Conditions: Arthritis, Rheumatoid
Keywords: Smyraf Rheumatoid Arthritis Peficitinib ASP015K
Allocation: NON_RANDOMIZED | Intervention model: SINGLE_GROUP
Enrollment: 843
Healthy volunteers: no

Brief summary:
This study evaluated the safety and efficacy of long-term administration of ASP015K in patients who have completed Phase IIb or Phase III studies.

Detailed description:
This study was an extension study conducted as an open-label multicenter study in rheumatoid arthritis (RA) participants who completed the Phase IIb Study of ASP015K \[015K-CL-RAJ1 (hereinafter referred to as study RAJ1)\], Phase III Study of ASP015K \[015K-CL-RAJ3 (RAJ3)\], or Phase III Study of ASP015K \[015K-CL-RAJ4 (RAJ4)\]. After the marketing approval in Japan on 26 Mar 2019, this study continued as "post marketing clinical study" in Japan. In Taiwan and Korea, this study continued as "clinical study".

Participants received oral ASP015K once daily (QD) after breakfast. The ASP015K dose was increased later for participants who have no safety problems but showed lack of efficacy.

The duration of treatment with the study drug was differed depending upon the participants.

Arms:
arm 1: Participants who completed 015K-CL-RAJ1 (NCT02305849) study and met eligible criteria received starting dose of 50 milligrams (mg) peficitinib tablet orally once daily after breakfast. Dose can be increased to 100mg or 150mg, and decreased to 50mg. For participants who did not have any safety problem, the dose was increased from 50 mg to 100 mg. For participants who did not have any safety problems, and a lack of clinical response (DAS28-ESR \>= 3.2 after 4 weeks of peficitinib treatment), dose was increased to 150mg. The treatment was given in this study up to 6 months after peficitinib was approved. arm 2: Participants who completed 015K-CL-RAJ3 (NCT02308163) study and met eligible criteria received 100mg peficitinib tablet orally once daily after breakfast. Dose can be increased to 100mg or 150mg, and decreased to 50mg. For participants who did not have any safety problem, the dose was increased from 50 mg to 100 mg. For participants who did not have any safety problems, and confirmed a lack of clinical response (DAS28-ESR \>= 3.2 after 4 weeks of peficitinib treatment), dose was increased to 150mg. The treatment was given in this study up to 6 months after peficitinib was approved. arm 3: Participants who completed 015K-CL-RAJ4 (NCT02305849) study and met eligible criteria received 100mg peficitinib tablet orally once daily after breakfast. Dose can be increased to 100mg or 150mg, and decreased to 50mg. For participants who did not have any safety problem, the dose was increased from 50 mg to 100 mg. For participants who did not have any safety problems, and confirmed a lack of clinical response (DAS28-ESR \>= 3.2 after 4 weeks of peficitinib treatment), dose was increased to 150mg. The treatment was given in this study up to 6 months after peficitinib was approved.

Interventions: intervention 1: Peficitinib
Intervention descriptions: intervention 1: Oral Tablet

Protocol document:
Prot_000.pdf: 
−Open-Label Extension Study in Rheumatoid Arthritis 
Patients Who Have Completed Phase IIb Study or Phase 
III Study of ASP015K−
ISN/Protocol 015K-CL-RAJ2
ClinicalTrials.gov Identifier: NCT01638013
Date of Protocol: Version 7.0, dated 29 March 2019
Sponsor: Astellas Pharma Inc. (API)
2-5-1 Nihonbashi-Honcho, Chuo-ku, Tokyo


Sponsor: Astellas Pharma Inc. 
ISN/Protocol <015K-CL-RAJ2> 
 
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29 March 2019 (Ver. 7.0) 
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Page 1 of 128 
 
 
 
Protocol for Extension Study/ Post-marketing Clinical Study of ASP015K 
–Open-Label Extension Study in Rheumatoid Arthritis Patients Who Have Completed Phase 
IIb Study or Phase III Study of ASP015K– 
 
 
 
Sponsor:  
Astellas Pharma Inc. (API) 
 
 
 
 
 
ISN/Protocol: 015K-CL-RAJ2 
 
Created 29 March 2019 (Ver. 7.0) 
This confidential document is the property of the sponsor. No unpublished information contained in this 
document may be disclosed without prior written approval of the sponsor. 
 
 
 
After ASP015K receives the marketing approval in Japan, this study will continue as a 
“post-marketing clinical study”. In this case, the term “clinical study” in this protocol 
should be read as “post-marketing clinical study.” In Korea and Taiwan, this study will 
continue as a “clinical study” after the marketing approval in Japan. 
 


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ISN/Protocol <015K-CL-RAJ2> 
 
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Table of Contents 
I. 
SIGNATURE ························································································ 7 
II. 
CONTACT DETAILS OF KEY SPONSOR’S PERSONNEL ····························· 8 
III. 
LIST OF ABBREVIATIONS AND KEY TERMS ·········································· 10 
IV. 
SYNOPSIS ·························································································· 14 
V. 
FLOW CHART AND SCHEDULE OF ASSESSMENTS ································· 25 
1 
INTRODUCTION ················································································· 30 
1.1 
Background ···················································································· 30 
1.2 
Non-clinical and Clinical Data ······························································ 31 
1.2.1 
Nonclinical Pharmacology and Safety Pharmacology ······························ 31 
1.2.2 
Pharmacokinetics and Pharmacodynamics ··········································· 32 
1.2.2.1 
Nonclinical Pharmacokinetics ···················································· 32 
1.2.2.2 
Clinical Pharmacokinetics and Pharmacodynamics ··························· 33 
1.2.3 
Toxicology ··············································································· 35 
1.2.4 
Efficacy ··················································································· 36 
1.3 
Summary of Key Safety Information for Study Drugs ··································· 36 
1.4 
Risk-Benefit Assessment ····································································· 43 
2 
STUDY OBJECTIVE(S), DESIGN, AND VARIABLES ·································· 44 
2.1 
Study Objectives ·············································································· 44 
2.2 
Study Design and Dose Rationale ··························································· 45 
2.2.1 
Study Design ············································································· 45 
2.2.2 
Dose Rationale ··········································································· 45 
2.3 
Variables ······················································································· 47 
2.3.1 
Safety Variables ········································································· 47 
2.3.2 
Efficacy Variables ······································································· 47 
2.3.3 
Pharmacodynamics Variables ·························································· 48 
3 
STUDY POPULATION ·········································································· 48 
3.1 
Selection of Study Population ······························································· 48 
3.2 
Inclusion Criteria ·············································································· 48 
3.3 
Exclusion Criteria ············································································· 49 
3.4 
Discontinuation Criteria for Individual Subjects ·········································· 53 
3.4.1 
Suspension, Interruption, and Resumption of the Study Drug ····················· 54 


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3.4.1.1 
Criteria for Suspension or Interruption of the Study Drug ···················· 55 
4 
STUDY DRUGS ··················································································· 57 
4.1 
Description of Study Drugs ·································································· 57 
4.1.1 
Test Drug(s) ·············································································· 57 
4.1.2 
Comparative Drug(s) ···································································· 57 
4.2 
Packaging and Labeling ······································································ 57 
4.2.1 
Packaging Form ········································································· 57 
4.2.2 
Labeling ·················································································· 58 
4.3 
Study Drug Handling ········································································· 60 
4.4 
Blinding ························································································ 60 
4.5 
Assignment and Allocation ·································································· 60 
5 
TREATMENTS AND EVALUATION ························································ 61 
5.1 
Dosing and Administration of Study Drugs and Other Medications ···················· 61 
5.1.1 
Dose/Dose Regimen and Administration Period ···································· 61 
5.1.2 
Increase or Reduction in Dose of the Study Drugs ·································· 61 
5.1.3 
Previous and Concomitant Medication (Drugs and Therapies) ···················· 62 
5.1.3.1 
Previous Medication (Drugs and Therapies) ··································· 63 
5.1.3.2 
Concomitant Medication (Drugs and Therapies) ······························ 64 
5.1.4 
Treatment Compliance ·································································· 67 
5.1.5 
Emergency Procedures and Management of Overdose ····························· 68 
5.1.6 
Compliance Rules to be Observed by Subjects throughout the Study ············ 68 
5.2 
Demographics and Baseline Characteristics ··············································· 69 
5.2.1 
Demographics ············································································ 69 
5.2.2 
Medical History ·········································································· 69 
5.2.3 
Duration, Severity, Drug History, and Treatment Response of Target 
Disease ···················································································· 69 
5.3 
Efficacy and Pharmacodynamics Assessments ············································ 69 
5.3.1 
Efficacy Assessments ··································································· 69 
5.3.1.1 
Tender and Swollen Joint Counts ················································ 69 
5.3.1.2 
Assessment of Pain and Overall Assessment of Disease Activity ··········· 70 
5.3.1.3 
Acute Phase Reactants (CRP and ESR) ········································· 70 
5.3.1.4 
EULAR Response Criteria ······················································· 70 
5.3.1.5 
DAS28 ·············································································· 71 
5.3.1.6 
SDAI Score ········································································· 71 


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5.3.1.7 
ACR Response Criteria Assessment ············································ 72 
5.3.1.8 
Patient Reported Outcomes/Assessments ······································· 72 
5.3.2 
Pharmacodynamics Assessments ······················································ 72 
5.3.2.1 
Lymphocyte Subsets ······························································ 72 
5.4 
Safety Assessment ············································································ 73 
5.4.1 
Vital Signs ················································································ 73 
5.4.2 
Body Weight ············································································· 73 
5.4.3 
Adverse Events ·········································································· 73 
5.4.4 
Laboratory Assessments ································································ 73 
5.4.4.1 
CPK Monitoring ··································································· 75 
5.4.4.2 
Liver Safety Monitoring and Assessment ······································ 75 
5.4.5 
Physical Examination ··································································· 76 
5.4.6 
12-lead Electrocardiogram (ECG) ····················································· 76 
5.4.7 
Radiography ·············································································· 76 
5.5 
Adverse Events and Other Safety Aspects ················································· 77 
5.5.1 
Definition of Adverse Events (AEs) ·················································· 77 
5.5.2 
Definition of Serious Adverse Events (SAEs) ······································· 77 
5.5.3 
Criteria for Causal Relationship to the Study Drug ································· 78 
5.5.4 
Criteria for Defining the Severity of an Adverse Event ···························· 79 
5.5.5 
Reporting of Serious Adverse Events (SAEs) ······································· 79 
5.5.6 
Follow-up to Adverse Events ·························································· 80 
5.5.7 
Procedure in Case of Pregnancy ······················································· 80 
5.5.8 
Supply of New Information Affecting the Conduct of the Study ·················· 81 
5.5.9 
Deviations from the Protocol and Other Actions Taken to Avoid Life-
Threatening Risks to Subjects ························································· 82 
5.6 
Test Drug Concentration ····································································· 82 
5.7 
Other Measurements, Assessments, or Methods ·········································· 83 
5.7.1 
Pharmacodynamic Parameters ························································· 83 
5.8 
Total Amount of Blood ······································································· 83 
6 
TERMINATION OF THE CLINICAL STUDY ············································ 84 
7 
STATISTICAL METHODOLOGY ··························································· 85 
7.1 
Sample Size ···················································································· 85 
7.2 
Analysis Set ···················································································· 85 
7.2.1 
Full Analysis Set (FAS) ································································ 85 


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7.2.2 
Safety Analysis Set (SAF) ······························································ 85 
7.2.3 
Pharmacodynamics Analysis Set (PDAS) ············································ 86 
7.3 
Demographics and Other Baseline Characteristics ········································ 86 
7.4 
Analysis of Efficacy ·········································································· 86 
7.5 
Analysis of Safety ············································································· 86 
7.5.1 
Adverse Events ·········································································· 86 
7.5.2 
Laboratory Measurements ······························································ 86 
7.5.3 
Vital Signs ················································································ 87 
7.5.4 
12-lead ECG ············································································· 87 
7.5.5 
Body Weight ············································································· 87 
7.6 
Other Analyses ················································································ 87 
7.6.1 
Analysis of Pharmacodynamics ······················································· 87 
7.7 
Interim Analysis (and Early Discontinuation of the Clinical Study) ···················· 87 
7.8 
Handling of Missing Data, Outliers, Visit Windows, and Other Information ········· 87 
7.8.1 
Handling of Schedule of Assessments of Efficacy Variables ······················ 88 
7.8.2 
Handling of Schedule of Assessments of Pharmacodynamics Variables ········· 91 
7.8.3 
Handling of Schedule of Assessments of Safety Variables ························ 91 
8 
OPERATIONAL AND ADMINISTRATIVE CONSIDERATIONS ···················· 94 
8.1 
Procedure for Clinical Study Quality Control ············································· 94 
8.1.1 
Data Collection ·········································································· 94 
8.1.2 
Specification of Source Documents ··················································· 95 
8.1.3 
Clinical Study Monitoring ······························································ 96 
8.1.4 
Direct Access to Source Data/Documents ············································ 96 
8.1.5 
Data Management ······································································· 96 
8.2 
Ethics and Protection of Subject Confidentiality ·········································· 96 
8.2.1 
Institutional Review Board (IRB)/Independent Ethic Committee (IEC) ········· 96 
8.2.2 
Ethical Conduct of the Study··························································· 96 
8.2.3 
Informed Consent of Subjects ························································· 96 
8.2.3.1 
Subject Information and Consent ················································ 96 
8.2.3.2 
Supply of New and Important Information Influencing the Subject’s 
Consent and Revision of the Written Information ····························· 97 
8.2.4 
Subject Confidentiality ································································· 98 
8.3 
Administrative Matters ······································································· 98 
8.3.1 
Arrangement for Use of Information and Publication of the Clinical Study ····· 98 


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8.3.2 
Retaining Documents and Records Related to the Clinical Study ················· 99 
8.3.3 
Protocol Amendment and/or Revision ·············································· 101 
8.3.4 
Insurance of Subjects and Others ···················································· 101 
8.3.5 
Signatory Investigator for Clinical Study Report ·································· 102 
9 
QUALITY ASSURANCE ······································································ 102 
10 
STUDY ORGANIZATION ···································································· 102 
10.1 
Independent Data and Safety Monitoring Board (DSMB) ····························· 102 
10.2 
Other Evaluation Committee(s) ··························································· 102 
10.3 
Other Study Organization ·································································· 102 
10.4 
Registration of Subjects ···································································· 103 
11 
REFERENCES ·················································································· 105 
12 
APPENDICES ··················································································· 108 
APPENDIX <1>: 
LIST OF PROHIBITED CONCOMITANT MEDICATION ········· 108 
APPENDIX <2>: 
LABORATORY TESTS ······················································ 110 
APPENDIX <3>: 
EVENTS ALWAYS CONSIDERED TO BE SERIOUS ················ 113 
APPENDIX <4>: 
CRITERIA FOR THE CLASSIFICATION OF GLOBAL 
FUNCTIONAL STATUS IN RA (1991 REVISED CRITERIA) ······················· 114 
APPENDIX <5>: 
CLASSIFICATION OF DISEASE STAGE/PROGRESSION OF 
RA 
114 
APPENDIX <6>: 
LIVER SAFETY MONITORING AND ASSESSMENT ··············· 115 
APPENDIX <7>: 
STUDY PROTOCOL VER. 1.3 (EXCERPT) ···························· 118 
 


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I. 
SIGNATURE 
AGREEMENT BETWEEN THE SPONSOR’S RESPONSIBLE PERSON AND THE 
INVESTIGATOR 
This clinical study will be conducted in adherence to GCP, GPSP, and applicable laws and 
regulatory requirements, as well as this study protocol. As the evidence of the agreement, the 
investigator (CHIKEN SEKININ ISHI) and responsible person of the sponsor (CHIKEN 
IRAI SEKININSHA) shall inscribe their signatures on the bipartite agreement. 


Sponsor: Astellas Pharma Inc. 
ISN/Protocol <015K-CL-RAJ2> 
 
- CONFIDENTIAL - 
29 March 2019 (Ver. 7.0) 
Astellas 
Page 8 of 128 
II. 
CONTACT DETAILS OF KEY SPONSOR’S PERSONNEL 
 
Contact Information for the Sponsor 
 
an 
TEL: 
 
FAX: 
 
Persons in charge: 
 
[Contact numbers during non-business hours and for emergency]: 
 
 
 
Contact Information for the Contract Research Organization (CRO) 
➢ Japan 
 
Location: 
 
TEL: 
 
FAX: 
 
Persons in charge: 
 
[Contact numbers during non-business hours and for emergency]: 
 
 
➢ Korea 
 
Location: 
 
TEL: 
 
FAX: 
 
Person in charge: 
 
[Contact numbers during non-business hours and for emergency]: 
 
 


Sponsor: Astellas Pharma Inc. 
ISN/Protocol <015K-CL-RAJ2> 
 
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29 March 2019 (Ver. 7.0) 
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Page 9 of 128 
➢ Taiwan 
 
Location: 
 
TEL: 
 
FAX: 
 
Person in charge: 
 
[Contact numbers during non-business hours and for emergency]: 
 


Sponsor: Astellas Pharma Inc. 
ISN/Protocol <015K-CL-RAJ2> 
 
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29 March 2019 (Ver. 7.0) 
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Page 10 of 128 
III. 
LIST OF ABBREVIATIONS AND KEY TERMS 
List of Abbreviations 
Abbreviations 
Description of abbreviations 
ACR 
American College of Rheumatology 
AE 
Adverse event 
ALP 
Alkaline phosphatase 
ALT 
Alanine aminotransferase (GPT)  
AST 
Aspartate aminotransferase (GOT)  
ASP015K 
Astellas Pharmaceuticals compound 015K 
AUC 
Area under the concentration – time curve 
AUCinf 
AUC from the time of dosing up to infinity with extrapolation of the terminal 
phase 
AUClast 
AUC from the time of dosing to the last measurable concentration 
BUN 
Blood urea nitrogen 
Cmax 
Maximum concentration 
Ctrough 
Trough concentration 
CK/CPK 
Creatine kinase/creatine phosphokinase 
CK-MB 
Creatine kinase MB isozyme 
CRF 
Case report form 
CRO 
Contract research organization 
CRP 
C-reactive protein 
CYP 
Cytochrome P450 
DAS 
Disease activity score 
DDI 
Drug-drug interaction 
DILI 
Drug induced liver injury 
DIP 
Distal interphalangeal joint 
DMARD 
Disease-modifying antirheumatic drug 
DNA 
Deoxyribonucleic acid 
DSMB 
Data and Safety Monitoring Board 
ECG 
Electrocardiogram 
eCRF 
Electronic case report form 
EDC 
Electronic data capture 
EDTA 
Ethylenediaminetetraacetic Acid 
ESR 
Erythrocyte sedimentation rate  
EU 
European Union 
EULAR 
European League Against Rheumatism 
F 
Bioavailability 
FACIT-Fatigue 
Functional Assessment of Chronic Illness Therapy-Fatigue 
FAS 
Full analysis set 
FDA 
Food and Drug Administration 
GCP 
Good Clinical Practice 
GFR 
Glomerular filtration rate 
GMP 
Good Manufacturing Practice  
GPSP 
Good Post-marketing Study Practice 
γ-GTP 
γ-glutamyl transpeptidase (GGT) 
HAQ-DI 
Health Assessment Questionnaire – Disability Index  
HBc antibody 
Hepatitis B core antibody 
HBs 
antigen/antibody 
Hepatitis B surface antigen/antibody 


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HBV 
Hepatitis B virus 
HCV 
Hepatitis C virus  
hERG 
Ether-a-go-go related gene  
HIV 
Human immunodeficiency virus  
HSA 
Human serum albumin  
ICH  
International Conference on Harmonization of Technical Requirements for 
Registration of Pharmaceuticals for Human Use  
IEC 
Independent Ethic Committee 
IL 
Interleukin 
IND 
Investigational new drug  
INR 
International normalized ratio  
IP 
Interphalangeal joint  
IRB 
Institutional review board  
ISN 
International study number  
IV 
Intravenous  
JAK 
Janus kinase  
LA-CRF 
Liver abnormality-CRF 
LDL 
Low-density lipoprotein 
LOCF 
Last observation carried forward  
MCP 
Metacarpophalangeal joint  
MedDRA 
Medical Dictionary for Regulatory Activities  
MMF 
Mycophenolate mofetil  
MMP-3 
Matrix metalloproteinase 3  
MPA 
Mycophenolic acid  
MPAG 
Mycophenolic acid glucuronide  
MTP 
Metatarsophalangeal joint  
MTX 
Methotrexate  
NCI-CTCAE 
National Cancer Institute Common Terminology Criteria for Adverse Events  
NDA 
New drug application  
NK 
Natural killer  
NOAEL 
No observed adverse effect level  
NSAIDs 
Non-steroidal anti-inflammatory Drugs  
NYHA 
New York Heart Association  
PASI 
Psoriasis area and severity index  
PD 
Pharmacodynamic 
PGA 
Physician’s Global Assessment of Arthritis  
PIP 
Proximal interphalangeal joint  
QOL 
Quality of life 
RA 
Rheumatoid arthritis  
RBC 
Red blood cell  
SAE 
Serious adverse event  
SAF 
Safety analysis set  
SDAI 
Simplified Disease Activity Index  
SF-36v2® 
Short form health survey – 36 questions, version 2: SF-36 v2®  
SFL 
Screening Failure Log  
SGA 
Subject’s Global Assessment of Arthritis  
SJC 
Swollen joint count  
SOP 
Standard operating procedure 
STAT5 
Signal transducers and activators of transcription 5 
SUSAR 
Suspected unexpected serious adverse reactions  


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TBL 
Total bilirubin 
TEAE 
Treatment emergent adverse event 
TJC 
Tender joint count 
TNF 
Tumor necrosis factor 
t1/2 
Apparent terminal elimination half-life 
tmax 
Time to attain Cmax 
TYK2 
Tyrosine kinase 2 
ULN 
Upper limit of normal 
VAS 
Visual analog scale 
WBC 
White blood cell 
WPAI 
Work Productivity and Activity Impairment Questionnaire 
 


Sponsor: Astellas Pharma Inc. 
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Page 13 of 128 
List of Key Study Terms 
Terms 
Definition of terms 
Adverse event 
An adverse event is as any untoward medical occurrence in a subject 
administered a study drug and which does not necessarily have a causal 
relationship with this treatment. 
Baseline 
The last measured values/findings prior to dosing 
Study discontinuation 
The act of concluding participation, prior to completion of all protocol-
required elements, in a study by an enrolled subject. Four categories of 
discontinuation are distinguished: a) dropout: Active discontinuation 
by a subject (also a noun referring to such a discontinued subject); b) 
discontinuation initiated by the investigator or other responsible 
personnel (e.g., for cause); c) loss to follow-up: cessation of 
participation without notice or action by the subject; d) sponsor-
initiated discontinuation. 
Note that subject discontinuation does not necessarily imply exclusion 
of subject data from analysis. 
Enroll 
To register or enter into a clinical study; transitively and intransitively. 
Informed consent precedes enrollment. 
Follow-up period 
The follow-up period begins at the completion of all 
assessments/measurements at end of treatment/early termination and 
ends upon completion of all assessments/measurements at end of study 
(at time of follow-up). 
Serious adverse event 
Any adverse event that is judged “serious” by the investigator/sub-
investigator or the sponsor and results in any of the following 
outcomes: death, a life-threatening condition, persistent or significant 
disability/incapacity or substantial disruption of the ability to conduct 
normal life functions, congenital anomaly/birth defect, hospitalization 
or prolongation of hospitalization, and other medically significant 
occurrences. 
Screening failure 
A subject from whom informed consent was obtained but who did not 
fulfill protocol inclusion and/or exclusion criteria and did not receive 
the study drug  
Study period 
Period of time from obtaining informed consent from subjects to the 
end of the final evaluation/observation specified in the protocol 
Subject 
An individual who participates in a clinical study, as a recipient of 
either the test drug(s) or comparative drug(s) 
Subject ID 
A unique identifier code assigned to each subject signing the informed 
consent. 
Variable 
Any quantity that varies; any attribute, phenomenon or event that can 
have different qualitative or quantitative values 
 


Sponsor: Astellas Pharma Inc. 
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IV. 
SYNOPSIS 
Title of Study 
Extension Study of ASP015K 
–Open-Label Extension Study in Rheumatoid Arthritis Patients Who Have 
Completed Phase IIb Study or Phase III Study of ASP015K– 
(Protocol Number: 015K-CL-RAJ2) 
Planned Study Period 
From February 2012 up to a maximum of 6 months after the NDA approval at 
one of the regions (After the NDA approval in Japan, the post-marketing 
clinical study will be ended once the study drug is available in the clinical sites 
as a commercially available product. The planned study period will be up to a 
maximum of 6 months after the NDA approval in Japan). Sponsor will 
immediately inform sites when the NDA approval date at one of the regions is 
confirmed. 
Study Objectives 
This is an extension study conducted in rheumatoid arthritis (RA) patients who 
have completed the Phase IIb Study of ASP015K [015K-CL-RAJ1 (hereinafter 
referred to as study RAJ1)], Phase III Study of ASP015K [015K-CL-RAJ3 
(RAJ3)], or Phase III Study of ASP015K [015K-CL-RAJ4 (RAJ4)] to 
investigate the safety and efficacy of long-term administration of ASP015K. 
 
