Clinical trial NCT03505008
Conditions: Rheumatoid Arthritis
Keywords: Methotrexate Adalimumab Autoimmune Disease Connective Tissue Diseases Rheumatic Disease Rheumatoid Arthritis
Sponsor: Keio University
Start date: 2018-04-18; Completion date: 2021-05-11
Enrollment: 300 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

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.

Arms: arm 1: 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 2: 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 3: 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.
Interventions: intervention 1: Methotrexate intervention 2: Adalimumab
Intervention descriptions: intervention 1: Route of Administration: Oral intervention 2: Route of Administration: Subcutaneous

Protocol documents:
Prot_000.pdf: 
 
 
 
 
 
MIRACLE 
(Methotrexate inadequate response patient with Rheumatoid Arthritis treated by 
Adalimumab in combination with Low-dose Methotrexate)  
 
 
 
 
Evaluation of the Optimal MTX Dose as an Add-on Therapy to Adalimumab for  
RA Patients in Japan, South Korea and Taiwan. (NCT03505008) 
 
 
 
 
Study Protocol 
 
Ver. 2.2 (Date prepared: November 15, 2019) 
 


D2E7-C000-401 
 
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Study Protocol 
 
 
MIRACLE (Methotrexate inadequate response patient with Rheumatoid Arthritis treated by 
Adalimumab in combination with Low-dose Methotrexate) Study 
 
 
 
 
< Lead Principal Investigator > 
Yuko Kaneko 
Division of Rheumatology, Department of Internal Medicine 
Keio University School of Medicine 
 
 
 
<Study Investigational Operator> 
Hiroya Tamai 
Division of Rheumatology, Department of Internal Medicine 
Keio University School of Medicine 
 
 
 
<Study Secretariat> 
Planning and Management Office 
Clinical and Translational Research Center 
Keio University Hospital 
 
 
 
Contract Medical Affairs 
Linical Co., Ltd. 
1-9-2 Higashi-Shimbashi, Minato-ku, Tokyo 105-0021, Japan 
TEL: +81-x-xxxx-xxxx  FAX: +81-x-xxxx-xxxx 
 
 
 
Ver. 2.2 (Date prepared: November 15, 2019) 


D2E7-C000-401 
 
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List of abbreviations 
Abbreviations 
Definitions 
ACR 
American College of Rheumatology 
ADA 
Adalimumab 
AE 
adverse event 
ALP 
alkaline phosphatase 
ALT 
alanine aminotransferase 
AST 
aspartate aminotransferase 
BUN 
blood urea nitrogen 
CCP 
cyclic citrullinated peptide 
CDAI 
clinical disease activity index 
CRP 
C-reactive protein 
Cr 
creatinine 
DAS 
disease activity score 
DMARDs 
disease-modifying antirheumatic drugs 
EDC 
electronic data capturing 
ESR 
erythrocyte sedimentation rate 
EULAR 
European League Against Rheumatism 
FAS 
full analysis set 
GCP 
Good Clinical Practice 
γ-GTP 
γ-glutamine transpeptidase 
HAQ 
Health Assessment Questionnaire 
Hb 
Hemoglobin 
HBc 
hepatitis B virus core 
HBs 
hepatitis B virus surface 
HCV 
hepatitis C virus  
ICH 
International Council for Harmonisation of Technical Requirements for 
Pharmaceuticals for Human Use 
IgA 
immunoglobulin A 
IgG 
immunoglobulin G 
IGRA 
interferon-gamma release assay 
IL 
Interleukin 
IWRS 
Interactive Web Response System 
JAK 
Janus kinase 
LDH 
lactate dehydrogenase 
LLT 
lowest level terms 
LOCF 
Last Observation Carried Forward 
MCV 
mean corpuscular volume 
MedDRA 
Medical Dictionary for Regulatory Activities 
MMP-3 
matrix metalloproteinase-3 


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Abbreviations 
Definitions 
mTSS 
modified Total Sharp Score 
MTX 
Methotrexate 
NSAIDs 
non-steroidal anti-inflammatory drugs 
Plt 
Platelet 
PPS 
per protocol set 
PT 
preferred term 
QOL 
quality of life 
RA 
rheumatoid arthritis 
RBC 
red blood cell 
RF 
rheumatoid factor 
RNA 
ribonucleic acid 
SAE 
serious adverse event 
SDAI 
simple disease activity index 
SOC 
system organ class 
Tmax 
time at which the highest drug concentration occurs 
TEAE 
treatment emergent adverse event 
TNF 
tumor necrosis factor 
UA 
uric acid 
VAS 
visual analog scale 
VEGF 
vascular endothelial growth factor 
WBC 
white blood cell 
 


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Table of contents 
List of abbreviations ........................................................................................................... 2 
Table of contents ................................................................................................................. 4 
0. SYNOPSIS .................................................................................................................... 9 
0.1 
Study title ..................................................................................................................... 9 
0.2 
Schema ......................................................................................................................... 9 
0.3 
Objective ...................................................................................................................... 9 
0.4 
Subjects ........................................................................................................................ 9 
0.5 
Study treatment ............................................................................................................ 9 
0.6 
Target number of subjects and study period .............................................................. 10 
0.7 
Contact ....................................................................................................................... 10 
1 
Overview ..................................................................................................................... 11 
1.1 
Study Information ...................................................................................................... 11 
1.1.1 Study title .............................................................................................................. 11 
1.1.2 Study identifying numbers .................................................................................... 11 
1.1.3 Version number and dates prepared and effective of the study protocol .............. 11 
1.2 
Study Organization .................................................................................................... 11 
1.2.1 Sponsor.................................................................................................................. 11 
1.2.2 Lead Principal Investigator ................................................................................... 11 
1.2.3 Study Investigational Operator ............................................................................. 12 
1.2.4 Coordinating Investigators .................................................................................... 12 
1.2.5 Study Efficacy and Safety Advisor ....................................................................... 12 
1.2.6 Imaging Review Committee ................................................................................. 12 
1.2.7 Study Sites and Principal Investigators ................................................................. 12 
1.2.8 Study Biostatistician ............................................................................................. 12 
1.2.9 Study Secretariat ................................................................................................... 12 
1.2.10 Data Center ........................................................................................................... 13 
1.2.11 Contract Research Organization ........................................................................... 14 
1.2.12 External laboratory ................................................................................................ 14 
2. Background information ........................................................................................... 15 
2.1 
Indication ................................................................................................................... 15 
2.1.1 Overview of indication.......................................................................................... 15 
2.1.2 Comorbidities related to the indication ................................................................. 15 


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2.1.3 Prognostic factors of the indication ...................................................................... 15 
2.1.4 Standard of care for the indication ........................................................................ 15 
2.2 
Study drug .................................................................................................................. 16 
2.2.1 Methotrexate (MTX) ............................................................................................. 16 
2.2.2 Adalimumab (ADA) ............................................................................................. 16 
2.3 
Nonclinical and clinical studies ................................................................................. 17 
2.3.1 Nonclinical studies ................................................................................................ 17 
2.3.2 Clinical studies ...................................................................................................... 17 
2.4 
Risks and benefits to subjects .................................................................................... 17 
2.4.1 Expected benefits .................................................................................................. 17 
2.4.2 Anticipated risks and disadvantage ....................................................................... 18 
2.5 
Route of administration, dosage and administration, and duration of treatment ....... 18 
2.6 
Applicable rules, etc. ................................................................................................. 19 
2.7 
Study population ........................................................................................................ 19 
2.8 
Reference and data ..................................................................................................... 19 
3 
Objective ..................................................................................................................... 19 
3.1 
Background ................................................................................................................ 19 
3.2 
Objective .................................................................................................................... 19 
3.3 
Purpose ...................................................................................................................... 19 
4 
Study design ................................................................................................................ 19 
4.1 
Endpoints ................................................................................................................... 19 
4.1.1 Primary endpoint ................................................................................................... 19 
4.1.2 Secondary endpoints ............................................................................................. 19 
4.1.3 Exploratory endpoints ........................................................................................... 20 
4.2 
Study method ............................................................................................................. 20 
4.3 
Bias ............................................................................................................................ 21 
4.3.1 Randomization ...................................................................................................... 21 
4.3.2 Blinding ................................................................................................................. 21 
4.4 
Information on study drug ......................................................................................... 21 
4.4.1 Methotrexate (MTX) ............................................................................................. 21 
4.4.2 Adalimumab (ADA) ............................................................................................. 22 
4.5 
Study period ............................................................................................................... 23 
4.6 
Study interruption/discontinuation ............................................................................ 23 
4.7 
Management of study drug ........................................................................................ 24 


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4.8 
Storage of randomization code, and unblinding process ........................................... 24 
4.9 
Specification of source data ....................................................................................... 24 
5 
Inclusion/exclusion/withdrawal criteria ................................................................... 24 
5.1 
Inclusion criteria ........................................................................................................ 24 
5.2 
Exclusion criteria ....................................................................................................... 25 
5.3 
Withdrawal criteria .................................................................................................... 26 
6 
Study treatment .......................................................................................................... 26 
6.1 
Treatment procedure .................................................................................................. 26 
6.1.1 Dose selection of MTX for study treatment.......................................................... 27 
6.2 
Concomitant therapies ............................................................................................... 28 
6.2.1 Allowed concomitant therapy ............................................................................... 28 
6.2.2 Prohibited concomitant therapy ............................................................................ 28 
6.3 
Compliance ................................................................................................................ 28 
7 
Assessments ................................................................................................................. 28 
7.1 
Demography .............................................................................................................. 28 
7.2 
Efficacy assessments ................................................................................................. 29 
7.2.1 X rays of hands and feet ........................................................................................ 29 
7.2.2 Tender joint count, swollen joint count, VAS (physician- and patient-
reported), and HAQ............................................................................................... 30 
7.2.3 CRP, ESR, MMP-3, RF, and anti-CCP antibody ................................................. 30 
7.2.4 SDAI ..................................................................................................................... 30 
7.2.5 CDAI ..................................................................................................................... 31 
7.2.6 ACR 20, 50, 70 response rates, and ACR-N ......................................................... 31 
7.2.7 DAS28-ESR .......................................................................................................... 31 
7.2.8 DAS28-CRP .......................................................................................................... 32 
7.3 
Biomarkers assessment (investigational blood sampling) ......................................... 32 
7.3.1 Erythrocyte MTX-polyglutamates concentration ................................................. 32 
7.3.2 Blood cytokine level ............................................................................................. 32 
7.3.3 Plasma micro RNA ............................................................................................... 33 
7.3.4 Serum anti-adalimumab antibody ......................................................................... 33 
7.4 
Safety assessment ...................................................................................................... 33 
7.4.1 Evaluation of AEs ................................................................................................. 33 
7.5 
Assessment schedule ................................................................................................. 35 
8 
Adverse events ............................................................................................................ 36 


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8.1 
Definition ................................................................................................................... 36 
8.1.1 Definition of adverse event (AE) .......................................................................... 36 
8.1.2 Definition of serious adverse events (SAE) .......................................................... 36 
8.1.3 Evaluation of severity ........................................................................................... 37 
8.1.4 Evaluation of causal relation with the study drug ................................................. 37 
8.2 
Procedures for collection, documentation, and reporting of SAEs ........................... 37 
8.2.1 Reportable events .................................................................................................. 38 
8.3 
Follow-up of subjects after AEs ................................................................................ 38 
8.3.1 Follow-up .............................................................................................................. 38 
8.3.2 Insurance for health damage ................................................................................. 39 
9 
Statistical analysis ...................................................................................................... 39 
9.1 
Statistical analysis set ................................................................................................ 39 
9.2 
Analytical method ...................................................................................................... 39 
9.2.1 Method of efficacy analysis .................................................................................. 39 
9.2.2 Method of biomarker analysis ............................................................................... 40 
9.2.3 Method of safety ................................................................................................... 40 
9.3 
Significance level ....................................................................................................... 41 
9.4 
Number of subjects .................................................................................................... 41 
9.4.1 Sample size selection ............................................................................................ 42 
9.5 
Study discontinuation criteria .................................................................................... 43 
9.6 
Handling of study data ............................................................................................... 43 
9.7 
Data evaluation .......................................................................................................... 44 
9.8 
Deviation from statistical analysis plan ..................................................................... 44 
10 Direct access to source data and document ............................................................. 44 
11 Monitoring and audit ................................................................................................. 44 
11.1 Monitoring ................................................................................................................. 44 
11.2 Audit .......................................................................................................................... 44 
12 Ethics ........................................................................................................................... 44 
12.1 Benefits and disadvantages to subjects ...................................................................... 44 
12.2 Informed consent ....................................................................................................... 45 
12.2.1 Inform patient ........................................................................................................ 45 
12.2.2 Consent.................................................................................................................. 46 
12.2.3 Representative ....................................................................................................... 47 
12.3 Protection of subjects' privacy and patient identification .......................................... 47 


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12.4 Certified Review Board/Ethical Review Board ......................................................... 47 
12.4.1 Approval................................................................................................................ 47 
12.4.2 Annual review ....................................................................................................... 47 
12.5 Disclosure of study-related information .................................................................... 47 
12.6 Handling of inquiry from subjects and related parties ............................................... 48 
12.7 Conflicts of interest .................................................................................................... 48 
12.8 Handling of subjects after end of study ..................................................................... 48 
12.9 Handling of important findings concerning genetic characteristics, etc. ................... 48 
12.10 Retention and future research use of clinical samples, and transfer thereof to 
other research facilities .............................................................................................. 48 
13 Handling of data, and retention of record ............................................................... 49 
13.1 Handling of data ........................................................................................................ 49 
13.2 Retention of records ................................................................................................... 49 
14 Economic burden on subjects, and insurance and other measures ....................... 49 
14.1 Economic burden on subjects .................................................................................... 49 
14.2 Insurance .................................................................................................................... 49 
15 Publication of study results ....................................................................................... 49 
16 Appendix ..................................................................................................................... 51 
16.1 Criteria for RA ........................................................................................................... 51 
16.1.1 ACR revised criteria (1987) .................................................................................. 51 
16.1.2 ACR/EULAR criteria (2010) ................................................................................ 51 
16.2 Reference ................................................................................................................... 52 
 


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0. SYNOPSIS 
0.1 
Study title 
MIRACLE (Methotrexate inadequate response patient with Rheumatoid Arthritis treated by 
Adalimumab in combination with Low-dose Methotrexate) Study 
 
0.2 
Schema 
 
 
 
 
0.3 
Objective 
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. 
 
0.4 
Subjects 
This study will be conducted in 300 patients with RA in Japan, South Korea, and Taiwan 
previously not treated with MTX, Janus kinase (JAK) inhibitor, or biological disease-
modifying antirheumatic drugs (bDMARDs), and whose duration of disease is within 2 years 
from diagnosis. 
RA patients (meeting the 1987 revised ACR criteria or 2010 ACR/EULAR criteria) aged ≥18 
years (≥20 years in Taiwan) whose disease activity at screening is SDAI >11. 
 
0.5 
Study treatment 
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 (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 
adverse drug reaction (ADR). 


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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 (ARM-1). 
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 bDMARD 
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. 
If a subject becomes intolerable to MTX ≥10 mg/week at Week 24 due to an ADR or other 
relevant reasons, the subject will be terminated from the study at that time. The subject will 
be also terminated from the study when subjects have received a non-ADA bDMARD or 
JAK inhibitor. 
The primary endpoint will be the SDAI remission rate at Week 48 in the ADA/MTX-MTD 
Group (ARM-2) and ADA/MTX-Reduced Dose Group (ARM-3). Key secondary endpoints 
will be the SDAI remission rate at Week 24, the SDAI remission rate at Week 48 in MTX 
Monotherapy Group, the modified total sharp score (mTSS) at each assessment timepoint and 
changes from baseline to each assessment timepoint, and ACR20, ACR50, and ACR70 
response rates at each assessment timepoint. Also, the correlation of the erythrocyte MTX-PG 
concentration to SDAI, mTSS, and ACR-N will be exploratorily evaluated. 
 
0.6 
Target number of subjects and study period 
Target number of subjects 
: 300 subjects 
Enrollment period 
: March 2018 to July 2020 (2 years 
and 5 months) 
Intervention period 
: 48 weeks 
Data retrieval, analysis, and report generation periods : 1 year 
Total study period 
: 4 years and 4 months 
 
0.7 
Contact 
Inclusion/exclusion criteria, and others that require clinical judgment: 
Lead Principal Investigator or Study 
Investigational Operator 
EDC entry, etc. 
: Data center 
AE reporting 
: SAE Report Center 
Others 
: Operation Center 
 


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1 
Overview 
1.1 
Study Information 
1.1.1 
Study title 
MIRACLE (Methotrexate inadequate response patient with Rheumatoid Arthritis treated by 
Adalimumab in combination with Low-dose Methotrexate) Study 
 
1.1.2 
Study identifying numbers 
Study protocol No. 
: D2E7-C000-401 
ClinicalTrials.gov Identifier 
: NCT03505008 
jRCT No. 
: jRCT1031180088 
UMIN study ID 
: UMIN000030584 
 
1.1.3 
Version number and dates prepared and effective of the study protocol 
Version number: 2.2 
Date prepared: 
November 15, 2019 
Effective date: 
The amended protocol becomes effective on the day of entry in jRCT after 
the approval by the Certified Review Board. 
 
