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

Phase 4

Completed

Conditions: Rheumatoid Arthritis

Interventions: Drug: Methotrexate
Drug: Adalimumab

Registration Number: NCT03505008

Lead Sponsor: Keio University

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.

Recruitment & Eligibility

Status: COMPLETED

Sex: All

Target Recruitment: 300

Inclusion Criteria

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)

Exclusion Criteria

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

Study & Design

Study Type: INTERVENTIONAL

Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
ADA/MTX-Maximum Tolerated Dose Group	Adalimumab	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.
ADA/MTX-Reduced Dose Group	Adalimumab	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.
MTX-Monotherapy Group	Methotrexate	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.
ADA/MTX-Maximum Tolerated Dose Group	Methotrexate	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.
ADA/MTX-Reduced Dose Group	Methotrexate	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.

Primary Outcome Measures

Name	Time	Method
Simple Disease Activity Index (SDAI) Remission Rate at Week 48 in mFAS	Week 48	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.

Secondary Outcome Measures

Name	Time	Method
Simple Disease Activity Index (SDAI) Remission Rate at Week 48 in PPS	Week 48	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.
American College of Rheumatology (ACR) 20 Response Rate at Week 48	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
American College of Rheumatology (ACR) 50 Response Rate at Week 48	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
American College of Rheumatology (ACR) 70 Response Rate at Week 48	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
Health Assessment Questionnaire - Disability Index ≤0.5 at Week 48	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.
Change in Modified Total Sharp Score ≤ 0.5 at Week 48	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).

Trial Locations

Locations (24): Chungbuk National University Hospital
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Cheongju, Korea, Republic of
China Medical University Hospital
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Taichung, Taiwan
Keio University Hospital
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Tokyo, Japan
Hiroshima University Hospital
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Hiroshima, Japan
Nippon Medical School Hospital
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Tokyo, Japan
National Taiwan University Hospital
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Taipei, Taiwan
Tokai University Hospital
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Kanagawa, Japan
National Hospital Organization Tokyo Medical Center
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Tokyo, Japan
Chiba University Hospital
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Chiba, Japan
Fujita Health University Hospital
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Aichi, Japan
Kawasaki Municipal Hospital
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Kanagawa, Japan
Seirei Hamamatsu General Hospital
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Shizuoka, Japan
Toho University Ohashi Medical Center
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Tokyo, Japan
Tohoku University Hospital
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Miyagi, Japan
Nagoya University Hospital
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Nagoya, Japan
Seoul National University Bundang Hospital
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Seongnam, Korea, Republic of
Seoul Metropolitan Government Seoul National University Boramae Medical Center
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Seoul, Korea, Republic of
Chungnam National University Hospital
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Daejeon, Korea, Republic of
The Catholic University of Korea, Seoul St. Mary's Hospital
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Seoul, Korea, Republic of
Kaohsiung Medical University Chung-Ho Memorial Hospital
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Kaohsiung, Taiwan
Chang Gung Medical Foundation, Kaohsiung Chang Gung Memorial Hospital
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Kaohsiung, Taiwan
National Cheng Kung University Hospital
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Tainan, Taiwan
Chang Gung Medical Foundation, Linkou Chang Gung Memorial Hospital
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Taoyuan, Taiwan
Gachon University Gil Medical Center
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Incheon, Korea, Republic of