic or hematological toxicity documented in Electronic
             case report form (eCRF), or per local requirement.

          8. Willing to continue or initiate treatment with oral folic acid (at least 5 mg/week) or
             equivalent and be treated during the entire study (mandatory co-medication for MTX
             treatment).

          9. Must have a posterior, anterior (PA) and lateral chest x-ray obtained within 3 months
             prior to Screening, or recorded during screening.

         10. A female participant of childbearing potential who is sexually active with a
             nonsterilized male partner agrees to routinely use adequate contraception from signing
             of the informed consent throughout the duration of the study until the end of the
             safety follow up (18 weeks after last dose).

         11. A male participant who is non-sterilized and sexually active with a female partner of
             childbearing potential agrees to use adequate contraception from signing of the
             informed consent throughout the duration of the study until the end of the safety
             follow up (18 weeks after last dose).

         12. Is able and willing to complete questionnaires at home using an electronic device in
             an approved language.

         13. Has either Inadequate response to methotrexate (MTX-IR) or Inadequate response to
             TNF-inhibitor (TNF-IR).

        Exclusion Criteria:

          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.