1.2 
Study Organization 
1.2.1 
Sponsor 
Keio Gijuku educational Corporation, Keio University School of Medicine 
35, Shinanomachi, Shinjuku-ku, Tokyo 160-8582, Japan 
Responsible person: Yuko Kaneko (Lead Principal Investigator) 
Role: Initiates and is responsible for this study except for its funding 
 
Eisai Co., Ltd. 
4-6-10 Koishikawa, Bunkyo-ku, Tokyo 112-8088, Japan 
Responsible person: xxxxxxxx xxxxxxxx (xxxxxxxx) 
Roles: Plans out this study (including the analysis plan) in conjunction with Keio 
University, approve the clinical study report, provide information concerning 
ADA, and fund the study. 
 
1.2.2 
Lead Principal Investigator 
Yuko Kaneko 
Associate Professor, Division of Rheumatology, Department of Internal Medicine, 
Keio University School of Medicine 
35 Shinanomachi, Shinjuku-ku, Tokyo 160-8582 
TEL: +81-3-5363-3786    FAX: +81-3-5379-5370 
E-mail: ykaneko@z6.keio.jp 
Roles: Represents the study group as a signatory to approve the protocol, and makes 
medical judgments on the whole study group as a medical expert to the study. 
 


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1.2.3 
Study Investigational Operator 
Hiroya Tamai 
Division of Rheumatology, Department of Internal Medicine, 
Keio University School of Medicine 
Roles: Prepare and control protocol and other relevant documents 
 
1.2.4 
Coordinating Investigators 
Tsutomu Takeuchi 
Professor, Division of Rheumatology, Department of Internal Medicine, Keio University 
School of Medicine 
Roles: Negotiate with study sites so as to efficiently carry out the study. 
 
1.2.5 
Study Efficacy and Safety Advisor 
The advisor comprises 2 physicians experienced in using ADA, designated by the Lead 
Principal Investigator, and selected from Department of Internal Medicine (1 from Division 
of Gastroenterology and 1 from Division of Rheumatology), Keio University School of 
Medicine. Principal investigator/sub-investigator may not be assigned as a member of the 
Study Efficacy and Safety Advisor. 
Roles: Provides suggestions concerning the acceptability to continue the study and the 
necessity of protocol amendment upon request of the Lead Principal Investigator. 
 
1.2.6 
Imaging Review Committee 
The committee comprises physicians designated by the Lead Principal Investigator. 
Roles: Reviews and evaluates the imaging data of hands and feet based on modified total 
sharp score (mTSS). 
 
1.2.7 
Study Sites and Principal Investigators 
See the Site List 
Roles: Conducts this study at each study site in accordance with the protocol upon 
approval of the Certified Review Board/Ethical Review Board and Site 
Management (principal investigator). 
 
1.2.8 
Study Biostatistician 
Yasunori Sato 
Head of Biostatistics Unit, Clinical and Translational Research Center, 
Keio University Hospital 
Roles: Prepare the statistical analysis plan, and perform statistical analysis based on the 
statistical analysis plan. 
 
1.2.9 
Study Secretariat 
< General Secretariat> 
Planning and Management Office, Clinical and Translational Research Center, 


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Keio University Hospital 
Roles: Supports Lead Principal Investigator and Study Investigational Operator to enable 
efficient study conduct. 
 
<Operation Center (Enrollment promotion, contract process, etc.)> 
Contract Medical Affairs, Linical Co., Ltd. 
Supervisor: xxxxxxxx xxxxxxxx, Staff: xxxxxxxx xxxxxxxx 
1-9-2 Higashi-Shimbashi, Minato-ku, Tokyo 105-0021, Japan 
TEL: +81-x-xxxx-xxxx, FAX: +81-x-xxxx-xxxx 
Roles: To plan out measures to facilitate proactive enrollment of subjects and process 
contracts with sites to enable efficient study conduct. 
 
<SAE Report Center> 
Linical Spain, S.L.  Pharmacovigilance Department 
 
Pharmacovigilance Officer: ________________ 
 
C/ Las Norias 92, Planta 2ª 28221 Majadahonda (Madrid), Spain 
 
TEL: +34-xx-xxx-xx-xx 
FAX: +34- xx-xxx-xx-xx 
 
e-mail address: xxxxxxxxx@xxxxx.com 
 
(Japan Contact) 
Contract Medical Affairs, Linical Co., Ltd. 
Supervisor: xxxxxxxx xxxxxxxx, Staff: xxxxxxxx xxxxxxxx 
1-9-2 Higashi-Shimbashi, Minato-ku, Tokyo 105-0021, Japan 
TEL: +81-x-xxxx-xxxx, FAX: +81-x-xxxx-xxxx 
Roles: Receives a report from Principal Investigator upon occurrence of a serious AE 
(SAE), and reports to Lead Principal Investigator. 
 
1.2.10 Data Center 
Linical Spain, S.L. 
Chief Operating Officer: ____________ 
C/ Las Norias 92, Planta 2ª 28221 Majadahonda (Madrid), Spain 
TEL: +34- xx-xxx-xx-xx, Fax: +34- xx-xxx-xx-xx 
 
(Japan Contact) 
Data Management, Clinical Development, Linical Co., Ltd. 
xxxxxxxx xxxxxxxx 
1-9-2 Higashi-Shimbashi, Minato-ku, Tokyo 105-0021, Japan 
TEL: +81-x-xxxx-xxxx, FAX: +81-x-xxxx-xxxx 
Roles: Prepares and amends the sample case report forms (CRF), designs databases, 
checks and fixes the data, and verifies and validates the data. 
 


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1.2.11 Contract Research Organization 
In addition to the operations of the Study Secretariat (Operation Center and SAE Report 
Center) and Data Center, monitoring and audit operations of this study will be entrusted to 
contract research organizations. The Lead Principal Investigator should review and approve 
the operational procedures prepared by the contract research organizations and have a 
periodic interview with the contract research organizations to supervise their operations. 
 
<Monitoring> 
Contract Medical Affairs, Linical Co., Ltd. 
Supervisor: xxxxxxxx xxxxxxxx, Staff: xxxxxxxx xxxxxxxx 
1-9-2 Higashi-Shimbashi, Minato-ku, Tokyo 105-0021, Japan 
TEL: +81-x-xxxx-xxxx, FAX: +81-x-xxxx-xxxx 
Roles: Reviews the study to ensure that it is conducted safely and in accordance with the 
protocol, and the data is collected accurately. 
 
<Audit> 
Audit Office, Linical Co., Ltd. 
Supervisor: xxxxxxxx xxxxxxxx 
1-6-1 Miyahara, Yodogawa-ku, Osaka-shi, Osaka 532-0003, Japan 
TEL: +81-x-xxxx-xxxx, FAX: +81-x-xxxx-xxxx 
Roles: Review the study to verify whether it is conducted in compliance with the protocol, 
ICH-GCP, and other relevant rules. 
 
1.2.12 External laboratory 
LSI Medience Corporation 
1-13-4 Uchikanda, Chiyoda-ku, Tokyo 101-8517, Japan 
TEL: +81-x-xxxx-xxxx, FAX: +81-x-xxxx-xxxx 
Roles: Retrieve and measure clinical specimens of investigational blood samples, and 
report the results 
 


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2. Background information 
2.1 
Indication 
2.1.1 
Overview of indication 
Rheumatoid arthritis (RA) is an autoimmune disease that causes chronic arthritis mutilans all 
over the body. The prevalence rate of RA is estimated to be about 1% worldwide (Firestein 
GS, 2017: 1115); 600,000 to 700,000 patients in Japan alone. The peak age of disease 
development in women is in their most productive years of 40's to 50's, resulting in not only 
physical disability, but also social restrictions, economic burden, and their family's mental 
strain. Main clinical manifestations include pain and swelling of joints in the hands and feet, 
as well as joint destruction and degeneration due to prolonged disease which not only 
generates chronic pain but also causes remarkable restriction on activities of daily living 
(ADL). About 70% of patients are said to develop bone erosion within 2 years if not 
appropriately treated (Howard A, et al. 1989: 585-91); thus, early therapeutic intervention is 
very important. 
 
2.1.2 
Comorbidities related to the indication 
RA causes pain, joint fracture, and joint degeneration due to destructive polyarthritis that 
chronically occurs all over the body. Inflammation, if persists, causes not only pain but also 
irreversible destructions in the joints, resulting in remarkable reduction of ADL. RA is known 
to be accompanied by not only joint symptoms but also a high frequency of extracapsular 
symptoms such as scleritis, airway lesion, interstitial pneumonia, pleurisy, vasculitis, 
secondary Sjogren's syndrome, and secondary amyloidosis. Pulmonary lesions particularly 
affect vital prognosis, and often causes acute exacerbation. Furthermore, RA patients are 
known to have poorer vital prognosis compared to general population due to persistent 
inflammation and immunological abnormality which are risk factors of arteriosclerosis and 
malignant disease (Wolfe F, et al. 1994: 481-94). Also, immunosuppression associated with 
typical treatment is a high risk factor of infection-related complications. 
 
2.1.3 
Prognostic factors of the indication 
Seropositive (rheumatoid factor and anti-CCP antibody), high disease activities, and bone 
erosion in early stage of disease are prognostic factors of future joint destruction, 
(Vastesaeger N, et al. 2009: 1114-21, Visser K, et al. 2010: 1333-7), and thus, are poor 
prognostic factors. Moreover, as mentioned above, the presence of interstitial pneumonia, 
vasculitis, and other extracapsular symptoms, and persistent inflammation are risk factors of 
arteriosclerosis and malignant disease. In addition, immunosuppression associated with 
typical treatment can cause serious infection, and thus can be a determining factor of 
prognosis. 
 
2.1.4 
Standard of care for the indication 
DMARDs are clinically used to ease inflammation and pain, and prevent joint destruction in 
RA patients. EULAR Recommendations 2016 recommends to start using methotrexate 
(MTX) promptly upon diagnosis of RA, unless contraindicated, with a therapeutic goal to 


D2E7-C000-401 
 
16 
 
achieve clinical remission in 6 months, and if unsuccessful, consider adding bDMARDs 
[tumor necrosis factor (TNF)-α inhibitor, abatacept, tocilizumab, and in some cases, 
rituximab] (Smolen JS, et al. 2017: 960-77). Low-dose steroid is used pertinent to an early 
therapeutic strategy up to 6 months, but the guideline recommends to reduce dose as 
promptly as clinically possible. Steroid pulse and high-dose steroid are also used sometimes 
for acute exacerbation of interstitial pneumonia and vasculitis. 
Among bDMARDs, the efficacy of some TNFα inhibitors are known to increase when used 
in combination with MTX (Nam JL, et al. 2014: 516-28); however, an optimal dose of MTX 
in such combination use is unknown. 
 
2.2 
Study drug 
2.2.1 
Methotrexate (MTX) 
MTX was approved in 1988 by the U.S. Food and Drug Administration as a drug for 
treatment of RA, and since then, has been widely used all around the world. MTX not only 
has a high response rate for treatment of arthritis, but also prevents the progression of joint 
destruction, and furthermore, its efficacy in improving QOL and vital prognosis have been 
demonstrated; thus, it became the first choice of standard treatment (Smolen JS, et al. 2017: 
960-77). 
It is also much inexpensive than bDMARDs. Because of such advantages, it is remains to a 
first-line drug recommended by EULAR Recommendations 2016 amid the presence of 
various bDMARDs today. A recommended maintenance dose of MTX is maximum tolerable 
dose of 25 to 30 mg/week (16 mg/week in Japan) when used in combination with folic acid. 
Also, TNFα inhibitor and other bDMARDs are now known to be more effective when used in 
combination with MTX than used alone. 
Meanwhile, gastrointestinal symptoms, hepatic impairment, and myelopathy are known to be 
dose-dependent ADRs of MTX. In ADRs of MTX, gastrointestinal symptoms and hepatic 
enzymes increased are known to be alleviated by concomitant use of folic acid preparation 
(Tishler M, et al. 1988: 906-9, Morgan SL, et al. 1990; 33: 9-18.). 
Also, while erythrocyte MTX-polyglutamates (PG) concentration has been reported to reflect 
the efficacy and safety of MTX (de Rotte MC, et al. 2015; 74:408-14), it has been pointed out 
that there is a possible difference in the MTX-PG concentration by ≥1.4 fold between the 
Japanese and Western populations given the same dosage of MTX (Takahashi C, et al. 2017: 
e000363), suggesting a possibility of lower dose MTX to generate efficacy in the Japanese 
population when used in combination with ADA. Moreover, there has been no Asian country 
other than Japan in which study evaluating MTX-PG has been reported. 
 
2.2.2 
Adalimumab (ADA) 
ADA was approved in the U.S. in 2002 as a drug for treatment of RA, and was launched in 
Japan in 2008 as the third anti-TNF-α inhibitor marketed in Japan. It has been marketed in 
South Korea and Taiwan since 2007. Its efficacy in preventing disease activities and progress 
of joint destruction has been confirmed in clinical studies (Breedveld FC, et al. 2006: 26-37). 
 


D2E7-C000-401 
 
17 
 
2.3 
Nonclinical and clinical studies 
2.3.1 
Nonclinical studies 
MTX inhibited hind paw inflammation, managed body weight gain, and inhibited joint 
destruction in mice with collagen-induced arthritis at repeated doses of 0.05 and 0.1 
mg/kg/day or 0.6 to 1.2 mg/kg/week divided into 3 doses per week. MTX also inhibited hind 
paw inflammation and joint destruction in the chronic phase in mice with group A 
streptococcal cell wall-induced arthritis, an adjuvant arthritis model, at repeated doses of 
0.125 mg/kg/day. MTX inhibited inflammation of the untreated paw in mice with adjuvant 
arthritis at intermittent oral doses of 0.15 to 0.6 mg/kg/week or 0.375 mg/kg/3 weeks. 
ADA (0.01, 0.1, 0.5, 1, and 10 mg/kg) prevented arthritis in transgenic mice bearing the 
human TNFα gene in a dose-dependent manner when administered intraperitoneally three 
times weekly from 1 to 8 weeks of age. The ED50s were 0.25 mg/kg (joint score) and 0.48 
mg/kg (histopathological score). 
 
2.3.2 
Clinical studies 
Like other TNFα inhibitors, the efficacy of ADA used in combination with MTX has been 
confirmed (Breedveld FC, et al. 2006: 26-37). 
Regarding dosage of MTX in combination with ADA, in a study conducted in Western MTX 
naïve patients which the combination of MTX with ADA was simultaneously started, the 
results showed no change in efficacy with dosage of MTX ≥10 mg/week (Burmester GR, et 
al. 2015:1037-44). Meanwhile, another study has been conducted in the U.S. to determine 
whether dosage of MTX may be reduced when ADA is added in MTX failure patients 
(Kaeley GS, et al. 2016: 1480-9), but no conclusion has been drawn. 
Also, there was a study (HOPEFUL 1) conducted in Japanese subjects to evaluate the 
efficacy of ADA in combination with MTX (Takeuchi T, et al. 2014: 536-43); however, this 
study was conducted back then when the MTX dose was restricted to 8 mg/week or lower in 
Japan. A stratified analysis on the results of post-marketing surveillance demonstrated that 
the efficacy hits plateau at an MTX dose of ≥6 mg/week as a concomitant use in bDMARDs 
naïve patients. Meanwhile, in terms of safety, infection and other risks increase at an MTX 
dose of ≥10 mg/week. Accordingly, MTX 8 mg/week is proposed for concomitant therapy in 
bDMARDs naïve patients. Yet, the results were based on a retrospective observational study, 
and further researches are required. 
 
2.4 
Risks and benefits to subjects 
2.4.1 
Expected benefits 
MTX is a drug for which the efficacy for RA as a first-line medication has been adequately 
proven, and is expected to effectively control RA in this study. Also, concomitant use of a 
bDMARD after 24 weeks of treatment with MTX is in compliance with EULAR 
Recommendations 2016. 
Furthermore, if low-dose MTX provides adequate therapeutic effect when used in 
combination with ADA, it would reduce MTX-related ADRs that dose-dependently increase, 
which may not be of a direct benefit for subjects taking in this study, but could help 


D2E7-C000-401 
 
18 
 
establishing more optimal drug usage, and eventually generate benefits for RA patients in the 
future. 
 
2.4.2 
Anticipated risks and disadvantage 
Possible risks in subjects include ADRs related to MTX and ADA. MTX-related ADRs 
include bone marrow depression, as well as infections such as interstitial pneumonia and 
pneumocystis pneumonia, gastrointestinal disorder and liver disorder, and also 
lymphoproliferative diseases. ADRs related to ADA include lupus-like syndrome and 
demyelinating disease (multiple sclerosis, etc.) in addition to those mentioned above. The 
usages of drugs in this study are in line with EULAR Recommendations 2016, and the 
benefits, that is, control of disease activities, and the risk of ADRs were considered when the 
guideline was prepared, and this study is also in line with the guideline. 
Investigational blood sampling may become disadvantage, but the amount of which is not 
much more than what would be required for usual clinical practice, and thus, the risk thereof 
should be negligible. 
There is a potential risk of invasion of privacy since this study involves clinical samples and 
medical information, but such risk will be minimized through anonymization. 
 