Another objective of this study is to devise rescue measures for providing the 
active drug to patients who participated in the Phase IIb Study or Phase III 
Study of ASP015K, as described in “Guidelines on methodology for clinical 
assessment of antirheumatic drugs” (PFSB/ELD Notification No. 0217001, 
dated 17 February, 2006). 
Planned Total Number of 
Study Centers and 
Location 
Approximately 170 centers 
Japan, Korea, and Taiwan 
Design and Methodology 
This study is an extension study conducted as an open-label, multicenter study 
in RA patients who have completed studies RAJ1, RAJ3, or RAJ4. 
 
The protocols (ver. 2.0 and ver. 3.0) will become applicable when they are 
approved by the Institutional Review Board (IRB) of each study center and 
when the study drugs after the change of specifications become available for 
use. 
In the protocol ver. 6.0, the clinical study will transfer to a post-marketing 
clinical study after the NDA approval in Japan. In Korea and Taiwan, this 
study will continue as a clinical study after the NDA approval in Japan. 
 
[Subjects who transferred from studies RAJ3 or RAJ4] 
Patients who meet all of the inclusion criteria and do not fall under any of the 
exclusion criteria will receive oral ASP015K 100 mg once daily (QD) after 
breakfast as the starting dose.  
 
[Subjects who transferred from study RAJ1] 
Patients who meet all of the inclusion criteria and do not fall under any of the 
exclusion criteria will be registered and will receive oral ASP015K 50 mg QD 
after breakfast as the starting dose. 
Subjects who have been receiving ASP015K at a dose of 50 mg/day before the 
revision of the protocol to ver. 2.0/ver. 3.0 shall be included in the clinical 
study under the protocol (ver. 2.0/ver. 3.0), and the need for a change in the 
dose shall be discussed when the study drugs after the change of specifications 
become available for use. Treatment extension with a dose of 50 mg/day 
should be allowed for subjects for whom the investigator or sub-investigator 
considers a dose increase to be inappropriate in terms of safety and treatment 
extension with a dose of 50 mg/day to provide greater therapeutic benefit for 
the treatment of RA. For subjects who have been receiving ASP015K at a dose 


Sponsor: Astellas Pharma Inc. 
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29 March 2019 (Ver. 7.0) 
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Page 15 of 128 
of 50 mg/day in Japan, the dose will be increased to 100 mg/day after the 
NDA approval in Japan. Any subjects for whom the dose cannot be increased 
should be withdrawn from the study. 
 
For subjects who have no safety problems but show a lack of efficacy, the 
dosage may later be increased from 100 mg/day to 150 mg/day.  
Only in Korea and Taiwan, the dosage may be reduced from 100 mg/day or 
150 mg/day to 50 mg/day at the discretion of the investigator or sub-
investigator. 
 
This study will be conducted as a post-marketing clinical study up to a 
maximum of 6 months after the NDA approval in Japan. (After the NDA 
approval in Japan, the post-marketing clinical study will be ended once the 
study drug is available in the clinical sites as a commercially available product. 
The planned study period will be up to a maximum of 6 months after the NDA 
approval in Japan). In Korea and Taiwan, this study will continue as a clinical 
study after the NDA approval in Japan. The duration of treatment with the 
study drug will differ depending on the subject. 
 
To prevent purposeless continuation of dosing without effect, the investigator 
or sub-investigator will assess each subject for efficacy and safety at each visit, 
confirm the appropriateness of continued administration for each individual, 
and decide whether or not to continue dosing. 
Number of Subjects 
Planned 
Approximately 800 subjects will receive the study drug. 
Selection Criteria 
[Subjects who transferred from study RAJ1] 
<Inclusion Criteria> 
Subject is eligible for the study if all of the following apply: 
1. 
Subject has received a full explanation of the study drug and this study in 
advance, and written informed consent to participate in the study has been 
obtained from the subject himself/herself. 
2. 
Subject has completed treatment with the study drug in study RAJ1 as 
specified in the protocol and has also completed the tests and assessment 
performed at the study visit in Week 16. 
3. 
The subject himself/herself wishes to continue taking the study drug, and 
the investigator or sub-investigator deems continued administration to be 
necessary or appropriate. 
4. 
Subject must be willing and able to comply with the study requirements. 
 
<Exclusion Criteria> 
Subject will be excluded from participation if any of the following apply: 
1. Subject has developed an adverse reaction related to the study drug in 
study RAJ1 and the risks of continuing treatment with this drug are 
expected to outweigh the benefits. 
2. There were abnormal findings in the x-ray taken at Week 0, and an acute 
or chronic infection, tuberculosis infection, or malignant tumor is 
suspected. 
3. Subject has received live or live attenuated virus vaccination within 30 
days prior to the first dose of study drug. 
4. Subject is a hepatitis B virus or hepatitis C virus carrier or has a history of 
a positive test for HIV infection. 
5. Subject has concurrent autoimmune disease (except Sjogren’s syndrome) 
other than RA or a history of it. 
6. Subject has a clinically significant infection or disease (requiring 
hospitalization or parenteral therapy). 
7. Subject has a history of any malignant tumor, except for successfully 


Sponsor: Astellas Pharma Inc. 
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29 March 2019 (Ver. 7.0) 
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treated basal or squamous cell carcinoma of the skin or in-situ carcinoma 
of the cervix, or subject has a concurrent malignant tumor. 
8. Subject has taken one of the following drugs between the end of the 
assessments at Week 12 of study RAJ1 and the start of treatment with the 
study drug in this extension study. 
 Biologic DMARD: Etanercept, adalimumab, golimumab, infliximab, 
tocilizumab, abatacept, rituximab 
 Non-biologic DMARD: Methotrexate (MTX), salazosulfapyridine, 
gold, D-penicillamine, leflunomide, lobenzarit, actarit, tacrolimus, 
mizoribine, bucillamine, iguratimod, tofacitinib (However, topical drugs 
other than those for the treatment of RA may be used concomitantly.) 
 Other drugs used in the treatment of RA: Cyclosporine, 
cyclophosphamide, azathioprine, minomycin, etc. 
9. Subject has received plasma exchange therapy between the end of the 
assessments at Week 12 of study RAJ1 and the start of treatment with the 
study drug in this extension study. 
10. Subject has received any of the following CYP3A substrates with narrow 
therapeutic range within 14 days prior to starting treatment with the study 
drug: 
Dihydroergotamine, ergotamine, fentanyl, pimozide, quinidine, and 
temsirolimus 
11. Subject has any of the following laboratory values at the study visit in 
Week 12 of study RAJ1: 
 Hemoglobin < 10 g/dL 
 White blood cell (WBC) count < 3000/μL 
 Absolute neutrophil count (ANC) < 2000/μL 
 Absolute lymphocyte count < 800/μL 
 Platelet count < 100000/μL 
 ALT ≥ 2 × ULN 
 AST ≥ 2 × ULN 
 Total bilirubin (TBL) ≥ 1.5 × ULN 
 Estimated glomerular filtration rate (GFR) ≤ 40 mL/min, as measured 
by the MDRD method 
 CPK > 1.5 × ULN 
 β-D-glucan ≥ 11 pg/mL 
12. Subject has symptomatic CPK elevation (CPK > 1.5 × ULN with myalgia, 
muscular weakness, or severe unusual muscle twitching) at the study visit 
in Week 12 of study RAJ1. 
13. Subject is found to have symptoms of myopathy such as myalgia, 
muscular weakness, and severe unusual muscle twitching regardless of 
CPK level that persist for at least 2 weeks or that worsen rapidly within 2 
weeks, at study visit in Week 12 of study RAJ1. 
14. Subject has concurrent cardiac failure with NYHA classification of Class 
III or higher, or a history of it. 
15. Subject has concurrent long QT syndrome or history of it. Subject exhibits 
QT interval prolonged at the study visit in Week 0. 
16. Subject has any ongoing severe, progressive, or uncontrolled renal, 
hepatic, hematological, gastrointestinal, metabolic, endocrine, pulmonary, 
cardiac, neurological, or infectious disease, or any ongoing illness which 
would make the subject unsuitable for the study as determined by the 
investigator/sub-investigator. 
17. Subject has any condition possibly affecting oral absorption (e.g., 
gastrectomy or clinically significant diabetic gastroenteropathy). 
18. Subject has received surgical treatment and the investigator/sub-
investigator judges there to be residual effects of surgical stress. Or, the 
subject plans to have surgical treatment that will require hospitalization 


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during the study period or surgery on the joints. 
19. The subject is a woman who is pregnant or might be pregnant, is nursing, 
wishes to conceive within 60 days after end of treatment drug, or for 
whom the possibility of pregnancy cannot be ruled out as a result of the 
pregnancy test given at Week 0. 
20. The subject is a man who cannot practice proper contraception with a 
condom from the time informed consent is given until 90 days after end of 
treatment, or the subject is a woman who could become pregnant and 
cannot practice proper contraception with a condom from the time 
informed consent is given until 60 days after end of treatment. 
21. The subject has been judged unsuitable to participate in the study for other 
reasons by the investigator/sub-investigator. 
 
[Subjects who transferred from studies RAJ3 or RAJ4] 
<Inclusion Criteria> 
Subject is eligible for the study if all of the following apply: 
1. 
Subject has received a full explanation of the study drug and this study in 
advance, and written informed consent to participate in the study has been 
obtained from the subject himself/herself. 
2. 
Subject who has completed treatment with the study drug in studies RAJ3 
or RAJ4 as specified in the protocol and has also completed the tests and 
assessments scheduled for the Week 52 visit.  
3. 
The subject himself/herself wishes to continue taking the study drug, and 
the investigator or sub-investigator deems continued administration to be 
necessary or appropriate. 
4. 
Subject must be willing and able to comply with the study requirements. 
 
<Exclusion Criteria> 
Subject will be excluded from participation if any of the following apply: 
1. 
The subject is a woman who is pregnant or might be pregnant, is nursing, 
wishes to conceive within 60 days after end of treatment drug, or for 
whom the possibility of pregnancy cannot be ruled out as a result of the 
pregnancy test given at Week 0. 
2. 
Subject is a man who cannot practice 2 or more methods of proper 
contraception from the time informed consent is given to 90 days after the 
end of treatment, or subject is a woman who could become pregnant and 
cannot practice 2 or more methods of proper contraception from the time 
informed consent is given to 60 days after the end of treatment.  
3. 
Subject is a man who cannot be prohibited from sperm donation from the 
time informed consent is given to 90 days after the end of treatment, or 
subject is a woman who cannot be prohibited from egg donation from the 
time informed consent is given to 60 days after the end of treatment. 
4. 
Subject who has tested positive for any of the following at screening for 
studies RAJ3 or RAJ4: HBs antigen, HBc antibody, HBs antibody, and 
HBV-DNA assay (However, if a subject is negative for HBs antigen and 
HBV-DNA assay, and positive for either or both HBc and HBs 
antibodies, the subject may be included provided that the subject is 
monitored by performing HBV-DNA assay at every scheduled visit after 
initiation of study drug administration.) 
5. 
Subject has received a prohibited concomitant medication or prohibited 
concomitant therapy during the time from the end of the assessments at 
Week 52 of studies RAJ3 or RAJ4 to the first dose of the study drug in 
this extension study.  
6. 
Subject has QTc < 300 msec on ECG measurements performed at the 
study site at Week 52 of studies RAJ3 or RAJ4 and has QTc < 300 msec 
at retest. 


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7. 
The subject has been judged unsuitable to participate in the study for 
other reasons by the investigator/sub-investigator. 
Discontinuation Criteria 
The investigator/sub-investigator should discontinue the study if any of the 
following criteria are met: 
 
1. 
Subject withdraws consent. 
2. 
The study drug is not sufficiently effective, and a change in treatment 
method is deemed to be in the subject’s best interest by the investigator or 
sub-investigator. 
3. 
Symptomatic CPK elevation, defined as CPK > 1.5 × ULN with severe 
unusual myalgia, muscular weakness, or muscle twitching. 
4. 
Any event of myopathy defined as severe unusual myalgia, muscular 
weakness, and muscle twitching regardless of CPK level that persists for 
at least 2 weeks or that worsens rapidly within 2 weeks. 
5. 
Subject infected with HBV who has tested positive for either of or both of 
HBc and HBs antibodies and is found to be positive for HBV-DNA assay 
during the study period.  
Abrupt discontinuance of immunosuppressive therapy may precipitate 
severe or fulminant hepatitis. Therefore, when HBV reactivates, nucleic 
acid analog therapy should be immediately initiated, and a hepatologist 
should be consulted regarding the continuation of ASP015K and 
concomitant DMARD (unique to Japan: as indicated by “Proposal for 
Management of Rheumatic Disease Patients with Hepatitis B Virus 
Infection Receiving Immunosuppressive Therapy” by the Japan College 
of Rheumatology.) 
6. 
Subject has a malignant tumor. 
7. 
Subject has an adverse event (AE) such as a serious infection, and the 
investigator or sub-investigator considers that it is not in the subject’s best 
interest to continue the study. 
8. 
Subject receives or requires a prohibited concomitant medication 
(including other study drugs) or prohibited concomitant therapy that may 
affect the evaluation of efficacy; subject receives or requires live vaccine 
or live attenuated vaccine.  
9. 
Subject receives or requires drug interruption for a longer period than that 
stipulated for interruption. 
10. Subject is deemed lost to follow-up by the investigator/sub-investigator 
(subject can no longer come to the study center; subject can no longer be 
contacted, etc.). 
11. It comes to light after the administration of the first dose of study drug 
that the inclusion criteria were not met at the time of case enrollment or 
that criteria for exclusion were met. It comes to light that there was some 
other major deviation from the protocol. 
12. Investigator or sub-investigator decides it is in the subject’s best interest 
to discontinue. 
13. The sponsor has requested that administration of the study drug be 
discontinued because of a safety problem in a particular subject, or the 
sponsor has decided to discontinue the study altogether. 
14. Subject has QTc < 300 msec on ECG measurements and has QTc < 300 
msec at retest. 
 
The Appendix 6 entitled “Liver Safety Monitoring and Assessment” describes 
liver function tests raised providing grounds for considering discontinuation. 
Refer to this if liver function tests raised is observed. 
Suspension, Interruption, 
and Resumption of the 
Study Drug 
If either of the below criteria for suspension or interruption of the study drug 
are met during the treatment period with the study drug, the investigator or 
sub-investigator is to suspend or interrupt administration of the study drug 


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without delay. Administration of the study drug may be resumed after the 
initiation of suspension or interruption if a retest shows that none of the 
following criteria are met, provided that the investigator or sub-investigator 
deems resumption to be in the subject’s best interest, taking the risk/benefit 
ratio into consideration: 
 
1. Subject has any of the following laboratory values: 
 
Hemoglobin < 8.0 g/dL 
 
ANC < 500/μL 
 
Absolute lymphocyte count < 500/μL 
 
Platelet count < 50000/μL 
 
Serum creatinine > 150% of baseline at 2 consecutive 
Scheduled Visits 
 
CPK > 10 × ULN 
2. β-D-glucan > ULN [in case of Japan: ≥ 11 pg/mL] 
3. Subject requires a concomitant medication that is prohibited because of a 
possible drug interaction. 
4. Suspected pregnancy. 
5. The investigator or sub-investigator considers suspension or interruption 
of the study drug to be in the subject’s best interest. 
6. The sponsor has requested suspension or interruption of the study drug 
because of a safety problem in a particular subject. 
 
Suspension of the study drug 
Administration of the study drug may be suspended within the scope of the 
below stipulations if the investigator or sub-investigator deems a temporary 
discontinuation (suspension) of dosing to be necessary. Suspension of the 
study drug beyond the scope of the following stipulation is handled as 
interruption: 
 
Suspension is defined as a temporary discontinuation of study drug 
administration for 7 days or less. 
 
If administration of the study drug is suspended repeatedly, the 
discontinuation of the clinical study for the particular subject should be 
considered in consultation with the sponsor.  
 
Interruption of the study drug 
Administration of the study drug may be interrupted within the scope of the 
below stipulations if the investigator or sub-investigator deems a temporary 
discontinuation (interruption) of dosing for a period exceeding 7 days to be 
necessary. If a subject requires interruption beyond the scope described below, 
the subject has to be withdrawn from the study. 
 
Interruption is defined as a temporary discontinuation of study drug 
administration for a period exceeding 7 days. 
 
Interruption may not exceed a maximum of 4 consecutive weeks. 
 
Up to 2 interruptions per year may be allowed. Moreover, they must be 
separated by an interval of 16 weeks or more. 
Test Drug 
Mode of Administration: 
Dose: 
Duration of Treatment: 
Test drug: ASP015K 50 mg, 100 mg, and 150 mg tablets 
Dose: [Subjects who transferred from study RAJ1] 
The starting dose will be 50 mg/day. 
[Subjects who transferred from studies RAJ3 or RAJ4] 
The starting dose will be 100 mg/day. 
 
For those subjects who have completed study RAJ1 and are continuing 
treatment with ASP015K at a dose of 50 mg/day, the need for a change in 
the dose shall be assessed at the initiation of the clinical study under the 
protocol ver. 2.0/ver. 3.0. If the dose is not increased to 100 mg, and 


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treatment is to be continued at a dose of 50 mg/day, the reason for this 
decision must be entered in the medical record.  
 
When the investigator or sub-investigator judges that there to be no safety 
problem in the subject, the dose may be increased from 50 mg to 100 mg. 
For subjects who have been receiving ASP015K at a dose of 50 mg/day 
in Japan, the dose will be increased to 100 mg/day after the NDA 
approval in Japan. Any subjects for whom the dose cannot be increased 
should be withdrawn from the study. 
 
The dose may be increased from 100 mg to 150 mg at the point in time 
when the following 2 conditions are fully met: 
1) 
Subject has taken ASP015K 100 mg for at least 4 weeks, and the 
DAS28-ESR score on the day of the study visit is 3.2 or higher 
(moderate disease activity or high disease activity). 
2) 
When the investigator or sub-investigator judges there to be no 
problem with safety for the subject in the assessment performed on 
the study visit day on which the DAS28-ESR of 3.2 score or higher 
was exhibited 
 
Only in Korea and Taiwan, the dose may be reduced from 100 mg/day or 
150 mg/day to 50 mg/day at the discretion of the investigator or sub-
investigator. The investigator or sub-investigator will decide whether or 
not to reduce the dosage on the basis of the following criterion. 
 
If an AE with an NCI-CTCAE grade classification of Grade 2 
or higher has developed. 
A dose increase after a dose reduction and a dose reduction after a dose 
increase are allowed according to the above criteria.  
 
