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

MIRACLE (Methotrexate Inadequate Response Patient With Rheumatoid Arthritis Treated by Adalimumab in Combination With Low-dose Methotrexate) Study

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.

Study Overview

• Status: Completed
• Conditions: Rheumatoid Arthritis
• Intervention / Treatment: Drug: Methotrexate; Drug: Adalimumab

Detailed Description

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

• Study Type: Interventional
• Enrollment (Actual): 300
• Phase: Phase 4

Contacts and Locations

Study Locations

• Japan
  • Aichi, Japan
    • Fujita Health University Hospital
  • Chiba, Japan
    • Chiba University Hospital
  • Hiroshima, Japan
    • Hiroshima University Hospital
  • Kanagawa, Japan
    • Kawasaki Municipal Hospital
  • Kanagawa, Japan
    • Tokai University Hospital
  • Miyagi, Japan
    • Tohoku University Hospital
  • Nagoya, Japan
    • Nagoya University Hospital
  • Shizuoka, Japan
    • Seirei Hamamatsu General Hospital
  • Tokyo, 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
• Korea, Republic of
  • Cheongju, Korea, Republic of
    • Chungbuk National University Hospital
  • Daejeon, Korea, Republic of
    • Chungnam national university hospital
  • Incheon, Korea, Republic of
    • Gachon University Gil Medical Center
  • Seongnam, Korea, Republic of
    • Seoul National University Bundang Hospital
  • Seoul, Korea, Republic of
    • The Catholic University of Korea, Seoul St. Mary's Hospital
  • Seoul, Korea, Republic of
    • Seoul Metropolitan Government Seoul National University Boramae Medical Center
• Taiwan
  • Kaohsiung, Taiwan
    • Kaohsiung Medical University Chung-Ho Memorial Hospital
  • Kaohsiung, Taiwan
    • Chang Gung Medical Foundation, Kaohsiung Chang Gung Memorial Hospital
  • Taichung, Taiwan
    • China Medical University Hospital
  • Tainan, Taiwan
    • National Cheng Kung University Hospital
  • Taipei, Taiwan
    • National Taiwan University Hospital
  • Taoyuan, Taiwan
    • Chang Gung Medical Foundation, Linkou Chang Gung Memorial Hospital

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

3

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: 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.	Drug: Methotrexate; Route of Administration: Oral; Other Names: MTX
Experimental: 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.	Drug: Methotrexate; Route of Administration: Oral; Other Names: MTX; Drug: Adalimumab; Route of Administration: Subcutaneous; Other Names: ADA
Experimental: 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.	Drug: Methotrexate; Route of Administration: Oral; Other Names: MTX; Drug: Adalimumab; Route of Administration: Subcutaneous; Other Names: ADA

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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 Outcome Measures

