臨床研究等提出・公開システム

MIRACLE (Methotrexate inadequate response patient with Rheumatoid Arthritis treated by Adalimumab in combination with Low-dose Methotrexate) Study (MIRACLE Study)

MIRACLE Study (MIRACLE Study)

300

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

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)

Safety analysis set: 291 Subjects with any adverese 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, gastrointesitinal 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

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).

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.

Jan. 30, 2023

No

not planed

https://jrct.mhlw.go.jp/latest-detail/jRCT1031180088

Kaneko Yuko

Keio University Hospital

35, Shinanomachi, Shinjuku-ku, Tokyo, Japan

ykaneko@z6.keio.jp

Tamai Hiroya

Keio University Hospital

35, Shinanomachi, Shinjuku-ku, Tokyo, Japan

+81-3-3353-1211

h.tamai@keio.jp

Complete

April. 18, 2018

Interventional

randomized controlled trial

open(masking not used)

dose comparison control

parallel assignment

treatment purpose

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 drug 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)

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

Both

Rheumatoid Arthritis

Subjects meeting all of the inclusion criteria and not applicable to any of the exclusion criteria will start receiving MTX 6 to 8 mg/week after the assessment at Week 0. Also, 10 mg of folic acid will be orally administered once a week 48 hours after the first MTX dosing day of the week to prevent ADRs related to MTX (A daily dosage of 1 mg folic acid is acceptable in South Korea on a condition that the dosage cannot be changed during the study period).
To achieve remission, the dosage of MTX will be promptly escalated to the maximum tolerable dose (MTD) <=25 mg/week (the maximum dose should be set according to the package insert of each country) 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 ADR. Weekly dose of MTX will be administered orally at once or twice a day in principle.
If the dosage of MTX is maintained >=10 mg/week and SDAI remission is achieved at Week 24, the MTX therapy will be continued until Week 48 (ARM-1).
If SDAI remission is not achieved despite the maintenance of >=10 mg/week MTX dose at Week 24, ADA 40 mg will be administered subcutaneously every other week until Week 48. Subjects then will be stratified by countries (Japan, South Korea, and Taiwan) as a stratification factor, and for each stratum, subjects will be randomized at a 1:1 ratio to either 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).
The MTX dosage shall be either 6 mg/week or 7.5 mg/week in subjects in ARM-3 whose maintenance dose of MTX at Week 24 is 10 mg/week.
Subjects in whom MTX at a dosage >=10 mg/week cannot be maintained at Week 24 due to ADR, etc. will be withdrawn from the study.
Subjects in whom MTX at a dosage of >=10 mg/week in ARM-2 or >=6 mg/week in ARM-3 cannot be maintained after Week 24 due to ADR, etc. will also be withdrawn from the study.
Also, subjects will be withdrawn from the study when an increased dosage of MTX is required after Week 24 due to loss of efficacy, etc.

Rheumatoid Arthritis

Methotrexate, Adalimumab

SDAI remission rate at Week 48

SDAI remission rate at Week 24, ACR20, ACR50, and ACR70 response rates, HAQ remission rate, and structural remission rate

+81-3-5363-3503

Dec. 03, 2018

South Korea/Taiwan