Mode of administration: To be orally administered QD after breakfast. The 
first dose should be given at each study center on the 
day of the Week 0 visit after all of the necessary 
assessments and tests have been completed. 
The duration of treatment: This study will be conducted as a post-marketing 
clinical study up to a maximum of 6 months after 
the NDA approval in Japan. (After the NDA 
approval in Japan, the post-marketing clinical study 
will be ended once the study drug is available in the 
clinical sites as a commercially available product. 
The planned study period will be up to a maximum 
of 6 months after the NDA approval in Japan). In 
Korea and Taiwan, this study will continue as a 
clinical study after the NDA approval in Japan.  
 
The duration of treatment will differ depending on 
the subject. To prevent purposeless continuation of 
dosing without effect, the investigator or sub-
investigator will assess each subject for efficacy and 
safety at each visit, confirm the appropriateness of 
continued administration for each individual, and 
decide whether or not to continue dosing. 
Comparative drug 
Mode of Administration: 
Dose: 
Duration of Treatment: 
Not applicable. 
Concomitant Treatment 
(1) The following concomitant medications and complimentary alternative 
treatments are prohibited as described. 


Sponsor: Astellas Pharma Inc. 
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Page 21 of 128 
➢ 
Administration or the use of the following medications and therapies will 
be prohibited from the end of the assessments at Week 12 of study RAJ1 
to the initiation of administration of the study drug in this extension 
study, or from the end of the assessments at Week 52 of studies RAJ3 or 
RAJ4 to the initiation of administration of the study drug in this 
extension study, as well as throughout the treatment period of this 
extension study: 
1) 
Biologic DMARDs: etanercept, anakinra, adalimumab, golimumab, 
infliximab, tocilizumab, abatacept, rituximab, certolizumab pegol, 
denosumab, sarilumab. 
2) 
Non-biologic DMARDs: 
⚫ 
Subjects who transferred from study RAJ1: MTX, 
salazosulfapyridine, gold, D-penicillamine, leflunomide, lobenzarit, 
actarit, tacrolimus, mizoribine, bucillamine, iguratimod, tofacitinib, 
baricitinib. 
⚫ 
Subjects who transferred from study RAJ3: non-biologic DMARDs 
other than those used concomitantly in study RAJ3. 
⚫ 
Subjects who transferred from study RAJ4: salazosulfapyridine, 
gold, D-penicillamine, leflunomide, lobenzarit, actarit, tacrolimus, 
mizoribine, bucillamine, iguratimod, tofacitinib, baricitinib. 
(However, topical drugs other than those for the treatment of RA may be 
used concomitantly.) 
3) 
Other drugs used in the treatment of RA: cyclosporine, 
cyclophosphamide, azathioprine, minocycline, etc. 
4) 
Plasma exchange therapy 
 
➢ 
Administration of the following medications and therapies will be 
prohibited from the end of the assessments at Week 12 of study RAJ1 to 
the initiation of administration of the study drug in this extension study, 
or from the end of the assessments at Week 52 of study RAJ3 or RAJ4 to 
the initiation of administration of the study drug in this extension study, 
as well as throughout the treatment period and follow-up period of this 
extension study: 
5) 
Live or live attenuated virus vaccines 
 
➢ 
Administration of the following medications is prohibited within 14 days 
prior to the start of treatment with the study drug, as well as throughout 
the treatment period and follow-up period: 
6) 
CYP3A substrates with a narrow therapeutic range: dihydroergotamine, 
ergotamine, fentanyl, pimozide, quinidine, temsirolimus, disopyramide, 
etc. 
 
➢ 
Concomitant use of the following drugs and therapies will be prohibited 
throughout the treatment period: 
7) 
Oral corticosteroids at doses that exceed the amount used from the 
initiation of studies RAJ1, RAJ3, or RAJ4 to the initiation of 
administration of the study drug in this extension study at a daily dose of 
prednisolone or equivalent.  
8) 
Intra-articular, intravenous, intramuscular, or endorectal corticosteroids 
(However, suppositories for anal diseases may be used concomitantly.) 
9) 
Oral morphine at doses exceeding 30 mg/day (or the equivalent amount 
of opioid analgesics).  
10) Intra-articular administration of articular cartilage protective agents into 
joints subject to the assessment. 
11) Drainage of fluid accumulated in the joint subject to the assessment, 
local anesthesia into joints subject to the assessment, and nerve block. 


Sponsor: Astellas Pharma Inc. 
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Page 22 of 128 
12) The surgical treatment of joints subject to the assessment. 
 
➢ 
Concomitant use of the following medications and therapies is prohibited 
throughout the treatment period and follow-up period: 
13) Other study drugs, study drugs from post-marketing clinical studies, or 
medical devices being studied in clinical studies 
 
(2) Restricted concomitant medications 
<Subjects who transferred from studies RAJ1, RAJ3, or RAJ4> 
During the treatment period, the following medications may be used 
concomitantly at the discretion of the investigator or sub-investigator if they 
meet the following conditions for concomitant use (Both new administration 
and change in dosage/administration are permitted). 
1) Non-steroidal anti-inflammatory drugs (NSAIDs) (excluding topical 
drugs with a local action). 
2) Oral morphine (≤ 30 mg/day, or the equivalent amount of opioid 
analgesics) 
3) Acetaminophen 
– Conditions for concomitant use – 
 
No changes in the dosage/administration of the drug are allowed within 
the period of 12 weeks. However, this shall exclude cases where the 
medication has caused an AE. Moreover, if, after discontinuation of the 
concomitant medication, it becomes apparent that the suspected 
medication was not the offending drug that caused the AE, administration 
may be resumed with the dose prior to discontinuation as the maximum 
dose. 
 
<Subjects who transferred from study RAJ3> 
Subjects who have been receiving any of the below drugs throughout the 
treatment period of study RAJ3 shall continue the use of the drug concerned 
from the end of the assessment at Week 52 of study RAJ3 to the initiation of 
administration of the study drug in this extension study, as well as throughout 
the treatment period of this study. 
It is permitted to discontinue the drug or to increase or decrease the dose 
within the range not exceeding or falling below the baseline dose in study 
RAJ3. 
Administration of the drug may be interrupted, or the dose may be reduced 
because of an AE. This interruption must not exceed a maximum of 28 days. 
Administration may be resumed with the baseline dose in study RAJ3 as the 
maximum dose. 
● 
If MTX is administered with study drug concurrently, the concomitant 
use of folic acid should be considered whenever possible. The dose of 
folic acid during the study period will, in principle, be within 10 mg per 
week, but it may be adjusted. If MTX is administered and ALT/AST 
becomes ≥ 3 × ULN, MTX must be interrupted, or the dose must be 
reduced, and daily administration of folic acid should be considered. 
 
 
Methotrexate (MTX) 
 
Hydroxychloroquine 
 
Salazosulfapyridine 
 
Gold 
 
D-penicillamine 
 
Lobenzarit 
 
Actarit 
 
Bucillamine 
 
Iguratimod 


Sponsor: Astellas Pharma Inc. 
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Page 23 of 128 
 
(3) Necessary concomitant medication 
<Concomitant use of MTX is specified only for subjects who transferred from 
study RAJ4> 
 
MTX must be used from the end of the assessments at Week 52 of study 
RAJ4 to the initiation of administration of the study drug in this extension 
study, as well as throughout the treatment period of this extension study. 
 
It is permitted to discontinue MTX or increase or decrease the dose 
within the range not exceeding or falling below the baseline dose in study 
RAJ4. 
 
Administration of MTX may be interrupted, or the dose may be reduced 
because of an AE. This interruption must not exceed a maximum of 28 
days. Administration may be resumed with the baseline dose in study 
RAJ4 as the maximum dose. 
 
Folic acid should be concomitantly administered whenever possible. The 
dosage of folic acid during the study period is not more than 10 mg/week 
in principle; dose adjustment is permitted. 
 
If ALT/AST is ≥ 3 × ULN, MTX should be interrupted or reduced, and 
daily administration of folic acid should be considered.  
 
(4) Rescue medications 
During the treatment period, the below medications can be used only when 
needed to treat AEs, complications, or worsening of the primary disease. 
However, these medications may not be taken within 24 hours prior to the joint 
assessment at each study visit. 
1) NSAIDs: Single use as needed, for a period of 3 days or less 
2) Analgesics other than NSAIDs (acetaminophen, opioid analgesics, all-in-
one cold and flu medications, etc.): For 7 consecutive days or less 
3) Intra-articular administration of corticosteroids, intra-articular 
administration of articular cartilage protective agents, drainage of fluid 
accumulated in joint, local anesthesia of joint, and nerve block: 
Performed once every 24 weeks (on up to 2 joints), starting at or after the 
Week 12 study visit 
However, joints on which intra-articular drug administration or rescue 
procedure has been performed will be assessed as showing disease activity 
(pain [tenderness]/swelling) after administration of the medication/therapy. 
Endpoints (Safety) 
• 
AEs 
• 
Vital signs (body temperature, pulse and blood pressure in sitting 
position) 
• 
Body weight 
• 
12-lead Electrocardiogram (ECG) 
• 
Chest radiography 
• 
Laboratory Assessments 
Endpoints 
(Pharmacodynamics) 
Changes from baseline in lymphocyte subsets (CD3, CD4, CD8, CD16, CD19, 
CD56, CD56/16) 
Endpoints (Efficacy) 
The following items at each study visit 
 
ACR 20 response rate 
 
ACR 50 response rate 
 
ACR 70 response rate 
 
Change from baseline in Tender Joint Count (TJC) (68 joints) 
 
Change from baseline in Swollen Joint Count (SJC) (66 joints) 
 
Change from baseline in DAS28-CRP and DAS28-ESR scores 
 
Percentage of subjects achieving DAS28-CRP score for remission 
 
Percentage of subjects achieving ACR/EULAR score for remission 
ACR/EULAR remission is defined as meeting all 4 of the following 


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Page 24 of 128 
criteria: 
o 
TJC ≤ 1 
o 
SJC ≤ 1 
o 
CRP ≤ 1 mg/dL  
o 
Subject’s Global Assessment of Arthritis (SGA) ≤ 1 cm (0-100 
mm on a VAS scale) 
 
Percentage of subjects with a SDAI score of ≤ 3.3 (SDAI remission) 
 
Change from baseline in Physician’s Global Assessment of Arthritis 
(PGA) (VAS) 
 
Change from baseline in SGA (VAS) 
 
Change from baseline in the subject’s assessment of pain (VAS) 
 
FACIT-Fatigue score 
 
Change from baseline in WPAI 
 
Change from baseline in HAQ-DI 
 
Change from baseline in SF-36v2® score 
 
Percentage of subjects in EULAR response criterion of “Good Response” 
 
Percentage of subjects in EULAR response criterion of “Moderate 
Response” 
 
Percentage of subjects in EULAR response criterion of “Good Response” 
or “Moderate Response” 
 
Incidence of subject withdrawal due to lack of efficacy 
Statistical Methods 
 
In the assessment of efficacy and safety, the following will be calculated 
for continuous variables: number of subjects, mean, standard deviation, 
minimum, median, and maximum; categorical variables will be expressed 
as frequency and percentage. 
 
AEs will be coded using the Medical Dictionary for Regulatory Activities 
(MedDRA). AEs occurring after administration of the first dose of the 
study drug will be tallied for the entire study period and for each 3-month 
sub-period. 
 
Laboratory test values (actually measured values and change from 
baseline), vital signs (actually measured values and change from 
baseline), and results of ECG assessment will be tallied at each time 
point. 
 
Incidence of subject withdrawal due to lack of efficacy will be tallied for 
the entire study period and each 3-month sub-period. Other efficacy 
variables will be tallied at each time point. 
 


Sponsor: Astellas Pharma Inc. 
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- CONFIDENTIAL - 
29 March 2019 (Ver. 7.0) 
Astellas 
Page 25 of 128 
V. 
FLOW CHART AND SCHEDULE OF ASSESSMENTS 
Flow Chart 
In Japan, this study will transfer to a post-marketing clinical study after the NDA approval 
in Japan.  
In Korea and Taiwan, this will continue as a clinical study after the NDA approval in Japan. 
 
 
 
 
 
 
NOTE 1: The study visit at Week 0 of this study 
● 
Will coincide with the day of the visit at Week 16/end of the study (follow-up) of study 
RAJ1, 
● 
Will coincide with the day of the visit at Week 52 of studies RAJ3 or RAJ4, or fall 
within 28 days from the day of the visit at Week 52 of studies RAJ3 or RAJ4. 
NOTE 2: 
● 
Subjects who transferred from study RAJ1 will be registered at Week 0 of the present 
extension study. 
● 
Subjects who plan to transfer from studies RAJ3 or RAJ4 will be registered at Week 52 
of studies RAJ3 or RAJ4 to proceed to study RAJ2. 
NOTE 3: 
● 
After the NDA approval in Japan, the post-marketing clinical study will be ended once 
the study drug is available in the clinical sites as a commercially available product. The 
planned study period will be up to a maximum of 6 months after the NDA approval in 
Japan [If the assessments and tests scheduled for the end of study (follow-up) are 
conducted, this visit should be conducted before 6 months after the NDA approval in 
Japan]. 
 
Start and End of Study 
Start of Study: Point in time where informed consent is obtained from the first subject 
End of Study: Point in time where final assessment specified in protocol has been performed 
in the last subject [If the assessments and tests scheduled for the end of study (follow-up) are 
not conducted, the end of treatment/early termination will be the last visit to the site.] 
Treatment period: Period from the initiation of administration of the study drug to completion 
of the tests and assessments stipulated at the end of treatment 
 Obtain 
informed 
consent 
 Complete 
studies RAJ1, 
RAJ3, or RAJ4 
Treatment Period 
Up to a maximum of 
6 months after the 
NDA approval in one 
of the regionsNote 3). 
Duration of treatment 
will differ depending 
on the subject. 
Follow-up Period: 
For 4 weeks after end 
of treatment 
The assessments and 
tests will be conducted 
only when the 
investigator / sub-
investigator decides 
necessary. 
Day 1 
(Week 0NOTE 1)): 
 Confirmation of 
inclusion/exclusion 
criteria 
 Case registrationNOTE 2) 


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Page 26 of 128 
Table 1. Schedule of Assessments 
Schedule 
Week 0b 
Treatment Periodc 
Follow-up 
Period 
Unscheduled 
Visit 
Visit Timing 
Week 2v 
Week 4v 
Week 8v 
Week 12 
Week 16v 
Week 20v 
Week 24 
Week 28v 
Week 32v 
Week 36 
Week 40v 
Week 44v 
Week 48 
Week 60 
Week 72 
Week 84 
Week 96 
Week 108 
Week 120 
Week 132w 
End of 
treatment/  
early 
terminationd 
End of study  
(Follow-up)e 
 
Visit Dayu 
1 
15 
29 57 
85 113 141 169 197 225 253 281 309 337 421 505 
589 673 
757 
841 
925 
–s 
28 days after 
end of 
treatment 
 
Allowable range 
from specified date 
– 
±3 ±7 ±7 ±7 
±7 
±7 
±7 
±7 
±7 
±7 
±7 
±7 
±7 
±14 ±14 ±14 ±14 ±14 
±14 
±14 
–s 
±7 
 
Assessment 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Informed consenta 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Inclusion/exclusion 
criteria 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Demographics/medica
l history 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Weight 
X* 
X 
X 
X 
X 
 
 
X 
 
 
X 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Xt 
Physical examinationf 
X* 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Xt 
Vital signs 
X* 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Xt 
Laboratory test 
(blood/urine)g 
X* 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Xt 
Fasting lipid profile 
testh 
X* 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Xt 
Blood sampling for 
pharmacodynamics 
(lymphocyte subsets)m 
X* 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
X 
 
 
 
X 
X 
Xt 
CRP and ESRi 
X* 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Xt 
Pregnancy testj 
X* 
 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Xt 
12-Lead ECGk 
X* 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
Xt 
Chest radiographyl 
X* 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
X 
 
 
 
Xx 
 
Xt 
Disease activity 
assessmentn 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
TJC/SJC 
X* 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Xt 
PGA and SGA 
(VAS) 
X* 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Xt 
SF-36v2® (from 
study RAJ1)o 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
 
X 
 
X 
 
X 
 
Xt 
SF-36v2® (from 
studies 
RAJ3/RAJ4)o 
X* 
 
 
 
 
 
 
X 
 
 
 
 
 
X 
 
X 
 
X 
 
X 
 
X 
 
Xt 
HAQ-DI 
X* 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Xt 


Sponsor: Astellas Pharma Inc. 
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Page 27 of 128 
Schedule 
Week 0b 
Treatment Periodc 
Follow-up 
Period 
Unscheduled 
Visit 
Visit Timing 
Week 2v 
Week 4v 
Week 8v 
Week 12 
Week 16v 
Week 20v 
Week 24 
Week 28v 
Week 32v 
Week 36 
Week 40v 
Week 44v 
Week 48 
Week 60 
Week 72 
Week 84 
Week 96 
Week 108 
Week 120 
Week 132w 
End of 
treatment/  
early 
terminationd 
End of study  
(Follow-up)e 
 
Visit Dayu 
1 
15 
29 57 
85 113 141 169 197 225 253 281 309 337 421 505 
589 673 
757 
841 
925 
–s 
28 days after 
end of 
treatment 
 
Allowable range 
from specified date 
– 
±3 ±7 ±7 ±7 
±7 
±7 
±7 
±7 
±7 
±7 
±7 
±7 
±7 
±14 ±14 ±14 ±14 ±14 
±14 
±14 
–s 
±7 
 
Assessment 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
WPAIp (from 
studies RAJ3/RAJ4) 
X* 
 
 
 
 
 
 
X 
 
 
 
 
 
X 
 
X 
 
X 
 
X 
 
X 
 
Xt 
Assessment of AEs 
and SAEsq 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
X 
X 
X 
Confirm study drug 
prescription/remaining 
drugr 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
Record concomitant 
medications and 
therapies 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
a. 
Be sure to obtain informed consent before beginning any of the procedures involved in the study. Regarding subjects from study RAJ1, informed consent 
should be obtained at the Week 12 visit of study RAJ1 in principle. Informed consent from subjects who transferred from studies RAJ3 or RAJ4 should be 
obtained before completion of all assessments at Week 52 of studies RAJ3 or RAJ4. 
b. 
[Subjects who transferred from study RAJ1] The assessments and tests at Week 0 should be performed on the day of the visit at Week 16/end of study 
(follow-up) of study RAJ1. For items marked with the * symbol, the results of the assessments and tests performed at Week 16/end of study (at time of 
follow-up) in study RAJ1 may be used. 
[Subjects who transferred from studies RAJ3 or RAJ4] The assessments and tests at Week 0 should be performed on the day of the Week 52 visit of studies 
RAJ3 or RAJ4 or within 28 days after the Week 52 visit. If the assessments and tests at Week 0 are performed on the day of the Week 52 visit, results of the 
assessments and tests at Week 52 of studies RAJ3 or RAJ4 may be used regarding the items marked with the * symbol. If they are not performed on the 
same day as the Week 52 visit, results of the assessments and tests of studies RAJ3 or RAJ4 during the follow-up period may be used. Only regarding chest 
radiography, it is allowed to use data obtained within 28 days prior to the Week 0 visit if available. 
c. 
The subject should be contacted twice every 4 weeks between the previous visit to the next scheduled visit to confirm the status of compliance with study 
drug dosing and the safety of the subject (subjects who transferred from study RAJ1 are to be contacted once a month from the time of the Week 48 visit 
onward). Because this study will end at the point in time when ASP015K is approved, the duration of treatment with the study drug will differ depending on 
the subject. Accordingly, the timing for the required visits to the study center will also differ from subject to subject. When administration of the study drug 
has ended, the assessments and tests scheduled to be performed at the end of treatment and end of study (at time of follow-up) will be performed. 
d. 
The assessments and tests to be performed at the end of treatment should be performed promptly after administration of the study drug has ended. If 
administration of the study drug has been terminated early, the assessments and tests specified to be performed at the end of treatment/early termination 


Sponsor: Astellas Pharma Inc. 
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should be performed within 2 days of the last dose of the study drug if possible. Moreover, even subjects who have had early termination during the 
scheduled treatment period should visit the study center at the end of study (at time of follow-up). The assessments and tests scheduled for the end of study 
(follow-up) should be conducted only if the investigator/ sub-investigator decides necessary. If the assessments and tests scheduled for end of study (follow-
up) are not conducted, the end of treatment/early termination will be the last visit to the site. 
e. 
The assessments and tests scheduled for end of study (at time of follow-up) should be performed 28 days after the end of administration of the study drug. 
These assessments and tests will be performed only if the investigator/ sub-investigator decides necessary. 
f. 
Confirmation of physical findings by questioning the subject during the physical examination should be performed at all study visits. A symptom directed 
physical examination for RA should also be performed at all study visits. See NOTE n with regard to the confirmation of RA symptoms. 
g. 
Hematology: Hemoglobin, hematocrit, RBC, WBC, WBC with differential, platelet count; Biochemistry: Na, K, Ca, Cl, Mg, HCO3, BUN, phosphorus, 
glucose, creatinine, ALP, AST (GOT), ALT (GPT), γ-GTP, TBL, total protein, albumin, uric acid, CPK, LDH, serum amylase, β-D-glucan, eGFR (see 
Section 5.4.4.1 for procedure at time of CPK elevation); Urinalysis: pH, specific gravity, protein, glucose, keton bodies, bilirubin, occult blood, and 
sediment 
h. 
Subject must fast for at least 8 hours prior to blood sampling for lipid profile (total cholesterol, LDL, HDL and triglycerides [TGs]). 
i. 
CRP and ESR tests will be performed at each study visit. CRP test will be performed by the Central Laboratory; ESR test should be performed by each study 
center. 
j. 
A urine pregnancy test should be performed at the study visits every 12 weeks from Week 0 onward, as well as at the end of treatment/early termination and 
end of study (at time of follow-up). If a urine pregnancy test is positive at any time, a negative serum pregnancy test is required for the subject to continue 
participation in the study. The pregnancy tests need not be performed if the possibility of pregnancy can clearly be ruled out, such as if the woman is 
postmenopausal and has not had a menstrual period for 1 year or more, or has had a hysterectomy, bilateral oophorectomy, etc. 
k. 
The 12-lead ECG exams must be performed at the study visits every 48 weeks from Week 0 onward, as well as at the end of treatment/early termination. If a 
cardiovascular AE is observed, a 12-lead ECG may be performed at any time as necessary, even in an unscheduled visit. Clinical interpretation of the results 
of the 12-lead ECG at Week 0 must be completed prior to the first dose of the study drug. 
l. 
[Subjects who transferred from study RAJ1] Chest radiography is taken at the Week 0 visit. 
[Subjects who transferred from studies RAJ3 or RAJ4] Chest radiography is taken at the Week 0 visit, or data obtained within 28 days prior to the Week 0 
visit may be used. 
If a respiratory AE is observed, a chest radiography may be taken at any time as necessary, even in an unscheduled visit. 
m. Blood samples for pharmacodynamics (lymphocyte subset assay) are collected before the first dose of the study drug on the day of the Week 0 visit. 
n. 
Assessment of disease activity: Physician – TJC (68 joints), SJC (66 joints), PGA (VAS); Subject – SGA (VAS), subject’s assessment of pain (VAS), 
HAQ-DI, WPAI, and SF-36V2®. 
o. 
SF-36v2® is administered every 4 weeks until Week 48 and every 24 weeks after Week 48 to subjects from study RAJ1 and every 24 weeks throughout the 
study period to subjects from studies RAJ3 or RAJ4. 
p. 
WPAI is administered only to subjects who transferred from studies RAJ3 or RAJ4. 
q. 
AEs must be collected from the time of the administration of the first dose of study drug to the end of all assessments at the end of study (at time of follow-
up). 


