UMIN-CTR Clinical Trial
| Unique ID issued by UMIN | UMIN000030584 |
|---|---|
| Receipt number | R000034918 |
| Scientific Title | MIRACLE (Methotrexate inadequate response patient with Rheumatoid Arthritis treated by Adalimumab in combination with Low-dose Methotrexate) Study |
| Date of disclosure of the study information | 2017/12/27 |
| Last modified on | 2023/04/08 11:50:42 |
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Basic information
Public title
MIRACLE (Methotrexate inadequate response patient with Rheumatoid Arthritis treated by Adalimumab in combination with Low-dose Methotrexate) Study
Acronym
MIRACLE Study
Scientific Title
MIRACLE (Methotrexate inadequate response patient with Rheumatoid Arthritis treated by Adalimumab in combination with Low-dose Methotrexate) Study
Scientific Title:Acronym
MIRACLE Study
Region
| Japan | Asia(except Japan) |
Condition
Condition
Rheumatoid Arthritis
Classification by specialty
| Clinical immunology | Orthopedics |
Classification by malignancy
Others
Genomic information
NO
Objectives
Narrative objectives1
This study is intended to evaluate the optimal dosage of methotrexate (MTX) as an add-on therapy to adalimumab (ADA) in patients with rheumatoid arthritis (RA) who do not achieve remission by MTX monotherapy, and to measure erythrocyte MTX-polyglutamates (MTX-PG) concentration to evaluate its relation to the efficacy and safety of MTX therapy in RA patients.
Basic objectives2
Safety,Efficacy
Basic objectives -Others
Trial characteristics_1
Trial characteristics_2
Developmental phase
Assessment
Primary outcomes
SDAI remission rate at Week 48
Key secondary outcomes
Base
Study type
Interventional
Study design
Basic design
Parallel
Randomization
Randomized
Randomization unit
Individual
Blinding
Open -no one is blinded
Control
Dose comparison
Stratification
Dynamic allocation
Institution consideration
Blocking
Concealment
Central registration
Intervention
No. of arms
3
Purpose of intervention
Treatment
Type of intervention
| Medicine |
Interventions/Control_1
Study treatment will start with MTX 6 to 8 mg/week, which will be promptly escalated to the maximum tolerable dose (MTD) <= 25 mg/week (<= 16 mg/week in Japan) in line with EULAR Recommendations 2016, and will be in principle maintained at the MTD from Week 12 onward. Also, the dosage of MTX will remain unchanged from Week 20 to 24 except for dose reduction/interruption due to an adverse drug reaction (ADR).
If the dosage of MTX is maintained >= 10 mg/week and remission (SDAI <= 3.3) is achieved at Week 24, the MTX therapy will be continued up to Week 48 (ARM-1).
Interventions/Control_2
Study treatment will start with MTX 6 to 8 mg/week, which will be promptly escalated to the maximum tolerable dose (MTD) <= 25 mg/week (<= 16 mg/week in Japan) in line with EULAR Recommendations 2016, and will be in principle maintained at the MTD from Week 12 onward. Also, the dosage of MTX will remain unchanged from Week 20 to 24 except for dose reduction/interruption due to an adverse drug reaction (ADR).
If SDAI remission is not achieved despite the dosage of MTX is maintained >= 10 mg/week at Week 24, a bDMARDs will be added to the treatment in line with EULAR Recommendations 2016. Subjects will subcutaneously receive ADA 40 mg as a bDMARDs every other week up to Week 48, and be randomized to a group in which the MTD of MTX (10 to 25 mg/week) will be maintained (ARM-2) and a group in which the dosage of MTX will be reduced to 6 to 8 mg/week (ARM-3). Then, the efficacy and safety will be evaluated.
Interventions/Control_3
Study treatment will start with MTX 6 to 8 mg/week, which will be promptly escalated to the maximum tolerable dose (MTD) <= 25 mg/week (<= 16 mg/week in Japan) in line with EULAR Recommendations 2016, and will be in principle maintained at the MTD from Week 12 onward. Also, the dosage of MTX will remain unchanged from Week 20 to 24 except for dose reduction/interruption due to an adverse drug reaction (ADR).
If SDAI remission is not achieved despite the dosage of MTX is maintained >= 10 mg/week at Week 24, a bDMARDs will be added to the treatment in line with EULAR Recommendations 2016. Subjects will subcutaneously receive ADA 40 mg as a bDMARDs every other week up to Week 48, and be randomized to a group in which the MTD of MTX (10 to 25 mg/week) will be maintained (ARM-2) and a group in which the dosage of MTX will be reduced to 6 to 8 mg/week (ARM-3). Then, the efficacy and safety will be evaluated.
Interventions/Control_4
Interventions/Control_5
Interventions/Control_6
Interventions/Control_7
Interventions/Control_8
Interventions/Control_9
Interventions/Control_10
Eligibility
Age-lower limit
| 18 | years-old | <= |
Age-upper limit
| Not applicable |
Gender
Male and Female
Key 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)
Key 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
Target sample size
300
Research contact person
Name of lead principal investigator
| 1st name | Yuko |
| Middle name | |
| Last name | Kaneko |
Organization
Keio University School of Medicine
Division name
Division of Rheumatology, Department of Internal Medicine
Zip code
160-8582
Address
35, Shinanomachi, Shinjuku-ku, Tokyo, Japan
TEL
03-5363-3786
ykaneko@z6.keio.jp
Public contact
Name of contact person
| 1st name | Hiroya |
| Middle name | |
| Last name | Tamai |
Organization
Keio University School of Medicine
Division name
Division of Rheumatology, Department of Internal Medicine
Zip code
160-8582
Address
35, Shinanomachi, Shinjuku-ku, Tokyo, Japan
TEL
03-5363-3786
Homepage URL
h.tamai@keio.jp
Sponsor or person
Institute
Keio University School of Medicine
Division of Rheumatology, Department of Internal Medicine
Institute
Department
Personal name
Funding Source
Organization
Eisai Co., Ltd.
