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
Trial Snapshot
- Phase
- Phase 3
- Status
- Completed
- Sponsor
- Astellas Pharma Inc
- Enrollment
- 519
- Locations
- 146
- Primary Endpoint
- Percentage of Participants With an American College of Rheumatology 20% (ACR20) C-Reactive Protein (CRP) Response at Week 12
Study Overview
Brief Summary
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
Detailed Description
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.
Study Design
- Study Type
- Interventional
- Allocation
- Randomized
- Intervention Model
- Parallel
- Primary Purpose
- Treatment
- Masking
- Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Eligibility Criteria
- Ages
- 20 Years to — (Adult, Older Adult)
- Sex
- All
- Accepts Healthy Volunteers
- No
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.
Arms & Interventions
Peficitinib 100 mg
Participants received 100 mg tablet of peficitinib orally once daily in combination with MTX for a period of 52 weeks.
Intervention: Peficitinib (Drug)
Peficitinib 100 mg
Participants received 100 mg tablet of peficitinib orally once daily in combination with MTX for a period of 52 weeks.
Intervention: Methotrexate (Drug)
Peficitinib 150 mg
Participants received 150 mg tablet of peficitinib orally once daily in combination with MTX for a period of 52 weeks.
Intervention: Peficitinib (Drug)
Peficitinib 150 mg
Participants received 150 mg tablet of peficitinib orally once daily in combination with MTX for a period of 52 weeks.
Intervention: Methotrexate (Drug)
Placebo
Participants who received placebo matching to peficitinib 100 mg or 150 mg orally once daily in combination with MTX until week 12 or 28 were switched to receive 100 mg or 150 mg tablet of peficitinib orally once daily in combination with MTX from week 12 or 28 to week 52.
Intervention: Placebo (Drug)
Placebo
Participants who received placebo matching to peficitinib 100 mg or 150 mg orally once daily in combination with MTX until week 12 or 28 were switched to receive 100 mg or 150 mg tablet of peficitinib orally once daily in combination with MTX from week 12 or 28 to week 52.
Intervention: Methotrexate (Drug)
Outcomes
Primary Outcomes
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)
ACR20 response: greater than and equal to (≥) 20 percent (%) improvement in tender and swollen joint count; and ≥ 20% improvement in at least 3 of the following 5 criteria compared with baseline: 1) physician's global assessment of disease activity, 2) participant's assessment of disease activity, 3) participant's assessment of pain, 4) participant's assessment of functional disability via a health assessment questionnaire, and 5) C-reactive protein at each visit.
Change From Baseline in mTSS at Week 28
Time Frame: Baseline and week 28/ET
mTSS was defined as the sum of joint erosion scores graded by assessing erosion severity in 44 joints (16 per hand and 6 per feet) and JSN scores graded by assessing narrowing of joint spaces in 42 joints (15 per hand and 6 per feet). Erosion score was scored from 0 (no erosion) to 5 (complete collapse of bone) and the score for erosion ranges from 0 to 160 in the hands and from 0 to 120 in the feet (the maximum erosion score for a joint in the foot is 10). JSN including subluxation, was scored from 0 (normal) to 4 (complete loss of joint space, bony ankylosis, or luxation), with a maximum JSN score of 168. mTSS scores ranged from 0 (normal) to 448 (worst possible total score). Change from baseline was calculated as score at week 28 (ET) minus score at baseline. An increase in mTSS from baseline represented disease progression and/or joint worsening, no change represented halting of disease progression, and a decrease represented improvement.