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r. 
After all of the assessments and tests scheduled for Week 0 have been completed, the subjects will receive the first dose of the study drug at each study 
center. 
s. 
[Subjects who transferred from study RAJ1] If the study is terminated before the Week 48 visit, the specified date for the study visit at the end of treatment 
will be the date of the previous visit + 28 days (allowable range, ± 7 days). If the study is terminated in or after the Week 48 visit, the specified date for the 
study visit at the end of treatment will be the date of the previous visit + 84 days (allowable range, ± 14 days). 
[Subjects who transferred from studies RAJ3 or RAJ4] The specified date for the study visit at the end of treatment will be the date of previous study visit + 
84 days (allowable range, ± 14 days). 
t. 
For unscheduled visits, these assessments and tests should be performed only if clinically indicated as determined by the investigator. 
u. 
In principle, the subject should visit the study center on the specified date. If it is not possible for subjects to visit the study center on the specified date, the 
date of the visit should be adjusted to the date closest to the reference date as possible. 
v. 
Only subjects who transferred from study RAJ1 should make study visits at Weeks 2, 4, 8, 16, 20, 28, 32, 40, and 44. 
w. 
At visits after Week 132, the tests and assessments shall be performed in the same manner as scheduled for Weeks 96 to 132.  
x. 
Chest radiography at the end of treatment/early termination is not necessary if one has been taken within 24 weeks from the day of the end of treatment/early 
termination. 
 


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1 
INTRODUCTION 
1.1 
Background 
RA is a chronic systemic inflammatory autoimmune disease that targets the synovial tissues 
[O’Dell, 2004]. The synovial inflammation is associated with irreversible cartilage 
destruction and erosion of bone, which may cause pain as well as decrease activity of daily 
living (ADL) due to functional impairment, and therefore reduce quality of life (QOL). The 
goal of RA treatment is to control the disease activity and achieve remission by preventing or 
controlling joint destruction, preventing loss of function, and relieving pain, thereby 
improving patient QOL. 
Conventional RA treatments have been based on pain control with nonsteroidal anti-
inflammatory drugs and inflammation control with corticosteroids, with which DMARDs 
have been combined [Nakajima, 2009]. Since the start of use of MTX and introduction of 
biologic agents, RA treatments have dramatically changed. Recently, therapeutic targets have 
shifted to prevention of joint destruction. The guidelines for the treatment of RA, published 
by the ACR in 2002 [American College of Rheumatology Subcommittee on Rheumatoid 
Arthritis Guidelines, 2002] and issued in Japan in 2004 [Clinical Practice Manual for the 
Treatment of RA (revised edition), 2004], recommend that pharmacotherapy is based on 
MTX, which primarily exerts inhibitory effects on activated T cells, because MTX offers the 
best balance of efficacy, safety and cost. In contrast, treatment of RA outside Japan now 
focuses on early, aggressive use of effective agents to halt disease progression and prevent 
joint destruction. The guidelines published by the ACR in 2008 [Saag et al, 2008] 
recommend the initiation of MTX or leflunomide monotherapy for patients with all disease 
durations and degrees of disease activity. In particular, MTX has established an impregnable 
position as the drug of first choice. In Japan, it can be stated that MTX is commonly 
recognized as such a drug of first choice. Treatment with MTX as an anchor drug in 
combination with later developed biologic agents such as TNF inhibitors enables 
approximately 30% of RA patients to achieve remission, almost conquering progression of 
joint destruction [Tanaka, 2009]. 
However, all of the existing treatments for RA do not cure the disease. It has been reported 
that approximately 30% of RA patients are resistant to therapy with TNF inhibitors, 
representative biologic agents, with only 30% to 50% of patients achieving remission 
[Yamaoka, 2008]. MTX inhibits cell proliferation nonspecifically, so adverse effects on other 
proliferating tissues such as the gut and bone marrow are common. These treatments are not 
without appreciable safety issues. Thus, there currently exists a need for effective new 
treatments with more targeted mechanism of action and an improved safety profile over 
existing therapies. Moreover, the need of intravenous or subcutaneous administration and the 
great financial burden of biologic agents make it difficult for many of the patients to continue 
treatment. In such a situation, much attention is now being given to low molecular weight 
compounds with relatively low costs and comparable efficacy to biologic agents. 


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JAK 3, an important protein in exerting biological activity of cytokines, is one of the tyrosine 
kinases and is activated intracellularly following cytokine binding to receptors. Because 
JAK3 deficiency may cause severe combined immunodeficiency (SCID) due to failure of 
lymphocyte differentiation, a compound to inhibit JAK3 is expected to be a novel 
immunosuppressant and has been developed. It is suggested that in the course of RA, 
inflammatory cytokines as well as autoreactive T cell proliferation and T cell products such 
as interleukin-2 (IL-2), interferon-gamma (IFN-γ), and IL-17 may contribute to the 
development of the disease, considering that inhibition of proliferation of T-, B-, and NK-
cells and reduction of their functions are essential for treating RA. 
ASP015K is an orally bioavailable JAK inhibitor discovered by the sponsor with selectivity 
for JAK3, a protein tyrosine kinase associated intracellularly with the common gamma chain 
(gamma c) which is a component of receptors of cytokines such as IL-2 produced through 
immunoreaction. ASP015K inhibits phosphorylation of signal transducer and activator of 
transcription (STAT) 5 by JAK3 activated following IL-2 receptor binding, thereby blocking 
differentiation and proliferation of T cells mediated by regulation of cytokine responsive 
gene expression by STAT5 in the nucleus [O'Shea, 2004]. Because JAK3 shows a restricted 
tissue expression (primarily hematopoietic cells), JAK3 inhibition is a desirable therapeutic 
target for immunosuppression in human organ transplantation and immunomodulation in 
autoimmune disorders [Papageorgiou & Wikman, 2004], without significantly affecting other 
organ systems [Kremer et al, 2009]. Thus, compounds that inhibit JAK3 activity may have a 
therapeutic effect on autoimmune diseases such as RA. 
Xeljanz® (tofacitinib) 5 mg is a JAK inhibitor approved by the US FDA in 2012 for the 
treatment of adult patients with moderate to severe RA who had an inadequate response to or 
are intolerant of MTX. In Japan, this drug was approved in March 2013 for treating RA 
patients who had an inadequate response to conventional therapies. 
Astellas Pharma is pursuing the development program of ASP015K for the indication of RA. 
In Japan, the Phase IIb dose-finding study (015K-CL-RAJ1, or RAJ1) has been completed, 
and its long-term extension study (015K-CL-RAJ2, or RAJ2) is ongoing. Overseas, 2 Phase 
II dose-finding studies (1 with MTX and the other without MTX) have been completed, and 
their follow-up extension study is underway, similar to the situation in Japan. The results of 
RAJ1 showed that ASP015K caused a significantly higher improvement in RA than placebo 
in terms of the ACR response rate, DAS28 score, and other efficacy variables, suggesting its 
usefulness for treating RA. 
 
1.2 
Non-clinical and Clinical Data 
1.2.1 
Nonclinical Pharmacology and Safety Pharmacology 
ASP015K is a novel oral immunosuppressant that exerts it pharmacological action by 
relatively selectively inhibiting JAK3, a key enzyme in the IL-2 signaling pathway. In vitro 
kinase studies showed that ASP015K also inhibited JAK1, JAK2, and TYK2, although less 
potently than it inhibited JAK3. The effects of ASP015K were investigated in a rat adjuvant-


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induced arthritis model. Data showed that prophylactic administration of ASP015K in which 
treatment was initiated before the occurrence of pedal edema prevented the event and 
reduced radiographic joint destruction scores. Therapeutic administration of ASP015K in 
which treatment was initiated after the occurrence of pedal edema also prevented the event 
and reduced joint destruction scores. 
In safety pharmacology studies, ASP015K showed no effect on human hERG current or 
action potential duration in isolated guinea pig papillary muscles at clinically relevant 
concentrations. ASP015K had no effect on the central nervous system (modified Irwin's 
method) of rats at up to 100 mg/kg orally. In monkeys, loose/watery stools and a tendency 
towards reduced blood potassium concentrations were observed at 60 mg/kg orally, but there 
were no effects on the central nervous system, cardiovascular system (ECG, blood pressure 
or heart rate), or respiratory system of monkeys at up to 60 mg/kg. 
1.2.2 
Pharmacokinetics and Pharmacodynamics 
1.2.2.1 Nonclinical Pharmacokinetics 
Absolute bioavailability ranged from 39.8% to 46.4% in rats and 18.9% to 19.2% in monkeys. 
Following a single oral dose of 3 mg/kg 14C-ASP015K in Sprague-Dawley rats, radioactivity 
distributed rapidly into tissues with no long-term tissue retention observed. In a study with 
pigmented rats, the dosed radioactivity was rapidly excreted within the first 24 hours after 
administration in almost all tissues with the exception of the eyeball (t1/2 of 1105.8 hours). No 
apparent differences were noted in radioactivity concentration-time profiles between 
nonpigmented and pigmented skin, and the radioactivity was not detected in these skins for a 
long time. These data suggest that ASP015K-related compounds may have bound to melanin, 
but binding was likely weak and reversible. In Sprague-Dawley rats orally administered 14C-
ASP015K 3 mg/kg once daily for 21 days, radioactivity was slowly eliminated from the lung, 
spleen, skin, bone marrow, testis, and thoracic aorta. With the exception of the thoracic aorta, 
the radioactivity levels 168 hours after the last dose were reduced to 19% or less of the levels 
measured 0.25 hours after the last dose. The mean radioactivity of the thoracic aorta at 168 
hours of the last dose was as low as less than 3 times the lower limit of quantification. 
The in vitro plasma protein binding rates of ASP015K and its metabolite AS2628528 (H2) 
were determined in the concentration range of 0.2–20 μg/mL. The plasma protein binding 
rates in mice, rats, rabbits, dogs, monkeys, and humans were in the ranges of 59%–95% for 
ASP015K and 84%–99% for H2. Among human plasma proteins, human serum albumin 
(HSA) most preferentially bound to ASP015K and H2. 
In pregnant and lactating rats administered a single oral dose of 14C-ASP015K 3 mg/kg, the 
radioactivity was distributed widely across different tissues of the dams, although the tissue 
radioactivity almost completely disappeared within 24 hours. Although the levels of placental 
radioactivity transfer were low, comparatively higher levels of radioactivity were rapidly 
transferred to the milk, leading to elevated radioactivity in pups via lactation. 
When 14C-ASP015K was orally administered alone to rats at a dose of 3 mg/kg, 3 
radioactivity peaks were detected in plasma on the radiochromatogram, with the main peak 


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being that of the unchanged drug. In vitro metabolic profile of 14C-ASP015K was performed 
in liver microsomes and cryopreserved hepatocytes from mice, rats, rabbits, dogs, 
cynomolgus monkeys, and humans. No human-specific metabolites were identified in either 
assay. In in vitro metabolic studies, ASP015K was metabolized to H2 by human 
sulfotransferase 2A1 (hSULT2A1) and to AS2604202 (H4) by human nicotinamide N-
methyltransferase (hNNMT). 
In rats administered 14C-ASP015K, urinary and biliary excretion of the dosed radioactivity 
within 72 hours was 25.2% and 46.7%, respectively, suggesting high oral absorption of 
ASP015K. In monkeys administered 14C-ASP015K, urinary and biliary excretion of the 
dosed radioactivity within 72 hours was 22.3% and 26.4%, respectively. 
1.2.2.2 Clinical Pharmacokinetics and Pharmacodynamics 
A total of 17 clinical studies of ASP015K have been completed till date. These studies 
included 14 pharmacokinetic studies in healthy adult volunteers, 1 pharmacokinetic study in 
RA patients, 1 efficacy and safety study in patients with psoriasis, and 1 efficacy and safety 
study in RA patients. More specifically, they were as follows: a single-dose and repeated-
dose study in Japanese and Caucasian subjects conducted in Japan (015K-CL-HV03), an 
overseas single ascending dose and food effect study (015K-CL-HV01), an overseas 
repeated-dose study (015K-CL-HV02), a mass balance study using radiolabeled ASP015K 
(015K-CL-PK03), a regional absorption study (015K-CL-PK15), 4 relative bioavailability 
and food effect studies (015K-CL-PK09, 015K-CL-PK18, 015K-CL-PK19, 015K-CL-PK51), 
5 drug–drug interaction (DDI) studies in healthy adult volunteers (015K-CL-PK01, 015K-
CL-PK02, 015K-CL-PK05, 015K-CL-PK16, and 015K-CL-PK26), 1 DDI study in RA 
patients (015K-CL-PK13), 1 efficacy and safety study in psoriasis patients (015K-CL-PS01), 
and 1 efficacy and safety study in RA patients (015K-CL-RAJ1). 
These completed studies involved 472 healthy adults and 296 RA patients; they received 
ASP015K doses ranging from 3 to 300 mg/day in single-dose studies and from 10 to 200 mg 
twice daily (BID) in repeated-dose studies. In addition, 124 patients with psoriasis were 
enrolled and were administered 10 to 100 mg BID or 50 mg once daily (QD). 
After a single dose of 3 to 300 mg/day administered under fasting conditions in Study 015K-
CL-HV01, ASP015K was rapidly absorbed with a median tmax ranging from 1.0 to 1.75 hours 
across the dose groups. The AUCinf, AUClast and Cmax of ASP015K increased dose 
proportionally. Elimination occurred in a multiphasic manner with a mean t1/2 value of 2.8 to 
18.5 hours. Compared to administration under fasting conditions, the mean Cmax of ASP015K 
administered under fed conditions increased by 5%. Similarly, the mean AUCinf increased by 
27% with tmax being prolonged for approximately 2.5 hours. Urinary excretion of ASP015K 
accounted for between 9% and 15% of the oral dose. ASP015K inhibited JAK3-mediated 
phosphorylation of STAT5 dose-dependently. Peak inhibition of JAK3-mediated 
phosphorylation of STAT5 was observed around 1 to 2 hours (median) following 
administration of ASP015K under fasting conditions. At a dose of 60 mg, the peak inhibition 
reached 84% of the maximum. The mean changes from baseline lymphocyte counts and 


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peripheral lymphocyte subsets suggested there were no time or dose-dependent changes after 
a single oral dose of ASP015K. 
Study 015K-CL-HV02, in which ASP015K was given at doses of 30 mg BID, 100 mg BID, 
or 200 mg BID for 14 days under non-fasting conditions, demonstrated no clear difference in 
pharmacokinetics of ASP015K after repeated dosing between the morning and evening doses, 
although the trough level after the morning dose tended to be lower. Steady state in plasma 
ASP015K concentrations was achieved by day 3. The mean accumulation factor on day 14 
was between 1.12 and 1.65 for Cmax, 1.38 and 1.65 for AUC12, and 2.02 and 2.71 for Ctrough, 
PM. At steady state, the peak-trough ratios (peak/trough levels) of ASP015K concentrations 
were between 8.8 and 18. Overall, Cmax and AUC12 values generally increased dose 
proportionally over the range of 30 to 100 mg BID. There was no sex difference in ASP015K 
exposure with the 100 mg BID dose. 
As a result of metabolite analysis of samples collected in 015K-CL-HV01 and 015K-CL-
HV02, 3 metabolites (H1, H2, H4) were identified from plasma samples and 6 metabolites 
(H1 to H6) were identified from urine samples. 
Results from the mass balance study (015K-CL-PK03) indicated that unchanged ASP015K 
accounted for 36% of the total radioactivity in plasma (metabolites accounted for the 
remaining 64%). Approximately 36.8% of the total radioactivity was excreted in urine and 
56.6% in feces. Unchanged ASP015K accounted for 36% of the total radioactivity in urine. 
In Study 015K-CL-HV03, Japanese had greater ASP015K exposure than Caucasian. After 
adjustment for dose and body weight, Cmax was 42.9% to 53.9% higher and AUCinf was 
22.5% to 44.9% higher in Japanese relative to Caucasian. JAK3 inhibition was dose-
dependent in Japanese and Caucasian. Consistent with the generally higher plasma 
concentrations of ASP015K in Japanese, the peak inhibition of JAK3 following a single dose 
of ASP015K was also higher in Japanese. Overall, the mean change from baseline for T cell 
subsets was similar with ASP015K single or repeated dosing, with little variation among 
ethnicity. 
Results from a regional absorption study (015K-CL-PK15) indicated that absorption 
primarily (≥ 50%) occurred in the proximal small bowel, and the rate and extent of 
absorption decreased as the delivery site became more distal within the gastrointestinal tract. 
In Study 015K-CL-PK19, subjects were administered ASP015K (5 tablets of 30 mg) after a 
meal (approximately 500 to 600 kcal, with fat accounting for 25% to 35% of the total 
calories). Compared with fasting conditions, tmax was extended by 0.5 hours, and Cmax and 
AUC increased by 34% and 27%, respectively. 
In the 6 DDI studies, the pharmacokinetic profile of ASP015K was investigated in the 
presence of: mycophenolate mofetil (MMF) (015K-CL-PK01), tacrolimus (015K-CL-PK02 
and 015K-CL-PK16), midazolam (015K-CL-PK05), MTX (015K-CL-PK13), and 
rosuvastatin (015K-CL-PK26). MMF, tacrolimus, midazolam, and rosuvastatin were 
administered in healthy adult volunteers, whereas MTX was used in RA patients. 


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Administration of ASP015K 100 mg BID had no effect on the pharmacokinetic profile of 
MTX in patients with RA or the MMF metabolites MPA and MPAG in healthy volunteers. 
ASP015K 60 mg and 100 mg BID did increase tacrolimus levels in whole blood following 
oral administration of tacrolimus 5 mg, but not when tacrolimus was administered as a 1 mg 
intravenous dose. Concomitant use of ASP015K elevated the plasma midazolam 
concentrations after a single oral dose of midazolam 3 mg. It also raised the plasma 
rosuvastatin levels following a single oral dose of rosuvastatin 10 mg. However, steady-state 
pharmacokinetics of ASP015K were not significantly impacted by MTX 15 to 25 mg, MMF 
1 g, midazolam 3 mg, oral tacrolimus 5 mg, or intravenous tacrolimus 1 mg doses. 
In Study 015K-CL-PS01 that enrolled patients with psoriasis, the administration of ASP015K 
10 to 100 mg BID elevated ASP015K exposure (Cmax, AUClast, and AUC6h) in a dose-
dependent manner. The median tmax values were in the range of approximately 1.0 to 1.8 
hours. STAT5 phosphorylation and JAK3 activity were inhibited in a dose-dependent manner. 
Although no consistent trends were noted for the absolute lymphocyte count, a slight dose-
dependent decreasing trend was noted for the proportions and absolute counts of NK and B 
cells. 
In Study 015K-CL-RAJ1 of Japanese patients with RA, matrix metalloproteinase 3 levels 
decreased in a dose-dependent manner following the administration of ASP015K 25 to 150 
mg QD. Although no consistent trends were noted for the absolute lymphocyte count, NK 
cell counts decreased and B cell counts increased in a dose-dependent manner. 
1.2.3 
Toxicology 
Nonclinical repeated-dose toxicity studies of ASP015K were conducted using rats (up to 26 
weeks) and monkeys (up to 52 weeks). Toxicities observed in these studies were mainly 
related to gastrointestinal, hematopoietic, muscular, and immune systems. All these findings 
were reversible and resolved upon the withdrawal of ASP015K. Muscle toxicity was 
observed in monkeys: mild multifocal muscle necrosis in 1 female at 60 mg/kg per day in the 
4-week preliminary study; elevation of CPK and LDH without histopathological change of 
the muscle in 2 males at 60 mg/kg per day in the 4-week preliminary study; elevation of CPK 
and LDH without histopathological changes in 1 male that was sacrificed in extremis in 13-
week study, and a transient increase of CPK without histopathological changes observed in 
another male in the same 13-week study. 
Genotoxicity studies were conducted in vitro and in vivo. ASP015K was negative in the 
reverse mutation test in bacteria but was positive in an in vitro chromosomal aberration test 
in Chinese hamster lung cells. ASP015K was negative in 2 in vivo genotoxicity studies, the 
unscheduled DNA synthesis test in rats and the micronucleus test in mice. These results 
suggested that ASP015K had little potential to induce chromosomal aberrations in in vivo. 
In toxicity studies on the fertility and early embryonic development in rats, the viability of 
embryos decreased after implantation and the number of live embryos decreased in the 
100 mg/kg per day group compared with the control group. ASP015K neither induced 
general toxicity nor impacted male or female fertility up to the dose of 100 mg/kg/day. In an 


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embryo–fetal development study in rats, increased incidences of skeletal abnormalities and 
variations and visceral variations were noted at 30 mg/kg/day and higher, while increased 
incidences of visceral and external abnormalities were observed at 300 mg/kg/day. NOAEL 
for embryo–fetal development in rats was 10 mg/kg/day. In an embryo–fetal developmental 
toxicity study in rabbits, no teratogenicity was observed; however, increased 
postimplantation loss and decreased numbers of live fetuses were noted at 10 mg/kg/day. 
Four- and 13-week toxicity studies of ASP015K administered in combination with tacrolimus, 
MMF, or MTX demonstrated no significant synergistic toxicities in rats. 
1.2.4 
Efficacy 
In a double-blind, placebo-controlled study conducted in Japan (015K-CL-RAJ1), the dose 
response for the efficacy and safety of once-daily oral ASP015K (25, 50, 100, 150 mg) 
administered for 12 weeks was investigated in 281 patients with moderate to severe RA. Its 
primary efficacy variable was the ACR20 response rate at Week 12. The ACR20 response 
rates were 10.7% for placebo, 23.6% for 25 mg, 31.6% for 50 mg, 54.5% for 100 mg, and 
65.5% for 150 mg groups. Significant improvements over placebo were noted for 50 mg 
(P=0.021), 100 mg (P<0.001), and 150 mg groups (P<0.001). In addition, logistic regression 
analysis demonstrated a statistically significant dose–response relationship (P<0.001). 
Secondary efficacy variables, the ACR50 response rate, ACR70 response rate, and DAS28-
CRP, exhibited significant improvements for ASP015K over placebo. A long-term extension 
study (015K-CL-RAJ2) for patients who completed this study is underway to investigate the 
efficacy and safety of ASP015K administered over an extended period of time. 
Overseas, 3 clinical studies of patients with moderate to severe RA have been completed 
(015K-CL-RA21, 015K-CL-RA22, 015K-CL-RA25). 015K-CL-RA21 and 015K-CL-RA22 
were dose-finding studies of ASP015K administered with and without MTX, respectively. 
015K-CL-RA25 was a long-term follow-up extension study that enrolled the patients who 
completed either of the 2 studies. 
In a US double-blind, placebo-controlled study in patients with moderate to severe psoriasis 
vulgaris (015K-CL-PS01), 124 subjects were orally administered ASP015K (10, 25, 60, 100 
mg BID or 50 mg QD) over 6 weeks. Compared with placebo, all ASP015K groups showed 
greater improvements in terms of change from baseline in the PASI score (primary efficacy 
variable), depicting a statistically significant difference in the overall therapeutic response. 
For secondary efficacy variables, the treatment success based on Physician’s Static Global 
Assessment (PSGA) and 75% reduction in the PASI score (PASI 75 response) demonstrated 
the efficacy of ASP015K. 
 