2.5 
Route of administration, dosage and administration, and duration of 
treatment 
<MTX> 
MTX should be started at a dosage of 6 to 8 mg/week, and 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), and in principle maintained at the MTD from Week 12 
onward. Also, the dosage of MTX should remain unchanged from Week 20 to 24 except for 
dose reduction/interruption due to an ADR. The drug will be taken orally. In principle, a 
weekly dosage should be taken once or twice in a day. The package insert of each country 
should be referred to for the details of dosage regimen. The duration of treatment will be 48 
weeks. 
The route of administration, and dosage and administration were selected within the range 
specified in the package insert of each country by referring to the EULAR Recommendations 
2016. The duration of treatment was defined as the duration required for the efficacy 
assessments in reference to the EULAR Recommendations 2016. 
 
<ADA> 
If a subject maintains MTX ≥10 mg/week and SDAI remission is not achieved at Week 24, 
the subject should start receiving ADA 40 mg subcutaneously every other week up to Week 
48 (thus, the duration of treatment will be 24 weeks). The package insert of each country 
should be referred to for the details of dosage regimen. 
The route of administration, and dosage and administration were selected according to the 
package insert. The duration of treatment was defined as the duration required for the efficacy 
assessments in reference to the EULAR Recommendations 2016. 


D2E7-C000-401 
 
19 
 
 
2.6 
Applicable rules, etc. 
All investigators involved in this study must comply with "World Medical Association, 
Declaration of Helsinki (Revised version dated October 2013)," "ICH-GCP," and this 
protocol when conducting this study. In Japan, "Clinical Trials Act" must also be complied. 
 
2.7 
Study population 
The study population will be patients with RA in Japan, South Korea, and Taiwan previously 
not treated with MTX, JAK inhibitor, or bDMARDs, and whose duration of disease is within 
2 years from diagnosis. Subjects will be stratified by countries (Japan, South Korea, and 
Taiwan) as a stratification factor. 
 
2.8 
Reference and data 
See Chapter 16.2. 
 
 
3 
Objective 
3.1 
Background 
The efficacy of ADA for treatment of RA patients is known to increase when used in 
combination with MTX. However, an optimal dose of MTX in such combination use is not 
fully studied, and thus, the dosage of MTX monotherapy is often continued to use clinically. 
 
3.2 
Objective 
This study is intended to evaluate the optimal dosage of MTX as an add-on therapy to ADA 
in patients with rheumatoid arthritis (RA) who did not achieve remission by MTX 
monotherapy, and to measure erythrocyte MTX-polyglutamates (PG) concentration to 
evaluate its relation to the efficacy and safety of MTX therapy in RA patients. 
 
3.3 
Purpose 
A lower dosage of MTX, which is effective in combination with ADA in MTX-refractory RA 
patients is expected to reduce MTX-related ADRs that dose-dependently increase. 
 
 
4 
Study design 
4.1 
Endpoints 
4.1.1 
Primary endpoint 
• SDAI remission rate at Week 48 in Concomitant ADA MTX Maximum Tolerable Dose 
Extended Treatment Group and Concomitant ADA MTX Dose Reduction Group 
 
4.1.2 
Secondary endpoints 
• SDAI remission rate at Week 24 
• SDAI remission rate at Week 48 in MTX Monotherapy Group 


D2E7-C000-401 
 
20 
 
• ACR20, ACR50, and ACR70 response rate at each assessment timepoint 
• HAQ remission rate at each assessment timepoint 
• SDAI, CDAI, DAS28-ESR, and DAS28-CRP at each assessment timepoint, and change 
from baseline to each assessment timepoint 
• Tender joint count, swollen joint count, VAS (physician- and patient-reported), HAQ, 
CRP, ESR, MMP-3, RF, and anti-CCP antibody at each assessment timepoint, and 
change from baseline to each assessment timepoint 
• Modified total sharp score (mTSS) at each assessment timepoint, and change from 
baseline to each assessment timepoint 
• Structural remission (mTSS ≤0.5) rate at each assessment timepoint 
• Vital signs and laboratory findings at each assessment timepoint, and change from 
baseline to each assessment timepoint 
• Status of AE (Up to Week 24, and up to Week 48 for each ARM) 
 
4.1.3 
Exploratory endpoints 
• Erythrocyte MTX-PG concentration at Weeks 0, 4, 8, 12, 24, 36, and 48 
• Blood cytokine (IL-6, VEGF) at Weeks 0, 24, and 48 
• Plasma micro RNA at Week 24 
• Serum anti-adalimumab antibody at Weeks 24 and 48 
 
 
 
4.2 
Study method 
This is a multicenter, open-label, randomized, interventional study conducted in patients with 
RA in Japan, South Korea, and Taiwan. 
Principal investigator/sub-investigator shall confirm the inclusion/exclusion criteria of each 
patient, and upon his/her consent, enter necessary information in IWRS. If there is no issue 
with the information entered in IWRS, the subject will be given a subject ID. The enrollment 
completes when the subject ID for a patient is entered into the EDC system. 
After obtaining the consent, a subject will start receiving MTX, and if the subject achieves 
the SDAI remission at Week 24, will continue to receive MTX until Week 48. If the subject 
does not achieve the SDAI remission, ADA 40 mg should be started as an add-on therapy up 
to Week 48, and the subject will be randomized to either a group in which the dosage of 
MTX is maintained or a group in which the dosage of MTX is reduced. 
 
[Rationale] 
RA may be clinically evaluated from 3 aspects; the activity, function, and structure 
of arthritis. The standard indices of RA assessments internationally recognized are 
SDAI and ACR20/50/70 for disease activity assessment, HAQ for functional 
assessment, and TSS for structural assessment. 
 


D2E7-C000-401 
 
21 
 
 
 
4.3 
Bias 
4.3.1 
Randomization 
If a subject does not achieve to clinical remission (SDAI ≤3.3) at Week 24 despite the 
maintenance of MTX dose at ≥10 mg/week, the subject will start receiving ADA as an add-
on therapy. 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). 
Upon completion of Week 24 assessments, principal investigator/sub-investigator shall enter 
the Week 24 dosage of MTX, tender joint count (28 joints), swollen joint count (28 joints), 
VAS (physician- and patient-reported; 10 cm scale), and CRP in IWRS. If all necessary 
information is entered, a relevant treatment group in line with the status of randomization 
(ARM-1, ARM-2 or ARM-3) will be issued by IWRS. 
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. 
 
4.3.2 
Blinding 
No blinding will be performed in this study. 
 
4.4 
Information on study drug 
4.4.1 
Methotrexate (MTX) 
Nonproprietary name: 
Methotrexate 
Brand name: 
Rheumatrex®, etc. 
Dosage form/Dosage: 
Capsules/Tablets, 2 mg/2.5 mg 
 
Pharmacokinetics: 
The maximum blood MTX concentration was in 1 to 2 hours postdose among 17 RA 
patients orally receiving MTX 6 mg/week for 12 weeks. MTX binds with albumin by 53% 
to 60% in the serum. Meanwhile, the MTX concentration in the erythrocyte remains the 
same throughout treatment with MTX even if the serum concentration is low. There are 3 


D2E7-C000-401 
 
22 
 
known metabolic pathways in human, including that by which it is metabolized to 7-OH-
MTX by aldehyde oxidase in the liver, that by which it is metabolized to MTX-PG via 
polyglutamate in the liver or erythrocyte, and that by which it is metabolized to APA by 
carboxy peptidase in enteric bacteria. 
 
Characteristics and action mechanism of the drug: 
MTX is an antifolic drug synthesized for the first time in 1947, and acts on DHFR which 
produces active folic acid necessary for nucleic acid synthesis, and inhibits thymidylate 
synthesis and purine synthesis to obstruct cellular proliferation. It has an 
immunosuppressive and anti-inflammatory effects against T cell, B cell, macrophage, 
neutrophil, vascular endothelial cell, and fibroblast cell, and by which, is thought to 
provide its antirheumatic action. Basically, it should be administered via weekly 
intermittent dose. 
 
Application to autoimmune disease: 
Upon synthesis in 1947, it was widely used for treatment of various types of malignant 
tumor, and then, later confirmed to have an efficacy for rheumatoid arthritis, and then, 
approved in 1988 in the U.S. as an antirheumatic drug. Thereafter, MTX was confirmed to 
have an effect to prevent progression of osteoclasis and to improve vital prognosis, and 
became a first-line drug for treatment of RA. In Japan, it was approved in 1999 after 
completion of phase III study. The maximum dose in Japan is about half of the standard 
dose used overseas, and was approved in February 2011 through an application for partial 
change in the authorization status, and a dosage up to 16 mg/week was allowed for use. 
Also, its efficacy in combination use with bDMARDs has been demonstrated; to date, it is 
still an anchor drug of RA treatment. 
 
Main ADRs (serious ADRs and other relevant reactions: Rheumatrex® Package Insert, 
version 20): 
Shock/anaphylaxis, bone marrow depression, infection, tuberculosis, fulminant 
hepatitis/hepatic failure, acute renal failure/tubular necrosis/severe nephropathy, interstitial 
pneumonia/pulmonary fibrosis/pleural effusion, toxic epidermal necrolysis 
(TEN)/oculomucocutaneous syndrome (Stevens-Johnson syndrome), hemorrhagic 
enterocolitis/necrotising enterocolitis, pancreatitis, osteoporosis, cerebropathy (including 
leukoencephalopathy), and lymphoproliferative disorder 
 
4.4.2 
Adalimumab (ADA) 
Nonproprietary name: 
Adalimumab (recombinant) 
Brand name: 
Humira® 
Dosage form/Dosage: 
Syringe/Pen, 40 mg 
 
Pharmacokinetics: 


D2E7-C000-401 
 
23 
 
The serum drug concentration increased dose-proportionally in subjects receiving a single 
dose of 20, 40, 80 mg; Tmax was 204 hours in the 40 mg group, and its half-life was 298.0 
hours. The steady-state trough concentration of ADA was about 3 μg/mL in Japanese RA 
patients subcutaneously receiving ADA 40 mg every other week. It is a human IgG, and 
like the intrinsic immunoglobulin metabolic process, is taken into the reticular system, and 
assumed to be broken down to its components, amino-acid and glucose in the endosome. 
 
Characteristics and action mechanism of the drug: 
It is the world's first human anti-human TNFα monoclonal antibody that neutralizes TNFα, 
which is a cytokine that involves in inflammatory response and immune reaction, and by 
which, reduces the concentration of TNFα. 
 
Application to autoimmune disease: 
It was approved in December 2002 in the U.S., and in September 2003 in EU. In Japan, 
the dosage of MTX in combination use was different from that in the development 
programs in the U.S. and Europe, and therefore, an ADA monotherapy study was 
conducted in Japan, and the efficacy and safety similar to Western RA patients were 
confirmed in Japanese RA patients, and upon which, it was approved in April 2008. Also, 
a clinical study was conducted in RA patients previously untreated with MTX or 
leflunomide and whose duration of disease was within 2 years, and in which, its efficacy 
in preventing progress of joint destruction was confirmed; upon which, the indication, 
"Rheumatoid arthritis (including prevention of structural joint injury)" was approved in 
August 2012. 
 
Key ADRs (serious ADRs: Humira® Package Insert, version 30): 
Serious infections such as sepsis/pneumonia, tuberculosis, Lupus-like syndrome, 
demyelinating disease, serious allergy, serious hematologic disorders 
(pancytopenia/thrombocytopenia/leukopenia/granulocytopenia), interstitial pneumonia, 
and hepatitis fulminant/hepatic impairment/jaundice/hepatic failure 
 
4.5 
Study period 
This study will be started upon the approval in each study site. The total study duration is 
assumed to be 4 years and 4 months, and the study is scheduled to be completed in June 
2022. 
Enrollment period:  
March 2018 to July 2020 (2 years 
and 5 months) 
Intervention period:  
48 weeks 
Data collection, analysis, and report generation periods: 1 year 
Total study period: 
4 years and 4 months 
 
4.6 
Study interruption/discontinuation 
The withdrawal criteria for individual subject are as shown in 5.3. 


D2E7-C000-401 
 
24 
 
The entire study will be discontinued if either of the below criteria is met. The Lead Principal 
Investigator shall notify the principal investigator of each study site promptly upon her 
decision to discontinue the study. Then, each principal investigator shall promptly notify 
his/her subjects, and provide appropriate medical intervention and take other necessary 
actions. 
1) Certified Review Board which the Lead Principal Investigator request to review 
recommends not to continue the study. 
2) There is a safety concern that prevents this study from continuing further. 
3) The Lead Principal Investigator judges that the entire study should be discontinued. 
 
4.7 
Management of study drug 
Study drug will be obtained and controlled in accordance with each country's relevant 
regulations. 
In Japan, the study drug will be used within the scope of the healthcare insurance; 
accordingly, subjects will obtain and use study drugs available in the market through 
pharmacies. 
 
4.8 
Storage of randomization code, and unblinding process 
Randomization code for this study will be retained in the IWRS system. This is not a blinded 
study, and therefore, no unblinding process will be specified. 
 
4.9 
Specification of source data 
All of the data recorded in EDC must be consistent with the source materials. Source 
materials are defined as documents, data, and records that were documented for the first time, 
such as subjects' informed consent form, medical record (clinical chart), clinical laboratory 
data, ECG data, and X-ray data. 
If the following information is not provided in medical or other record, EDC will be 
considered as the source data. 
• Status of study drug administration (e.g., reason for treatment discontinuation, reason 
for dose modification, etc.) 
• Reason for using concomitant therapy (including drugs and non-drug therapies) 
• Information concerning study discontinuation (e.g., lost to follow) 
• Information concerning AEs (e.g., severity, causality, outcomes, etc.) 
 
 
5 
Inclusion/exclusion/withdrawal criteria 
RA patients meeting all of the following inclusion criteria and not applicable to any of the 
following exclusion criteria will be eligible for this study. 
 
5.1 
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 


D2E7-C000-401 
 
25 
 
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 study drugs and 
hydroxychloroquine (only in South Korea and Taiwan) 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) 
 
5.2 
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, 
or 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 
 


D2E7-C000-401 
 
26 
 
5.3 
Withdrawal criteria 
Subjects should be withdrawn from this study if applicable to any of the discontinuation 
criteria presented below. Upon withdrawal, subjects should undergo assessments and tests for 
early termination. Also, the reason for withdrawal should be as necessary explained to the 
subject, and treatment after withdrawal should be given in a faithful manner to ensure there 
will be no disadvantage to the subject. 
Principal investigator/sub-investigator shall record the date of and reason for withdrawal in 
EDC. Also, for the traceable subjects, their clinical courses are followed up and reported to 
the Study Secretariat. Subjects withdrawn from this study do not need to be replaced 
regardless of the reason for withdrawal. 
1) Subject wishes to discontinue his/her study treatment 
2) Subject wishes to withdraw his/her consent 
3) Serious (or significant) AE occurs, and the study treatment is determined to be 
difficult to continue 
4) A comorbidity (complication, etc.) exacerbates, and the study treatment is determined 
to be difficult to continue 
5) Definitive exacerbation of RA is confirmed 
6) Use of bDMARDs other than ADA or use of JAK inhibitor 
7) MTX at a dosage ≥10 mg/week cannot be maintained at Week 24 due to ADR, etc. 
8) MTX at a specified dosage (ARM-2: 10 to 25 mg/week [the maximum dose should be 
set according to the package insert of each country], ARM-3: 6 to 8 mg/week) cannot 
be maintained after Week 24 due to ADR, etc. 
9) An increased dosage of MTX is required after Week 24 due to loss of efficacy, etc. 
10) Confirmed pregnancy 
11) Confirmed critical protocol deviation 
12) Found to be applicable to an exclusion criterion after enrollment in the study 
13) Other reasons by which the study is not appropriate for continuation as judged by 
principal investigator/sub-investigator 
 
 
6 
Study treatment 
6.1 
Treatment procedure 
Subjects who fulfill the above inclusion criteria, do not meet any of the exclusion criteria, 
will start receiving MTX 6 to 8 mg/week after completing assessments 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 


D2E7-C000-401 
 
27 
 
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. 
The dose status of MTX, folic acid, and ADA, as well as the treatment groups in Week 24 
onward (ARM-1 to -3) should be recorded in EDC. 
 
6.1.1 
Dose selection of MTX for study treatment 
This study is intended to evaluate the optimal dosage of MTX in combination with ADA by 
comparing between a group (ARM-2) maintaining the dosage of MTX at the maximum 
tolerable dose (MTD； ≥10 mg/week) and a group (ARM-3) reducing the dosage of MTX to 
6 to 8 mg/week. 
In ARM-2, MTX is maintained at the MTD. Not overlapping the dosage of MTX in ARM-3, 
the lower limit of MTD was determined to be 10 mg/week based on the results of the HAWK 
post-marketing surveillance study of ADA in which the mean dosage of the combined use of 
MTX was 12.7 mg/week, and it also showed the dosage of MTX of ≥10 mg/week could be 
maintained in combination with ADA (Tanaka Y, et al. 2018: 1-9) and the results of the 
CONCERTO study conducted in the US and Europe, which confirmed no differences in 
efficacy among MTX doses of ≥10 mg/week in combination with ADA (Burmester GR, et al. 
2015:1037-44).  
The dosage of MTX in ARM-3 was determined based on the results of the HOPEFUL 1 
study, which confirmed that MTX is effective at doses of 6 to 8 mg/week in combination 
with ADA (Takeuchi T, et al. 2014: 536-43). 
 