Organization
Division
Category of Funding Organization
Profit organization
Nationality of Funding Organization
Other related organizations
Co-sponsor
Eisai Co., Ltd.
Name of secondary funder(s)
IRB Contact (For public release)
Organization
Certified Review Board of Keio
Address
Tokyo 35, Shinanomachi, Shinjuku-ku, Tokyo, Japan
Tel
03-5363-3503
med-rinri-jimu@adst.keio.ac.jp
Secondary IDs
Secondary IDs
YES
Study ID_1
jRCT1031180088
Org. issuing International ID_1
Japan Registry of Clinical Trials
Study ID_2
NCT03505008
Org. issuing International ID_2
ClinicalTrials.gov
IND to MHLW
Institutions
Institutions
慶應義塾大学病院(東京都)
東邦大学医療センター大橋病院(東京都)
日本医科大学付属病院(東京都)
国立病院機構 東京医療センター(東京都)
東北大学病院(宮城県)
千葉大学医学部附属病院(千葉県)
川崎市立 川崎病院(神奈川県)
東海大学医学部付属病院(神奈川県)
社会福祉法人 聖隷福祉事業団 総合病院 聖隷浜松病院(静岡県)
広島大学病院(広島県)
藤田医科大学病院(愛知県)
名古屋大学医学部附属病院(愛知県)
Other administrative information
Date of disclosure of the study information
| 2017 | Year | 12 | Month | 27 | Day |
Related information
URL releasing protocol
https://jrct.niph.go.jp/latest-detail/jRCT1031180088
Publication of results
Published
Result
URL related to results and publications
Lancet Rheumatology. 2023 Apr;5(4):e215-e224.
Number of participants that the trial has enrolled
300
Results
This study demonstrated that in patients with rheumatoid arthritis with inadequate response to methotrexate, the efficacy of adalimumab with reduced dose of concomitant methotrexate was not inferior to that with maximum tolerable dose of methotrexate. There was no significant difference about HAQ remission rate and structural remission rate between the two groups. The incidence of AEs was numerically lower in reduced dose group than in maximum tolerable dose group.
Results date posted
| 2023 | Year | 04 | Month | 08 | Day |
Results Delayed
Results Delay Reason
Date of the first journal publication of results
Baseline Characteristics
Full analysis set (FAS) 291 subjects
Japan 194, South Korea 55, Taiwan 42
The mean age 57.7+/-15.2 years old
Sex: Male 25.4% Female 74.6%
The mean RA duration 21.1+/-56.2 days
Participant flow
Number of subjects
Screened: 323
Enrolled: 300
IP administered: 298
Full analysis set (FAS): 291
discontinuation before week 24 allocation: 52
allocation at week 24: 239
(ARM-1: 105, ARM-2: 68, ARM-3: 66)
Modified full analysis set (mFAS): 127
(ARM-2: 66, ARM-3: 61)
Study completion of week 48: 218
(ARM-1: 101, ARM-2: 59, ARM-3: 58)
Adverse events
Safety analysis set: 291
Subjects with any adverse events: 169
before week 24 allocation: 132
after week 24 allocation: 79
(ARM-1: 42, ARM-2: 24, ARM-3: 13)
Most frequently reported AE in safety analysis set by SOC:
infections and infestations: 56, investigations: 51, gastrointestinal disorders: 46
Subjects with SAE: 23
before week 24 allocation: 9
after week 24 allocation: 14
(ARM-1: 6, ARM-2: 5, ARM-3: 3)
Most frequently reported SAE in safety analysis set by SOC:
Injury, poisoning and procedural complications: 7, Infections and infestations: 5
Death: 0
Suspected, unexpected, SAE: 0
Outcome measures
Primary end point:
In the mFAS population, 38.4% of the subjects in ARM-2 and 44.8% of the subjects in ARM-3 achieved the SDAI remission at Week 48, resulting in an adjusted risk difference of ARM-3 to ARM-2 of 6.4% (-7.0% to 19.8%, 90% CI), which met the criterion for noninferiority with the margin of -15%.
Secondary end points (main results):
In the FAS population, the adjusted risk difference of HAQ remission rates at Week 48 of ARM-3 to ARM-2 was 2.9% (-13.1%, 18.8%, 95% CI) (p value=0.72).
In the FAS population, the adjusted risk difference of the structural remission (dmTSS =< 0.5) rates at Week 48 of ARM-3 to ARM-2 was -4.4% (-20.4%, 11.7%, 95% CI) (p value=0.59).
Plan to share IPD
IPD sharing Plan description
Progress
Recruitment status
Completed
Date of protocol fixation
| 2017 | Year | 09 | Month | 21 | Day |
Date of IRB
| 2017 | Year | 12 | Month | 27 | Day |
Anticipated trial start date
| 2018 | Year | 04 | Month | 18 | Day |
Last follow-up date
| 2021 | Year | 06 | Month | 30 | Day |
Date of closure to data entry
Date trial data considered complete
Date analysis concluded
Other
Other related information
Management information
Registered date
| 2017 | Year | 12 | Month | 27 | Day |
Last modified on
| 2023 | Year | 04 | Month | 08 | Day |
Link to view the page
Value
https://center6.umin.ac.jp/cgi-open-bin/ctr_e/ctr_view.cgi?recptno=R000034918
