A Study to Evaluate Efficacy and Safety of ASP015K in Patients With Rheumatoid Arthritis (RA) Who Had an Inadequate Response to Methotrexate (MTX) Treatment

Phase 3 Study of ASP015K - A Randomized, Double-blind, Placebo-controlled Confirmatory Study of the Efficacy and Safety of ASP015K in Patients With Rheumatoid Arthritis Who Had an Inadequate Response to MTX

The objective of this study was to verify the efficacy of ASP015K versus placebo administrated in combination with methotrexate (MTX) over placebo in terms of efficacy in participants with rheumatoid arthritis (RA) who had an inadequate response to MTX

This study was a multi-center, randomized, placebo-controlled, double-blind, parallel-group, confirmatory study to evaluate the efficacy and safety of ASP015K (100 and 150 mg/day) administered in combination with MTX in participants with RA who had an inadequate response to MTX.

Participants orally received ASP015K 100 mg, ASP015K 150 mg or placebo once daily (QD) in combination with MTX after breakfast for 52 weeks.

At Week 12, inadequate responders in the placebo group, as determined by a < 20% improvement from baseline (i.e., treatment initiation day) in tender or painful joint count (TJC) and swollen joint count (SJC), were switched to either ASP015K 100 mg or ASP015K 150 mg, and the dosage was maintained until the end of treatment (EOT). In addition, participants who received placebo at Week 28 were switched to either ASP015K 100 mg or ASP015K 150 mg, and the dosage was maintained until the EOT.

The ASP015K dose that was started for placebo group participants at Week 12 or Week 28 was randomly chosen at baseline. The dose was switched under the blinded condition.

Participants who completed this study were eligible for participation in the open-label extension study (015K-CL-RAJ2). Participants made a follow-up visit after the week 52 visit if they did not enroll into the extension study on the day of the week 52 visit.

Inclusion Criteria:

• Subject has RA of < 10 years duration at baseline that was diagnosed according to the 1987 American College of Rheumatology (ACR) criteria or the 2010 American College of Rheumatology/European League against Rheumatism (ACR/EULAR) criteria

• Subject who did not receive the following drugs, or received the drugs with stable dosage for at least 28 days prior to the baseline (start of treatment) for RA treatment:

  • Non-steroidal anti-inflammatory drugs (NSAIDs; excluding topical formulations with a local action), oral morphine or equivalent opioid analgesics (≤ 30 mg/day), acetaminophen, or oral corticosteroids (≤ 10 mg/day in prednisolone equivalent)

• At screening subject has active RA as evidenced by both of the following:

  • ≥ 6 tender/painful joints (using 68-joint assessment)
  • ≥ 6 swollen joints (using 66-joint assessment)

• CRP (latex agglutination test) of ≥ 1.00 mg/dL at screening.

• Subject meets the ACR 1991 Revised Criteria for the Classification of Global Functional Status in RA Class I, II or, III at screening

• Inadequate responders to MTX which was continuously administered for at least 90 days prior to screening and MTX ≥ 8 mg/week for at least 28 days prior to baseline. However, inadequate responder to MTX < 8 mg/week is eligible if intolerance precludes dose increase and defined as MTX-IR

• Subject is able to continue stable dose of MTX (a maximum of 16 mg/week) from at least 28 days prior to screening until the end of treatment

• Subject has bone erosion at the joint (as evidenced by x-rays of hands and feet) assessed in mTSS and any of the following apply at screening. Bone erosion may be evidenced by x-rays within 90 days prior to baseline.

  • Positive anti-CCP antibody: ≥ 4.5 U/mL
  • Positive rheumatoid factor: > 15 IU/mL

Exclusion Criteria:

• Subject has received a biologic DMARD within the specified period

• Inadequate responders to biologic DMARD as determined by investigator/sub-investigator

• Subject has received intra-articular, intravenous, intramuscular or endorectal (excluding suppositories for anal diseases) corticosteroid within 28 days prior to baseline

• Subject has participated in any study of ASP015K and has received ASP015K or placebo

• Subject has received other investigational drugs within 90 days or within 5 half-lives, whichever is longer, prior to baseline

• Subject has received plasma exchange therapy within 60 days prior to baseline

• Subject has undergone joint drainage, has received local anesthesia and nerve block, or has received articular cartilage protectant at the assessed joint within 28 days prior to baseline

• Subject has undergone surgery and has residual effects in the assessed joints at the discretion of investigator/sub-investigator, or is scheduled to undergo surgery that may affect the study evaluation of the assessed joints at the discretion of investigator/sub-investigator

• A diagnosis of inflammatory arthritis (psoriatic arthritis, ankylosing spondylitis, SLE, sarcoidosis, etc.) other than RA

• Any of the following laboratory values at screening:

  • Hemoglobin < 9.0 g/dL
  • Absolute neutrophil count < 1000/μL
  • Absolute lymphocyte count < 800/μL
  • Platelet count < 75000/μL
  • ALT ≥ 2 ×ULN
  • AST ≥ 2 × ULN
  • Total bilirubin (TBL) ≥ 1.5 × ULN
  • Estimated GFR ≤ 40 mL/min as measured by the MDRD method
  • β-D-glucan ≥ 11 pg/mL
  • Positive HBs antigen, HBc antibody, HBs antibody or HBV-DNA quantitation (However, subject with negative HBs antigen and HBV-DNA quantitation, and positive HBc antibody and/or HBs antibody is eligible if HBV-DNA is monitored by HBV-DNA quantitation at every scheduled visit after initiation of study drug administration.)
  • Positive HCV antibody

• Subject has a history of or concurrent active tuberculosis (TB)

• Subject has a history of or concurrent interstitial pneumonia and investigator/sub-investigator judges that it is inappropriate for the subject to participate in this study

• Subject has a history of or concurrent malignant tumor (except for successfully treated basal cell carcinoma)

• Subject has received live or live attenuated virus vaccination within 56 days prior to baseline. (Inactivated vaccines including influenza and pneumococcal vaccines are allowed.)

• Subject has any ongoing severe, progressive, or uncontrolled renal, hepatic, hematological, gastrointestinal, metabolic, endocrine, pulmonary, cardiac, neurological, infectious, or autoimmune disease except for RA (excluding Sjogren's syndrome and chronic thyroiditis), or any ongoing illness which would make the subject unsuitable for the study as determined by the investigator/sub-investigator

• Subject has a history of clinically significant allergy. (Clinically significant allergy includes allergies such as systemic urticaria induced by specific antigens and drugs, anaphylaxis, and allergy associated with shock necessitating hospitalized treatment.)

• Subject has concurrent cardiac failure, defined as NYHA classification Class III or higher, or a history of it

• Subject has concurrent prolonged QT syndrome or a history of it. Subject has prolonged QT interval (defined as QTc ≥ 500 msec. Subject has QTc ≥ 500 msec at retest will be excluded) at screening

• Subject has a history of positive HIV infection

• Subject has congenital short QT syndrome or a history of it. Subject has shortened QT interval (defined as QTc < 330 msec. Subject has QTc < 330 msec at retest will be excluded) at screening.