D2E7-C000-401 
 
28 
 
6.2 
Concomitant therapies 
Allowed concomitant therapy and prohibited concomitant therapy are as follows. The dosage 
and administration route of drugs used for treatment of RA during the study should be 
recorded in EDC. 
 
6.2.1 
Allowed concomitant therapy 
Oral and suppository formulations (both ≤10 mg/day prednisolone equivalents) and external 
application (dermatologics, eye-drops, nasal drops, and inhalants) of corticosteroids and 
NSAIDs are allowed for concomitant use; provided that the dosages of corticosteroid oral 
drug and suppository should in principle remain unchanged from Week 24 to 48. Moreover, 
subjects are allowed to use corticosteroids via an intracapsular administration (except for 28 
days before efficacy assessment), intravenous corticosteroids (10 mg/day prednisolone 
equivalents) temporarily prescribed because of difficulties in oral administration and other 
reasons, and corticosteroids temporarily prescribed for indications other than rheumatoid 
arthritis. 
 
6.2.2 
Prohibited concomitant therapy 
DMARDs other than MTX and ADA are prohibited during the study. Concomitant use of 
Hydroxychloroquine in South Korea and Taiwan is acceptable, on condition that in principle 
the dosage should not change between Week 24 and 48. Subjects receiving a non-ADA 
bDMARD or JAK inhibitor will be withdrawn from the study immediately upon the start of 
such treatment. 
Concomitant use of opioid analgesics except for Tramadol is prohibited in this study. 
Although the use of Tramadol is possible, when used it should be administered except for 3 
days prior to the efficacy assessment. 
 
6.3 
Compliance 
Principal investigator/sub-investigator shall verify with each subject at each visit the status of 
dose (self-administration) concerning MTX, folic acid, and ADA to ensure their dose 
compliance. The patient compliance instruction should be provided at any time upon finding 
non-compliance to the instruction on dose (self-administration) given by the doctor. The data 
on dose compliance concerning study drugs to be recorded in EDC must be based on the 
record of actual dose (self-administration). 
 
 
7 
Assessments 
7.1 
Demography 
The following information should be collected and recorded in EDC at Screening (within 8 
weeks before the start of study treatment). In addition to the information, subject ID, the 
status of informed consent, and the results of eligibility assessment should also be recorded in 
EDC. 
1) Gender 


D2E7-C000-401 
 
29 
 
2) Age (at consent) 
3) Race 
4) Height and body weight 
5) Time of RA diagnosis 
6) Compliance to 1987 ACR revised criteria or 2010 ACR/EULAR criteria 
7) RA treatment history (steroid, DMARDs, NSAIDs, etc.) 
8) History of RA surgery 
9) Medical history/Complication 
10) Smoking history 
11) 12-lead ECG (Not required if performed within 12 weeks before consent) 
12) Infection disease test (Not required if performed within 2 years before consent): 
• Either skin tuberculin test or interferon gamma release assay (IGRA) 
• HBs antigen, HBs antibody, HBc antibody, and anti-HCV antibody 
When a HBs Antigen (Ag)-negative subject is HBs Antibody (Ab) positive and/or HBc Ab 
positive, the subject must be tested for HBV-DNA quantification for at least once every 6 
months. 
 
7.2 
Efficacy assessments 
7.2.1 
X rays of hands and feet 
In accordance with the assessment schedule presented in the following table, X rays of 
subjects' hands and feet will be performed at screening, and Weeks 24 and 48 (or at early 
termination). The X-rays of the hands and feet are unnecessary to be performed for early 
termination if early termination occurs within 28 days after the last X-rays. The X-ray image 
of the hands and feet should be sent to the study secretariat along with the subject ID. 
The X-ray image of the hands and feet will be independently reviewed by the X-ray Imaging 
Review Committee to evaluate bone erosions in the regions specified on the left side of the 
figure shown below, and also to evaluate joint space narrowing in the regions specified on the 
right side of the figure shown below, both in terms of mTSS, and the results will be sent to 
the data center. 
Bone erosions will be evaluated for each region in accordance with the following score: 
Score 1: Small bone erosion 
Score 2: Large bone erosion (Not extend over the imaginary middle of the bone) 
Score 3: Large bone erosion (Extends over the imaginary middle of the bone) 
Score 5: Complete collapse of the joint 
The score will be 0 to 5 for each hand region, and 0 to 10 for each foot region. 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 in accordance with the following 
score: 
Score 1: Localized or merely suspected 
Score 2: Generalized narrowing (≥50% joint space remaining) 
Score 3: Generalized narrowing (≤50% joint space remaining) or subluxation 


D2E7-C000-401 
 
30 
 
Score 4: Disappearance of joint space, or anchylosis 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. 
 
  
 
 
Source: Swinkels HL, et al. 2001: 176-90 
 
7.2.2 
Tender joint count, swollen joint count, VAS (physician- and patient-
reported), and HAQ 
In accordance with the assessment schedule presented in the following table, tender joint 
count, swollen joint count, VAS (physician- and patient-reported disease activities, and 
patient-reported pain score), and HAQ will be evaluated, and the results will be recorded in 
EDC. 
HAQ score ≤0.5 is defined as functional remission. 
 
7.2.3 
CRP, ESR, MMP-3, RF, and anti-CCP antibody 
In accordance with the assessment schedule presented in the following table, blood samples 
for CRP, ESR, MMP-3, RF, and anti-CCP antibody will be collected and evaluated. In South 
Korea and Taiwan, MMP-3 will be measured at the external laboratory only at the essential 
time points (blood collection at screening will be performed at Week 0 together with other 
assessments measured at the external laboratory). The results of measurement will be 
recorded in EDC. 
 
7.2.4 
SDAI 
SDAI will be calculated with the following formula and based on the evaluation results of 
tender joint count, swollen joint count, VAS (physician- and patient-reported; 10 cm scale), 
and CRP. 
• Tender joint count (28 joints) + Swollen joint count (28 joints) + Patient-reported 
disease activity / 10 + Physician-reported disease activity / 10 + CRP 
Disease activities will be categorized to High disease activity: >26, Moderate disease activity: 
>11 to ≤26, Low disease activity: ≤11, and Remission: ≤3.3. 
 


D2E7-C000-401 
 
31 
 
7.2.5 
CDAI 
CDAI will be calculated with the following formula and based on the evaluation results of 
tender joint count, swollen joint count, and VAS (physician- and patient-reported; 10 cm 
scale). 
• Tender joint count (28 joints) + Swollen joint count (28 joints) + Patient-reported 
disease activity / 10 + Physician-reported disease activity / 10 
Disease activities will be categorized to High disease activity: >22, Moderate disease activity: 
>10 to ≤22, Low disease activity: ≤10, and Remission: ≤2.8. 
 
7.2.6 
ACR 20, 50, 70 response rates, and ACR-N 
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 
ACR 50 response, ACR 50 response rate, ACR 70 response, and ACR 70 response rate are 
defined by the standards that 20% improvement of ACR 20 response and ACR 20 response 
rate is replaced to 50% and 70% improvement, respectively. 
Also, ACR-N will be the lowest improvement rate among the following 3 parameters: 
• Improvement rate of the tender joint count (of the total 68 joints) compared to Week 0 
of treatment 
• Improvement rate of the swollen joint count (of the total 66 joints) compared to Week 0 
of treatment 
• The 3rd highest improvement rate among the 5 parameters (physician- and patient-
reported disease activities, patient-reported pain score, HAQ, and CRP) compared to 
Week 0 of treatment 
 
7.2.7 
DAS28-ESR 
DAS28-ESR will be calculated with the following formula and based on the evaluation 
results of tender joint count, swollen joint count, VAS (patient-reported; 100 mm scale), and 
ESR. 
• DAS28-ESR = 0.56 × √ [Tender joint count (28 joints)] + 0.28 × √ [Swollen joint count 
(28 joints)] + 0.70 × ln (ESR) + 0.014 × Patient-reported disease activity 
Disease activities will be categorized to High disease activity: >5.1, Moderate disease 
activity: >3.2 to ≤5.1, Low disease activity: ≤3.2, and Remission: <2.6. 
 


D2E7-C000-401 
 
32 
 
7.2.8 
DAS28-CRP 
DAS28-CRP will be calculated with the following formula and based on the evaluation 
results of tender joint count , swollen joint count, VAS (patient-reported; 100 mm scale), and 
CRP. 
• DAS28-CRP = 0.56 × √ [Tender joint count (28 joints)] + 0.28 × √ [Swollen joint count 
(28 joints)] + 0.36 × ln (CRP × 10 + 1) + 0.014 × Patient-reported disease activity + 
0.96 
Disease activities will be categorized to High disease activity: >4.1, Moderate disease 
activity: >2.7 to ≤4.1, Low disease activity: ≤2.7, and Remission: <2.3. 
 
7.3 
Biomarkers assessment (investigational blood sampling) 
7.3.1 
Erythrocyte MTX-polyglutamates concentration 
In accordance with the assessment schedule presented in the following table, an 
anticoagulant-containing blood collection tube (EDTA-2K) will be used to draw blood (≤3 
mL) for the measurement of erythrocyte MTX-polyglutamates (PG) concentration. The 
erythrocyte layer will be separated in accordance with the following sample processing 
procedure, and submitted to the external laboratory along with the subject ID. The 
measurement will be performed by the external laboratory, and the results will be sent to the 
data center directly from the laboratory. 
<Sample processing procedure> 
[1] Draw and collect the blood in EDTA-2K, and immediately centrifuge the sample in 
the collection tube (1,400×g, 5 minutes, 4°C). 
[2] Remove the plasma and leucocyte layers. 
[3] Add normal saline by the same amount as the erythrocyte layer, and invert and mix 
the sample. 
[4] Centrifuge the sample (1,400×g, 5 minutes, 4°C) to remove the layer of the normal 
saline. 
[5] Transfer the erythrocyte layer (about ≥300 μL) to a polypropylene microfuge tube, 
and store it in a freezer at a temperature -20°C to -80°C. 
The specimen should be handled at 4°C or in icy environment as much as possible. 
If the sample cannot be centrifuged immediately following blood collection in EDTA-2K, the 
sample tube should be stored in a refrigerator, and processed in principle within the same day 
(within 24 hours at the latest). 
 
7.3.2 
Blood cytokine level 
In accordance with the assessment schedule presented in the following table, a blood sample 
(≤20 mL) will be collected for measurement of blood cytokine (IL-6: serum, VEGF: plasma). 
The sample (serum and plasma) should be processed in accordance with the procedures 
separately specified, and submitted to the external laboratory along with the subject ID. The 
measurement will be performed by the external laboratory, and the results will be sent to the 
data center directly from the laboratory. 
 


D2E7-C000-401 
 
33 
 
7.3.3 
Plasma micro RNA 
A blood sample (3 mL) for measurement of plasma micro RNA will be collected at Week 24 
visit. The plasma sample should be processed in accordance with the procedures separately 
specified, and submitted to the external laboratory along with the subject ID. The 
measurement of plasma micro RNA will be performed only for subjects receiving ADA 
(ARM-2 and ARM-3); the samples will be measured by the external laboratory, and the 
results will be sent to the data center directly from the laboratory. 
 
7.3.4 
Serum anti-adalimumab antibody 
In accordance with the assessment schedule presented in the following table, a blood sample 
(3 mL in Japan, 5 mL in South Korea and Taiwan) will be collected for measurement of 
serum anti-adalimumab antibody. The sample should be processed in accordance with the 
procedures separately specified, and submitted to the external laboratory along with the 
subject ID. The measurement of serum anti-adalimumab antibody will be performed only for 
subjects receiving ADA (ARM-2 and ARM-3); the samples will be measured by the external 
laboratory, and the results will be sent to the data center directly from the laboratory. 
 
7.4 
Safety assessment 
In accordance with the assessment schedule presented in the following table, the following 
assessments and tests will be performed, and the results will be recorded in EDC. Clinical 
laboratory should be performed in the study site. 
1) General symptoms 
2) Vital signs (blood pressure, pulse rate, and body temperature) 
3) Height and body weight 
4) Chest X ray 
5) Physical examinations 
6) Clinical laboratory 
[1] Hematology: WBC, differential count, RBC, Hb, MCV, and Plt 
[2] Chemistry: BUN, Cr, UA, total bilirubin, AST, ALT, LDH, γGTP, ALP, total 
protein, and albumin 
[3] Immunology: IgG 
 
7.4.1 
Evaluation of AEs 
Principal investigator/sub-investigator shall monitor for possible occurrence of AEs 
throughout the course of this study, and record in EDC all AEs that occur in the study. 
The following ADRs are known for the study drug; for which, treatment should be given 
according to respective symptoms. Also, any event suspected to be related to the study drug 
or for which treatment discontinuation is expected to improve conditions or prevent 
progression should be managed with dose reduction or treatment discontinuation. 
<MTX> 
1) Shock, anaphylaxis 
2) Bone marrow depression 


D2E7-C000-401 
 
34 
 
3) Infection 
4) Tuberculosis 
5) Hepatitis fulminant/hepatic failure 
6) Acute renal failure, tubular necrosis, severe nephropathy 
7) Interstitial pneumonia/pulmonary fibrosis/pleural effusion 
8) Toxic epidermal necrolysis (TEN), oculomucocutaneous syndrome (Stevens-Johnson 
syndrome) 
9) Enterocolitis haemorrhagic, necrotising enterocolitis 
10) Pancreatitis 
11) Osteoporosis 
12) Encephalopathy (including leukoencephalopathy) 
13) Lymphoproliferative disorder 
 
<ADA> 
1) Serious infections such as sepsis/pneumonia 
2) Tuberculosis 
3) Lupus-like syndrome 
4) Demyelinating disease 
5) Serious allergy 
6) Serious hematologic disorders (pancytopenia, thrombocytopenia, leucopenia, 
granulocytopenia) 
7) Interstitial pneumonia 
8) Fulminant hepatitis, hepatic impairment, jaundice, hepatic failure 
 


D2E7-C000-401 
 
35 
 
7.5 
Assessment schedule 
Assessments should be performed in accordance with the following schedule. 
Screening period will be within 8 weeks before the start of study treatment. Assessment time 
points are counted from Week 0, and assessments should be performed within ±1 week from 
each timepoint (Week 4 to 12), and ±2 weeks from each timepoint (Week 24 onward).  
Assessments 
Screening 
period 
Wk 0 
Wk 4 
Wk 8 
Wk 12 Wk 24 Wk 36 
Wk 48 or 
ET 
Informed consent 
    ○*1 
 
 
 
 
 
 
 
Demographics 
○ 
 
 
 
 
 
 
 
Eligibility 
○ 
 
 
 
 
 
 
 
History of disease/surgery 
○ 
 
 
 
 
 
 
 
Concomitant therapy 
General symptoms 
○ 
○ 
○ 
○ 
○ 
○ 
○ 
○ 
Vital signs 
(○) 
○ 
 
 
 
○ 
 
○ 
Height, body weight 
○ 
 
 
 
 
○ 
 
○ 
Physical examinations 
○ 
○ 
○ 
○ 
○ 
○ 
○ 
○ 
Tender joint count, swollen 
joint count 
○ 
○ 
○ 
○ 
○ 
○ 
○ 
○ 
Evaluation using VAS 
(physician- and patient-
reported) 
○ 
○ 
○ 
○ 
○ 
○ 
○ 
○ 
Assessment using HAQ 
(○) 
○ 
○ 
○ 
○ 
○ 
○ 
○ 
12-lead ECG 
    ○*2 
 
 
 
 
 
 
 
Chest X ray 
    ○*2 
 
 
 
 
○ 
 
○ 
X ray of hands and feet 
    ○*2 
 
 
 
 
○ 
 
○*4 
Infection disease test 
    ○*3 
 
 
 
 
 
 
 
Clinical laboratory 
(hematology, chemistry) 
(○) 
○ 
○ 
○ 
○ 
○ 
○ 
○ 
IgG 
    ○*2 
 
 
 
 
○ 
 
○ 
CRP, ESR 
○ 
○ 
○ 
○ 
○ 
○ 
○ 
○ 
MMP-3, RF 
    ○*2 
(○) 
(○) 
(○) 
○ 
○ 
○ 
○ 
Anti-CCP antibody 
    ○*3 
 
 
 
 
 
 
(○) 
MTX-PG 
 
○ 
○ 
○ 
○ 
○ 
○ 
○ 
Cytokine 
 
○ 
 
 
 
○ 
 
○ 
Micro RNA 
 
 
 
 
 
○ 
 
 
Anti-adalimumab antibody 
 
 
 
 
 
○ 
 
○ 
AEs 
*1：The informed consent of the study should be obtained prior to the screening test. However, the data before obtaining 
the consent may be included in the study if they have been assessed within the designated period. 
*2：The test results may be used if they were obtained within 12 weeks before consent. Also, the test may be performed 
at Week 0 
*3：The test results may be used if they were obtained within 2 years before consent. Also, the test may be performed at 
Week 0 
*4：The X rays of the hands and feet is unnecessary to be performed for early termination if early termination occurs 
within 28 days after the last X-rays. 
○: Essential items, (○): Optional items 
 
 


D2E7-C000-401 
 
36 
 
8 
Adverse events 
8.1 
Definition 
8.1.1 
Definition of adverse event (AE) 
AE is any untoward medical occurrence in a subject administered the study drug, whether or 
not it is related to the study treatment. That is, an adverse event is any exacerbation of 
conditions pre-existed prior to the start of study treatment, any untoward or unintended 
clinical signs, and abnormal change in vital signs. 
Exacerbation of the underlying disease (RA) should also be handled as an AE if such 
exacerbation is beyond the scope of initial expectation. An abnormal change in clinical 
laboratory value or vital sign should be handled as an AE if it results in discontinuation of 
study treatment, requires intervention, or is otherwise determined to be an AE by principal 
investigator or sub-investigator. 
AEs that occur or exacerbate after the initial dose and no later than Week 48 of study 
treatment shall be handled as an AE. 
 
