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

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

The objective of this study was to verify the superiority of ASP015K alone or in combination with disease-modifying antirheumatic drugs (DMARDs) over placebo in terms of efficacy in participants with rheumatoid arthritis (RA) who had an inadequate response to DMARDs

This was a multi-center, randomized, placebo-controlled, double-blind, parallel-group, confirmatory study to evaluate the efficacy and safety of ASP015K alone or in combination with DMARDs in participants with RA who had an inadequate response to DMARDs.

Etanercept was also administered as the reference drug in an open-label manner. The study drug was orally administered once daily (QD) after breakfast for 52 weeks. Etanercept was administered subcutaneously QD for 52 weeks. At Week 12, participants in the placebo group were switched to ASP015K.

The dose of ASP015K to be started at Week 12 for the placebo group was determined randomly at baseline in advance and switched in a blinded manner.

Participants in ASP015K group or placebo groups who had completed the study were eligible for participation in an open-label extension study (015K-CL-RAJ2).

Inclusion Criteria:

• Subject has RA 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), 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 > 0.50 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 responder to (including subjects who were intolerant of) at least one DMARD administered for at least 90 days prior to screening

Exclusion Criteria:

• Subject has received a biologic DMARD within the specified period

• Subject has received etanercept

• Inadequate responder to at least 3 biologic DMARDs 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 > ULN [in case of Japan: ≥ 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 or reference 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 a history of or concurrent demyelinating disorders

• 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.