1.3 
Summary of Key Safety Information for Study Drugs 
The safety and tolerability of ASP015K were evaluated in 14 studies in healthy adult 
volunteers (13 overseas and 1 Japanese), 2 studies in RA patients (1 each overseas and 
Japanese), and 1 study in patients with psoriasis (overseas). In these studies, a single dose of 
3 to 300 mg and repeated doses of 10 to 200 mg BID were administered in 423 healthy adults 


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and 14 RA patients. In addition, 225 RA patients received repeated doses of 25 to 150 mg 
QD, and 95 psoriasis patients received repeated doses of 10 to 200 mg BID or 50 mg QD. 
Treatment-emergent adverse events (TEAEs) that occurred relatively frequently in these 
studies included gastrointestinal disorders (e.g., diarrhoea, nausea, flatulence, vomiting) and 
nervous system disorders (e.g., headache). 
There were 7 subjects in the following 3 overseas studies who experienced a TEAE that 
resulted in discontinuation. In the overseas repeated-dose study of ASP015K in healthy 
volunteers (015K-CL-HV02), 2 subjects discontinued ASP015K due to neutrophil count 
decreased (1 male in the 200 mg BID group and 1 female in the 100 mg BID group) that was 
considered probably related to study drug. The neutrophil count decreased resolved the day 
after discontinuation in both cases. A third subject, a male in the 100 mg BID group, 
discontinued ASP015K due to moderate vomiting that was considered probably related to the 
study drug. 
In the single-dose, mass balance study of ASP015K 10 mg (015K-CL-PK03), 3 subjects were 
withdrawn from the study, 2 due to upper respiratory tract infection and 1 due to 
nasopharyngitis, which all occurred during a washout period. These TEAEs were mild in 
severity and were considered to be unrelated to ASP015K. 
In the study in psoriasis patients (015K-CL-PS01), 1 patient in the 60 mg BID group was 
withdrawn from the study due to neutrophil count decreased, which was mild in severity and 
was considered to be possibly related to ASP015K by a physician. 
The more common TEAEs across the 11 completed clinical studies were gastrointestinal 
disorders (e.g., diarrhoea, nausea, flatulence, vomiting) and headache. 
In the overseas single-dose study (015K-CL-HV01), there was no evidence of clinically 
significant safety findings in subjects who received single oral doses of ASP015K (3, 10, 30, 
60, 120, 200 and 300 mg) under fasted conditions or a single 120 mg oral dose in the fed 
state. The more common TEAEs in this study that occurred in multiple subjects were 
headache (7 subjects; moderate in 1 and mild in 6), mild tension headache (3 subjects); 
flatulence (3 subjects; moderate in 1 and mild in 2), and mild, asymptomatic bradycardia (2 
subjects). 
In the overseas repeat-dose study (015K-CL-HV02), the more common TEAEs in the 36 
subjects receiving ASP015K were neutropenia (14 subjects; severe in 1 subject, moderate in 
3 subjects, and mild in 10 subjects); headache (7 subjects; moderate in 2 subjects and mild in 
5 subjects); mild abdominal pain (6 subjects); mild, diarrhoea (4 subjects) and nausea (4 
subjects; moderate in 1 subject and mild in 3 subjects). Dose-dependent gastrointestinal 
disorders (e.g., nausea, diarrhoea, dyspepsia, and abdominal pain) and neutropenia were 
observed, especially in approximately two-thirds of subjects (6 of 9 subjects) in the highest 
dose group (ASP015K 200 mg BID). In this repeat-dose study, 2 subjects experienced severe 
TEAEs and 8 experienced moderate TEAEs. Severe TEAEs included elevated lipase and 
CPK elevation that occurred in 1 male subject (200 mg BID group) and neutropenia in 1 
female subject (100 mg BID group). 


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In the single-dose and repeated-dose study in Japanese and Caucasian volunteers (015K-CL-
HV03), the only TEAE observed in at least 1 subject after a single dose of ASP015K was 
mild white blood cell count increased in 2 of 6 Japanese subjects receiving ASP015K 60 mg 
and 1 of 6 Japanese subjects receiving ASP015K 200 mg. TEAEs observed in at least 1 
subject who received repeated doses of ASP015K were mild neutrophil count decreased in 3 
of 6 Japanese male subjects receiving ASP015K 100 mg BID; mild white blood cell count 
increased in 2 of 6 Japanese male subjects receiving ASP015K 30 mg BID and 1 of 6 
Japanese male subjects receiving ASP015K 10 mg BID; and mild alanine aminotransferase 
increased in 1 of 6 Japanese male subjects receiving ASP015K 10 mg BID and in 1 of 6 
Japanese male subjects receiving ASP015K 100 mg BID. 
There were no vital sign or ECG findings observed in subjects following administration of 
ASP015K in the previous clinical pharmacology studies that were considered clinically 
relevant, except mild, asymptomatic bradycardia (possible related; recovered) in 2 subjects in 
the overseas single-dose study (015K-CL-HV01), and intermittent, mild arrhythmia (not 
related; recovered) lasting for approximately 5 hours in 1 subject after a single dose of 
ASP015K 100 mg in the DDI study of ASP015K with midazolam (015K-CL-PK05). 
DDI studies involving MTX, MMF, midazolam, tacrolimus, and rosuvastatin (015K-CL-
PK01, 015K-CL-PK02, 015K-CL-PK05, 015K-CL-PK13, 015K-CL-PK16, 015K-CL-PK26) 
demonstrated that ASP015K administered in combination with these agents was well 
tolerated, and reported TEAE incidence rates comparable with those documented for 
ASP015K as single-agent therapy. 
In the Japanese clinical trial in RA patients (015K-CL-RAJ1), the incidence rates of AEs in 
the ASP015K 25 mg, 50 mg, 100 mg, and 150 mg groups were 70.9%, 64.9%, 52.7%, and 
67.2%, respectively. These rates were comparable with that of the placebo group (64.3%). 
The incidence rates of AEs whose relationship to the study drug could not be ruled out for the 
ASP015K 25 mg, 50 mg, 100 mg, and 150 mg groups were 38.2%, 43.9%, 29.1%, and 
55.2%, respectively. These rates were higher than that reported for the placebo group 
(28.6%). By severity (NCI-CTCAE), most were either Grade 1 or Grade 2. In the placebo 
and ASP015K 25 mg, 50 mg, 100 mg, and 150 mg groups, the numbers of subjects with 
serious adverse events (SAEs) were 1 (1.8%), 1 (1.8%), 2 (3.5%), 3 (5.5%), and 0, 
respectively. Death was reported from 1 subject of the 50 mg group (cerebral haemorrhage). 
AEs resulted in treatment discontinuation in 10 (17.9%), 7 (12.7%), 5 (8.8%), 6 (10.9%), and 
4 (6.9%) subjects of the placebo, 25 mg, 50 mg, 100 mg, and 150 mg groups, respectively. 
The most common reason was rheumatoid arthritis aggravated (21/32). Rheumatoid arthritis, 
nasopharyngitis, blood creatine phosphokinase (CPK) increased, diarrhoea, cystitis, 
constipation, stomatitis, dyspepsia, lipids increased, and blood triglycerides increased were 
reported at ≥ 5% incidence rates from 1 or more groups. By the MedDRA System Organ 
Class (SOC), Infections and infestations, Gastrointestinal disorders, Musculoskeletal and 
connective tissue disorders, and Investigations showed high incidence rates. Blood creatine 
phosphokinase increased were observed in 0, 2 (3.6%), 1 (1.8%), 1 (1.8%), and 7 (12.1%) 
subjects of the placebo, 25 mg, 50 mg, 100 mg, and 150 mg groups, respectively. Most cases 
were transient, and all subjects except 1 who prematurely discontinued the study recovered or 


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were recovering. With regard to clinical laboratory testing, compared with the placebo group, 
the ASP015K groups showed decreased levels of neutrophils, platelets, and estimated 
glomerular filtration rate (eGFR) and elevated levels of CPK, hemoglobin, lymphocytes, 
creatinine, total cholesterol, LDL, HDL, and triglycerides. No noteworthy changes were 
detected in vital signs or ECG recordings. 
In the overseas study in psoriasis patients (015K-CL-PS01), none of the AEs observed were 
apparently dose-dependent, although the overall incidence of AEs in patients receiving 
ASP015K was higher than in those receiving placebo. No SAEs were reported. However, 1 
subject treated with 60 mg BID prematurely discontinued the study owing to mild neutrophil 
count decreased, and this case was judged possibly related to the study drug. The more 
common AEs were pharyngitis, diarrhoea, and flatulence, which did not occur more 
frequently in a specific treatment group including the placebo group. Mild neutrophil count 
decreased was observed in patients receiving ASP015K, with none having neutrophil count 
of less than 1000/mm3. The mean CPK level increased with dose. A total of 4 AEs of creatine 
phosphokinase increased were reported, each in the placebo, 10 mg BID, 25 mg BID, and 
100 mg BID groups, none of which were associated with symptoms suggestive of myopathy. 
During this study, no anaemia occurred. While mild to moderate increases in HDL, TGs, and 
total cholesterol were observed, there was no change from baseline in LDL. 
For more information regarding the efficacy and safety of ASP015K, refer the current 
version of the Investigator’s Brochure. 
 
The following shows the summary of safety results of two completed phase 3 studies (015K-
CL-RAJ3 and 015K-CL-RAJ4). 
For the 015K-CL-RAJ3 study, which Japanese, Korean and Taiwanese were included, from 
week 0 through week 12, TEAEs were reported in 54 (53.5%), 59 (56.7%) and 55 (53.9%) 
patients in the placebo, ASP015K 100 mg and ASP015K 150 mg groups, respectively. Drug-
related TEAEs were reported in 29 (28.7%), 33 (31.7%) and 38 (37.3%) patients in the 
placebo, ASP015K 100 mg and ASP015K 150 mg groups, respectively. The majority of 
TEAEs were grade 1 or 2 in severity.  
In the etanercept group, TEAEs were reported in 119 (59.5%) patients and drug-related 
TEAEs were reported in 75 (37.5%) patients.  
For overall period, no major differences were observed in the overview of TEAEs compared 
with from week 0 through week 12. TEAEs were reported in 92 (88.5%) and 89 (87.3%) 
patients in the ASP015K 100 mg and 150 mg groups, respectively. The majority of TEAEs 
were grade 1 or 2 in severity. TEAEs occurring in ≥ 5% of patients in the placebo or 
ASP015K groups included nasopharyngitis (5.9%, 9.6% and 18.6% in the placebo, ASP015K 
100 mg and ASP015K 150 mg groups, respectively), rheumatoid arthritis (10.9%, 2.9% and 
2.0%) and hepatic function abnormal (3.0%, 0% and 6.9%). 


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Drug-related TEAEs occurring in ≥ 5% of patients in the placebo or ASP015K groups 
included nasopharyngitis (3.0%, 4.8% and 7.8% in the placebo, ASP015K 100 mg and 
ASP015K 150 mg groups, respectively). 
TEAEs occurring in ≥ 5% of patients in the etanercept group included injection site reaction 
(12.5%), nasopharyngitis (8.0%) and hepatic function abnormal (5.0%). Drug-related TEAEs 
occurring in ≥ 5% of patients in the etanercept group included injection site reaction (12.5%). 
For overall period, TEAEs occurring in ≥ 5% of patients in the ASP015K 100 mg or 
ASP015K 150 mg groups included nasopharyngitis (28.8% and 28.4% in the ASP015K 100 
mg and ASP015K 150 mg groups, respectively), blood creatine phosphokinase increased 
(9.6% and 10.8%), influenza (6.7% and 5.9%), upper respiratory tract infection (5.8% and 
6.9%), cough (5.8% and 6.9%), nausea (7.7% and 3.9%), rheumatoid arthritis (5.8% and 
4.9%), upper respiratory tract inflammation (4.8% and 5.9%), hepatic function abnormal 
(1.9% and 7.8%), pharyngitis (6.7% and 2.9%), bronchitis (6.7% and 1.0%) and eczema 
(1.9% and 5.9%).  
Drug-related TEAEs occurring in ≥ 5% of patients in the ASP015K 100 mg or ASP015K 150 
mg groups included nasopharyngitis (14.4% and 13.7% in the ASP015K 100 mg and 
ASP015K 150 mg groups, respectively), blood creatine phosphokinase increased (7.7% and 
7.8%), nausea (5.8% and 2.9%) and bronchitis (5.8% and 1.0%). 
Death after the end of study was reported in 1 patient due to thyroid cancer in the etanercept 
group and was considered to be possibly related to etanercept. 
From week 0 through week 12, SAEs were reported in 4 (4.0%), 3 (2.9%) and 2 (2.0%) 
patients in the placebo, ASP015K 100 mg and ASP015K 150 mg groups, respectively. From 
week 0 through week 12, no serious TEAEs occurred in ≥ 2 patients in the placebo or 
ASP015K groups.  
For overall period, SAEs were reported in 7 (6.7%) and 8 (7.8%) patients in the ASP015K 
100 mg and 150 mg groups, respectively. Drug-related SAEs were reported in 3 (2.9%) and 3 
(2.9%) patients in the ASP015K 100 mg and 150 mg groups, respectively. For overall period, 
no serious TEAEs occurred in ≥ 2 patients in the ASP015K 100 mg or ASP015K 150 mg 
groups except for spinal compression fracture (2 patients in the ASP015K 150 mg group). 
AEs leading to permanent discontinuation of study drug were reported in 4 (4.0%), 6 (5.8%) 
and 3 (2.9%) patients in the placebo, ASP015K 100 mg and ASP015K 150 mg groups, 
respectively. Drug-related AEs leading to permanent discontinuation of study drug were 
reported in 1 (1.0%), 4 (3.8%) and 2 (2.0%) patients in the placebo, ASP015K 100 mg and 
ASP015K 150 mg groups, respectively. From week 0 through week 12, TEAEs leading to 
permanent discontinuation of study drug occurring in ≥ 2 patients in the placebo or ASP015K 
groups included rheumatoid arthritis (3 and 2 patients in the placebo and ASP015K 100 mg 
groups, respectively). 
For overall period, AEs leading to permanent discontinuation of study drug were reported in 
13 (12.5%) and 6 (5.9%) patients in the ASP015K 100 mg and 150 mg groups, respectively. 
Drug-related AEs leading to permanent discontinuation of study drug were reported in 7 


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(6.7%) and 4 (3.9%) patients in the ASP015K 100 mg and 150 mg groups, respectively. 
TEAEs leading to permanent discontinuation of study drug occurring in ≥ 2 patients in the 
ASP015K 100 mg and ASP015K 150 mg groups included rheumatoid arthritis (3 patients in 
the ASP015K 100 mg group). 
With regard to the analysis per 100 patient-years for serious infections and herpes zoster 
related disease (herpes zoster and varicella), the incidence rates of serious infections and 
herpes zoster related disease (herpes zoster and varicella) were higher in the ASP015K 
groups compared with the placebo group; however, no dose dependency was observed 
between the ASP015K 100 mg and 150 mg groups.  
There was no major difference among the treatment groups for malignancy.  
Increases in creatine kinase were observed in the ASP015K groups compared with the 
placebo group. Increases in hemoglobin, creatinine, total cholesterol, low-density lipoprotein 
(LDL) cholesterol, high-density lipoprotein (HDL) cholesterol and triglycerides, and 
decreases in lymphocytes, platelets, total cholesterol/HDL ratio and LDL/HDL ratio were 
also observed.  
No notable trend was observed in vital signs or ECG findings. 
 
 For the 015K-CL-RAJ4 study, which only Japanese are included, from week 0 through week 
12, TEAEs were reported in 84 (49.4%), 89 (51.1%) and 104 (59.8%) patients in the placebo, 
ASP015K 100 mg and ASP015K 150 mg groups, respectively. Drug-related TEAEs were 
reported in 47 (27.6%), 57 (32.8%) and 80 (46.0%) patients in the placebo, ASP015K 100 
mg and ASP015K 150 mg groups, respectively. The majority of TEAEs were grade 1 or 2 in 
severity. 
No major differences were observed in the overview of TEAEs from week 12 through week 
28 compared with from week 0 through week 12. 
No major differences were observed in the overview of TEAEs from week 28 through week 
52 compared with from week 0 through week 12.  
For overall period, no major differences were observed in the overview of TEAEs compared 
with from week 0 through week 12. TEAEs were reported in 154 (88.5%) and 153 (87.9%) 
patients in the ASP015K 100 mg and 150 mg groups, respectively. Drug-related Treatment-
emergent Adverse Events were reported in 118 (67.8%) and 123(70.7%) patients in the 
ASP015K 100mg and 150mg groups, respectively. The majority of TEAEs were grade 1 or 2 
in severity. 
TEAEs occurring in ≥ 5% of patients in any treatment group included nasopharyngitis (8.2%, 
10.9% and 9.2% in the placebo, ASP015K 100 mg and ASP015K 150 mg groups, 
respectively). Drug-related TEAEs occurring in ≥ 5% of patients in any treatment group 
included nasopharyngitis (4.1%, 6.3% and 6.9% in the placebo, ASP015K 100 mg and 
ASP015K 150 mg groups, respectively).  