8.1.2 
Definition of serious adverse events (SAE) 
SAE is any untoward medical event occurring regardless of the dosage of study drug that; 
• Results in death; 
• Is life-threatening (the term "life-threatening" in this definition refers to an event in 
which the subject is at immediate risk of death given the nature of event that is present; 
it does not refer to an event that hypothetically might cause death if it were more 
severe, or the study treatment had continued); 
• Requires inpatient hospitalization or prolongation of existing hospitalization; 
• Results in perpetual or significant disability/incapacity; or 
• Is a congenital anomaly/birth defect (that is observed in a child of a patient who has 
been exposed to the study drug) 
Other important medical events that may not be immediately life-threatening or result in 
death or hospitalization but, when based on appropriate medical judgment, may jeopardize 
the subject or may require intervention to prevent one of the outcomes in the definition of 
SAE listed above should also be considered SAEs. 
The principal investigator judges whether an AE is a “SAE” or not. 
An SAE shall be followed up until it is resolved, or its symptoms stabilize if not expected to 
be resolved. 
Meanwhile, hospitalization not accompanied by an AE shall not be handled as an SAE, such 
as; 
• Hospitalization for temporary recuperation due to a reason other than AEs; 
• Hospitalization that has been scheduled prior to informed consent (for conditions that 
required hospitalization before the start of study treatment, and remain unchanged after 
the start of study treatment); 
• Hospitalization required for the administration of study drug; or 
• Hospitalization intended for periodic maintenance of medical device (e.g., battery 
replacement) that has been used since before the start of study treatment. 


D2E7-C000-401 
 
37 
 
 
8.1.3 
Evaluation of severity 
Principal investigator or sub-investigator shall evaluate the severity of AEs for 3 levels (mild, 
moderate, and severe), and record the results in EDC. 
• Mild: Discomforting but not to an extent that obstructs activities of daily living 
• Moderate: Discomfort that obstructs activities of daily living 
• Severe: Unable to work or carry out normal activities of daily living 
The severity assessment of AEs is different from the assessment of seriousness (See section 
8.1.2). 
 
8.1.4 
Evaluation of causal relation with the study drug 
Causal relation of AEs with each study drug shall be evaluated for the following 2 levels, and 
accordingly recorded in EDC. 
• Related: There is a possible reasonable causality between the study treatment and AE. 
• Unrelated: There is no reasonable causality between the study treatment and AE. 
 
Causality between the study treatment and AE should be evaluated in consideration of; 
• Temporal relationship between the timing of AE and the start of study treatment; 
• Clinical course of AE, especially the effect of discontinuation and/or resumption of 
study treatment if applicable; 
• Whether the AE is known for the study drug or drugs of the same class; 
• The presence/absence of risk factor that may increase the incidence of AE in subjects 
with the underlying disease; and 
• The presence/absence of confounding factors related to AE but unrelated to the study 
drug. 
 
8.2 
Procedures for collection, documentation, and reporting of SAEs 
Upon detection of an SAE, the principal investigator shall report all SAEs regardless of the 
causality with the study drug to the study secretariat (SAE Report Center) as promptly as 
possible (within 1 business day in principle) using the SAE report form (Attachment 1). The 
principal investigator shall also report the information to Hospital Director (also to the 
Ethical Review Board in South Korea and Taiwan) if he/she judges that the SAE is causally 
“related” to the study drug. When sub-investigators, etc. other than the principal investigator 
detect a suspected SAE, they shall report it to the principal investigator promptly. 
The study secretariat (SAE Report Center) reports to the Lead Principal Investigator and 
Eisai Co., Ltd. within 2 business days after receiving the information. The Lead Principal 
Investigator reports a drug-related SAE to the Certified Review Board within the period 
specified by the Clinical Trials Act and also should report it to the principal investigators of 
the other study sites. In Japan, the principal investigators who receive the report shall report 
the event to Hospital Director of the study site to which they belong. 
All SAEs that occur on or before the final study-related visit should be collected regardless of 
the causality with the study treatment. All SAEs must be followed up until they are resolved, 


D2E7-C000-401 
 
38 
 
or their symptoms stabilize if not expected to be resolved. Any SAE after study completion, 
for which a causality with the study drug (or protocol-specified procedures) cannot be ruled 
out as judged by the principal investigator or sub-investigator, must be reported to the study 
secretariat regardless of the time from study completion. 
It is important to complete the initial SAE report Form as detailed as possible including the 
evaluation of causality with the study treatment as determined by the principal investigator or 
sub-investigator. 
Any follow-up information received on SAEs should be forwarded by the principal 
investigator to the study secretariat within 1 business day of its receipt. If the follow-up 
information changes the investigator’s assessment of causality, this should also be noted on 
the follow-up SAE report form. 
Preliminary SAE reports should be followed as soon as possible by detailed descriptions 
including copies of hospital case reports, autopsy reports, and other documents requested by 
the study secretariat. 
 
8.2.1 
Reportable events 
All SAEs that occur between the commencement of study treatment and the final study visit 
are reportable regardless of causality with the study treatment or protocol-defined procedures. 
For subjects receiving ADA, all cases of premalignancies and malignancies, pregnancy, and 
breastfeeding from subjects who received ADA should also be reported to the study 
secretariat (SAE Report Center) using the same SAE report form. Furthermore, the overdose, 
misuse, abuse, medication error, off-label use, occupational exposure, accidental exposure, 
and unexpected therapeutic effect of ADA and AEs attributable to suspected transmission of 
any infectious agent should also be reported using the SAE report form (see section 8.2). 
Among these events, regarding AEs attributable to suspected transmission of any infectious 
agent from subjects receiving ADA, the Lead Principal Investigator should report a drug-
related AE to the Certified Review Board within the period specified by the Clinical Trials 
Act and also should report it to the principal investigators of the other study sites. In Japan, 
the principal investigators receiving the report shall report the event to Hospital Director of 
the study site to which they belong to. All other events will be handled as an SAE only if 
applicable to the definition of SAE in section 8.1.2; those not applicable as an SAE do not 
need to be reported to Certified Review Board (Japan)/Ethical Review Board (South Korea 
and Taiwan) nor Hospital Director. Meanwhile, all of these AEs should be recorded in EDC 
whether applicable to the above SAE definition or not. 
 
8.3 
Follow-up of subjects after AEs 
8.3.1 
Follow-up 
All AEs must be followed up for 70 days from the final dose of study drug or until recovery, 
whichever comes first; provided that an SAE must be followed up until it is resolved, or its 
symptoms stabilize if not expected to be resolved. 
 


D2E7-C000-401 
 
39 
 
8.3.2 
Insurance for health damage 
A health damage related to the study treatment should be handled pertinent to the subject's 
healthcare insurance coverage. Patients will incur the cost for treatment of health damage 
based on the health system of each country. 
A clinical study insurance will be purchased by sponsor as a measures for a compensation for 
death and severe impairment (grade 1 or 2) that may occur in subjects taking part in this 
study. 
 
 
9 
Statistical analysis 
9.1 
Statistical analysis set 
(1) Full analysis set (FAS) 
FAS is defined as a group of subjects who receive study drug (MTX) and have evaluable 
efficacy data at 1 or more time points following the administration of study drug. 
Modified FAS (mFAS) is defined as a group of subjects who are randomized after Week 24, 
receive study drug (ADA), and have evaluable efficacy endpoint at 1 or more time points 
following the administration of study drug. 
 
(2) Per Protocol Set (PPS) 
PPS is defined as a group of subjects among mFAS who adequately complied with the 
protocol. The detailed criteria to determine the suitability of subjects to the analysis sets will 
be finalized before database lock, and specified in the statistical analysis plan. 
 
(3) Safety analysis set: 
Safety analysis set is defined as a group of subjects who receive study drug (MTX) and have 
evaluable safety data at 1 or more time points following the administration of study drug. 
 
9.2 
Analytical method 
9.2.1 
Method of efficacy analysis 
The analysis of primary efficacy endpoint will be performed on mFAS as the main analysis 
set, and on PPS as a supplementary analysis set. All other analyses will be performed 
exclusively on FAS. 
 
9.2.1.1 
Method of analysis for primary efficacy endpoint 
The primary analysis for this study is intended to demonstrate the non-inferiority of 
ADA/MTX-Reduced Dose Group (ARM-3) to ADA/MTX-MTD Group (ARM-2) in terms of 
the primary endpoint, that is, SDAI remission rate at Week 48. The intergroup difference in 
the SDAI remission rate and its two-tailed 90% confidence interval will be calculated based 
on a stratified analysis with country as a factor in mFAS as the main statistical analysis set. 
The non-inferiority margin shall be -15%. 


D2E7-C000-401 
 
40 
 
Moreover, a multivariate statistical analysis on the SDAI remission rate at Week 48 will be 
performed for the following variables; age, gender, autoantibody profile, SDAI at screening, 
and change in mTSS from screening to Week 24. 
 
9.2.1.2 
Method of analysis for secondary efficacy endpoints 
SDAI remission rate at Week 24, SDAI remission rate at Week 48 in MTX Monotherapy 
Group (ARM-1), ACR20, ACR50, and ACR70 response rates, HAQ remission rate, and 
structural remission rate at each assessment timepoint, and their two-tailed 95% confidence 
intervals will be calculated for each ARM. Furthermore, ARM-2 and ARM-3 at Week 48 will 
be compared using a stratified analysis with country as a factor. 
Summary statistics (mean, standard deviation, median, and range) in each ARM at each 
assessment timepoint will be calculated for SDAI, CDAI, DAS28-ESR, DAS28-CRP, tender 
joint count, swollen joint count, VAS (physician- and patient-reported), HAQ, CRP, ESR, 
MMP-3, RF, anti-CCP antibody, and mTSS, and their changes from baseline to each 
assessment timepoint. For mTSS at Week 48, changes from Week 24 will also be analyzed 
for the summary statistics. In addition, ARM-2 and ARM-3 will be compared in terms of 
changes from Week24 to Week 48 using a stratified analysis with country as a factor. 
 
9.2.2 
Method of biomarker analysis 
The biomarker analysis will be performed on FAS. 
Summary statistics in each ARM will be calculated for erythrocyte MTX-PG concentrations 
and blood cytokine levels, as well as change from baseline and % change from baseline. 
Also, the correlation of SDAI, mTSS, and ACR-N to erythrocyte MTX-PG concentration will 
be evaluated. Furthermore, the correlation of SDAI and ACR-N to plasma microRNA will be 
evaluated. 
For serum anti-adalimumab antibody, the frequency of and the proportion of subjects with the 
antibody expression will be calculated. 
 
9.2.3 
Method of safety 
The safety analysis will be performed on the safety analysis set. Summary statistics 
concerning safety data (Continuous variables: the number of subjects, mean, standard 
deviation, median, minimum, and maximum, and Categorical variables: the number and 
proportion of subjects) will be computed for each ARM. Variables of safety analysis include 
AEs, clinical laboratory, and vital signs. 
 
9.2.3.1 
Adverse events (AEs) 
AEs recorded in EDC will be reinterpreted with ICH Medical Dictionary for Regulatory 
Activities (MedDRA). AEs recorded in EDC will be reinterpreted to the closest MedDRA 
lowest level terms (LLT) (Ver. 19.0 or later version). Preferred term (PT) and system organ 
class (SOC) will also be entered in the database. 


D2E7-C000-401 
 
41 
 
Treatment-emergent adverse events (TEAE) means AEs not confirmed before the study 
treatment (MTX) and emerges for the first time after the start of study treatment. TEAE also 
includes: 
• Events confirmed before the study treatment which disappears immediately before the 
start of study treatment, but reemerges during the study treatment; and 
• Events confirmed before the study treatment, which becomes severer during the study 
treatment compared to the level of severity before the start of study treatment. 
TEAE will be used for the analysis of AEs. The number (proportion) of subjects with TEAE 
in each ARM will be tabulated in SOC and PT. Two or more AEs with the same MedDRA 
term may be reported in a single subject; in such case, the AEs will be interpreted and 
counted as 1 subject pertinent to the analysis, and also the AE with the highest severity will 
be counted in for the analysis on the number (proportion) of subjects with the TEAE. 
Furthermore, the number (proportion) of subjects with TEAE will be tabulated by the 
presence/absence of causality. 
In addition, TEAE for which causality with the study treatment cannot be ruled out (ADR) 
will be tabulated in terms of SOC and PT, and the AEs with the highest severity will be 
counted in for the analysis on the number (proportion) of subjects. 
The incidence of TEAE that occur from Week 24 to 48 will be compared between ARM-2 
and ARM-3 using a Fisher's exact test or other relevant method. 
 
9.2.3.2 
Clinical laboratory 
For continuous variables, summary statistics of measurements at each timepoint and their 
changes from baseline will be calculated. 
As an order categorical variable, clinical laboratory values will be categorized to Lower than 
the reference (L), Within the reference (N), and Higher than the reference (H), and then the 
number and proportion of subjects by L, N, and H will be presented in a shift table (baseline 
vs. each visit during treatment) for each ARM. In addition, the maximum and minimum 
values after the start of treatment will be presented in a shift table for comparison with 
baseline. 
 
9.2.3.3 
Vital signs and body weight 
Summary statistics of vital signs (diastolic blood pressure, systolic blood pressure, pulse rate, 
body temperature) and body weight at each assessment timepoint and their changes from 
baseline will be computed for each ARM. 
 
9.3 
Significance level 
The analysis on non-inferiority will be performed with a two-tailed confidence interval of 
90%. A two-tailed significance level of 5% will be used for all other analyses unless specified 
otherwise. 
 
9.4 
Number of subjects 
• Target number of subjects to be enrolled 


D2E7-C000-401 
 
42 
 
300 subjects (target number of subjects to be enrolled in each study site is shown in the list 
of study sites.) 
• Randomization ratio 
Subjects will be stratified by countries (Japan, South Korea, and Taiwan) as a stratification 
factor, and for each stratum, randomized to ARM-2 and ARM-3 at the ratio of 1:1. 
 
9.4.1 
Sample size selection 
Assuming that the SDAI remission rate is 30% for both ARM-2 and ARM-3, and the non-
inferiority margin is -15%, the number of subjects required for the lower bound of a two-
tailed 90% confidence interval for the intergroup difference in SDAI remission rate to exceed 
the non-inferiority margin at 80% power of detection would be 220 subjects in total (110 in 
each group). 
Past reports suggest that the remission rate of MTX monotherapy is about 15%. Also, it has 
been reported that about 10% of patients cannot continuously receive MTX ≥10 mg/week 
(Atsumi T, et al. 2016: 75-83). Thus, in order to randomize 220 subjects between ARM-2 and 
ARM-3, 288 subjects need to be enrolled, and considering some dropouts, a sample size of 
300 subjects was selected as the target number of subjects to be enrolled. 
 
<Justification for the estimated SDAI remission rate in ADA/MTX-Reduced Dose Group 
(ARM-3)> 
The estimated SDAI remission rate in ARM-3 was calculated in reference to the results of 
the MTX Monotherapy  ADA+MTX Group in HOPEFUL 1 Study in which Japanese 
MTX naïve patients receiving ADA+MTX or MTX alone for 26 weeks, and then, all 
subjects receiving ADA+MTX for another 26 weeks (Takeuchi T, et al. 2014: 536-43). 
Since the maximum dosage of MTX in HOPEFUL 1 Study was 8 mg/week (6.6±0.8 
mg/week: Mean±SD), the results cannot be directly extrapolated to this study in which the 
maximum dosage of MTX up to Week 24 will be 16 mg/week; yet, the results would be 
appropriate to use as a reference for the SDAI remission rate in ARM-3 in which the 
dosage of MTX will be reduced to 6 to 8 mg/week from Week 24 onward. 
ARM-3 is designed for patients who have not achieved to SDAI remission at Week 24; 
thus, assuming that the subjects with SDAI remission at Week 26 in HOPEFUL 1 Study 
(20 subjects = 163 subjects × 12%) remain to be remission at Week 52, the Week-52 
SDAI remission rate among the subjects with SDAI non-remission at Week 26 was 
calculated to be 31.5% [45/143 subjects, that is (65 subjects - 20 subjects)/(163 subjects - 
20 subjects)]. Therefore, the SDAI remission rate in ARM-3 was assumed to be 30%. 
 
<Justification for the estimated SDAI remission rate of ≤3.3 in ARM-2 (ADA/MTX-MTD 
Group)> 
There is no data on SDAI remission rate on ADA as add-on therapy given in Japanese 
patients previously receiving adequate amount of MTX for ≥6 months. However, it has 
been reported that there was no difference in efficacy of MTX at dosage ≥10 mg/week in a 
clinical study in which Western MTX naïve patients started concomitantly receiving ADA 


D2E7-C000-401 
 
43 
 
and MTX at the same time (Burmester GR, et al. 2015:1037-44), and that there was no 
difference in DAS28-ESR remission rate between a low-dose concomitant MTX group (8 
to ≤12 mg/week) and high-dose concomitant MTX group (>12 to 16 mg/week) according 
to a stratified analysis on a study in which Japanese MTX naïve patients started 
concomitantly receiving certolizumab pegol (CZP) and MTX at the same time (Atsumi T, 
et al. 2016: 75-83). Thus, the SDAI remission rate in ARM-2 was assumed to be 30% just 
like in ARM-3. 
 
