Evaluation of the Optimal MTX Dose as an Add-on Therapy to Adalimumab for RA Patients in Japan, South Korea and Taiwan

NCT03505008 | Completed Phase 4 Results DMC

• 1 other identifier: D2E7-C000-401
• Study Type: interventional
• Target: 300
• Locations: 3 countries
• Sites: 24

Brief Summary

This study will be conducted in Japan, South Korea and Taiwan to evaluate the optimal dosage of methotrexate (MTX) as an add-on therapy to adalimumab (ADA) in participants with rheumatoid arthritis (RA) who have not achieved remission by MTX monotherapy.

Conditions

Rheumatoid Arthritis

Keywords

Methotrexate; Adalimumab; Autoimmune Disease; Connective Tissue Diseases; Rheumatic Disease; Rheumatoid Arthritis

Outcome Measures

Primary Outcomes (1)

• Simple Disease Activity Index (SDAI) Remission Rate at Week 48 in mFAS

  SDAI is a validated combined index of rheumatoid arthritis disease activity, defined as the sum of Swollen Joint Count (0-28), Tender Joint Count (0-28), Patient's Global Assessment of Disease Activity (measured on a visual analogue scale with a range of 0 \[none\] to 10 \[most severe\]), Physician's Global Assessment of Disease Activity (measured on a visual analogue scale with a range of 0 \[none\] to 10 \[most severe\]), and C-reactive protein (mg/dL). Higher scores represent higher disease activity. SDAI ≤ 3.3 indicates disease remission, \> 3.4 to 11 = low disease activity, \> 11 to 26 = moderate disease activity, and \> 26 = high disease activity.

  Week 48

Secondary Outcomes (6)

• Simple Disease Activity Index (SDAI) Remission Rate at Week 48 in PPS

  Week 48

• American College of Rheumatology (ACR) 20 Response Rate at Week 48

  Week 48

• American College of Rheumatology (ACR) 50 Response Rate at Week 48

  Week 48

• American College of Rheumatology (ACR) 70 Response Rate at Week 48

  Week 48

• Health Assessment Questionnaire - Disability Index ≤0.5 at Week 48

  Week 48

Study Arms (3)

MTX-Monotherapy Group

EXPERIMENTAL

Participants will receive Methotrexate (MTX) at a starting dose of 6 to 8 mg/week, which will be promptly escalated to the maximum tolerated dose (MTD) of ≤25 mg/week up to Week 12, and maintained until Week 24. If the dosage of MTX is maintained ≥ 10 mg/week and simple disease activity index (SDAI) remission is achieved at Week 24, the MTX therapy will continue until Week 48.

Drug: Methotrexate

ADA/MTX-Maximum Tolerated Dose Group

EXPERIMENTAL

Participants will receive Methotrexate (MTX) at a starting dose of 6 to 8 mg/week, which will be promptly escalated to the MTD of ≤25 mg/week up to Week 12, and maintained until Week 24. If the dosage of MTX is maintained ≥ 10 mg/week and SDAI remission is not achieved at Week 24, Adalimumab (ADA) 40 mg will be administered subcutaneously every other week in addition to the MTX therapy until Week 48.

Drug: Methotrexate; Drug: Adalimumab

ADA/MTX-Reduced Dose Group

EXPERIMENTAL

Participants will receive Methotrexate (MTX) at a starting dose of 6 to 8 mg/week, which will be promptly escalated to the MTD of ≤25 mg/week up to Week 12, and maintained until Week 24. If the dosage of MTX is maintained ≥ 10 mg/week and SDAI remission is not achieved at Week 24, Adalimumab (ADA) 40 mg will be administered subcutaneously every other week in addition to low-dose MTX (6 to 8 mg/week) treatment until Week 48.

Drug: Methotrexate; Drug: Adalimumab

Interventions

Methotrexate DRUG

Route of Administration: Oral

Also known as: MTX

ADA/MTX-Maximum Tolerated Dose Group; ADA/MTX-Reduced Dose Group; MTX-Monotherapy Group

Adalimumab DRUG

Route of Administration: Subcutaneous

Also known as: ADA

ADA/MTX-Maximum Tolerated Dose Group; ADA/MTX-Reduced Dose Group

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Patients aged ≥18 years (≥20 years in Taiwan) at the time of informed consent
• Patients who meet the 1987 revised ACR criteria or 2010 ACR/EULAR criteria
• Patients who have RA within 2 years from initial diagnosis to informed consent
• Patients who were previously untreated with MTX, JAK inhibitor, or bDMARDs
• Patients who have disease activity of SDAI \>11 at screening
• Patients who are no need for concomitant use of DMARDs other than hydroxychloroquine (only in South Korea and Taiwan) and study drugs during the study as judged by principal investigator/sub-investigator at screening
• Patients who are no need for concomitant use of corticoid steroid equivalent to \>10 mg/day prednisolone during the study as judged by principal investigator/sub-investigator at screening.
• Female of child-bearing potential who can use appropriate contraceptive during the study, female in whom time from menopause to informed consent is ≥1 year, or female of no child-bearing potential through sterilization (bilateral tubal ligation, bilateral ovariectomy or hysterectomy, etc.)
• Virile male who can use appropriate contraceptive during the study
• Patients who can adequately understand this study procedures, and voluntarily consent in writing to take part in this study (consent of a legally-acceptable representative is also required for patients aged \<20 years in Japan and aged \<19 years in South Korea)

You may not qualify if:

• Patients who currently have a malignant tumor, except for non-melanoma forms of skin cancer limited within epidermis, and uterine cervix cancer limited within epidermis
• Patients who have serious infections such as sepsis
• Patients who have active tuberculosis
• Patients who have a history or current complication of demyelinating disease such as multiple sclerosis
• Patients who have congestive heart failure
• Pregnant female, or female who intend to conceive during the study period
• Patients who have bone marrow depression and whom investigator considered ineligible
• Patients who have chronic liver disease and whom investigator considered ineligible, and who is positive for HBs antigen
• Patients who have nephropathy and whom investigator considered ineligible
• Lactating female
• Patients who have pleural effusion or ascites
• Patients with a known hypersensitivity to MTX or ADA
• Patients otherwise whom principal investigator/sub-investigator considered medically ineligible to participate in the study

Sponsors & Collaborators

• Keio University: lead
• Eisai Co., Ltd.: collaborator

Study Sites (24)

Fujita Health University Hospital

Aichi, Japan

Location

Chiba University Hospital

Chiba, Japan

Location

Hiroshima University Hospital

Hiroshima, Japan

Location

Kawasaki Municipal Hospital

Kanagawa, Japan

Location

Tokai University Hospital

Kanagawa, Japan

Location

Tohoku University Hospital

Miyagi, Japan

Location

Nagoya University Hospital

Nagoya, Japan

Location

Seirei Hamamatsu General Hospital

Shizuoka, Japan

Location

Keio University Hospital

Tokyo, Japan

Location

National Hospital Organization Tokyo Medical Center

Tokyo, Japan

Location

Nippon Medical School Hospital

Tokyo, Japan

Location

Toho University Ohashi Medical Center

Tokyo, Japan

Location

Chungbuk National University Hospital

Cheongju-si, South Korea

Location

Chungnam National University Hospital

Daejeon, South Korea

Location

Gachon University Gil Medical Center

Incheon, South Korea

Location

Seoul National University Bundang Hospital

Seongnam, South Korea

Location

Seoul Metropolitan Government Seoul National University Boramae Medical Center

Seoul, South Korea

Location

The Catholic University of Korea, Seoul St. Mary's Hospital

Seoul, South Korea

Location

Chang Gung Medical Foundation, Kaohsiung Chang Gung Memorial Hospital

Kaohsiung City, Taiwan

Location

Kaohsiung Medical University Chung-Ho Memorial Hospital

Kaohsiung City, Taiwan

Location

China Medical University Hospital

Taichung, Taiwan

Location

National Cheng Kung University Hospital

Tainan, Taiwan

Location

National Taiwan University Hospital

Taipei, Taiwan

Location

Chang Gung Medical Foundation, Linkou Chang Gung Memorial Hospital

Taoyuan District, Taiwan

Location

Related Publications (2)

• Tamai H, Ikeda K, Miyamoto T, Taguchi H, Kuo CF, Shin K, Hirata S, Okano Y, Sato S, Yasuoka H, Kuwana M, Ishii T, Kameda H, Kojima T, Nishi Y, Mori M, Miyagishi H, Toshima G, Sato Y, Tsai WC, Takeuchi T, Kaneko Y; MIRACLE Study Group. Association of methotrexate polyglutamates concentration with methotrexate efficacy and safety in patients with rheumatoid arthritis treated with predefined dose: results from the MIRACLE trial. Ann Rheum Dis. 2025 Jan;84(1):41-48. doi: 10.1136/ard-2024-226350. Epub 2025 Jan 2.

  PMID: 39874232 DERIVED

• Tamai H, Ikeda K, Miyamoto T, Taguchi H, Kuo CF, Shin K, Hirata S, Okano Y, Sato S, Yasuoka H, Kuwana M, Ishii T, Kameda H, Kojima T, Taninaga T, Mori M, Miyagishi H, Sato Y, Tsai WC, Takeuchi T, Kaneko Y; MIRACLE study collaborators. Reduced versus maximum tolerated methotrexate dose concomitant with adalimumab in patients with rheumatoid arthritis (MIRACLE): a randomised, open-label, non-inferiority trial. Lancet Rheumatol. 2023 Apr;5(4):e215-e224. doi: 10.1016/S2665-9913(23)00070-X.

  PMID: 38251524 DERIVED

MeSH Terms

Conditions

Arthritis, Rheumatoid; Autoimmune Diseases; Connective Tissue Diseases; Rheumatic Diseases

Interventions

Methotrexate; Adalimumab

Condition Hierarchy (Ancestors)

Arthritis; Joint Diseases; Musculoskeletal Diseases; Skin and Connective Tissue Diseases; Immune System Diseases

Intervention Hierarchy (Ancestors)

Aminopterin; Pterins; Pteridines; Heterocyclic Compounds, 2-Ring; Heterocyclic Compounds, Fused-Ring; Heterocyclic Compounds; Antibodies, Monoclonal, Humanized; Antibodies, Monoclonal; Antibodies; Immunoglobulins; Immunoproteins; Blood Proteins; Proteins; Amino Acids, Peptides, and Proteins; Serum Globulins; Globulins

Results Point of Contact

• Title: Prof. Y Kaneko
• Organization: Keio University School of Medicine

ykaneko@z6.keio.jp

+81-3-5363-3786

Study Officials

• Yuko Kaneko, MD, PhD

  Division of Rheumatology, Department of Internal Medicine, Keio University School of Medicine

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: Yes
• Restrictive Agreement: No

Study Design

• Study Type: interventional
• Phase: phase 4
• Allocation: RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Study Principal Investigator

Study Record Dates

• First Submitted: April 16, 2018
• First Posted: April 20, 2018
• Study Start: April 18, 2018
• Primary Completion: May 11, 2021
• Study Completion: May 11, 2021
• Last Updated: March 6, 2025
• Results First Posted: March 6, 2025

Record last verified: 2025-03

Locations

KR (6); TW (6); JP (12)