A Study to Assess Safety and Efficacy of ASP015K in Participants With Rheumatoid Arthritis (RA) Who Had an Inadequate Response or Intolerance to Methotrexate (MTX)

A Randomized, Double-Blind, Placebo-Controlled Confirmatory Study of the Safety and Efficacy of ASP015K in Patients With Rheumatoid Arthritis (RA) Who Had an Inadequate Response or Intolerance to MTX

The purpose of this study is to verify the superiority of ASP015K in combination with MTX or with other disease-modifying antirheumatic drugs (DMARDs) over placebo in terms of efficacy in participants with rheumatoid arthritis (RA) who had an inadequate response or intolerance to MTX, as measured by the American College of Rheumatology (ACR) 20 response rate at Week 24.

This study will also evaluate the pharmacokinetics and safety of ASP015K as well as efficacy and safety of long-term treatment with ASP015K (52 weeks).

Participants will be randomized in a 1:1:1 ratio to the ASP015K dose-A group, ASP015K dose-B group or placebo group at Week 0.

Inclusion Criteria:

• Subject is a man or woman and considered to be an adult, according to the local legal definition, at the time of informed consent.

• 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 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).

• 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)

• Subject has CRP > 0.50 mg/dL. The re-test of CRP will be allowed, if the subject's CRP value at the time of screening test is more than 0.30 mg/dL and also his/her most recent CRP value which was carried out up to 90 days before the date of screening test was more than 0.5 mg/dL.

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

• Subject has inadequate response or intolerance for MTX.

• For inadequate responder to MTX, subject has had regular use of MTX for at least 90 days prior to screening at a dose that, in accordance with local clinical practice, is considered acceptable to adequately assess clinical response. The dose of MTX must have been a stable, unchanging oral dose of 7.5 to 20 mg/week (or the equivalent injectable dose) for at least the 28 days prior to screening. Subject is able to continue stable dose of MTX from at least 28 days prior to screening until the end of the administration period of study drug.

• For subject who is intolerant of MTX, subject has had regular use of the following DMARDs, and when the following DMARDs are concomitantly administered to subject, the drugs must be administered for at least 90 days prior to screening, and must be stable from at least 28 days prior to screening until the end of the administration period of study drug.

  • Hydroxychloroquine
  • Salazosulfapyridine
  • Gold
  • D-penicillamine
  • Lobenzarit
  • Actarit
  • Bucillamine
  • Iguratimod

Exclusion Criteria:

• Subject has received a biologic DMARD within the specified period:

  • Anakinra: within 28 days prior to baseline
  • Etanercept: within 28 days prior to baseline
  • Adalimumab, infliximab: within 56 days prior to baseline
  • Golimumab, certolizumab pegol: within 70 days prior to baseline
  • Abatacept, tocilizumab: within 84 days prior to baseline
  • Denosumab: within 150 days prior to baseline
  • Rituximab: within 180 days prior to baseline

• Subject has inadequate response to at least 3 biologic DMARDs.

• Subject has received a non-biologic DMARD listed below or other drugs used in the treatment of RA within 28 days prior to baseline. Leflunomide is prohibited within 90 days prior to baseline. Alternatively, leflunomide is prohibited at least 28 days prior to baseline if washout with cholestyramine for at least 17 days is completed within 28 days prior to baseline. However, topical drugs other than those for the treatment of RA may be used concomitantly.

  • Leflunomide
  • Tacrolimus
  • Cyclosporine
  • Cyclophosphamide
  • Azathioprine
  • Minocycline
  • Mizoribine

• Subject has received Chinese herbal medicines listed below or other herbal drugs used in the treatment of RA within 28 days prior to baseline.

  • Tripterygium wilfordii
  • Total glucosides of paeony
  • Tsuduranine

• Subject has received tofacitinib, baricitinib or other JAK inhibitor (including other investigational drugs).

• Subject has received intra-articular, intravenous, intramuscular, or endorectal (including 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 (such as glucosamine sulfate, chondroitin sulfate these DMORD medicine) at the assessed joint within 28 days prior to baseline.

• Subject has undergone surgery and has residual effects in the assessed joints or is scheduled to undergo surgery that may affect the study evaluation of the assessed joints.

• Subject is diagnosed as inflammatory arthritis (psoriatic arthritis, ankylosing spondylitis, SLE, sarcoidosis, etc.) other than RA.

• Subject has any of the following laboratory values:

  • Hemoglobin < 9.0 g/dL
  • Absolute neutrophil count < 1000/μL
  • Absolute lymphocyte count < 800/μL
  • Platelet count < 75000/μL
  • Alanine aminotransferase (ALT) ≥ 2 × upper limit of normal (ULN)
  • Aspartate aminotransferase (AST) ≥ 2 × ULN
  • Total bilirubin (TBL) ≥ 1.5 × ULN
  • Estimated glomerular filtration rate (eGFR) ≤ 40 mL/min as measured by the MDRD method
  • β-D-glucan > ULN

• Subject has a history of or concurrent active tuberculosis (TB). Eligibility criteria for TB are tabulated below:

• Subject meets any of the following in terms of infection except for TB:

  • History of or concurrent severe herpes zoster (associated with Hunt syndrome or having ulcerative lesions) or disseminated herpes zoster
  • History of multiple recurrences (at least twice) of localized herpes zoster
  • Serious infection requiring hospitalization within 90 days prior to baseline
  • Subject has received intravenous antibiotics within 90 days prior to baseline. (However, prophylactic antibiotics are allowed.)
  • Subject with high risk of infection (e.g., subject with urinary catheter)

• Subject has a history of or concurrent interstitial pneumonia and inappropriate 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.

• 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 received medications that are CYP3A substrates with narrow therapeutic range within 14 days prior to baseline. These medications include: dihydroergotamine, ergotamine, fentanyl, pimozide, quinidine, temsirolimus, and disopyramide.

• Subject has concurrent cardiac failure, defined as New York Heart Association (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).

• 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).

• Subject has a history of positive HIV infection.

• Female subject is pregnant or might be pregnant, is nursing, wishes to conceive for a period running from the time informed consent is given within 60 days after end of treatment, or for whom the possibility of pregnancy cannot be ruled out as a result of the serum pregnancy test given at the time of screening.

• Male subject cannot practice at least 2 types of contraception from the time of informed consent to 90 days after end of treatment, or subject is a woman with childbearing potential who cannot practice at least 2 types of contraception from the time of informed consent to 60 days after end of treatment.

• Male subject does not agree not to donate sperm starting at informed consent and through the treatment period and for at least 90 days after final study drug administration. Female subject who do not agree not to donate ova starting at informed consent through the treatment period and for 60 days after final study drug administration.

• Subject has a history or complication of lymphatic diseases such as lymphoproliferative disorder, lymphoma, and leukemia.