<Justification for the non-inferiority margin> 
Both ARM-2 and ARM-3 are designed for patients who have not achieved to SDAI 
remission at Week 24; thus, assuming the SDAI remission rate is 0% in patients 
continuously receiving MTX alone without adding bDMARDs, a half of the SDAI 
remission rate of 30% in ARM-2, which is 15%, was selected as a non-inferiority margin. 
 
<Justification for the estimated SDAI remission rate in MTX Monotherapy Group> 
In studies conducted in Japanese MTX naïve patients, the SDAI remission rate in 6 
months of treatment with MTX alone was 12.3% (21/171 subjects) and 29.3% (46/157 
subjects) (Atsumi T, et al. 2016: 75-83, Takeuchi T, et al. 2014: 536-43). Also, in studies 
conducted in Western MTX naïve patients, the SDAI remission rate in 6 months of 
treatment with MTX alone was 11.2% (13/116 subjects) and 16.4% (47/287 subjects) 
(Emery P, et al. 2015: 19-26, Smolen JS, et al. 2016: 1081-91.). Accordingly, the 
remission rate of MTX monotherapy was estimated to be 15%. 
 
9.5 
Study discontinuation criteria 
The entire study will be discontinued if either of the below criteria is applicable. The Lead 
Principal Investigator shall notify the principal investigator of each study site promptly upon 
his/her decision to discontinue the study. Then, each principal investigator shall promptly 
notify his/her subjects, and provide appropriate medical intervention and take other necessary 
actions. 
• 
The number of subjects enrolled is much below the target number or many subjects 
achieve SDAI remission at Week 24 so that only a small group of the subjects are 
assigned to ARM-2 or ARM-3; from either of which the Lead Principal Investigator 
or Study Biostatistician judges it difficult to achieve the goal even if the study 
continues. 
 
9.6 
Handling of study data 
Subjects with missing data at an assessment timepoint of SDAI remission, ACR20, ACR50, 
and ACR70 response, HAQ remission, and structural remission due to study discontinuation 
or other relevant reasons will be considered as a “non-responder” at the specific timepoint. 
Any missing data on SDAI, CDAI, DAS28-ESR, and DAS28-CRP will be considered as 
missing at the specific timepoint. A missing data on the assessment of SDAI, CDAI, DAS28-


D2E7-C000-401 
 
44 
 
ESR, DAS28-CRP, and mTSS will be complemented with the last observation carried 
forward (LOCF).  
 
9.7 
Data evaluation 
Prior to the final analysis, the data obtained before randomization will be summarized in the 
course of the study for the purpose of presentations at academic conferences. The summary of 
the data are allowed to be presented at academic conferences after the completion of subject 
enrollment in principle. This study will not be biased as the data obtained before 
randomization are collected. 
 
9.8 
Deviation from statistical analysis plan 
If there is a revision required in the statistical analysis plan after the start of this study, the 
Lead Principal Investigator shall determine the effect of such revision on this study, and how 
to apply such revision. The details of the revision shall be specified in the clinical study 
report of this study. 
 
 
10 Direct access to source data and document 
Principal investigators and study sites must allow direct access to the study-related source 
data and documents during study monitoring, audit, Certified Review Board’s/Ethical Review 
Board's review, and authorities' inspection. 
 
 
11 Monitoring and audit 
11.1 Monitoring 
Monitoring will be performed on this study to ensure the compliance with ICH-GCP, the 
Clinical Trials Act, study protocol, and all other applicable regulations and procedures, 
accurate data collection, appropriate informed consent process, and adequate safety assurance 
of subjects. 
Monitoring will include central monitoring of EDC data and on-site monitoring, both of 
which will be conducted in accordance with the monitoring plan to be separately set out. 
 
11.2 Audit 
To enhance the assurance activities of this intervention study, audit staff will examine this 
study to ensure its compliance to ICH-GCP, the Clinical Trials Act, the study protocol, and 
all other regulations and procedures. 
 
 
12 Ethics 
12.1 Benefits and disadvantages to subjects 
It is unlikely that this study offers direct benefits to the subjects since the study treatment is a 
standard treatment within usual clinical practice. However, the results of the study to 


D2E7-C000-401 
 
45 
 
establish the optimal usage of ADA and MTX is expected to eventually generate benefits for 
RA patients in the future. 
Meanwhile, potential disadvantages associated with this study may be ADRs of MTX and 
ADA, as with other standard treatments. Also, investigational blood sampling may become a 
disadvantage. However, this is only additional collection of very small volume blood to 
routine blood collection in clinical practice; thus, the risk thereof will be negligible. 
 
12.2 Informed consent 
12.2.1 Inform patient 
Before enrollment of each patient, the principal investigator/sub-investigator shall hand out to 
the patient the informed consent document approved by the Certified Review Board 
(Japan)/Ethical Review Board (South Korea and Taiwan), and orally describe in words easy 
to understand; 
1) The study title, the research aspect of the study, and the fact that the study is approved 
by the head of the study site; 
2) The name of the study site, and the name of the principal investigator; 
3) Study objective and purpose: 
4) Study methodology (including the treatment given in the study, the probability to be 
randomized to each group, study procedures including all invasive procedures, and the 
purpose for use of samples and information obtained from subjects), as well as the 
anticipated duration of subjects' enrollment in this study, and the number of subjects 
taking part in the study; 
5) Reason for the patient to be selected as a study subject; 
6) Subjects' responsibilities, the experimental aspect of this study, the burden on 
subjects, and anticipated risks and benefits; 
7) Subjects' rights to withdraw their consent at any time even after having consented to 
start or continue the study; 
8) Assurance that in no event will subjects or any other related-party be penalized in any 
way for not consenting to start or continue the study, or withdrawing their consent; 
9) Method used to publicly release study-related information; 
10) Subjects' rights to obtain or review the protocol and other materials on study 
procedures within the scope that would not interfere with the protection of other 
subjects’ personal information or the originality of this study, and the method to 
obtain or review such materials; 
11) Handling of personal information, etc. (Protection of confidential information that 
could track down subjects' identifies unless otherwise required by laws, and protection 
of subjects' identity even if the study results are publicly released); 
12) Method for storage and disposal of samples and information; 
13) Source of funding for the study, conflict of interest and individuals' profits concerning 
the study at the site, and conflict of interest among study staff; 


D2E7-C000-401 
 
46 
 
14) Handling of consultation requested by subjects and other related personnel (liaison for 
subjects' further inquiry on information concerning this study and the subjects' rights 
thereto related, or subjects' reporting of health damage that occur in the study); 
15) Economic burden or benefit for subjects, and the contents thereof; 
16) Other therapeutic options if the study involves a medical intervention beyond the 
scope of ordinary clinical practice; 
17) Medical intervention to be provided to subjects after the study if the study involves a 
medical intervention beyond the scope of ordinary clinical practice; 
18) Handling of study results concerning individual subjects (including incidental 
findings) if there is a possibility to obtain important information concerning subjects' 
health, genetic characteristics transmitted to the descendants, or other finding 
pertinent to this study; 
19) Health damage that could occur in the study and the presence/absence and contents of 
any compensation program if the study involves invasive procedures; 
20) Possible uses of subjects samples and information for future researches that are not 
identified at the time of subjects' informed consent, possible transfer of subjects' 
samples and information to other research facilities, and the contents thereof 
anticipated at the time of informed consent; 
21) Disclosure of subjects' samples and information to persons conducting 
monitoring/audit, Certified Review Board/Ethical Review Board, and regulatory 
agency to an extent necessary and under an assumption that subjects' confidentiality 
will be protected, if the study involves invasive procedures(except for minor invasive 
procedure), and that the signature on the consent form is construed as the subject's and 
his/her legally-acceptable representative's acceptance to allow for direct access to such 
source documents; 
22) Procedures by which any information that could affect the subjects' willingness to 
continue taking part in the study will be communicated to subjects and their legally-
acceptable representatives at an appropriate timing; and 
23) Conditions by which subjects' withdrawal from the study can be anticipated, and the 
reason therefor. 
 
12.2.2 Consent 
Request the patient to take part in this study only after completing the patient briefing and 
confirming that the patient has fully understood the study contents. 
Upon the subject's consent to take part in the study, the consent form approved by the 
Certified Review Board (Japan)/Ethical Review Board (South Korea and Taiwan) should be 
used to record the name of the briefing physician, the name of the consenting patient, the date 
of consent, and to have signature of the physician and patient. Three copies of the identical 
consent form should be in principle prepared; 1 copy should be handed to the patient, 1 
should be retained by the principal investigator, and 1 should be submitted to the on-site 
study secretariat while the actual procedures should be in compliance with each site's 
operating procedures. 


D2E7-C000-401 
 
47 
 
 
12.2.3 Representative 
A legally-acceptable representative needs to be assigned and consent in writing on behalf of a 
subject aged <20 years in Japan and <19 years in South Korea at the time of informed 
consent. 
Even if the consent is to be obtained from such a legally-acceptable representative, the patient 
should still be requested to take part in this study after completing the patient briefing and 
confirming that the patient has fully understood the study contents; in which case, a written 
consent should be separately obtained from the patient. 
 
12.3 Protection of subjects' privacy and patient identification 
The data concerning a subject enrolled in this study will be entered in EDC after anonymized 
and encoded to a subject ID issued at the registration; subject's name, address, telephone 
number, and other information that could directly identify an individual subject will not be 
recorded in the database. 
Also, in no event shall any information concerning subjects' privacy be divulged to a third 
party by a study staff exposed to such information during this study. 
 
12.4 Certified Review Board/Ethical Review Board 
12.4.1 Approval 
Before conducting this study, the Lead Principal Investigator shall submit the protocol, 
written information for patient, written informed consent form, and other necessary 
documents to the Certified Review Board and obtain its approval to conduct this study. 
Also in South Korea and Taiwan, the principal investigator shall submit the necessary 
documents to the Ethical Review Board, and obtain its approval to conduct this study. Upon 
obtaining approval of the site, the approval format shall be retained at the site, and its copy 
shall be sent to the study secretariat (Operation Center). 
 
12.4.2 Annual review 
The Lead Principal Investigator must report study progress (e.g., the number of subjects 
enrolled, status of AEs, protocol deviation, etc.) to the Certified Review Board at least once a 
year , and have the Certified Review Board review and approve the continuation of this 
study. 
In South Korea and Taiwan, the principal investigator must report to the Ethical Review 
Board at least once a year of the study progress, and have the Ethical Review Board review 
and approve the continuation of this study. 
 
12.5 Disclosure of study-related information 
This study will be registered in ClinicalTrials.gov, Japan Registry of Clinical Trials (jRCT), 
and UMIN Clinical Trial Registration (UMIN-CTR) to disclose its information. 
 


D2E7-C000-401 
 
48 
 
12.6 Handling of inquiry from subjects and related parties 
If a staffer other than principal investigator/sub-investigator receives an inquiry from subjects 
or related party, such staffer will promptly contact the principal investigator or sub-
investigator, and the inquiry will be handled by the principal investigator or sub-investigator, 
or as necessary by the Lead Principal Investigator. 
 
12.7 Conflicts of interest 
This study is a collaborative research conducted by Keio University School of Medicine and 
Eisai Co., Ltd., the distributor of Humira® and funded by Eisai Co., Ltd. under a collaborative 
research contract between the parties that define the responsibilities of each party. While this 
study is conducted based on the specified responsibilities and roles, Eisai Co., Ltd. shall not 
be involved in data management including database access during the study as well as 
statistical operation so as to prevent possible bias of the study results; provided that Eisai will 
be involved in the preparation of and changes to the protocol (including statistical analysis 
plan), approval of the clinical study report, and delivery of relevant information. Pfizer Japan 
Inc., the marketing authorization holder of Rheumatrex® and AbbVie GK, the marketing 
authorization holder of Humira® shall not be involved in this study. 
Also, necessary information concerning conflicts of interest associated with principal 
investigators/sub-investigators and Study Biostatistician of this study and Eisai Co., Ltd., 
AbbVie GK, and Pfizer Japan Inc. will be disclosed to a department in charge of the 
management of conflicts of interest at each study site and then will be appropriately 
managed. Furthermore, in Japan, the conflicts-of-interest management plan will be reviewed 
by the Certified Review Board in accordance with the Clinical Trials Act. 
 
12.8 Handling of subjects after end of study 
Treatment after completion and discontinuation of this 48-week study will not be specified. 
 
12.9 Handling of important findings concerning genetic characteristics, etc. 
Genetic characteristics will not be analyzed in this study, and thus, important findings thereto 
related are not anticipated. 
 
12.10 Retention and future research use of clinical samples, and transfer 
thereof to other research facilities 
Investigational blood samples collected in this study will be retained at an external laboratory 
until study completion, and in principle all be disposed of immediately upon study 
completion; 
However, upon a separate consent of subjects and approval of Certified Review Board, the 
clinical samples will be retained in Keio University for future research use for 5 years from 
the date of study completion report or 3 years from the publication of study results, 
whichever comes later, and may be transferred to other research facilities as necessary. 
 
 


D2E7-C000-401 
 
49 
 
13 Handling of data, and retention of record 
13.1 Handling of data 
In this study, subject ID will be issued through IWRS, and all data except for SAE report will 
be collected through EDC. The principal investigator or sub-investigator will enter data in 
EDC promptly upon completion of the evaluation/assessment in each subject. 
Based on a separate data management plan, the data center shall send reminders for overdue 
data, investigate the data and generate data clarification, correct the data according to the data 
clarification, manage the database, and also, prepares a dataset for statistical analysis based 
on the data entered in the database. 
 
13.2 Retention of records 
Principal investigator shall appropriately retain the data and records concerning this study for 
at least 5 years from the date of study completion report or 3 years from the last publication 
date of study results, whichever comes later. 
 
 
14 Economic burden on subjects, and insurance and other measures 
14.1 Economic burden on subjects 
The medical cost associated with this study including that for drugs and tests (except for off-
label use of special tests) during the study will be paid in accordance with each country's 
healthcare scheme. In Japan, the study treatment to be provided is within the scope of general 
clinical practice using the approved drugs, and the cost will be paid by the health insurance 
and subjects. 
Reward for subjects to take part in this study shall be paid in accordance with each country's 
rule. 
 
14.2 Insurance 
Adequate caution shall be in place for treatment of known SAEs. Upon occurrence of an AE 
during this study, the principal investigator/sub-investigator shall promptly take necessary 
actions (tests, treatment, study discontinuation, etc.) to ensure the safety of the subject, and 
with technologies covered by the insurance, take initiative in to provide the best available 
treatment and other procedures for the subject. 
The sponsor shall carry a clinical study insurance as a measures to secure the compensation 
for death and severe impairment (grade 1 or 2) that may occur in this study. 
 
 
15 Publication of study results 
Key study results will be published in a journal in English language upon completion of the 
final analysis. Presentation at academic conferences will be arranged and performed by Lead 
Principal Investigator, Study Investigational Operator, and Coordinating Investigators. The 
presenter will be selected by Lead Principal Investigator upon approval of Eisai Co., Ltd. 


D2E7-C000-401 
 
50 
 
Prior to the publication of key study results, the data collected before randomization may be 
analyzed in the course of the study for the purpose of presentations at academic conferences. 
Also in this case, presentation at academic conferences will be arranged and performed by the 
Lead Principal Investigator, Study Investigational Operator, and Coordinating Investigators, 
and the presenter will be selected by the Lead Principal Investigator upon approval of Eisai 
Co., Ltd. 
 


D2E7-C000-401 
 
51 
 
16 Appendix 
16.1 Criteria for RA 
In the past, a set of criteria released in 1987 has been used widely, but in order to facilitate 
early diagnosis and early treatment, a new set of criteria was released in 2010. In this study, 
those meeting 1987 revised ACR criteria or 2010 ACR/EULAR criteria are considered as 
RA. 
 
16.1.1 ACR revised criteria (1987) 
[1] Morning stiffness of ≥1 hour for ≥6 weeks 
[2] ≥3 swollen joints for ≥6 weeks 
[3] Swollen wrist joint, metacarpophalangeal (MCP) joint, or proximal interphalangeal 
(PIP) joint for ≥6 weeks 
[4] Symmetrical swollen joint for ≥6 weeks 
[5] Radiological findings of bone erosion typical with RA, or clear bone decalcification in 
the hands 
[6] Rheumatoid nodule (subcutaneous nodule) 
[7] Rheumatoid factor positive 
A condition meeting 4 of the above 7 is categorized as RA. 
 
