UMIN-CTR Clinical Trial

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

Rheumatoid Arthritis

Classification by specialty

Clinical immunology

Orthopedics

Classification by malignancy

Others

Genomic information

NO

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

Primary outcomes

SDAI remission rate at Week 48

Key secondary outcomes

Study type

Interventional

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

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

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

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

Email

ykaneko@z6.keio.jp

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

Email

h.tamai@keio.jp

Institute

Keio University School of Medicine
Division of Rheumatology, Department of Internal Medicine

Institute

Department

Personal name

Organization

Eisai Co., Ltd.

Organization

Division

Category of Funding Organization

Profit organization

Nationality of Funding Organization

Co-sponsor

Eisai Co., Ltd.

Name of secondary funder(s)

Organization

Certified Review Board of Keio

Address

Tokyo 35, Shinanomachi, Shinjuku-ku, Tokyo, Japan

Tel

03-5363-3503

Email

med-rinri-jimu@adst.keio.ac.jp

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

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)

Date of disclosure of the study information

2017

Year

12

Month

27

Day

URL releasing protocol

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

Publication of results

Published

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

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 related 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