Outcome Measure	Measure Description	Time Frame
Simple Disease Activity Index (SDAI) Remission Rate at Week 48 in PPS	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
American College of Rheumatology (ACR) 20 Response Rate at Week 48	ACR 20 response is defined as a subject meeting all of the following 3 criteria based on the evaluation results of tender joint count, swollen joint count, VAS (physician- and patient reported), HAQ, and CRP. Also, the proportion of ACR 20 response will be referred to as ACR 20 response rate.; ≥20% improvement in the tender joint count (of the total 68 joints) compared to Week 0 of treatment; ≥20% improvement in the swollen joint count (of the total 66 joints) compared to Week 0 of treatment; ≥20% improvement in ≥3 of 5 parameters (physician- and patient-reported disease activities, patient-reported pain score, HAQ, and CRP) compared to Week 0 of treatment	Week 48
American College of Rheumatology (ACR) 50 Response Rate at Week 48	ACR 50 response is defined as a subject meeting all of the following 3 criteria based on the evaluation results of tender joint count, swollen joint count, VAS (physician- and patient reported), HAQ, and CRP. Also, the proportion of ACR 50 response will be referred to as ACR 50 response rate.; ≥50% improvement in the tender joint count (of the total 68 joints) compared to Week 0 of treatment; ≥50% improvement in the swollen joint count (of the total 66 joints) compared to Week 0 of treatment; ≥50% improvement in ≥3 of 5 parameters (physician- and patient-reported disease activities, patient-reported pain score, HAQ, and CRP) compared to Week 0 of treatment	Week 48
American College of Rheumatology (ACR) 70 Response Rate at Week 48	ACR 70 response is defined as a subject meeting all of the following 3 criteria based on the evaluation results of tender joint count, swollen joint count, VAS (physician- and patient reported), HAQ, and CRP. Also, the proportion of ACR 70 response will be referred to as ACR 70 response rate.; ≥70% improvement in the tender joint count (of the total 68 joints) compared to Week 0 of treatment; ≥70% improvement in the swollen joint count (of the total 66 joints) compared to Week 0 of treatment; ≥70% improvement in ≥3 of 5 parameters (physician- and patient-reported disease activities, patient-reported pain score, HAQ, and CRP) compared to Week 0 of treatment	Week 48
Health Assessment Questionnaire - Disability Index ≤0.5 at Week 48	HAQ-DI is a patient-reported questionnaire, consists of 20 questions in 8 domains: dressing/grooming, arising, eating, walking, hygiene, reach, grip, and daily activities. Participants assessed their ability to do each task over the past week as: without any difficulty (0); with some difficulty (1); with much difficulty (2); unable to do (3). Scores on each task were summed and averaged to provide an overall score from 0 to 3, where 0=no disability and 3=very severe, high-dependency disability. Normal physical function is defined by HAQ-DI score of < 0.5.	Week 48
Change in Modified Total Sharp Score ≤ 0.5 at Week 48	Bone erosions will be evaluated for each region from a scale of 0 (no damage) to 5 (complete collapse of the joint). The score will be 0 to 5 for each hand joint, and 0 to 10 for each foot joint. The maximum total erosion score of both hands will be 160 points, and that of both feet will be 120 points. Joint space narrowing will be evaluated for each region from a scale of 0 (no damage) to 4 (ankylosis or luxation). The maximum total joint space narrowing score of both hands will be 120 points, and that of both feet will be 48 points. Erosion scores and joint space narrowing scores were added to obtain the mTSS (range from 0 to 448).	Week 48

Collaborators and Investigators

• Sponsor: Keio University
• Collaborators: Eisai Co., Ltd.
• Investigators: Principal Investigator: Yuko Kaneko, MD, PhD, Division of Rheumatology, Department of Internal Medicine, Keio University School of Medicine

Study record dates

Study Major Dates

• Study Start (Actual): April 18, 2018
• Primary Completion (Actual): May 11, 2021
• Study Completion (Actual): May 11, 2021

Study Registration Dates

• First Submitted: April 16, 2018
• First Submitted That Met QC Criteria: April 16, 2018
• First Posted (Actual): April 20, 2018

Study Record Updates

• Last Update Posted (Actual): March 25, 2025
• Last Update Submitted That Met QC Criteria: March 3, 2025
• Last Verified: March 1, 2025

More Information

Terms related to this study

• Keywords: Methotrexate; Connective Tissue Diseases; Rheumatoid Arthritis; Rheumatic Disease; Adalimumab; Autoimmune Disease
• Additional Relevant MeSH Terms: Musculoskeletal Diseases; Joint Diseases; Rheumatic Diseases; Connective Tissue Diseases; Autoimmune Diseases; Immune System Diseases; Arthritis; Arthritis, Rheumatoid; Tumor Necrosis Factor Inhibitors; Antineoplastic Agents; Immunosuppressive Agents; Immunologic Factors; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Anti-Inflammatory Agents; Enzyme Inhibitors; Antirheumatic Agents; Abortifacient Agents, Nonsteroidal; Abortifacient Agents; Reproductive Control Agents; Antimetabolites, Antineoplastic; Antimetabolites; Dermatologic Agents; Folic Acid Antagonists; Nucleic Acid Synthesis Inhibitors; Adalimumab; Methotrexate
• Other Study ID Numbers: D2E7-C000-401

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No