16.1.2 ACR/EULAR criteria (2010) 
Patients meeting both of the following criteria will be applicable, and scored accordingly. 
1) At least one joint with definite clinical synovitis (swelling) 
2) Synovitis is not better explained by another disease 
Scoring: ≥6 points = Definitive RA 
A. Joint involvement 
• 1 large joint 
0 points 
• 2 - 10 large joints 
1 point 
• 1 - 3 small joints (with or without involvement of large joints)  
2 points 
• 4 - 10 small joints (with or without involvement of large joints)  
3 points 
• ≥ 11 joints (at least 1 small joint) 
5 points 
B. Serology (at least 1 tests result is needed for classification) 
• Negative RF and negative anti-CCP antibody  
0 points 
• Low-positive RF or low-positive anti-CCP antibody 
2 points 
• High- positive RF or high-positive anti-CCP antibody 
3 points 
C. Acute-phase reactant (at least 1 tests result is needed for the classification) 
• Normal CRP and normal ESR 
0 points 
• Abnormal CRP or abnormal ESR 
1 point 
D. Duration of symptoms 
• <6 weeks 
0 points 
• ≥6 weeks 
1 point 
 


D2E7-C000-401 
 
52 
 
16.2 Reference 
Atsumi T, et al. The first double-blind, randomised, parallel-group certolizumab pegol study 
in methotrexate-naive early rheumatoid arthritis patients with poor prognostic factors, C-
OPERA, shows inhibition of radiographic progression. Ann Rheum Dis.2016;75:75-83. 
 
Breedveld FC, et al. The PREMIER study: A multicenter, randomized, double-blind clinical 
trial of combination therapy with adalimumab plus methotrexate versus methotrexate alone or 
adalimumab alone in patients with early, aggressive rheumatoid arthritis who had not had 
previous methotrexate treatment. Arthritis Rheum.2006;54:26-37. 
 
Burmester GR, et al. Efficacy and safety of ascending methotrexate dose in combination with 
adalimumab: the randomised CONCERTO trial. Ann Rheum Dis.2015;74:1037-44 
 
de Rotte MC, et al. Methotrexate polyglutamates in erythrocytes are associated with lower 
disease activity in patients with rheumatoid arthritis. Ann Rheum Dis.2015;74:408-14 
 
Emery P, et al. Evaluating drug-free remission with abatacept in early rheumatoid arthritis: 
results from the phase 3b, multicentre, randomised, active-controlled AVERT study of 24 
months, with a 12-month, double-blind treatment period. Ann Rheum Dis 2015;74:19?26 
 
Firestein GS. Kelley and Firestein's Textbook of Rheumatology 10th ed. Philadelphia: 
Elsevier, 2017, p1115 
 
Howard A, et al. Evidence of Significant Radiographic Damage in Rheumatoid Arthritis 
Within the First 2 Years of Disease. J Rheumatol.1989;16:585-91. 
 
Kaeley GS, et al. Methotrexate Dosage Reduction Upon Adalimumab Initiation: Clinical and 
Ultrasonographic Outcomes from the Randomized Noninferiority MUSICA Trial. J 
Rheumatol.2016;43:1480-9. 
 
Morgan SL, et al. The effect of folic acid supplementation on the toxicity of low-dose 
methotrexate in patients with rheumatoid arthritis. Arthritis Rheum.1990;33:9-18. 
 
Nam JL, et al. Efficacy of biological disease-modifying antirheumatic drugs: a systematic 
literature review informing the 2013 update of the EULAR recommendations for the 
management of rheumatoid arthritis. Ann Rheum Dis.2014;73:516-28. 
 
Smolen JS, et al. Clinical trials of new drugs for the treatment of rheumatoid arthritis: focus 
on early disease. Ann Rheum Dis.2016;75:1081-91. 
 


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53 
 
Smolen JS, et al. EULAR recommendations for the management of rheumatoid arthritis with 
synthetic and biological disease-modifying antirheumatic drugs:2016 update. Ann Rheum 
Dis.2017;76:960-77. 
 
Swinkels HL, et al. Modified sharp method: factors influencing reproducibility and 
variability. Arthritis Rheum.2001;31:176-90 
 
Takahashi C, et al. Association of erythrocyte methotrexate- polyglutamate levels with the 
efficacy and hepatotoxicity of methotrexate in patients with rheumatoid arthritis: a 76-week 
prospective study.RMD Open.2017;3:e000363. 
 
Takeuchi T, et al. Adalimumab, a human anti-TNF monoclonal antibody, outcome study for 
the prevention of joint damage in Japanese patients with early rheumatoid arthritis: the 
HOPEFUL 1 study. Ann Rheum Dis.2014;73:536-43. 
 
Tanaka Y, et al. Effectiveness and safety of initiating adalimumab plus ≥12 mg/week 
methotrexate with adjustable dosing in biologic-naïve patients with early rheumatoid arthritis: 
HAWK study postmarketing surveillance in Japan. Mod Rheumatol. 2018; 11: 1-9. 
 
Tishler M, et al. The effects of leucovorin (folinic acid) on methotrexate therapy in 
rheumatoid arthritis patients. Arthritis Rheum.1988;31:906-8. 
 
Vastesaeger N, et al. A pilot risk model for the prediction of rapid radiographic progression 
in rheumatoid arthritis.Rheumatology.2009;48:1114-21 
 
Visser K, et al. A matrix risk model for the prediction of rapid radiographic progression in 
patients with rheumatoid arthritis receiving different dynamic treatment strategies: post hoc 
analyses from the BeSt study. Ann Rheum Dis.2010;69:1333-7 
 
Wolfe F, et al. The mortality of rheumatoid arthritis. Arthritis Rheum.1994;37:481-94 
 

SAP_001.pdf: 
 
 
 
 
 
MIRACLE 
(Methotrexate inadequate response patient with Rheumatoid Arthritis treated by 
Adalimumab in combination with Low-dose Methotrexate)  
 
 
 
 
Evaluation of the Optimal MTX Dose as an Add-on Therapy to Adalimumab for  
RA Patients in Japan, South Korea and Taiwan. (NCT03505008) 
 
 
 
 
Statistical Analysis Plan 
 
Ver. 1.1 (Date prepared: July 27, 2021) 
 


Version 1.1 (7/27/2021) 
 
 
 
 
MIRACLE (Methotrexate inadequate response patient with 
Rheumatoid Arthritis treated by Adalimumab in combination 
with Low-dose Methotrexate) Study 
Statistical Analysis Plan 
 
 
 
 
 
 
 
 
Principal Investigator: 
Yuko Kaneko, Professor, Division of Rheumatology, 
Department of Internal Medicine, Keio University School of Medicine 
 
Study Biostatistician: 
Yasunori Sato,  
Associate Professor, Department of Preventive Medicine and Public Health, 
Keio University School of Medicine 
Head of Biostatistics Unit, Clinical and Translational Research Center, 
Keio University Hospital 
 
Revision History: 
Version 1.0 
Prepared on October 18, 2018 
Version 1.1 
Prepared on July 27, 2021 
 
 
 


Version 1.1 (7/27/2021) 
 
 
Table of Contents 
1. 
Objectives of the Specified Clinical Trial ................................................................................. 1 
1.1. 
Primary Endpoint ................................................................................................................ 1 
1.2. 
Secondary Endpoints ......................................................................................................... 1 
1.3. 
Exploratory Endpoints ....................................................................................................... 1 
2. 
Considerations for Statistical Analysis .................................................................................... 2 
2.1. 
Data Evaluation .................................................................................................................. 2 
2.2. 
Data Monitoring .................................................................................................................. 2 
2.3. 
Handling of Study Data ..................................................................................................... 2 
2.4. 
Handling of Missing Values ............................................................................................... 2 
2.5. 
Variable Transformation .................................................................................................... 3 
2.6. 
Significance and Confidence Levels ............................................................................... 3 
2.7. 
Descriptive Statistics .......................................................................................................... 3 
2.8. 
Multiplicity Adjustment ....................................................................................................... 3 
3. 
Statistical Analysis Set ............................................................................................................... 3 
3.1. 
Definition of Statistical Analysis Set................................................................................. 3 
3.1.1. 
Full analysis set (FAS) ............................................................................................... 3 
3.1.2. 
Per protocol set (PPS) ............................................................................................... 3 
3.1.3. 
Safety analysis set ..................................................................................................... 4 
3.2. 
Statistical Analysis Set for Each Endpoint ...................................................................... 4 
4. 
Analysis Plan of Subject Disposition and Overall Exposure ................................................ 4 
4.1. 
Subject Disposition ............................................................................................................. 4 
4.2. 
Summarizing Discontinuations ......................................................................................... 5 
4.3. 
Statistical Analysis Set for Each Analysis ....................................................................... 5 
4.4. 
Exposure to MTX ................................................................................................................ 5 
5. 
Analysis Plan of Demographic Characteristics ...................................................................... 5 
6. 
Efficacy Analysis ......................................................................................................................... 5 
6.1. 
Analysis Plan of Primary Endpoint .................................................................................. 5 
6.2. 
Analysis Plan of Secondary Endpoints ........................................................................... 6 
7. 
Safety Analysis ........................................................................................................................... 8 
7.1. 
Analysis Plan of Adverse Events (AEs) .......................................................................... 8 
7.2. 
Analysis Plan of Clinical Laboratory Values and Vital Signs........................................ 9 
8. 
Analysis Plan of Exploratory Endpoints .................................................................................. 9 
8.1. 
Erythrocyte MTX-PG Concentration at Weeks 0, 4, 8, 12, 24, 36, and 48 ................ 9 
8.2. 
Blood Cytokine (IL-6, VEGF) at Weeks 0, 24, and 48 .................................................. 9 


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8.3. 
Plasma Micro RNA at Week 24 ...................................................................................... 10 
8.4. 
Serum Anti-adalimumab Antibody at Weeks 24 and 48 ............................................. 10 
9. 
Revision History ........................................................................................................................ 11 
9.1. 
Revision from Protocol .................................................................................................... 11 
9.2. 
Revision History of the Statistical Analysis Plan .......................................................... 11 
10. Organization and Environment for Statistical Analyses ...................................................... 11 
10.1. Study Biostatistician ......................................................................................................... 11 
10.2. Person in Charge of Statistical Analysis ....................................................................... 11 
10.3. Software Environment ..................................................................................................... 11 
11. Signature ................................................................................................................................... 12 
 
 


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1. Objectives of the Specified Clinical Trial 
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. 
 
1.1. Primary Endpoint 
 SDAI remission rate at Week 48 in concomitant ADA MTX maximum tolerable dose 
extended treatment group and concomitant ADA MTX dose reduction group 
 
1.2. Secondary Endpoints 
[Efficacy] 
 SDAI remission rate at Week 24 
 SDAI remission rate at Week 48 in MTX monotherapy group 
 Percentage of disease activity category by SDAI, CDAI, DAS28-ESR and DAS28-CRP 
at each assessment timepoint 
 SDAI, CDAI, DAS28-ESR, and DAS28-CRP at each assessment timepoint, and change 
from baseline to each assessment timepoint 
 ACR20, ACR50, and ACR70 response rate at each assessment timepoint 
 Tender joint count, swollen joint count, VAS (physician- and patient-reported), HAQ, 
CRP, ESR, MMP-3, RF, and anti-CCP antibody at each assessment timepoint, and 
change from baseline and Week 24 to each assessment timepoint 
 Modified total sharp score (mTSS) at each assessment timepoint, and change from 
baseline to each assessment timepoint 
 Structural remission (mTSS ≤0.5) rate at each assessment timepoint 
 HAQ remission rate at each assessment timepoint 
 
[Safety] 
 Vital signs and laboratory values at each assessment timepoint, and change from 
baseline to each assessment timepoint 
 Status of AE (Up to Week 24, and up to Week 48 for each ARM) 
 
1.3. Exploratory Endpoints 
 Erythrocyte MTX-PG concentration at Weeks 0, 4, 8, 12, 24, 36, and 48 
 Blood cytokine (IL-6, VEGF) at Weeks 0, 24, and 48 
 Plasma micro RNA at Week 24 
 Serum anti-adalimumab antibody at Weeks 24 and 48 
 


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2. Considerations for Statistical Analysis 
2.1. Data Evaluation 
The interim analysis will not be conducted in this study. However, prior to the final 
analysis, the data obtained before randomization will be summarized in the course of the 
study for the purpose of presentations at academic conferences. The summary of the 
data is allowed to be presented at academic conferences after the completion of subject 
enrollment in principle. This study will not be biased as the data obtained before 
randomization are collected. 
 
2.2. Data Monitoring 
Monitoring will be performed on this study to ensure the compliance with the study 
protocol, accurate data collection, appropriate informed consent process, and adequate 
safety assurance of subjects. 
Monitoring will include central monitoring of EDC data and on-site monitoring, both of 
which will be conducted in accordance with the monitoring plan to be separately set out. 
 
2.3. Handling of Study Data 
 Fixed data after the completion of follow-up will be used for statistical analyses. 
 For subjects who were enrolled more than once, statistical analyses will be conducted 
by removing the data that became unnecessary. 
 Data handling meeting will be held prior to the database lock to discuss and determine 
how to handle individual data after removing the information on which treatment arm 
each subject was randomized to. 
 For clinical laboratory values that exceed or fall below detection limits, detection limits 
will be substituted for actual values. 
 As a rule, baseline is defined as Week 0. If the value at Week 0 is missing or not 
measured, the time of screening is regarded as baseline. 
 Change and percentage change are defined as follows: 
Change = measured value after intervention – measured value at baseline 
Percentage change = (change/measured value at baseline) x 100 (%) 
 
2.4. Handling of Missing Values 
 Subjects with missing data at an assessment time point of SDAI remission, ACR20, 
ACR50, and ACR70 response, HAQ remission, and structural remission due to study 
discontinuation or other relevant reasons will be considered as a “non-responder” at the 
time point of missing data. 
 Subjects with missing data at an assessment time point of CDAI, DAS28-ESR, DAS28-
CRP remission due to study discontinuation or other relevant reasons will be considered 
as a “non-responder” at the time point of missing data. 
 Any missing data on SDAI, CDAI, DAS28-ESR, and DAS28-CRP will be considered as 
missing at the time point of missing data. 


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 
If there is a missing data on the assessment of SDAI, CDAI, DAS28-ESR, DAS28-
CRP, and mTSS, the sensitivity analysis of GEE or MMRM method will be performed. If 
the result does not converge, a missing data will be imputed with the last observation 
carried forward (LOCF). In addition, for the sensitivity analysis of primary endpoint, a 
missing data on the final scheduled visit will be imputed with data on End of Study. 
 
2.5. Variable Transformation 
If the distribution of measured values is largely deviated from the normal distribution, 
variable transformation will be conducted such as logarithmic transformation where 
necessary. 
 
2.6. Significance and Confidence Levels 
The analysis on non-inferiority will be performed with a two-tailed confidence interval of 
90%. A two-tailed significance level of 5% with a two-tailed 95% confidence interval will be 
used for all other analyses unless specified otherwise. 
 
2.7. Descriptive Statistics 
Descriptive statistics (number of subjects, mean, standard deviation, minimum, median, 
and maximum as continuous variables, and number and proportion [%] of subjects as 
nominal variables) will be computed. 
 
2.8. Multiplicity Adjustment 
Multiplicity will not be adjusted in this study. 
 
3. Statistical Analysis Set 
3.1. Definition of Statistical Analysis Set 
3.1.1. Full analysis set (FAS) 
FAS is defined as a group of subjects who receive study drug (MTX) and have evaluable 
efficacy data at 1 or more time points following the administration of study drug (including 
subjects who discontinued the study before Week 24 as well as those randomized to 
ARM-1, 2 or 3). 
Modified FAS (mFAS) is defined as a group of subjects who are randomized after Week 
24, receive study drug (ADA), and have evaluable efficacy endpoint at 1 or more time 
points following the administration of study drug (only the subjects randomized to ARM-2 
or 3). 
 
3.1.2. Per protocol set (PPS) 
PPS is defined as a group of subjects among mFAS who adequately complied with the 
protocol after excluding subjects with the following significant protocol deviations, e.g. 
study procedures, concomitant medications (only the subjects randomized to ARM-2 or 
3). 
 Deviation from the inclusion/exclusion criteria 


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 Deviation from the discontinuation criteria 
 Deviation from prohibited concomitant therapies 
 Subjects without follow-up data 
 Subjects with the study drug compliance of <75% 
 
3.1.3. Safety analysis set 
The Safety Analysis Set is defined as a group of subjects who receive study drug (MTX) 
and have evaluable safety data at 1 or more time points following the administration of 
study drug (including subjects who discontinued the study before Week 24 as well as 
those randomized to ARM-1, 2 or 3). 
 
3.2. Statistical Analysis Set for Each Endpoint 
The analysis of primary efficacy endpoint will be performed on mFAS as the main analysis 
set, and on PPS as a supplementary analysis set. All other efficacy and exploratory 
analyses will be performed exclusively on FAS. Meanwhile, the analysis of safety variables 
will be performed on the Safety Analysis Set. 
 
 
4. Analysis Plan of Subject Disposition and Overall Exposure 
4.1. Subject Disposition 
The following numbers will be calculated: Number of subjects enrolled; number of subjects 
who received the study drug (MTX), number of subjects with evaluable/non-evaluable SDAI 
at Week 24; number of subjects included in the Safety Analysis Set; number of subjects 
included in FAS. In addition, the following numbers will also be calculated: Number of 
subjects who withdrew the informed consent; number of subjects who had not received any 
study drug after enrollment, number of subjects without any data on the primary endpoint; 
number of subjects who did not meet the inclusion criteria; number of subjects who met the 
exclusion criteria. 
Of subjects who satisfied the criteria for SDAI remission at Week 24 and were randomized 
to ARM-1, the number of subjects who did/did not have SDAI remission at Week 48, 
number of subjects included in the Safety Analysis Set, and number of subjects included in 
FAS will be calculated. Furthermore, the number of subjects who had not received any 
study drug after Week 24, and number of subjects without any data on the primary endpoint 
at Week 24 onward will also be calculated. 
Of subjects who did not achieve SDAI remission at Week 24, the following numbers will be 
calculated for ARM-2 and ARM-3, respectively: Number of subjects randomized; number of 
subjects who did/did not achieve SDAI remission at Week 48; number of subjects included 
in the Safety Analysis Set, FAS, mFAS, and PPS, respectively. In addition, the number of 
subjects who had not received any study drug after randomization, and number of subjects 
without any data on the primary endpoint after randomization, will also be calculated. 
 


