rheumatoid arthritis (RA) who had an inadequate response to DMARDs

To verify the superiority of ASP015K alone or in combination with disease-modifying antirheumatic drugs (DMARDs) over placebo in terms of efficacy, at doses of 100 mg/day and 150 mg/day, in patients with rheumatoid arthritis (RA) who had an inadequate response to DMARDs, as measured by the ACR20 response rate at Week 12, which is the primary variable; To evaluate the pharmacokinetics, pharmacodynamics, and safety of ASP015K; To evaluate the efficacy and safety of long-term treatment with ASP015K (52 weeks); and To use open-label etanercept, an existing anti-TNF agent, as the reference drug.

ASP015K

ASP015K

Tablet

100mg
150mg

Primary Outcome Measures :
1. Percentage of Participants With an American College of Rheumatology 20% (ACR20) C-Reactive Protein (CRP) Response at Week 12 [ Time Frame: Baseline and Week 12/early termination (ET) ]
The ACR20 response required that all criteria from (1) to (3) below be met.
a. Tender joint count (TJC) : ≥ 20% reduction compared with baseline.
b. Swollen joint count (SJC) : ≥ 20% reduction compared with baseline.
c. ≥ 20% improvement in 3 or more of the following 5 parameters compared with baseline
(3) ≥ 20% improvement in 3 or more of the following 5 parameters compared with baseline: Subject's assessment of pain, Subject's Global Assessment of Arthritis (SGA), Physician's Global Assessment of Arthritis (PGA), Health Assessment Questionnaire - Disability Index (HAQ-DI), C-Reactive Protein (CRP).

Inclusion Criteria
Subject is eligible for the study if all of the following apply:
1. Subject has received a full explanation of the study drug and this study in advance, and
written informed consent to participate in the study has been obtained from the subject
himself/herself.
2. Subject is a man or woman aged ≥ 20 years at the time of informed consent.
3. 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.
4. 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).
5. 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)
6. CRP (latex agglutination test) > 0.50 mg/dL at screening.
7. Subject meets the ACR 1991 Revised Criteria for the Classification of Global Functional
Status in RA Class I, II, or III at screening.
8. Inadequate responder to (including subjects who were intolerant of) at least one
DMARD administered for at least 90 days prior to screening.
9. 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 or
reference drug.
 Methotrexate (MTX)
 Hydroxychloroquine
 Salazosulfapyridine
 Gold
 D-penicillamine
 Lobenzarit
 Actarit
 Bucillamine
 Iguratimod
10. Subject must be willing and able to comply with the study requirements.

Exclusion Criteria
Subject will be excluded from participation if any of the following applies:
1. Subject has received a biologic DMARD within the specified period:
 Anakinra: 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
2. Subject has received etanercept.
3. Inadequate responder to at least 3 biologic DMARDs as determined by
investigator/sub-investigator.
4. 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 180
days prior to baseline. Alternatively, leflunomide is prohibited within 28 days prior to
baseline if washout with cholestyramine for at least 17days is completed at least 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
5. Subject has received tofacitinib or other JAK inhibitor (including other investigational
drugs).
6. Subject has received intra-articular, intravenous, intramuscular, or endorectal (excluding
suppositories for anal diseases) corticosteroid within 28 days prior to baseline.
7. Subject has participated in any study of ASP015K and has received ASP015K or
placebo.
8. Subject has received other investigational drugs within 90 days or within 5 half-lives,
whichever is longer, prior to baseline.
9. Subject has received plasma exchange therapy within 60 days prior to baseline.
10. 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.
11. 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.
12. A diagnosis of inflammatory arthritis (psoriatic arthritis, ankylosing spondylitis, SLE,
sarcoidosis, etc.) other than RA.
13. Any of the following laboratory values during the screening test period:
 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
14. Subject has a history of or concurrent active tuberculosis (TB). Eligibility criteria for TB
are tabulated below:
15. Subject meets any of the following in terms of infections 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) at the
discretion of investigator/sub-investigator
16. 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.
17. Subject has a history of or concurrent malignant tumor (except for successfully treated
basal cell carcinoma).
18. Subject has received live or live attenuated virus vaccination within 56 days prior to
baseline. (Inactivated vaccines including influenza and pneumococcal vaccines are
allowed.)
19. Subject has a history of or concurrent demyelinating disorders.
20. 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.
21. 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.)
22. 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.
23. Subject has concurrent cardiac failure, defined as NYHA classification Class III or
higher, or a history of it.
24. 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.
25. Subject has a history of positive HIV infection.
26. Subject is a woman who 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 (including reference drug), 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.
27. Subject is a man who cannot practice at least 2 types of contraception from the time of
informed consent to 90 days after end of treatment (including reference drug), 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
(including reference drug).
28. Male subject who do 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 (or reference
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 (or
reference drug) administration.
29. The subject has been judged unsuitable to participate in the study for other reasons by
the investigator/sub-investigator.
30. The subject has a history or complication of lymphatic diseases such as
lymphoproliferative disorder, lymphoma, and leukemia.
31. 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.