Secondary Outcomes
- Percentage of Participants Achieving DAS28-CRP Score < 2.6 at Week 12(Week 12/ET)
- Percentage of Participants With a European League Against Rheumatism (EULAR) Good Response Using DAS28-CRP at Week 12(Week 12/ET)
- Percentage of Participants With a EULAR Good Response Using DAS28-CRP Through Week 52(Weeks 4, 8, 12, 16, 20, 24, 28, 32, 36, 40, 44, 48, 52 and EOT)
- Percentage of Participants Achieving DAS28-ESR Score <= 3.2 at Week 12(Week 12/ET)
- Percentage of Participants Achieving DAS28-ESR Score <= 3.2 Through Week 52(Weeks 4, 8, 12, 16, 20, 24, 28, 32, 36, 40, 44, 48, 52 and EOT)
- Change From Baseline in CRP at Week 12(Baseline and week 12/ET)
- Change From Baseline in CRP Through Week 52(Baseline, weeks 4, 8, 12, 16, 20, 24, 28, 32, 36, 40, 44, 48, 52 and EOT)
- Change From Baseline in ESR at Week 12(Baseline and week 12/ET)
- Change From Baseline in ESR Through Week 52(Baseline, weeks 4, 8, 12, 16, 20, 24, 28, 32, 36, 40, 44, 48, 52 and EOT)
- Percentage of Participants Achieving DAS28-CRP Score < 2.6 Through Week 52(Weeks 4, 8, 12, 16, 20, 24, 28, 32, 36, 40, 44, 48, 52 and EOT)
- Change From Baseline in SJC (66 Joints) at Week 12(Baseline and week 12/ET)
- Change From Baseline in SJC (66 Joints) Through Week 52(Baseline, weeks 4, 8, 12, 16, 20, 24, 28, 32, 36, 40, 44, 48, 52 and EOT)
- Percentage of Participants Achieving DAS28-CRP Score <= 3.2 Through Week 52(Weeks 4, 8, 12, 16, 20, 24, 28, 32, 36, 40, 44, 48, 52 and EOT)
- Percentage of Participants With a Good or Moderate EULAR Response Using DAS28-CRP Through Week 52(Weeks 4, 8, 12, 16, 20, 24, 28, 32, 36, 40, 44, 48, 52 and EOT)
- Percentage of Participants With an ACR20-CRP Response Through Week 52(Baseline, weeks 4, 8, 12, 16, 20, 24, 28, 32, 36, 40, 44, 48, 52 and EOT)
- Percentage of Participants With an ACR50-CRP Response at Week 12(Baseline and week 12/ET)
- Percentage of Participants With an ACR50-CRP Response Through Week 52(Baseline, weeks 4, 8, 12, 16, 20, 24, 28, 32, 36, 40, 44, 48, 52 and EOT)
- Percentage of Participants With an ACR70-CRP Response at Week 12(Baseline and week 12/ET)
- Percentage of Participants With an ACR70-CRP Response Through Week 52(Baseline, weeks 4, 8, 12, 16, 20, 24, 28, 32, 36, 40, 44, 48, 52 and EOT)
- Change From Baseline in mTSS at Week 52(Baseline and week 52/ET)
- Change From Baseline in JSN Score at Week 28 and Week 52(Baseline and weeks 28/ET and 52/ET)
- Change From Baseline in Erosion Score at Week 28 and Week 52(Baseline and weeks 28/ET and 52/ET)
- Percentage of Participants With a Good or Moderate EULAR Response Using DAS28-CRP at Week 12(Week 12/ET)
- Percentage of Participants Achieving Change From Baseline in mTSS <= 0.5 at Week 28 and Week 52(Baseline and week 28/ET and 52/ET)
- Change From Baseline in Disease Activity Score (DAS) 28-CRP at Week 12(Baseline and week 12/ET)
- Change From Baseline in DAS28-CRP Through Week 52(Baseline, weeks 4, 8, 12, 16, 20, 24, 28, 32, 36, 40, 44, 48, 52 and EOT)
- Change From Baseline in DAS28-ESR at Week 12(Baseline and week 12/ET)
- Change From Baseline in DAS28-ESR Score Through Week 52(Baseline, weeks 4, 8, 12, 16, 20, 24, 28, 32, 36, 40, 44, 48, 52 and EOT)
- Change From Baseline in TJC (68 Joints) at Week 12(Baseline and week 12/ET)
- Change From Baseline in TJC (68 Joints) Through Week 52(Baseline, weeks 4, 8, 12, 16, 20, 24, 28, 32, 36, 40, 44, 48, 52 and EOT)
- Percentage of Participants Achieving DAS28-ESR Score < 2.6 at Week 12(Week 12/ET)
- Percentage of Participants Achieving DAS28-ESR Score < 2.6 Through Week 52(Weeks 4, 8, 12, 16, 20, 24, 28, 32, 36, 40, 44, 48, 52 and EOT)
- Percentage of Participants Achieving DAS28-CRP Score <= 3.2 at Week 12(Week 12/ET)
- Percentage of Participants With a EULAR Good Response Using DAS28-ESR at Week 12(Week 12/ET)
- Percentage of Participants With a EULAR Good Response Using DAS28-ESR Through Week 52(Weeks 4, 8, 12, 16, 20, 24, 28, 32, 36, 40, 44, 48, 52 and EOT)