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4.2. Summarizing Discontinuations 
The number of subjects who discontinued the study before Week 24, or at Week 24 onward 
will be summarized with the reasons for discontinuations for each ARM in FAS, mFAS, 
PPS, and the Safety Analysis Set, respectively, and prepare a list (subjects who 
discontinued the study before Week 24 as well as subjects randomized to ARM-1, 2, or 3 
included in FAS and the Safety Analysis Set; only the subjects randomized to ARM-2 or 3 
included in mFAS and PPS). 
 
4.3. Statistical Analysis Set for Each Analysis 
The analysis of primary efficacy endpoint will be performed on mFAS as the main analysis 
set, and on PPS as a supplementary analysis set. All other efficacy and exploratory 
analyses will be performed exclusively on FAS. Meanwhile, the analysis of safety variables 
will be performed on the Safety Analysis Set. 
 
4.4. Exposure to MTX 
Descriptive statistics of MTX oral dose during each treatment week will be computed. In 
addition, descriptive statistics will be computed by country for each ARM. 
 
 
5. Analysis Plan of Demographic Characteristics 
The distribution of subjects’ demographic characteristics and descriptive statistics will be 
calculated for each ARM in FAS, mFAS, PPS, and the Safety Analysis Set, respectively 
(subjects who discontinued the study before Week 24 as well as subjects randomized to 
ARM-1, 2, or 3 included in FAS and the Safety Analysis Set; only the subjects randomized 
to ARM-2 or 3 included in mFAS and PPS). The data will be compared between ARM-2 and 
ARM-3 in each analysis set using chi-square test for nominal variables (Fisher's exact test 
as needed), Wilcoxon rank sum test for ordinal variables, and t-test for continuous 
variables. 
 
 
6. Efficacy Analysis 
6.1. Analysis Plan of Primary Endpoint 
The primary analysis for this study is intended to demonstrate the non-inferiority of 
ADA/MTX-reduced dose group (ARM-3) to ADA/MTX-MTD group (ARM-2) in terms of the 
primary endpoint, that is, SDAI remission rate at Week 48. The adjusted intergroup risk 
difference and its two-tailed 90% confidence interval in terms of SDAI remission rate at 
Week 48 will be calculated by Mantel-Haenszel test with country as a stratification factor to 
verify non-inferiority of ARM-3 to ARM-2 with the non-inferiority margin of -15%. 
As a sensitivity analysis, point estimates and their 95% confidence interval for changes in 
SDAI remission rate from baseline to each assessment timepoint will be calculated by 
generalized linear mixed model (Breslow NE, Clayton DG, J Am Stat Assoc 1993;88(421): 
9-25, Wolfinger RD, O'Connell MA, J Stat Comput Sim 1993; 48: 233-243.). Unstructured 


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will be selected as a correlation structure, and if the analysis does not converge, Toeplitz, 
Autoregressive, Compound-symmetry structure will be used in order. 
In addition, a missing data on the final scheduled visit will be imputed with data on End of 
Study to assess SDAI remission rate. 
Furthermore, multiple logistic regression analysis will be conducted to assess potential 
effects of each explanatory variable on the response variable with SDAI remission/non-
remission at Week 48 as the response variable, and age, sex, autoantibody profile, SDAI 
score at screening, change in mTSS from screening to Week 24 as explanatory variables, 
for which a model to minimize the AIC is to be adopted in principle by choosing appropriate 
variables. 
 
6.2. Analysis Plan of Secondary Endpoints 
6.2.1. SDAI remission rate at Week 24 
SDAI remission rate at Week 24 and its two-tailed 95% confidence interval will be 
calculated for each ARM (ARM-1, 2, and 3). 
 
6.2.2. SDAI remission rate at Week 48 in MTX monotherapy group 
SDAI remission rate at Week 48 and its two-tailed 95% confidence interval in MTX 
Monotherapy Group (ARM-1) will be calculated. 
 
6.2.3. ACR20, ACR50, and ACR70 response rate at each assessment timepoint 
ACR20, ACR50, and ACR70 response rates and their two-tailed 95% confidence interval at 
each assessment timepoint will be calculated for each ARM (ARM-1, 2, and 3). 
Furthermore, Mantel-Haenszel test (risk difference) with country as a stratification factor will 
be performed to compare response rates at Week 48 between ARM-2 and ARM-3, and 
calculate the estimate of difference between the treatment arms and its two-tailed 95% 
confidence interval. 
As a sensitivity analysis, point estimates and their 95% confidence interval for changes in 
ACR20, ACR50, and ACR70 response rates from baseline to each assessment timepoint 
will be calculated by generalized linear mixed model (Breslow NE, Clayton DG, J Am Stat 
Assoc 1993;88(421): 9-25, Wolfinger RD, O'Connell MA, J Stat Comput Sim 1993; 48: 233-
243.). Unstructured will be selected as a correlation structure, and if the analysis does not 
converge, Toeplitz, Autoregressive, Compound-symmetry structure will be used in order. 
 
6.2.4. HAQ remission rate at each assessment timepoint 
HAQ remission rate and its two-tailed 95% confidence interval at each assessment 
timepoint will be calculated for each ARM (ARM-1, 2, and 3). Furthermore, Mantel-
Haenszel test (risk difference) with country as a stratification factor will be performed to 
compare HAQ remission rates at Week 48 between ARM-2 and ARM-3, and calculate the 
estimate of difference between the treatment arms and its two-tailed 95% confidence 
interval. 
As a sensitivity analysis, point estimates and their 95% confidence interval for changes in 


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HAQ remission rate from baseline to each assessment timepoint will be calculated by 
generalized linear mixed model (Breslow NE, Clayton DG, J Am Stat Assoc 1993;88(421): 
9-25, Wolfinger RD, O'Connell MA, J Stat Comput Sim 1993; 48: 233-243.). Unstructured 
will be selected as a correlation structure, and if the analysis does not converge, Toeplitz, 
Autoregressive, Compound-symmetry structure will be used in order. 
 
6.2.5. SDAI, CDAI, DAS28-ESR, and DAS28-CRP at each assessment timepoint, and 
change from baseline to each assessment timepoint 
Descriptive statistics for SDAI, CDAI, DAS28-ESR, and DAS28-CRP at each assessment 
timepoint and their changes from baseline to each assessment timepoint will be calculated 
for each ARM (ARM-1, 2, and 3). Furthermore, analysis of covariance (ANCOVA) adjusted 
by country will be performed to compare changes from baseline to Week 48 between ARM-
2 and ARM-3, and calculate the estimate of difference between the treatment arms and its 
two-tailed 95% confidence interval. 
As a sensitivity analysis, point estimates and their 95% confidence interval for changes in 
measured values from baseline to each assessment timepoint will be calculated by 
generalized linear mixed model (Breslow NE, Clayton DG, J Am Stat Assoc 1993;88(421): 
9-25, Wolfinger RD, O'Connell MA, J Stat Comput Sim 1993; 48: 233-243.). Unstructured 
will be selected as a correlation structure, and if the analysis does not converge, Toeplitz, 
Autoregressive, Compound-symmetry structure will be used in order. 
 
6.2.6. Percentage of disease activity category by SDAI, CDAI, DAS28-ESR and DAS28-
CRP at each assessment timepoint 
The frequency of and the proportion of subjects classified into each disease activity 
category by SDAI, CDAI, DAS28-ESR and DAS28-CRP at each assessment timepoint will 
be calculated for each ARM (ARM-1, 2, or 3). Furthermore, Mantel-Haenszel test (risk 
difference) with country as a stratification factor will be performed to compare low disease 
activity and remission rate at each assessment timepoint between ARM-2 and ARM-3, and 
calculate the estimate of difference between the treatment arms and its two-tailed 95% 
confidence interval. 
 
6.2.7. Tender joint count, swollen joint count, VAS (physician- and patient-reported), HAQ, 
CRP, ESR, MMP-3, RF, and anti-CCP antibody at each assessment timepoint, and 
change from baseline to each assessment timepoint 
Descriptive statistics  for tender joint count, swollen joint count, VAS (physician- and 
patient-reported), HAQ, CRP, ESR, MMP-3, RF, and anti-CCP antibody at each 
assessment timepoint and their changes from baseline to each assessment timepoint will 
be calculated for each ARM (ARM-1, 2, and 3). Furthermore, analysis of covariance 
(ANCOVA) adjusted by country will be performed to compare changes from baseline to 
Week 48 between ARM-2 and ARM-3, and calculate the estimate of difference between the 
treatment arms and its two-tailed 95% confidence interval. 
 


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6.2.8. Modified total sharp score (mTSS) at each assessment timepoint, and change from 
baseline to each assessment timepoint 
Descriptive statistics for mTSS at each assessment timepoint and change from baseline to 
each assessment timepoint will be calculated for each ARM (ARM-1, 2, and 3). 
Furthermore, analysis of covariance (ANCOVA) adjusted by country will be performed to 
compare changes from baseline to Week 48 between ARM-2 and ARM-3, and calculate the 
estimate of difference between the treatment arms and its two-tailed 95% confidence 
interval. As with changes from baseline, descriptive statistics for changes from Week 24 to 
Week 48 will also be calculated for each ARM (ARM-1, 2, and 3). Furthermore, analysis of 
covariance (ANCOVA) adjusted by country will be performed to compare changes from 
Week 24 to Week 48 between ARM-2 and ARM-3, and calculate the estimate of difference 
between the treatment arms and its two-tailed 95% confidence interval. 
 
6.2.9. Structural remission (mTSS ≤0.5) rate at each assessment timepoint 
Structural remission rate and its two-tailed 95% confidence interval at each assessment 
timepoint will be calculated for each ARM (ARM-1, 2, and 3). Furthermore, Mantel-
Haenszel test (risk difference) with country as a stratification factor will be performed to 
compare structural remission rates at Week 48 between ARM-2 and ARM-3, and calculate 
the estimate of difference between the treatment arms and its two-tailed 95% confidence 
interval. 
 
7. Safety Analysis 
7.1. Analysis Plan of Adverse Events (AEs) 
7.1.1. Onset of AEs 
Number and proportion of subjects with AEs among all the subjects enrolled in this study 
(i.e., subjects randomized to ARM-1, 2 or 3, and those who discontinued the study before 
Week 24) will be tabulated by System Organ Class (SOC) and Preferred Term (PT) (see 
the Protocol for the details of categories and summarization). Two or more AEs with the 
same MedDRA term may be reported in a single subject; in such case, the AEs will be 
interpreted and counted as 1 subject to the analysis. Furthermore, the number and 
proportion of subjects with AEs by highest severity will be tabulated by presence/absence 
of causality with the study treatment for each ARM. 
Furthermore, the number and proportion of subjects with AEs will be tabulated for each 
treatment period (Week 0 to Week 24, and Week 24 to Week 48) by SOC and PT. 
Moreover, the number and proportion of subjects with AEs at Week 24 onward will be 
tabulated for each ARM (ARM-1, 2, and 3) by SOC and PT. 
 
7.1.2. Incidences of AEs for which causality with the study treatment cannot be ruled out 
Treatment-emergent adverse events (TEAE) for which causality with the study treatment 
cannot be ruled out will be tabulated at each assessment timepoint for each ARM (ARM-1, 
2, and 3) by SOC and PT. In addition, the number and proportion of subjects with AEs by 
highest severity will be tabulated for each ARM. The incidences of TEAEs for which 


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causality with the study treatment cannot be ruled out that occur from Week 24 to 48 will be 
compared between ARM-2 and ARM-3 using a Fisher's exact test. 
 
7.2. Analysis Plan of Clinical Laboratory Values and Vital Signs 
For continuous variables, descriptive statistics of measurements at each assessment 
timepoint and their changes from baseline will be calculated for each ARM (ARM-1, 2, and 
3). Furthermore, analysis of covariance (ANCOVA) adjusted by country will be performed to 
make a comparison between ARM-2 and ARM-3, and calculate the estimate of difference 
between the treatment arms and its two-tailed 95% confidence interval. In addition, 
descriptive statistics will be calculated, being stratified by country. 
As an order categorical variable, clinical laboratory values will be categorized to Lower than 
the reference (L), Within the reference (N), and Higher than the reference (H), and then the 
number and proportion of subjects by L, N, and H will be presented in a shift table (baseline 
vs. each visit during treatment) for each ARM (ARM-1, 2, and 3). In addition, the maximum 
and minimum values after the start of treatment will be presented in a shift table for 
comparison with baseline. Furthermore, Wilcoxon rank sum test will be performed to make 
a comparison between ARM-2 and ARM-3. 
Descriptive statistics of vital signs (diastolic blood pressure, systolic blood pressure, pulse 
rate, body temperature) and body weight at each assessment timepoint and their changes 
from baseline will be computed for each ARM (ARM-1, 2, and 3). Furthermore, analysis of 
covariance (ANCOVA) adjusted by country will be performed to make a comparison 
between ARM-2 and ARM-3, and calculate the estimate of difference between the 
treatment arms and its two-tailed 95% confidence interval. 
 
 
8. Analysis Plan of Exploratory Endpoints 
8.1. Erythrocyte MTX-PG Concentration at Weeks 0, 4, 8, 12, 24, 36, and 48 
Descriptive statistics for erythrocyte MTX-PG concentrations as well as change from 
baseline and change rate from baseline will be calculated by country. In addition, 
descriptive statistics for Week 24 onward will be calculated at each assessment timepoint 
for each ARM (ARM-1, 2, and 3). 
Pearson's product-moment correlation coefficient, Spearman's rank correlation coefficient, 
and their 95% confidence interval will be calculated at each assessment timepoint to 
evaluate the correlation of exposure to MTX, SDAI, mTSS, and ACR-N to erythrocyte MTX-
PG concentration. Furthermore, cutoff values for AST increased, ALT increased, and WBC 
decreased, and their differences among the participating countries will be discussed. 
 
8.2. Blood Cytokine (IL-6, VEGF) at Weeks 0, 24, and 48 
Descriptive statistics  for blood cytokine (IL-6, VEGF) levels as well as change from 
baseline and change rate from baseline will be calculated at each assessment timepoint for 
each ARM (ARM-1, 2, and 3). 
 


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8.3. Plasma Micro RNA at Week 24 
Pearson's product-moment correlation coefficient, Spearman's rank correlation coefficient, 
and their 95% confidence interval will be calculated to evaluate the correlation of SDAI and 
ACR-N to plasma micro RNA levels at Week 24. 
 
8.4. Serum Anti-adalimumab Antibody at Weeks 24 and 48 
For serum anti-adalimumab antibody, the frequency of and the proportion of subjects with 
the antibody expression will be calculated at each assessment timepoint for each ARM 
(ARM-1, 2, and 3). 


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9. Revision History 
9.1. Revision from Protocol 
Date 
Name 
Addresses 
for 
distribution 
Revised contents 
Not 
applicable 
 
 
 
 
9.2. Revision History of the Statistical Analysis Plan 
Date 
Name 
Addresses 
for 
distribution 
Revised contents 
7/27/2021 
Yasunori 
Sato 
 
 
Add wording that a missing data on the 
final scheduled visit will be imputed with 
data on End of Study for a sensitivity 
analysis of primary endpoint 
 
Update title of PI 
 
Typographical correction 
 
Update statistical software version 
 
 
 
 
 
 
 
 
 
 
 
10. Organization and Environment for Statistical Analyses 
10.1. Study Biostatistician 
Yasunori Sato, Associate Professor, Department of Preventive Medicine and Public Health, 
Keio University School of Medicine 
 
10.2. Person in Charge of Statistical Analysis 
Hirokazu Yamada, Clinical Study Support Division, Soiken, Inc. 
xxxxxxxx xxxxxxx, xxxxxx xxxxxx xxxxxxx xxxxxxx, xxxxxx, xxx. 
 
10.3. Software Environment 
Statistical analyses described in this Statistical Analysis Plan will be conducted, and Tables, 
Figures, and Lists will be prepared using SAS version 9.4 on Windows 10 or above. The 
analyses results will be available as PDF file, Microsoft Word 2016 Rich Text Format, or 
Excel 2016 Worksheet. The use of any statistical software other than SAS or self-
developed software should be specified in the Statistical Analysis Report if applicable. 
Validations for SAS programs that are prepared for individual analyses will not be 
conducted. 
 


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11. Signature 
I hereby guarantee that the contents of this Statistical Analysis Plan are appropriate for 
“MIRACLE (Methotrexate inadequate response patient with Rheumatoid Arthritis treated by 
Adalimumab in combination with Low-dose Methotrexate) Study”, and this Statistical 
Analysis Plan was finalized before the final data analysis. 
 
 
 
 
Day/Month/Year 
 
 
 
(Seal)