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The incidences of common AEs and drug-related AEs from week 12 through week 28 were 
generally similar to those from week 0 through week 12. 
The incidences of common AEs and drug-related AEs from week 28 through week 52 were 
generally similar to those from week 0 through week 12. 
For overall period, TEAEs occurring in ≥ 5% of patients in any treatment group included 
nasopharyngitis (29.9% and 33.3% in the ASP015K 100 mg and ASP015K 150 mg groups, 
respectively), blood creatine phosphokinase increased (5.7% and 11.5%), hepatic function 
abnormal (6.9% and 6.9%), pharyngitis (6.3% and 6.9%), upper respiratory tract infection 
(5.7% and 6.9%), bronchitis (4.6% and 6.3%), herpes zoster (6.9% and 3.4%), hypertension 
(4.0% and 6.3%), diarrhoea (4.0% and 5.7%), dental caries (5.7% and 2.9%), headache (1.7% 
and 6.9%), stomatitis (2.9% and 5.2%), lymphocyte count decreased (5.2% and 2.9%), cough 
(2.9% and 5.2%) and gastritis (1.7% and 5.2%).  
Drug-related TEAEs occurring in ≥ 5% of patients in any treatment group included 
nasopharyngitis (17.8% and 17.8% in the ASP015K 100 mg and ASP015K 150 mg groups, 
respectively), blood creatine phosphokinase increased (5.2% and 7.5%), hepatic function 
abnormal (5.7% and 4.6%), upper respiratory tract infection (4.0% and 6.3%), herpes zoster 
(6.9% and 2.9%), pharyngitis (5.2% and 4.0%), lymphocyte count decreased (5.2% and 
2.9%) and hypertension (2.3% and 5.7%). 
Death was reported in 1 patient due to completed suicide in the placebo/100 mg (week 28) 
group after switching to ASP015K 100 mg and was considered to be not related to the study 
drug. 
From week 0 through week 12, SAEs were reported in 4 (2.4%), 5 (2.9%) and 3 (1.7%) 
patients in the placebo, ASP015K 100 mg and ASP015K 150 mg groups, respectively. Drug-
related SAEs were reported in 2 (1.2%), 3 (1.7%) and 3 (1.7%) patients in the placebo, 
ASP015K 100 mg and ASP015K 150 mg groups, respectively. No serious TEAEs occurred 
in ≥ 2 patients in any treatment groups.  
For overall period, SAEs were reported in 19 (10.9%) and 13 (7.5%) patients in the 
ASP015K 100 mg and ASP015K 150 mg groups, respectively. Drug-related SAEs were 
reported in 10 (5.7%) and 8 (4.6%) patients in the ASP015K 100 mg and ASP015K 150 mg 
groups, respectively. Serious TEAEs occurring in ≥ 2 patients in any treatment group 
included pneumonia (3 and 2 patients in the ASP015K 100 mg and ASP015K 150 mg groups, 
respectively), spinal compression fracture (2 and 1 patients in the ASP015K 100 mg and 
ASP015K 150 mg groups, respectively) and cellulitis (2 patients in the ASP015K 150 mg 
group). 
From week 0 through week 12, AEs leading to permanent discontinuation of study drug were 
reported in 7 (4.1%), 5 (2.9%) and 5 (2.9%) patients in the placebo, ASP015K 100 mg and 
ASP015K 150 mg groups, respectively. Drug-related AEs leading to permanent 
discontinuation of study drug were reported in 6 (3.5%), 3 (1.7%) and 5 (2.9%) patients in 
the placebo, ASP015K 100 mg and ASP015K 150 mg groups, respectively. No TEAEs 


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leading to permanent discontinuation of study drug occurring in ≥ 2 patients in any treatment 
group.  
For overall period, AEs leading to permanent discontinuation of study drug were reported in 
13 (7.5%) and 12 (6.9%) patients in the ASP015K 100 mg and ASP015K 150 mg groups, 
respectively. Drug-related AEs leading to permanent discontinuation of study drug were 
reported in 7 (4.0%) and 11 (6.3%) patients in the ASP015K 100 mg and ASP015K 150 mg 
groups, respectively. TEAEs leading to permanent discontinuation of study drug occurring in 
≥ 2 patients in any treatment group included rheumatoid arthritis (2 and 1 patients in the 
ASP015K 100 mg and ASP015K 150 mg groups, respectively). 
With regard to the analysis per 100 patient-years for serious infections and herpes zoster 
related disease (herpes zoster and varicella), the incidence rates were higher in theASP015K 
groups compared with the placebo group; however, no dose dependency was observed. 
There was no major difference among the treatment groups for malignancy.  
Increases in creatine kinase were observed in the ASP015K groups compared with the 
placebo group. Decreases in absolute neutrophil count, lymphocytes, platelets, total 
cholesterol/high-density lipoprotein (HDL) ratio and low-density lipoprotein (LDL)/HDL 
ratio and increases in hemoglobin, creatinine, total cholesterol, LDL cholesterol, HDL 
cholesterol and triglycerides were also observed. 
No notable trend was observed in vital signs or ECG findings. 
1.4 
Risk-Benefit Assessment 
Findings from nonclinical studies of ASP015K suggest that the primary areas of toxicity are 
the gastrointestinal system, hematopoietic system, and muscle tissue. The commonly 
observed AEs during clinical studies conducted to date included reversible neutrophil count 
decreased, gastrointestinal disorders (e.g., diarrhoea, nausea, flatulence, vomiting), blood 
creatine phosphokinase increased without evidence of myopathy, and headache. In the 
clinical trial of ASP015K in Japanese patients with RA (015K-CL-RAJ1), 1 or more groups 
reported rheumatoid arthritis, nasopharyngitis, blood creatine phosphokinase increased, 
diarrhoea, cystitis, constipation, stomatitis, dyspepsia, lipids increased, and blood 
triglycerides increased at incidence rates of ≥ 5%. By the MedDRA System Organ Class 
(SOC), Infections and infestations, Gastrointestinal disorders, Musculoskeletal and 
connective tissue disorders, and Investigations showed high incidence rates. Thus, these 
events may occur in the present study. 
In the 015K-CL-QT01 study to evaluate the effect of ASP015K on cardiac function (QT 
interval), single doses of ASP015K 150 mg and 450 mg shortened the QTcF interval (QT 
interval corrected using Fridericia’s Correction). The maximum decrease in the mean change 
from placebo- and baseline-adjusted QTcF occurred at 2 and 4 hours post dose with values of 
-12.0 and -14.7 msec for the 150 mg and 450 mg treatments, respectively. Therefore, 
shortened QT interval may be observed in the present study. The risk of drug-induced QT 
shortening is uncertain. 


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Because ASP015K is an immunosuppressive agent, it may increase the risk of infections and 
reactivation of latent, chronic infections. In particular, excessive immunosuppression can 
lead to serious infections. Of note is the fact that Xeljanz® (tofacitinib) 5 mg, a member of 
the class of JAK inhibitors to which ASP015K belongs, has been associated with new onset 
or aggravation of serious infections such as tuberculosis, pneumonitis, sepsis, viral infections, 
and opportunistic infectious diseases including fungal infections. In addition, several cases of 
malignant tumors have been reported, although their causal relation to the agent has not been 
established. Based on the data pooled from 5 domestic and overseas comparative studies of 
Xeljanz® (tofacitinib) 5 mg, the incidence density of malignancies (excluding non-melanoma 
skin cancers) among RA patients treated with 5 mg BID for a maximum of 1 year was 
0.55/100 person-years (incidence rate 0.5% < 5/1216) [Xeljanz® Pharmaceutical Interview 
Form (in Japanese)]. These findings suggest that investigators pay particular attention to the 
possible development of infections and malignancies and take appropriate measures. Three 
cases of malignancies (stomach cancer, uterine sarcoma, chronic myelogenous leukemia) 
have been reported as of the cut-off date of 5 December 2013, from completed and ongoing 
national and international studies of ASP015K. Only the case of uterine sarcoma was judged 
as related to ASP015K. 
In the Japanese clinical trial in patients with moderate to severe RA (015K-CL-RAJ1), 50 mg 
and higher doses of ASP015K significantly improved the ACR20 response rate versus 
placebo. Xeljanz® (tofacitinib) 5 mg, which acts via the same mechanism as ASP015K, was 
approved by the US FDA in 2012 for the treatment of adult patients with moderate to severe 
RA who had an inadequate response to or are intolerant of MTX. In March 2013, Xeljanz® 
(tofacitinib) 5 mg tablets was authorized for marketing in Japan for treating RA patients who 
had an inadequate response to conventional therapies. Therefore, a potential benefit of JAK 
inhibitor ASP015K is to improve RA. 
Furthermore, the long-term control of RA disease activity with prolonged administration of 
ASP015K is expected to improve patient QOL. 
For further information in detail, refer to the latest investigator’s brochure. 
 
2 
STUDY OBJECTIVE(S), DESIGN, AND VARIABLES 
2.1 
Study Objectives 
This is an extension study conducted in RA patients who have completed the Phase IIb Study 
of ASP015K [015K-CL-RAJ1 (hereinafter referred to as study RAJ1)], Phase III Study of 
ASP015K [015K-CL-RAJ3 (RAJ3)], or Phase III Study of ASP015K [015K-CL-RAJ4 
(RAJ4)] to investigate the safety and efficacy of long-term administration of ASP015K. 
Another objective of this study is to devise rescue measures for providing the active drug to 
patients who participated in the Phase IIb Study or Phase III Study of ASP015K, as described 
in the “Guidelines on methodology for clinical assessment of antirheumatic drugs” 
(PFSB/ELD Notification No. 0217001, dated 17 February, 2006).  


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2.2 
Study Design and Dose Rationale 
2.2.1 
Study Design 
This study is an extension study conducted as an open-label, multicenter study in RA patients 
who have completed studies RAJ1, RAJ3, or RAJ4. 
Patients who meet all the inclusion criteria and do not fall under any of the exclusion criteria 
will receive oral ASP015K 100 mg QD after breakfast as the starting dose. For subjects who 
have been receiving ASP015K at a dose of 50 mg/day in Japan, the dose will be increased to 
100 mg/day after the NDA approval in Japan. Any subjects for whom the dose cannot be 
increased should be withdrawn from the study. Subjects who have no safety problems but 
show lack of efficacy may later increase the dose to 150 mg/day. Only in Korea and Taiwan, 
the dosage may be reduced from 100 mg/day or 150 mg/day to 50 mg/day at the discretion of 
the investigator or sub-investigator. The starting dose for subjects who transferred from study 
RAJ1 is 50 mg/day. For subjects who transferred from study RAJ1 and are continuing to 
receive 50 mg/day, treatment extension using a dose of 50 mg/day should be allowed when 
the investigator or sub-investigator considers a dose increase to be inappropriate in terms of 
safety and treatment extension with a dose of 50 mg/day to provide greater therapeutic 
benefit for the treatment of RA. 
This study will be conducted as a post-marketing clinical study up to a maximum of 6 
months after the NDA approval in Japan. (After the NDA approval in Japan, the post-
marketing clinical study will be ended once the study drug is available in the clinical sites as 
a commercially available product. The planned study period will be a maximum of 6 months 
after the NDA approval in Japan). In Korea and Taiwan, this study will continue as a clinical 
study after the NDA approval in Japan. The duration of treatment will differ depending on 
the subject. To prevent purposeless continuation of dosing without effect, the investigator or 
sub-investigator will assess each subject for efficacy and safety at each visit, confirm the 
appropriateness of continued administration for each individual, and decide whether or not to 
continue dosing. 
2.2.2 
Dose Rationale 
[Rationale for setting dose] 
The starting dose for this extension study will be 100 mg/day, to be increased to 150 mg/day 
at the time of dose escalation.  
The dose levels for study RAJ1 have been set at ASP015K 0 mg/day (placebo), 25 mg/day, 
50 mg/day, 100 mg/day, and 150 mg/day. As a result, the ACR20 response rate at Week 12 
(or early termination) in ASP015K groups receiving 50 mg/day or more showed a 
statistically significant increase over the placebo group; the increase in the ACR20 response 
rate was dose dependent up to 150 mg. Compared with the placebo group, a significant and 
dose-dependent decrease was also found in the reduction of DAS28-CRP score at Week 12 
(or early termination) in the 50 mg, 100 mg, and 150 mg groups. A comparison of the 


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interview forms of Enbrel®, Simponi®, Xeljanz®, and Humira® showed that ASP015K at a 
dose of 100 mg or higher was found to have the same efficacy as the other drugs at their 
approved doses. Based on these results, the dose levels for the Phase III studies (RAJ3 and 
RAJ4) have been set at ASP015K 100 mg/day and 150 mg/day. 
Due to safety considerations, the starting dose for this extension study has been set at 100 
mg/day, which was the lower of the two doses set for the Phase III studies. For subjects who 
have no safety problems but show a lack of efficacy, the dosage may later be increased from 
100 mg/day to 150 mg/day. However, in subjects who transferred from study RAJ1, the 
extension study is performed using a dosage design with 50 mg/day as the starting dose and 
100 mg/day as the increased dose. Subjects who completed study RAJ1 and are continuing 
the treatment with ASP015K at a dose of 50 mg/day shall be included in the clinical study 
under the protocol ver. 2.0/ver. 3.0; later, when the study drugs after the change in 
specifications become available for use, the dose shall be increased to 100 mg/day, with the 
exception of the subjects for whom the investigator or sub-investigator considers a dose 
increase to be inappropriate in terms of safety and treatment extension with a dose of 50 
mg/day to provide greater therapeutic benefit for the treatment of RA. If treatment is to be 
continued at a dose of 50 mg/day, the reason for this decision must be recorded in the 
medical record.  
For subjects who have been receiving ASP015K at a dose of 50 mg/day in Japan, the dose 
will be increased to 100 mg/day in accordance with the dosage and administration section of 
the package insert. Any subjects for whom the dose cannot be increased should be withdrawn 
from the study. 
Only in Korea and Taiwan, the dosage may be reduced from 100 mg/day or 150 mg/day to 
50 mg/day at the discretion of the investigator or sub-investigator. 
[Rationale for mode of administration] 
Findings from nonclinical studies suggest that AUC is the pharmacokinetic parameter, which 
is most correlated with the pharmacological effects of ASP015K. In Study 015K-CL-PS01 
with a different target disease, i.e., in psoriasis patients, no major differences in efficacy and 
safety were observed between the dose levels of 50 mg QD and 25 mg BID. With reference 
to this, and out of consideration for the convenience of the patients and for adherence, the 
mode of administration adopted for this study is once-daily administration. Moreover, the 
period after breakfast was selected as the timing for taking the study drug, out of 
consideration for adherence. The once-daily administration after breakfast was also adopted 
in study RAJ1 and resulted in good adherence and efficacy in terms of the ACR20 response 
rate, etc. 
[Rationale for treatment period] 
The treatment period for this study has been set as the period of time until ASP015K is 
approved for the purpose of devising rescue measures for providing the active drug to 
patients who have reached the end of the 12-week period of treatment with the study drug in 
the preceding study RAJ1 or the end of the 52-week period in studies RAJ3 or RAJ4, without 


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any safety problems, as described in “Guidelines on methodology for clinical assessment of 
antirheumatic drugs” (PFSB/ELD Notification No. 0217001, dated 17 February 2006). This 
study will be conducted as a post-marketing clinical study up to a maximum of 6 months 
after the NDA approval in Japan. (After the NDA approval in Japan, the post-marketing 
clinical study will be ended once the study drug is available in the clinical sites as a 
commercially available product. The planned study period will be up to a maximum of 6 
months after the NDA approval in Japan). In Korea and Taiwan, this study will continue as a 
clinical study after the NDA approval in Japan. 
However, because no safety data on treatment periods longer than 12 weeks are available at 
the present time for administration at 150 mg/day, an independent DSMB will be established 
to study the advisability of continuing or discontinuing the study, or changing the protocol 
while confirming the safety data on individual subjects obtained through this study as well as 
the safety data on the study as a whole, periodically or as urgent contingency requires. 
Moreover, in order to prevent treatment from continuing purposely without effect, the 
investigator or the sub-investigator will investigate efficacy and safety at each study visit, 
confirm the appropriateness of continuing treatment for each individual subject, and decide 
whether or not to continue treatment.  
2.3 
Variables 
2.3.1 
Safety Variables 
● 
AEs 
● 
Vital signs (body temperature, pulse and blood pressure in sitting position) 
● 
Body weight 
● 
12-lead ECG 
● 
Chest radiography 
● 
Laboratory assessments 
2.3.2 
Efficacy Variables 
● 
The following items at each study visit: 
• 
ACR20 response rate 
• 
ACR50 response rate 
• 
ACR70 response rate 
• 
Change from baseline in Tender Joint Count (TJC) (68 joints) 
• 
Change from baseline in Swollen Joint Count (SJC) (66 joints) 
• 
Change from baseline in DAS28-CRP and DAS28-ESR scores 
• 
Percentage of subjects achieving DAS28-CRP score for remission 
• 
Percentage of subjects achieving ACR/EULAR score for remission 
ACR/EULAR remission is defined as meeting all 4 of the following criteria:  
➢ TJC ≤ 1 
➢ SJC ≤ 1 
➢ CRP ≤ 1 mg/dL  
➢ Subject’s Global Assessment of Arthritis (SGA) ≤ 1 cm (0-100 mm on a VAS scale) 
• 
Percentage of subjects with a SDAI score of ≤ 3.3 (SDAI remission) 


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• 
Change from baseline in Physician’s Global Assessment of Arthritis (PGA) (VAS) 
• 
Change from baseline in SGA (VAS) 
• 
Change from baseline in the subject’s assessment of pain (VAS) 
• 
FACIT-Fatigue score (only in subjects who transferred from study RAJ1)  
• 
Change from baseline in WPAI (only in subjects who transferred from studies RAJ3 or 
RAJ4) 
• 
Change from baseline in HAQ-DI 
• 
Change from baseline in SF-36v2® score 
• 
Percentage of subjects in EULAR response criterion of “Good Response” 
• 
Percentage of subjects in EULAR response criterion of “Moderate Response” 
• 
Percentage of subjects in EULAR response criterion of “Good Response” or “Moderate 
Response” 
• 
Incidence of subject withdrawal due to lack of efficacy 
[Rationale for efficacy variables] 
The efficacy variables were established with reference to “Guidelines on methodology for 
clinical assessment of antirheumatic drugs” (PFSB/ELD Notification No. 0217001, dated 17 
February, 2006), overseas clinical studies of ASP-015K, and other recently reported clinical 
studies conducted in RA patients.  
2.3.3 
Pharmacodynamics Variables 
Changes from baseline in lymphocyte subsets (CD3, CD4, CD8, CD16, CD19, CD56, 
CD56/16) 
 
3 
STUDY POPULATION 
3.1 
Selection of Study Population 
The target population for this extension study is RA patients who have completed studies 
RAJ1, RAJ3, or RAJ4, who wish to continue treatment with the study drug, and for whom 
the investigator or sub-investigator deems continued treatment to be necessary or appropriate. 
 
3.2 
Inclusion Criteria 
Subject is eligible for the study if all of the following apply:  
[Subjects who transferred from study RAJ1] 
1. Subject has received a full explanation of the study drug and this study in advance, and 
written informed consent to participate in the study has been obtained from the subject 
himself/herself. 
2. Subject has completed treatment with the study drug in study RAJ1 as specified in the 
protocol and has also completed the tests and assessment performed at the study visit in 
Week 16. 


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3. The subject himself/herself wishes to continue taking the study drug, and the investigator 
or sub-investigator deems continued administration to be necessary or appropriate. 
4. Subject must be willing and able to comply with the study requirements. 
 
[Rationale for inclusion criteria] 
1: 
Established with consideration for ethics of conducting the study. 
2: 
Established to select RA patients for inclusion in the study population for this 
extension study. 
3: 
Established with consideration for ethics of conducting the study. 
4: 
Established to select subjects in whom clinical assessments of this study can be 
appropriately conducted.  
[Subjects who transferred from studies RAJ3 or RAJ4] 
1. Subject has received a full explanation of the study drug and this study in advance, and 
written informed consent to participate in the study has been obtained from the subject 
himself/herself. 
2. Subject who has completed treatment with the study drug in studies RAJ3 or RAJ4 as 
specified in the protocol and has also completed the tests and assessments scheduled for 
the Week 52 visit.  
3. The subject himself/herself wishes to continue taking the study drug, and the investigator 
or sub-investigator deems continued administration to be necessary or appropriate. 
4. Subject must be willing and able to comply with the study requirements. 
 
[Rationale for inclusion criteria] 
1: 
Established with consideration for ethics of conducting the study. 
2: 
Established to select RA patients for inclusion in the study population for this 
extension study. 
3: 
Established with consideration for ethics of conducting the study. 
4: 
Established to select subjects in whom clinical assessments of this study can be 
appropriately conducted.  
 
3.3 
Exclusion Criteria 
Subject will be excluded from participation if any of the following apply:  
[Subjects who transferred from study RAJ1] 
1. Subject has developed an adverse reaction related to the study drug in study RAJ1 and 
the risks of continuing treatment with this drug are expected to outweigh the benefits. 


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2. There were abnormal findings in the X-ray taken at Week 0, and an acute or chronic 
infection, tuberculosis infection, or malignant tumor is suspected. 
3. Subject has received live or live attenuated virus vaccination within 30 days prior to the 
first dose of study drug. 
4. Subject is a hepatitis B virus or hepatitis C virus carrier or has a history of a positive test 
for HIV infection. 
5. Subject has a concurrent autoimmune disease (except Sjogren’s syndrome) other than 
RA or a history of it. 
6. Subject has a clinically significant infection or disease (requiring hospitalization or 
parenteral therapy). 
7. Subject has a history of any malignant tumor, except for successfully treated basal or 
squamous cell carcinoma of the skin or in-situ carcinoma of the cervix, or subject has a 
concurrent malignant tumor. 
8. Subject has taken one of the following drugs between the end of the assessments at 
Week 12 of study RAJ1 and the start of treatment with the study drug in this extension 
study. 
• 
Biologic DMARDs: Etanercept, adalimumab, golimumab, infliximab, tocilizumab, 
abatacept, rituximab 
• 
Non-biologic DMARDs: MTX, salazosulfapyridine, gold, D-penicillamine, 
leflunomide, lobenzarit, actarit, tacrolimus, mizoribine, bucillamine, iguratimod, 
tofacitinib (However, topical drugs other than those for the treatment of RA may be 
used concomitantly.) 
• 
Other drugs used in the treatment of RA: Cyclosporine, cyclophosphamide, 
azathioprine, minomycin, etc. 
9. Subject has received plasma exchange therapy between the end of the assessments at 
Week 12 of study RAJ1 and the start of treatment with the study drug in this extension 
study. 
10. Subject has received any of the following CYP3A substrates with narrow therapeutic 
range within 14 days prior to starting treatment with the study drug: Dihydroergotamine, 
ergotamine, fentanyl, pimozide, quinidine, and temsirolimus 
11. Subject has any of the following laboratory values at the study visit in Week 12 of study 
RAJ1:  
• 
Hemoglobin < 10 g/dL 
• 
White blood cell (WBC) count < 3000/μL 
• 
Absolute neutrophil count (ANC) < 2000/μL 
• 
Absolute lymphocyte count < 800/μL 
• 
Platelet count < 100000/μL 
• 
ALT ≥ 2 × ULN 
• 
AST ≥ 2 × ULN 
• 
Total bilirubin (TBL) ≥ 1.5 × ULN 
• 
Estimated GFR ≤ 40 mL/min, as measured by the MDRD method 
• 
CPK > 1.5 × ULN 
• 
β-D-glucan ≥ 11 pg/mL 


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12. Subject has symptomatic CPK elevation (CPK > 1.5 × ULN with myalgia, muscular 
weakness, or severe unusual muscle twitching*) at the study visit in Week 12 of study 
RAJ1. 
* Muscle twitching: A condition in which there is a cramp in a muscle, such as cramps 
in the calves 
13. Subject is found to have symptoms of myopathy such as myalgia, muscular weakness, 
and severe unusual muscle twitching* regardless of CPK level that persist for at least 2 
weeks or that worsen rapidly within 2 weeks, at study visit in Week 12 of study RAJ1. 
* Muscle twitching: A condition in which there is a cramp in a muscle, such as cramps 
in the calves 
14. Subject has concurrent cardiac failure with NYHA classification of Class III or higher, or 
a history of it. 
15. Subject has concurrent long QT syndrome or a history of it. Subject exhibits QT interval 
prolonged at the study visit in Week 0. 
16. Subject has any ongoing severe, progressive, or uncontrolled renal, hepatic, 
hematological, gastrointestinal, metabolic, endocrine, pulmonary, cardiac, neurological, 
or infectious disease, or any ongoing illness which would make the subject unsuitable for 
the study as determined by the investigator/sub-investigator. 
17. Subject has any condition possibly affecting oral absorption (e.g., gastrectomy or 
clinically significant diabetic gastroenteropathy). 
18. Subject has received surgical treatment and the investigator/sub-investigator judges there 
to be residual effects of surgical stress. Or, the subject plans to have surgical treatment 
that will require hospitalization during the study period or surgery on the joints. 
19. The subject is a woman who is pregnant or might be pregnant, is nursing, wishes to 
conceive for a period running from the time informed consent is given within 60 days 
after end of treatment, or for whom the possibility of pregnancy cannot be ruled out as a 
result of the pregnancy test given at Week 0. 
20. The subject is a man who cannot practice proper contraception with a condom from the 
time informed consent is given until 90 days after end of treatment, or the subject is a 
woman who could become pregnant and cannot practice proper contraception with a 
condom from the time informed consent is given until 60 days after end of treatment. 
21. The subject has been judged unsuitable to participate in the study for other reasons by 
the investigator/sub-investigator. 
 