- Percentage of Participants With a EULAR Good or Moderate Response Using DAS28-ESR at Week 12(Week 12/ET)
- Percentage of Participants With a EULAR Good or Moderate Response Using DAS28-ESR Through Week 52(Weeks 4, 8, 12, 16, 20, 24, 28, 32, 36, 40, 44, 48, 52 and EOT)
- Percentage of Participants Achieving ACR / EULAR Remission at Week 12(Week 12/ET)
- Percentage of Participants Achieving ACR / EULAR Remission Through Week 52(Weeks 4, 8, 12, 16, 20, 24, 28, 32, 36, 40, 44, 48, 52 and EOT)
- Percentage of Participants Achieving Simplified Disease Activity Index (SDAI) Remission <=3.3 at Week 12(Week 12/ET)
- Percentage of Participants Achieving SDAI Remission Score <=3.3 Through Week 52(Weeks 4, 8, 12, 16, 20, 24, 28, 32, 36, 40, 44, 48, 52 and EOT)
- Change From Baseline in SDAI Score at Week 12(Baseline and week 12/ET)
- Change From Baseline in SDAI Score Through Week 52(Baseline, weeks 4, 8, 12, 16, 20, 24, 28, 32, 36, 40, 44, 48, 52 and EOT)
- Change From Baseline in PGA at Week 12(Baseline and week 12/ET)
- Change From Baseline in PGA Through Week 52(Baseline, weeks 4, 8, 12, 16, 20, 24, 28, 32, 36, 40, 44, 48, 52 and EOT)
- Change From Baseline in SGA at Week 12(Baseline and week 12/ET)
- Change From Baseline in SGA Through Week 52(Baseline, weeks 4, 8, 12, 16, 20, 24, 28, 32, 36, 40, 44, 48, 52 and EOT)
- Change From Baseline in SGAP at Week 12(Baseline and week 12/ET)
- Change From Baseline in SGAP Through Week 52(Baseline, weeks 4, 8, 12, 16, 20, 24, 28, 32, 36, 40, 44, 48, 52 and EOT)
- Number of Participants Who Withdrew Due to Lack of Efficacy(Up to week 52)
- Change From Baseline in HAQ-DI at Week 12(Baseline and week 12/ET)
- Change From Baseline in HAQ-DI Through Week 52(Baseline, weeks 4, 8, 12, 16, 20, 24, 28, 32, 36, 40, 44, 48, 52 and EOT)
- Change From Baseline in Short Form Health Survey - 36 Questions, Version 2 (SF-36v2) Physical Component Summary Score at Week 12(Baseline and week 12/ET)
- Change From Baseline in SF-36v2 Physical Component Summary Score Through Week 52(Baseline, weeks 4, 8, 12, 28, 52 and EOT)
- Change From Baseline in SF-36v2 Mental Component Summary Score at Week 12(Baseline and week 12/ET)
- Change From Baseline in SF-36v2 Mental Component Summary Score Through Week 52(Baseline, weeks 4, 8, 12, 28, 52 and EOT)
- Change From Baseline in SF-36v2 Role/Social Component Summary Score at Week 12(Baseline and week 12/ET)
- Change From Baseline in SF-36v2 Role/Social Component Summary Score Through Week 52(Baseline, weeks 4, 8, 12, 28, 52 and EOT)
- Change From Baseline in Work Productivity and Activity Impairment Questionnaire (WPAI) Percent Work Time Missed at Week 12(Baseline and week 12/ET)
- Change From Baseline in WPAI Percent Work Time Missed Through Week 52(Baseline, weeks 4, 8, 12, 28, 52 and EOT)
- Change From Baseline in WPAI Percent Impairment While Working at Week 12(Baseline and week 12/ET)
- Change From Baseline in WPAI Percent Overall Work Impairment Through Week 52(Baseline, weeks 4, 8, 12, 28, 52 and EOT)
- Change From Baseline in WPAI Percent Activity Impairment at Week 12(Baseline and week 12/ET)
- Change From Baseline in WPAI Percent Activity Impairment Through Week 52(Baseline, weeks 4, 8, 12, 28, 52 and EOT)
- Number of Participants With Treatment-Emergent Adverse Events (TEAEs) During the First 12 Weeks(Week 0 to week 12)
- Number of Participants With TEAEs From Week 12 to Week 28(Week 12 to week 28)
- Number of Participants With TEAEs From Week 28 to Week 52(Week 28 to week 52, plus 28 days after the week 52 visit for participants who did not enroll in the extension study)
- Change From Baseline in WPAI Percent Impairment While Working Through Week 52(Baseline, weeks 4, 8, 12, 28, 52 and EOT)
- Change From Baseline in Percent Overall Work Impairment at Week 12(Baseline and week 12/ET)