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

Primary Purpose

Rheumatoid Arthritis

Status
Unknown status
Phase
Phase 4
Locations
International
Study Type
Interventional
Intervention
Methotrexate
Adalimumab
Sponsored by
Keio University
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Rheumatoid Arthritis focused on measuring Methotrexate, Adalimumab, Autoimmune Disease, Connective Tissue Diseases, Rheumatic Disease, Rheumatoid Arthritis

Eligibility Criteria

18 Years - undefined (Adult, Older Adult)All SexesDoes not accept healthy volunteers

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

Sites / Locations

  • Fujita Health University Hospital
  • Chiba University Hospital
  • Hiroshima University Hospital
  • Kawasaki Municipal Hospital
  • Tokai University Hospital
  • Tohoku University Hospital
  • Nagoya University Hospital
  • Seirei Hamamatsu General Hospital
  • Keio University Hospital
  • National Hospital Organization Tokyo Medical Center
  • Nippon Medical School Hospital
  • Toho University Ohashi Medical Center
  • Chungbuk National University Hospital
  • Chungnam National University Hospital
  • Gachon University Gil Medical Center
  • Seoul National University Bundang Hospital
  • Seoul Metropolitan Government Seoul National University Boramae Medical Center
  • The Catholic University of Korea, Seoul St. Mary's Hospital
  • Chang Gung Medical Foundation, Kaohsiung Chang Gung Memorial Hospital
  • Kaohsiung Medical University Chung-Ho Memorial Hospital
  • China Medical University Hospital
  • National Cheng Kung University Hospital
  • National Taiwan University Hospital
  • Chang Gung Medical Foundation, Linkou Chang Gung Memorial Hospital

Arms of the Study

Arm 1

Arm 2

Arm 3

Arm Type

Experimental

Experimental

Experimental

Arm Label

MTX-Monotherapy Group

ADA/MTX-Maximum Tolerated Dose Group

ADA/MTX-Reduced Dose Group

Arm Description

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.

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.

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.

Outcomes

Primary Outcome Measures

Simple Disease Activity Index (SDAI) Remission Rate
SDAI Remission Rate at Week 48 in ADA/MTX-Maximum Tolerated Dose Group and ADA/MTX-Reduced Dose Group

Secondary Outcome Measures

Full Information

First Posted
April 16, 2018
Last Updated
August 31, 2021
Sponsor
Keio University
Collaborators
Eisai Co., Ltd.
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1. Study Identification

Unique Protocol Identification Number
NCT03505008
Brief Title
Evaluation of the Optimal MTX Dose as an Add-on Therapy to Adalimumab for RA Patients in Japan, South Korea and Taiwan
Official Title
MIRACLE (Methotrexate Inadequate Response Patient With Rheumatoid Arthritis Treated by Adalimumab in Combination With Low-dose Methotrexate) Study
Study Type
Interventional

2. Study Status

Record Verification Date
August 2021
Overall Recruitment Status
Unknown status
Study Start Date
April 18, 2018 (Actual)
Primary Completion Date
May 11, 2021 (Actual)
Study Completion Date
June 30, 2022 (Anticipated)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Principal Investigator
Name of the Sponsor
Keio University
Collaborators
Eisai Co., Ltd.

4. Oversight

Studies a U.S. FDA-regulated Drug Product
No
Studies a U.S. FDA-regulated Device Product
No
Data Monitoring Committee
Yes

5. Study Description

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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Rheumatoid Arthritis
Keywords
Methotrexate, Adalimumab, Autoimmune Disease, Connective Tissue Diseases, Rheumatic Disease, Rheumatoid Arthritis

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 4
Interventional Study Model
Parallel Assignment
Masking
None (Open Label)
Allocation
Randomized
Enrollment
300 (Actual)

8. Arms, Groups, and Interventions

Arm Title
MTX-Monotherapy Group
Arm Type
Experimental
Arm Description
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.
Arm Title
ADA/MTX-Maximum Tolerated Dose Group
Arm Type
Experimental
Arm Description
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.
Arm Title
ADA/MTX-Reduced Dose Group
Arm Type
Experimental
Arm Description
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.
Intervention Type
Drug
Intervention Name(s)
Methotrexate
Other Intervention Name(s)
MTX
Intervention Description
Route of Administration: Oral
Intervention Type
Drug
Intervention Name(s)
Adalimumab
Other Intervention Name(s)
ADA
Intervention Description
Route of Administration: Subcutaneous
Primary Outcome Measure Information:
Title
Simple Disease Activity Index (SDAI) Remission Rate
Description
SDAI Remission Rate at Week 48 in ADA/MTX-Maximum Tolerated Dose Group and ADA/MTX-Reduced Dose Group
Time Frame
Week 48

10. Eligibility

Sex
All
Minimum Age & Unit of Time
18 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
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
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Yuko Kaneko, MD, PhD
Organizational Affiliation
Division of Rheumatology, Department of Internal Medicine, Keio University School of Medicine
Official's Role
Principal Investigator
Facility Information:
Facility Name
Fujita Health University Hospital
City
Aichi
Country
Japan
Facility Name
Chiba University Hospital
City
Chiba
Country
Japan
Facility Name
Hiroshima University Hospital
City
Hiroshima
Country
Japan
Facility Name
Kawasaki Municipal Hospital
City
Kanagawa
Country
Japan
Facility Name
Tokai University Hospital
City
Kanagawa
Country
Japan
Facility Name
Tohoku University Hospital
City
Miyagi
Country
Japan
Facility Name
Nagoya University Hospital
City
Nagoya
Country
Japan
Facility Name
Seirei Hamamatsu General Hospital
City
Shizuoka
Country
Japan
Facility Name
Keio University Hospital
City
Tokyo
Country
Japan
Facility Name
National Hospital Organization Tokyo Medical Center
City
Tokyo
Country
Japan
Facility Name
Nippon Medical School Hospital
City
Tokyo
Country
Japan
Facility Name
Toho University Ohashi Medical Center
City
Tokyo
Country
Japan
Facility Name
Chungbuk National University Hospital
City
Cheongju
Country
Korea, Republic of
Facility Name
Chungnam National University Hospital
City
Daejeon
Country
Korea, Republic of
Facility Name
Gachon University Gil Medical Center
City
Incheon
Country
Korea, Republic of
Facility Name
Seoul National University Bundang Hospital
City
Seongnam
Country
Korea, Republic of
Facility Name
Seoul Metropolitan Government Seoul National University Boramae Medical Center
City
Seoul
Country
Korea, Republic of
Facility Name
The Catholic University of Korea, Seoul St. Mary's Hospital
City
Seoul
Country
Korea, Republic of
Facility Name
Chang Gung Medical Foundation, Kaohsiung Chang Gung Memorial Hospital
City
Kaohsiung
Country
Taiwan
Facility Name
Kaohsiung Medical University Chung-Ho Memorial Hospital
City
Kaohsiung
Country
Taiwan
Facility Name
China Medical University Hospital
City
Taichung
Country
Taiwan
Facility Name
National Cheng Kung University Hospital
City
Tainan
Country
Taiwan
Facility Name
National Taiwan University Hospital
City
Taipei
Country
Taiwan
Facility Name
Chang Gung Medical Foundation, Linkou Chang Gung Memorial Hospital
City
Taoyuan
Country
Taiwan

12. IPD Sharing Statement

Learn more about this trial

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

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