[Rationale for exclusion criteria] 
1-7: Established out of consideration for the safety of the subjects. 
8-9: Established to eliminate factors affecting the evaluation. 
10-16: Established out of consideration for the safety of the subjects. 
17: 
Established to eliminate factors affecting the evaluation. 


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18: 
Established out of consideration for the safety of the subjects and to eliminate 
factors affecting the evaluation.  
19-20: Established on the basis of general considerations for clinical studies. 
21: 
In addition to 1 through 20 above, the exclusion criteria were established in light 
of scientific and ethical aspects of the study, envisioning situations in which the 
investigator/sub-investigator would deem a potential subject to be unsuited to 
participating in this study.  
 
[Subjects who transferred from studies RAJ3 or RAJ4] 
1. The subject is a woman who is pregnant or might be pregnant, is nursing, wishes to 
conceive within 60 days after end of treatment drug, or for whom the possibility of 
pregnancy cannot be ruled out as a result of the pregnancy test given at Week 0. 
2. Subject is a man who cannot practice 2 or more methods of proper contraception from 
the time informed consent is given to 90 days after the end of treatment, or subject is a 
woman who could become pregnant and cannot practice 2 or more methods of proper 
contraception from the time informed consent is given to 60 days after the end of 
treatment (if the possibility of pregnancy can be completely ruled out by other tests, the 
subject is eligible for enrollment).  
3. Subject is a man who cannot be prohibited from sperm donation from the time informed 
consent is given to 90 days after the end of treatment, or subject is a woman who cannot 
be prohibited from egg donation from the time informed consent is given to 60 days after 
the end of treatment. 
4. Subject who has tested positive for any of the following at screening for studies RAJ3 or 
RAJ4: HBs antigen, HBc antibody, HBs antibody, and HBV-DNA assay (However, if a 
subject is negative for HBs antigen and HBV-DNA assay, and positive for either or both 
HBc and HBs antibodies, the subject may be included provided that the subject is 
monitored by performing HBV-DNA assay at every scheduled visit after initiation of 
study drug administration.) 
5. Subject has received a prohibited concomitant medication or prohibited concomitant 
therapy during the time from the end of the assessments at Week 52 of studies RAJ3 or 
RAJ4 to the first dose of the study drug in this extension study. 
6. Subject has QTc < 300 msec on ECG measurements performed at the study site at Week 
52 of studies RAJ3 or RAJ4 and has QTc < 300 msec at retest. 
7. The subject has been judged unsuitable to participate in the study for other reasons by 
the investigator/sub-investigator. 
 
[Rationale for exclusion criteria] 
1-3: Established on the basis of general considerations for clinical studies. 
4, 6:  Established out of consideration for the safety of the subjects. 


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5: 
Established to eliminate factors affecting the evaluation and out of consideration 
for the safety of the subjects. 
7: 
In addition to 1 through 6 above, the exclusion criteria were established in light 
of scientific and ethical aspects of the study, envisioning situations in which the 
investigator/sub-investigator would deem a potential subject to be unsuited to 
participating in this study.  
 
3.4 
Discontinuation Criteria for Individual Subjects 
A discontinuation means that a subject who has enrolled in the study prematurely terminates 
study treatment prior to the completion of all protocol-required elements. 
The subject is free to withdraw from the study treatment and/or study for any reason and at 
any time without giving reason for doing so and without penalty or prejudice. The 
investigator is also free to terminate a subject’s involvement in the study at any time if this is 
considered necessary because of the subject’s clinical condition. 
 
Discontinuation Criteria for Individual Subjects: 
The investigator/sub-investigator should discontinue the study if any of the following criteria 
are met: 
1. Subject withdraws consent. 
2. The study drug is not sufficiently effective, and a change in treatment method is deemed 
to be in the subject’s best interest by the investigator or sub-investigator. 
3. Symptomatic CPK elevation, defined as CPK > 1.5 × ULN with severe unusual myalgia, 
muscular weakness, or muscle twitching*. 
* Muscle twitching: A condition in which there is a cramp in a muscle, such as cramps 
in the calves 
4. Any event of myopathy defined as severe unusual myalgia, muscular weakness, and 
muscle twitching* regardless of CPK level that persists for at least 2 weeks or that 
worsens rapidly within 2 weeks. 
* Muscle twitching: A condition in which there is a cramp in a muscle, such as cramps 
in the calves 
5. Subject infected with HBV who has tested positive for either of or both of HBc and HBs 
antibodies and is found to be positive for HBV-DNA assay during the study period.  
Abrupt discontinuance of immunosuppressive therapy may precipitate severe or 
fulminant hepatitis. Therefore, when HBV reactivates, nucleic acid analog therapy 
should be immediately initiated, and a hepatologist should be consulted regarding the 
continuation of ASP015K and concomitant DMARD (unique to Japan: as indicated by 
“Proposal for Management of Rheumatic Disease Patients with Hepatitis B Virus 
Infection Receiving Immunosuppressive Therapy” by the Japan College of 
Rheumatology). 


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6. Subject has a malignant tumor. 
7. Subject has an adverse event (AE) such as a serious infection, and the investigator or 
sub-investigator considers that it is not in the subject’s best interest to continue the study. 
8. Subject receives or requires a prohibited concomitant medication (including other study 
drugs) or prohibited concomitant therapy that may affect the evaluation of efficacy; 
subject receives or requires live vaccine or live attenuated vaccine. 
9. Subject receives or requires drug interruption for a longer period than that stipulated for 
interruption. 
10. Subject is deemed lost to follow-up by the investigator/sub-investigator (subject can no 
longer come to the study center; subject can no longer be contacted, etc.). 
11. It comes to light after the administration of the first dose of study drug that the inclusion 
criteria were not met at the time of case enrollment or that criteria for exclusion were met. 
It comes to light that there was some other major deviation from the protocol.  
12. Investigator or sub-investigator decides it is in the subject’s best interest to discontinue. 
13. The sponsor has requested that administration of the study drug be discontinued because 
of a safety problem in a particular subject, or the sponsor has decided to discontinue the 
study altogether. 
14. Subject has QTc < 300 msec on ECG measurements and has QTc < 300 msec at retest. 
 
Subjects who discontinue early from the study should be given the necessary tests and 
assessments specified to be performed at end of treatment/early termination within 2 days 
after taking the final dose of the study drug if possible (see “Table 1, Schedule of 
Assessments”). Moreover, these subjects should receive the tests and assessments scheduled 
for end of study (at time of follow-up). These assessments and tests will be conducted only if 
the investigator/ sub-investigator decides necessary. 
If the discontinuation has been for reasons of AEs, appropriate treatment should be provided 
as necessary. 
Subjects with early termination will be treated as discontinuations, and the investigator/sub-
investigator must clearly identify the date of discontinuation and the reason for 
discontinuation, as well as retain all clinical study data on the discontinuations and submit it 
to the sponsor in the CRF, report of follow-up investigation, etc.  
The Appendix 6 entitled “Liver Safety Monitoring and Assessment” describes liver function 
tests raised that provide grounds for discontinuation. Refer to this if liver function tests raised 
is observed. 
 
3.4.1 
Suspension, Interruption, and Resumption of the Study Drug 
If either of the criteria in Section 3.4.1.1, Criteria for Suspension or Interruption of the Study 
Drug, is met during the treatment period with the study drug, the investigator or sub-
investigator is to suspend or interrupt administration of the study drug without delay. 
Administration of the study drug may be resumed after the initiation of suspension or 


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interruption if a retest shows that none of the following criteria are met, provided that the 
investigator or sub-investigator deems resumption to be in the subject’s best interest, taking 
the risk/benefit ratio into consideration. 
Suspension of the study drug 
Administration of the study drug may be suspended within the scope of the below 
stipulations if the investigator or sub-investigator deems a temporary discontinuation 
(suspension) of dosing to be necessary. Suspension of the study drug beyond the scope of the 
following stipulation is handled as interruption: 
● 
Suspension is defined as a temporary discontinuation of study drug administration for 7 
days or less. 
● 
If administration of the study drug is suspended repeatedly, the discontinuation of the 
clinical study for the particular subject should be considered in consultation with the 
sponsor. 
Interruption of the study drug 
Administration of the study drug may be interrupted within the scope of the below 
stipulations if the investigator or sub-investigator deems a temporary discontinuation 
(interruption) of dosing for a period exceeding 7 days to be necessary. If a subject requires 
interruption beyond the scope described below, the subject has to be withdrawn from the 
study. 
● 
Interruption is defined as a temporary discontinuation of study drug administration for a 
period exceeding 7 days. 
● 
Interruption may not exceed a maximum of 4 consecutive weeks. 
● 
Up to 2 interruptions per year may be allowed. Moreover, they must be separated by an 
interval of 16 weeks or more. 
3.4.1.1 Criteria for Suspension or Interruption of the Study Drug 
If either of the below criteria is met during the treatment period with the study drug, the 
investigator or sub-investigator is to suspend or interrupt the administration of the study drug 
without delay. The administration of the study drug may be resumed after the initiation of 
suspension or interruption if a retest shows that none of the following criteria are met: 
1. Subject has any of the following laboratory values. Administration of the study drug is to 
be discontinued until a retest shows that none of the following criteria are met: 
• 
Hemoglobin < 8.0 g/dL 
• 
ANC < 500/μL 
• 
Absolute lymphocyte count < 500/μL 
• 
Platelet count < 50000/μL 
• 
Serum creatinine > 150% of baseline at 2 consecutive Scheduled Visits 
• 
CPK > 10 × ULN 
2. β-D-glucan > ULN [in case of Japan: ≥ 11 pg/mL] 


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3. Subject requires a concomitant medication that is prohibited because of a possible drug 
interaction. 
4. Suspected pregnancy. 
5. The investigator or sub-investigator considers suspension or interruption of the study 
drug to be in the subject’s best interest. 
6. The sponsor has requested suspension or interruption of the study drug because of a 
safety problem in a particular subject. 
 


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4 
STUDY DRUGS 
4.1 
Description of Study Drugs 
The test drugs for this study are ASP015K tablets of 50 mg, 100 mg, and 150 mg doses.  
 
4.1.1 
Test Drug(s) 
Code name 
ASP015K 
Generic Name 
Peficitinib hydrobromide 
Chemical name 
4-{[(1R,2S,3S,5S,7S)-5-hydroxy-2-adamantyl]amino}-1H-pyrrolo[2,3-
b]pyridine-5-carboxamide monohydrobromide 
Molecular formula 
(molecular weight) 
C18H22N4O2 · HBr (407.30) 
Content and dosage form 
ASP015K tablet 50 mg: A round, yellow, film-coated tablet containing 
the ASP015K drug substance at 50 mg (as free form) 
ASP015K tablet 100 mg: An elliptical, pale-red, film-coated tablet 
containing the ASP015K drug substance at 100 mg (as free form) 
ASP015K tablet 150 mg: An elliptical, yellow, film-coated tablet 
containing the ASP015K drug substance at 150 mg (as free form) 
Manufacturer 
Astellas Pharma Inc. (API) 
Lot No. 
Noted in SOP for handling of study drugs 
Storage method 
Store at room temperature 
Expiration date 
Noted in SOP for handling of study drugs 
4.1.2 
Comparative Drug(s) 
Not applicable. 
 
4.2 
Packaging and Labeling 
All medication used in this study will be manufactured, packaged, and labeled under the 
responsibility of the Quality Assurance Manager in accordance with sponsor’s SOP, GMP 
guidelines, GCP, and applicable local laws/regulations. (Refer to the study drug handling 
manual for details) 
4.2.1 
Packaging Form 
1. For 50 mg/day administration  
ASP015K tablets will be supplied in sheets holding 14 days’ worth of medication (14 of the 
ASP015K tablets 50 mg). These sheets will be packaged 4 sheets to a small box.  


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[Test drug count] 
 
ASP015K tablets 
50 mg 
Per day 
1 tablet 
Per sheet (14 days’ worth) 
14 tablets 
Per box (8 weeks’ worth) 
56 tablets 
 
2. For 100 mg/day administration  
ASP015K tablets will be supplied in sheets holding 14 days’ worth of medication (14 of the 
ASP015K tablets 100 mg). These sheets will be packaged 4 sheets to a small box.  
[Test drug count] 
 
ASP015K tablets 
100 mg 
Per day 
1 tablet 
Per sheet (14 days’ worth) 
14 tablets 
Per box (8 weeks’ worth) 
56 tablets 
 
3. For 150 mg/day administration 
ASP015K tablets will be supplied in sheets holding 14 days’ worth of medication (14 of the 
ASP015K tablets 150 mg). These sheets will be packaged 4 sheets to a small box. 
[Test drug count] 
 
ASP015K tablets 
150 mg 
Per day 
1 tablet 
Per sheet (14 days’ worth) 
14 tablets 
Per box (8 weeks’ worth) 
56 tablets 
 
4.2.2 
Labeling 
In case of Japan (Package design of study drug for Korea and Taiwan is described in the 
study drug handling manual): 
The following labels will be affixed to the small boxes. After transferring to the post-
marketing clinical study, the label “for clinical study use” will be replaced as “for post-
marketing clinical study use” and the study drug will be used throughout the post-marketing 
clinical study. 


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1. For 50 mg/day administration 
 
Lot No.○○○○○○ 
56 tablets (14 tablets × 4 sheets) 
 
Extension Study of ASP015K 
For 50 mg dose level 
 
Caution: 
Please retain any remaining medication and this box without discarding them until 
they are collected by the sponsor.  
Storage method: Store at room temperature 
Expiration date: Specified in SOP for handling of study drugs 
 
 
Astellas Pharma Inc. (API) 
2-5-1 Nihonbashi-Honcho, Chuo-ku, Tokyo  
 
 
2. For 100 mg/day administration 
 
Lot No.○○○○○○ 
56 tablets (14 tablets × 4 sheets) 
 
Extension Study of ASP015K 
For 100 mg dose level 
 
Caution: 
Please retain any remaining medication and this box without discarding them until 
they are collected by the sponsor.  
Storage method: Store at room temperature. 
Expiration date: Specified in SOP for handling of study drugs 
 
 
Astellas Pharma Inc. (API) 
2-5-1 Nihonbashi-Honcho, Chuo-ku, Tokyo  
 
 
3. For 150 mg/day administration 
 
Lot No.○○○○○○ 
56 tablets (14 tablets × 4 sheets) 
 
Extension Study of ASP015K 
For 150 mg dose level 
 
Caution: 
Please retain any remaining medication and this box without discarding them until 
they are collected by the sponsor.  
Storage method: Store at room temperature. 
Expiration date: Specified in SOP for handling of study drugs 
 
 
Astellas Pharma Inc. (API) 
2-5-1 Nihonbashi-Honcho, Chuo-ku, Tokyo  
 
 
Lot No. is given in SOP on handling of study drugs.  
 
For clinical study 
For clinical study 
For clinical study 


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4.3 
Study Drug Handling 
Japan: 
The head of the study center or the study drug storage manager should take accountability for 
the study drugs as following issues:  
● 
The study drug storage manager should store and take accountability for the study drugs 
in conformity with the procedures for handling the study drugs created by the sponsor. 
● 
The study drug storage manager should prepare and retain records of the study drug's 
receipt, the inventory at the study center, the use by each subject, and the return to the 
sponsor or alternative disposal of unused study drugs. These records should include dates, 
quantities, batch/serial numbers, expiration dates (if applicable), and the subject 
identification codes. 
● 
The study drug storage manager should prepare and retain records that document 
adequately that the subjects were provided the doses specified in the protocol, and 
reconcile all the study drugs supplied from the sponsor. 
 
Korea and Taiwan: 
The procedures will be specified separately in the study drug handling manual in accordance 
with the local requirements. 
 
4.4 
Blinding 
Not applicable. 
 
4.5 
Assignment and Allocation 
Not applicable. 
 


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5 
TREATMENTS AND EVALUATION 
5.1 
Dosing and Administration of Study Drugs and Other Medications 
5.1.1 
Dose/Dose Regimen and Administration Period 
(1) 
Starting dose (100 mg/day as ASP015K) 
The subjects will take 1 tablet of ASP015K 100 mg orally QD after breakfast. The first dose 
will be administered at each study center at the Week 0 visit after all the scheduled 
assessments and tests have been completed.  
* The starting dose for subjects who transferred from study RAJ1 is 50 mg/day. After 
implementation of the study protocol (ver. 2.0/ver. 3.0), only subjects who transferred from 
studies RAJ3 or RAJ4 will be enrolled newly. 
(2) 
Increased dose (150 mg/day as ASP015K) 
The subjects will take 1 tablet of ASP015K 150 mg orally QD after breakfast. 
 
For the subjects who have completed study RAJ1 and are continuing treatment with 
ASP015K at a dose of 50 mg/day, the need for a change in the dose shall be assessed at the 
initiation of the clinical study under the protocol ver. 2.0/ver. 3.0. If the dose is not increased 
to 100 mg and treatment is to be continued at a dose of 50 mg/day, the reason for this 
decision must be entered in the medical record. 
For subjects who have been receiving ASP015K at a dose of 50 mg/day in Japan, the dose 
will be increased to 100 mg/day after approval in Japan. Any subjects for whom the dose 
cannot be increased should be withdrawn from the study. This study will be conducted as a 
post-marketing clinical study up to a maximum of 6 months after the NDA approval in Japan. 
(After the NDA approval in Japan, the post-marketing clinical study will be ended once the 
study drug is available in the clinical sites as a commercially available product. The planned 
study period will be up to a maximum of 6 months after the NDA approval in Japan). In 
Korea and Taiwan, this study will continue as a clinical study after the NDA approval in 
Japan. The duration of treatment will differ depending on the subject. Moreover, in order to 
prevent treatment from continuing purposelessly without effect, the investigator or the sub-
investigator will investigate efficacy and safety at each study visit, confirm the 
appropriateness of continuing treatment for each individual subjects, and decide whether or 
not to continue treatment. 
5.1.2 
Increase or Reduction in Dose of the Study Drugs 
The dose increase/reduction of study drugs is allowed only when the following criteria are 
met. For subjects who have been receiving ASP015K at a dose of 50 mg/day in Japan, the 
dose will be increased to 100 mg/day after approval in Japan. Any subjects for whom the 
dose cannot be increased should be withdrawn from the study. 
[The increase in dose from 50 mg/day to 100 mg/day] 


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Japan: For subjects who have been receiving ASP015K at a dose of 50 mg/day in Japan, the 
dose will be increased to 100 mg/day after approval. Any subjects for whom the dose cannot 
be increased should be withdrawn from the study. 
Korea and Taiwan: When the investigator or sub-investigator judges that there is no safety 
problem in the subject, the dose may be increased from 50 mg to 100 mg. 
 
[The increase in dose from 100 mg/day to 150 mg/day] 
The dose may be increased from 100 mg to 150 mg at the time point when the following 2 
conditions are met:  
1) 
The subject has taken ASP015K 100 mg for at least 4 weeks, and the DAS28-
ESR score is 3.2 or higher (moderate disease activity or high disease activity) on 
the study visit days. 
2) 
When the investigator or sub-investigator judges there to be no problem with 
safety for the subject in the assessment performed on the study visit day on which 
the DAS28-ESR score of 3.2 or higher was exhibited. 
 
[The reduction in dose from 100/day mg or 150 mg/day to 50 mg/day] 
Japan: After the NDA approval in Japan, dose reduction for the study drugs is not allowed. 
Korea and Taiwan: After the dose increase, the dose may be reduced from 100 mg/day or 150 
mg/day to 50 mg/day at the discretion of the investigator or sub-investigator.  
The investigator or sub-investigator will decide whether or not to reduce the dosage on the 
basis of the following criterion.  
● 
If an AE with NCI-CTCAE grade classification of Grade 2 or higher has developed.  
A dose increase after a dose reduction and a dose reduction after a dose increase are allowed 
according to the above criteria. 
If the dose of study drug has been increased or reduced, the investigator or sub-investigator 
should record this information in the CRF.  
5.1.3 
Previous and Concomitant Medication (Drugs and Therapies) 
The survey period and survey method for previous and concomitant medication (drugs and 
therapies) will be as follows. Previous medications do not need to be recorded in the CRF for 
this study. 
(1) 
Concomitant medications 
The survey period will be from the start of administration of the study drug to the end of 
study (day of follow-up). The pharmaceutical name, daily dose, route of administration, 
treatment period, and reason for administration of DMARD, limited concomitant medications, 
rescue medications, and prohibited concomitant medications shall be collected. 


