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

NCT ID: NCT03505008

Last Updated: 2025-03-06

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: PHASE4
• Total Enrollment: 300 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2018-04-18
• Study Completion Date: 2021-05-11

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.

Detailed Description

The erythrocyte MTX-polyglutamates (MTX-PG) concentration will be measured to evaluate its relationship to the efficacy and safety of MTX therapy.

Conditions

Rheumatoid Arthritis

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: TREATMENT
• Blinding Strategy: NONE

Study Groups

MTX-Monotherapy Group

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.

Group Type: EXPERIMENTAL

Methotrexate

Intervention Type: DRUG

Route of Administration: Oral

ADA/MTX-Maximum Tolerated Dose Group

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.

Group Type: EXPERIMENTAL

Methotrexate

Intervention Type: DRUG

Route of Administration: Oral

Adalimumab

Intervention Type: DRUG

Route of Administration: Subcutaneous

ADA/MTX-Reduced Dose Group

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.

Group Type: EXPERIMENTAL

Methotrexate

Intervention Type: DRUG

Route of Administration: Oral

Adalimumab

Intervention Type: DRUG

Route of Administration: Subcutaneous

Interventions

Methotrexate

Route of Administration: Oral

Intervention Type: DRUG

Adalimumab

Route of Administration: Subcutaneous

Intervention Type: DRUG

Other Intervention Names

MTX; ADA

Eligibility Criteria

Inclusion Criteria

1. Patients aged ≥18 years (≥20 years in Taiwan) at the time of informed consent

2. Patients who meet the 1987 revised ACR criteria or 2010 ACR/EULAR criteria

3. Patients who have RA within 2 years from initial diagnosis to informed consent

4. Patients who were previously untreated with MTX, JAK inhibitor, or bDMARDs

5. Patients who have disease activity of SDAI >11 at screening

6. 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

7. 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.

8. 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.)

9. Virile male who can use appropriate contraceptive during the study

10. 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)

Exclusion Criteria

1. 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

2. Patients who have serious infections such as sepsis

3. Patients who have active tuberculosis

4. Patients who have a history or current complication of demyelinating disease such as multiple sclerosis

5. Patients who have congestive heart failure

6. Pregnant female, or female who intend to conceive during the study period

7. Patients who have bone marrow depression and whom investigator considered ineligible

8. Patients who have chronic liver disease and whom investigator considered ineligible, and who is positive for HBs antigen

9. Patients who have nephropathy and whom investigator considered ineligible

10. Lactating female

11. Patients who have pleural effusion or ascites

12. Patients with a known hypersensitivity to MTX or ADA

13. Patients otherwise whom principal investigator/sub-investigator considered medically ineligible to participate in the study

• Minimum Eligible Age: 18 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

Eisai Co., Ltd.

INDUSTRY

Sponsor Role: collaborator

Keio University

OTHER

Sponsor Role: lead

Responsible Party

Yuko Kaneko

Study Principal Investigator

Responsibility Role: PRINCIPAL_INVESTIGATOR

Principal Investigators

Yuko Kaneko, MD, PhD

Role: PRINCIPAL_INVESTIGATOR

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

Locations

Fujita Health University Hospital

Aichi, , Japan

Chiba University Hospital

Chiba, , Japan

Hiroshima University Hospital

Hiroshima, , Japan

Kawasaki Municipal Hospital

Kanagawa, , Japan

Tokai University Hospital

Kanagawa, , Japan

Tohoku University Hospital

Miyagi, , Japan

Nagoya University Hospital

Nagoya, , Japan

Seirei Hamamatsu General Hospital

Shizuoka, , Japan

Keio University Hospital

Tokyo, , Japan

National Hospital Organization Tokyo Medical Center

Tokyo, , Japan

Nippon Medical School Hospital

Tokyo, , Japan

Toho University Ohashi Medical Center

Tokyo, , Japan

Chungbuk National University Hospital

Cheongju-si, , South Korea

Chungnam National University Hospital

Daejeon, , South Korea

Gachon University Gil Medical Center

Incheon, , South Korea

Seoul National University Bundang Hospital

Seongnam, , South Korea

Seoul Metropolitan Government Seoul National University Boramae Medical Center

Seoul, , South Korea

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

Seoul, , South Korea

Chang Gung Medical Foundation, Kaohsiung Chang Gung Memorial Hospital

Kaohsiung City, , Taiwan

Kaohsiung Medical University Chung-Ho Memorial Hospital

Kaohsiung City, , Taiwan

China Medical University Hospital

Taichung, , Taiwan

National Cheng Kung University Hospital

Tainan City, , Taiwan

National Taiwan University Hospital

Taipei, , Taiwan

Chang Gung Medical Foundation, Linkou Chang Gung Memorial Hospital

Taoyuan District, , Taiwan

Countries

Japan; South Korea; Taiwan

References

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.

Reference Type: DERIVED

PMID: 39874232 (View on PubMed)

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.

Reference Type: DERIVED

PMID: 38251524 (View on PubMed)

Provided Documents

Document Type: Study Protocol

View Document

Document Type: Statistical Analysis Plan

View Document

Other Identifiers

D2E7-C000-401

Identifier Type: -

Identifier Source: org_study_id