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The pharmaceutical name, route of administration, treatment period, and reason for 
administration shall be collected with regard to medications other than DMARD, limited 
concomitant medications, rescue medications, prohibited concomitant medications, and 
medications listed below:  
➢ Diluent solution (water for injection, saline solution), antiseptic solution, wash, topical 
anesthesia used in tests and treatments (Xylocaine jelly, etc.), contrast medium for 
examination (barium, non-iodine based contrast media, etc.), anticoagulants for 
indwelling iv line, effervescent agents and purgatives used in examinations, and topical 
drugs with local action other than those for the treatment of RA. 
*Medications used for the treatment of AEs shall be recorded in the CRF. 
(2) 
Concomitant therapies 
The name, duration, and reason for therapies used to treat RA or AEs from the start of 
administration of the study drug to the end of study (day of follow-up) shall be collected. 
Procedures related to surgery (such as change in gauze) and therapies (rehabilitation therapy, 
etc.) are excluded. 
5.1.3.1 Previous Medication (Drugs and Therapies) 
The following stipulations will apply to previous treatment used before the start of 
administration of the study drug.  
(1) 
Administration or use of the following drugs and therapies will be prohibited from the 
end of the assessments at Week 12 of study RAJ1 to the initiation of administration of 
the study drug in this extension study or from the end of the assessments at Week 52 of 
studies RAJ3 or RAJ4 to the initiation of administration of the study drug in this 
extension study.  
1) 
Biologic DMARDs: etanercept, anakinra, adalimumab, golimumab, infliximab, 
tocilizumab, abatacept, rituximab, certolizumab pegol, denosumab, sarilumab. 
2) 
Non-biologic DMARDs:  
⚫ Subjects who transferred from study RAJ1: MTX, salazosulfapyridine, gold, D-
penicillamine, leflunomide, lobenzarit, actarit, tacrolimus, mizoribine, bucillamine, 
iguratimod, tofacitinib, baricitinib. 
⚫ Subjects who transferred from study RAJ3: non-biologic DMARDs other than 
those concomitantly used in study RAJ3. 
⚫ Subjects who transferred from study RAJ4: salazosulfapyridine, gold, D-
penicillamine, leflunomide, lobenzarit, actarit, tacrolimus, mizoribine, bucillamine, 
iguratimod, tofacitinib, baricitinib. 
 (However, topical drugs other than those for the treatment of RA may be used 
concomitantly.)  


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3) 
Other drugs used in the treatment of RA: cyclosporine, cyclophosphamide, 
azathioprine, minocycline, etc.  
4) 
Live or live attenuated virus vaccines  
5) 
Plasma exchange therapy  
(2) 
The following CYP3A substrates with narrow therapeutic range within 14 days prior to 
first dose of study drug:  
Dihydroergotamine, ergotamine, fentanyl, pimozide, quinidine, temsirolimus, 
disopyramide, etc.  
[Rationale for prohibitions on previous medications (drugs and therapies)] 
The aforementioned prohibitions on previous medications (drugs, therapies) were established 
taking into account the possibility that use of the previous medication immediately prior to 
administration of the study drug could affect the evaluation of the study drug, as well safety 
of the subjects.  
5.1.3.2 Concomitant Medication (Drugs and Therapies) 
(1) 
The following concomitant medications and complimentary alternative treatments are 
prohibited as described. 
Concomitant use of the following drugs and therapies is prohibited during the treatment 
period:  
1) 
Biologic DMARDs: etanercept, anakinra, adalimumab, golimumab, infliximab, 
tocilizumab, abatacept, rituximab, certolizumab pegol, denosumab, sarilumab. 
2) 
Non-biologic DMARDs:  
⚫ Subjects who transferred from study RAJ1: MTX, salazosulfapyridine, gold, D-
penicillamine, leflunomide, lobenzarit, actarit, tacrolimus, mizoribine, bucillamine, 
iguratimod, tofacitinib, baricitinib. 
⚫ Subjects who transferred from study RAJ3: non-biologic DMARDs other than 
those used concomitantly in study RAJ3. 
⚫ Subjects who transferred from study RAJ4: salazosulfapyridine, gold, D-
penicillamine, leflunomide, lobenzarit, actarit, tacrolimus, mizoribine, bucillamine, 
iguratimod, tofacitinib, baricitinib. 
 (However, topical drugs other than those for the treatment of RA may be used.)  
3) 
Other drugs used in the treatment of RA: cyclosporine, cyclophosphamide, 
azathioprine, minocycline, etc.  
4) 
Oral corticosteroids at doses that exceed the amount used from the initiation of 
studies RAJ1, RAJ3, or RAJ4 to the initiation of administration of the study drug 
in this extension study at a daily dose of  prednisolone equivalent  


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5) 
Intra-articular, intravenous, intramuscular, or endorectal corticosteroids 
(However, suppositories for anal diseases may be used concomitantly.)  
6) 
Oral morphine at doses exceeding 30 mg/day (or the equivalent amount of opioid 
analgesics). 
7) 
Intra-articular administration of articular cartilage protective agents into joints 
subject to the assessment. 
8) 
Drainage of fluid accumulated in the joint subject to the assessment, local 
anesthesia into joints subject to the assessment, and nerve block. 
9) 
Plasma exchange therapy. 
10) The surgical treatment of joints subject to the assessment. 
 
The following drugs and therapies are also prohibited during the treatment period and follow-
up period:  
11) CYP3A substrates with narrow therapeutic range: dihydroergotamine, ergotamine, 
fentanyl, pimozide, quinidine, temsirolimus, disopyramide, etc.  
12)  Live or live attenuated virus vaccines  
13)  Other study drugs, study drugs from post-marketing clinical studies, or medical 
devices being studied in clinical studies 
[Rationale for prohibitions on concomitant drugs and therapies] 
The prohibitions were established because there is a possibility that concomitant use of the 
aforementioned drugs and therapies might affect the evaluation of efficacy and safety of the 
study drug.  
 
(2) 
Limited concomitant medications 
<Subjects who transferred from studies RAJ1, RAJ3, or RAJ4> 
During the treatment period, the following medications may be used concomitantly at the 
discretion of the investigator or sub-investigator if they meet the following conditions for 
concomitant use (Both new administration and change in dosage/administration are 
permitted). 
1) 
Non-steroidal anti-inflammatory drugs (NSAIDs) (excluding topical drugs with a 
local action) 
2) 
Oral morphine ( 30 mg/day, or the equivalent amount of opioid analgesics)  
3) 
Acetaminophen 
- Conditions for concomitant use - 


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● 
No changes in the dosage/administration of the drug are allowed within the period 
of 12 weeks. However, this shall exclude cases where the medication has caused an 
AE. Moreover, if, after discontinuation of the concomitant medication, it becomes 
apparent that the suspected medication was not the offending drug that caused the 
AE, administration may be resumed with the dose prior to discontinuation as the 
maximum dose. 
[Rationale for establishing limitations on the aforementioned drugs] 
Limitations were imposed upon use of these drugs because they act to improve QOL for RA 
patients within a short period of time and frequent changes in dosage/administration could 
greatly influence the efficacy evaluation for this study drug, and a prohibition has been 
placed upon changing the dosage/administration for the same limited medication within a 
period of 12 weeks. 
 
<Subjects who transferred from study RAJ3> 
Subjects who have been receiving any of the below drugs throughout the treatment period of 
study RAJ3 shall continue the use of the drug concerned from the end of the assessment at 
Week 52 of study RAJ3 to the initiation of administration of the study drug in this extension 
study, as well as throughout the treatment period of this study. 
It is permitted to discontinue the drug or to increase or decrease the dose within the range not 
exceeding or falling below the baseline dose in study RAJ3. 
Administration of the drug may be interrupted, or the dose may be reduced because of an AE. 
This interruption must not exceed a maximum of 28 days. Administration may be resumed 
with the baseline dose in study RAJ3 as the maximum dose. 
● 
If MTX is administered with study drug concurrently, the concomitant use of folic acid 
should be considered whenever possible. The dose of folic acid during the study period 
will, in principle, be within 10 mg per week, but it may be adjusted. If MTX is 
administered and ALT/AST becomes ≥ 3 × ULN, MTX must be interrupted, or the dose 
must be reduced, and daily administration of folic acid should be considered. 
 
● 
Methotrexate (MTX) 
● 
Hydroxychloroquine 
● 
Salazosulfapyridine 
● 
Gold 
● 
D-penicillamine 
● 
Lobenzarit 
● 
Actarit 
● 
Bucillamine 
● 
Iguratimod 
(3) 
Necessary concomitant medication  


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<Concomitant use of MTX is specified only for subjects who transferred from study RAJ4> 
● 
MTX must be used from the end of the assessments at Week 52 of study RAJ4 to the 
initiation of administration of the study drug in this extension study, as well as 
throughout the treatment period of this extension study. 
● 
It is permitted to discontinue MTX or increase or decrease the dose within the range not 
exceeding or falling below the baseline dose in study RAJ4. 
● 
Administration of MTX may be interrupted, or the dose may be reduced because of an 
AE. This interruption must not exceed a maximum of 28 days. Administration may be 
resumed with the baseline dose in study RAJ4 as the maximum dose. 
● 
Folic acid should be concomitantly administered whenever possible. The dosage of folic 
acid during the study period is not more than 10 mg/week in principle; dose adjustment 
is permitted. 
● 
If ALT/AST is ≥ 3 × ULN, MTX should be interrupted or reduced, and daily 
administration of folic acid should be considered. 
(4) 
Rescue medications 
During the treatment period, the below medications can be used only when needed to treat 
AEs, complications, or worsening of the primary disease. However, these medications may 
not be taken within 24 hours prior to the joint assessment at each study visit. 
1) 
NSAIDs: Single use as needed, for a period of 3 days or less  
2) 
Analgesics other than NSAIDs (acetaminophen, opioid analgesics, all-in-one cold 
and flu medications, etc.): For 7 consecutive days or less 
3) 
Intra-articular administration of corticosteroids, intra-articular administration of 
articular cartilage protective agents, drainage of fluid accumulated in joint, local 
anesthesia of joint, and nerve block: Performed once every 24 weeks (on up to 2 
joints), starting at or after the Week 12 study visit. 
However, joints on which intra-articular drug administration or rescue procedure 
has been performed will be assessed as showing disease activity (pain 
[tenderness]/swelling) after administration of the medication/therapy.  
5.1.4 
Treatment Compliance 
The investigator, sub-investigator, or study drug storage manager will provide the subjects 
with an explanation of how to take the study drug, paying particular attention to the 
following points when they hand the study drug to each subject.  
1. Do not take multiple doses all at once if doses of the study drug have been missed.  
2. Bring any remaining study drug with you to the next scheduled examination.  
3. If you do not have sufficient study drug until the next visit, for example, because it has 
been misplaced, inform the investigator, sub-investigator, or collaborator without delay. 
The investigator/sub-investigator will confirm each subject’s compliance status during the 
period of treatment with the study drug on the basis of the information given by the subject 
and the number of tablets of the study drug collected from the subject and record the 


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compliance status in the CRF. If there is judged to be a problem with the rate of compliance, 
patient compliance guidance should be provided to the subject again to improve the rate of 
compliance after investigating the reasons for the problem.  
In addition, the subject should be contacted twice every 4 weeks between the previous visit to 
the next scheduled visit to confirm the status of compliance with study drug administration 
and the safety of the subject (subjects who transferred from study RAJ1 are to be contacted 
from the Week 48 visit onward). 
5.1.5 
Emergency Procedures and Management of Overdose 
If any symptoms have developed as a result of an overdose of ASP015K, the 
investigator/sub-investigator will provide emergency treatment appropriate for each symptom 
to ensure the safety of the subject.  
Experience with the administration of ASP015K to humans remains limited, and overdose of 
ASP015K has not been reported. However, based on the data on AEs reported from previous 
studies, the first signs of overdose of ASP015K may be nausea, diarrhea, other GI symptoms, 
CPK increased, lymphocyte count decreased, or neutropenia.  
 
5.1.6 
Compliance Rules to be Observed by Subjects throughout the Study 
The investigator, sub-investigator, or collaborator will explain the following to the subjects 
during the study period.  
● 
The subject should come to the study center on the day of each study visit without taking 
that day’s dose of the study drug prior to the visit. The subject must also fast for at least 
8 hours prior to the blood sampling at the time of the study visit. If need arises for the 
subject to visit the study center on an unscheduled day after taking that day’s dose, for 
reasons such as AE, the subject should visit the study center regardless of whether and 
when the study drug and meal have been taken. 
● 
If a new treatment (starting to take a new drug or use a new therapy, etc.) has been 
prescribed by another department or another medical institution during the study period, 
the subject should contact the investigator/sub-investigator before starting to use the new 
treatment, and follow the instructions given by the investigator/sub-investigator. If it is 
not possible to contact the investigator or sub-investigator in advance, the subject should 
contact one of them, or the collaborator, as soon as possible.  
● 
Any subject who wishes to take a prescription medicine or over-the-counter drug 
unconfirmed by the investigator/sub-investigator should consult with the 
investigator/sub-investigator or collaborator in advance.  
● 
Because the effects that the study drug may have upon pregnancy and the unborn child 
remain unclear, subjects should be certain to practice 2 or more methods of proper 
contraception that shall be used by male subjects throughout the study period and for 90 
days after end of treatment, and by female subjects throughout the study period and for 
60 days after end of treatment.  


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● 
Female subjects must not nurse during the study period and for 60 days after the end of 
treatment. 
● 
In principle, the subject will come to the study center for the study visits on the specified 
dates. If it is not possible to come on the specified date, the date of the visit will be 
adjusted to the nearest possible date.  
● 
The subject should visit the study center without delay when instructed by the 
investigator or sub-investigator to do so because, for example, the laboratory testing has 
revealed CPK or liver function values to be in the range that requires CPK monitoring or 
liver function monitoring. 
 
5.2 
Demographics and Baseline Characteristics 
5.2.1 
Demographics 
The date of obtaining informed consent, date of birth, sex, and study region will be recorded 
in the eCRF (date of birth and study region will be entered only for subjects who transferred 
from studies RAJ3 or RAJ4). Sex and weight will be confirmed at Week 0 and recorded in 
the CRF.  
5.2.2 
Medical History 
Diseases that remain uncured at the time of the first dose of study drug will be regarded as 
concurrent diseases. All concurrent diseases will be investigated, and the name of the 
diagnosis and the time of onset will be recorded in the medical record or other source 
document, as well as in the CRF (for subjects who were transferred from studies RAJ3 or 
RAJ4, the onset date of concurrent diseases does not need to be recorded in the CRF). 
Moreover, AEs that have continued to be present since studies RAJ1, RAJ3, or RAJ4 will be 
recorded in the CRF.  
Previous diseases need not be recorded in the CRF.  
5.2.3 
Duration, Severity, Drug History, and Treatment Response of Target Disease 
The following items of information will be obtained at Week 0 and recorded in the CRF.  
● 
RA dysfunction classification (1991 revised criteria) (Appendix 4)  
● 
Duration of RA and classification of degree of progression (Appendix 5)  
 
5.3 
Efficacy and Pharmacodynamics Assessments 
5.3.1 
Efficacy Assessments 
5.3.1.1 Tender and Swollen Joint Counts 
(1) 
Tender joint count 


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At the time of each study visit (see Table 1, Schedule of Assessments), the investigator/sub-
investigator will examine the subject for tender joints, assessing the 68 joints listed below, 
and confirm the location of each tender joint.  
temporomandibular joint (2), sternoclavicular joints (2), acromioclavicular joint (2), shoulder 
joints (2)*, elbow joints (2)*, wrist joints (2)*, DIP joints (8), PIP joints of both hands (10)*, 
MCP joints (10)*, hip joints (2), knee joints (2)*, ankle joints (2), tarsal bones (2), MTP 
joints (10), interphalangeal joint joints of toes (2), PIP joints of both feet (8) 
*: Joints subject to DAS28 assessment 
(2) 
Number of swollen joints 
At the time of each study visit (see Table 1, Schedule of Assessments), the investigator/sub-
investigator will examine the subject for swollen joints, assessing the 66 joints representing 
the aforementioned with the exception of the hip joints (2), and confirm the location of the 
swollen joints. 
5.3.1.2 Assessment of Pain and Overall Assessment of Disease Activity 
The following assessments will be performed at each study visit.  
(1) 
Subject’s assessment of pain: The subject assesses his own pain severity on a VAS of 
0-100 mm.  
(2) 
SGA: The subject assesses his own disease activity on a VAS of 0-100 mm.  
(3) 
PGA: The investigator/sub-investigator assesses the subject’s disease activity on a VAS 
of 0-100 mm.  
5.3.1.3 Acute Phase Reactants (CRP and ESR) 
CRP and ESR will be measured at each study visit. The measurement of CRP will be 
performed by the central laboratory, and the measurement of ESR will be performed by each 
study center. These results will be used to calculate DAS28 (see Section 5.3.1.5, DAS28), 
SDAI (see Section 5.3.1.6, SDAI), and ACR response criteria assessment (see Section 5.3.1.7, 
ACR Response Criteria Assessment). ESR will be performed at the end of 1 hour, and the 
dates and results of measurements will be recorded in the eCRF. 
5.3.1.4 EULAR Response Criteria 
EULAR Response Criteria categorize response to treatment as “No response,” “Moderate 
response,” or “Good response,” according to the definitions given in TTable 2 [van Gestel et 
al, 1996; van Gestel et al, 1998].  


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Table 2 
Definition of EULAR Response Criteria Assessment 
DAS28 after treatment 
DAS28 improvement (DAS28 before treatment - DAS28 after treatment) 
> 1.2 
> 0.6 and ≤ 1.2 
≤ 0.6 
≤3.2 
Good response 
Moderate response 
No response 
> 3.2 and ≤ 5.1 
Moderate response 
Moderate response 
No response 
> 5.1 
Moderate response 
No response 
No response 
5.3.1.5 DAS28 
The subject’s DAS28 will be calculated at each study visit (see Table 1, Schedule of 
Assessments), using data from the following assessments, together with the formula shown 
below [Prevoo et al, 1995; van der Heijde et al, 1990; Fransen et al, 2003; Mallya et al, 1982; 
Wolfe, 1997]. 
● 
TJC (28 joints) 
● 
SJC (28 joints) 
● 
CRP or ESR 
● 
SGA 
[When CRP is used] 
DAS28 = 0.56√(TJC) + 0.28√(SJC) + 0.36 ln (CRP + 1) + 0.014 × SGA + 0.96 
 
[When ESR is used] 
DAS28 = 0.56√(TJC) + 0.28√(SJC) + 0.70 ln ESR + 0.014 × SGA 
DAS28 score is assessed as below. 
High disease activity: DAS28 score exceeding 5.1 
Moderate disease activity: DAS28 score exceeding 3.2 to 5.1  
Low disease activity: DAS28 score of less than or equal to 3.2 
If the DAS28 score is less than 2.6, the subject will be considered to be in DAS28 remission 
[van Gestel et al, 1998; Fransen and van Riel, 2005].  
5.3.1.6 SDAI Score 
The SDAI score at each study visit will be calculated using data from the following 
assessments, together with the formula shown below [Smolen et al, 2003; Aletaha and 
Smolen, 2005; Felson et al, 2011].  
● 
TJC (28 joints) 
● 
SJC (28 joints) 
● 
SGA 
● 
PGA 
● 
CRP (mg/dL) 
SDAI = TJC + SJC + SGA + PGA + CRP 
The SDAI score is assessed as below. 
• 
High disease activity: SDAI score exceeding 26 
• 
Moderate disease activity: SDAI score exceeding 11 and not greater than 26  


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• 
Low disease activity: SDAI score exceeding 3.3 and not greater than 11  
If the SDAI score is 3.3 or less, the subject will be considered to be in SDAI remission.  
5.3.1.7 ACR Response Criteria Assessment 
ACR Response Criteria [Felson et al, 1995] measure improvement in TJC, SJC, subject’s 
assessment of pain, SGA, PGA, assessment of physical function using the Disability Index of 
the HAQ-DI, and acute phase reactant (CRP or ESR). 
ACR20 response requires that all criteria (1) through (3) below be met. ACR50 response 
indicates a 50% improvement for all criteria (1) through (3) below, and ACR70 response 
similarly indicates a 70% improvement. For [5], assessment in this study is separately 
performed with regard to CRP and ESR.  
(1) 
TJC:  20% reduction compared to before administration of study drug  
(2) 
SJC:  20% reduction compared to before administration of the study drug  
(3) 
 20% improvement in 3 of the following 5 parameters, compared to before 
administration of study drug  
[1] Subject’s assessment of pain 
[2] SGA 
[3] PGA 
[4] Disability Index (HAQ-DI) 
[5] CRP or ESR 
5.3.1.8 Patient Reported Outcomes/Assessments 
Subjects will complete the following questionnaires according to Table 1, Schedule of 
Assessments. The answers written in the questionnaire will be recorded in the eCRF.  
● 
HAQ-DI [Fries et al, 1982; Ramey et al, 1992] 
● 
SF-36v2® [Ware, 2004] 
● 
WPAI [Takeuchi T, 2011; Reilly MC, 1993] (WPAI is only administered to subjects 
who transferred from studies RAJ3 or RAJ4) 
5.3.2 
Pharmacodynamics Assessments 
Blood samples will be collected on the assessment days after the baseline as specified in the 
Schedule of Assessments. The measurements will be performed by the central laboratory. 
See Table 1, Schedule of Assessments, for the testing schedule. Results of the assessments 
and tests at Week 52 or follow-up of studies RAJ3 or RAJ4 that are to be used as the baseline 
data of this extension study will be reported to the sponsor and the study center after 
unblinding of the studies RAJ3 or RAJ4. 
5.3.2.1 Lymphocyte Subsets 
Lymphocyte subsets CD3, CD4, CD8, CD16, CD19, CD56, and CD56/16 will be determined, 
and changes from baseline will be calculated. The day of blood sampling will be recorded in 
the eCRF. 


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5.4 
Safety Assessment 
The following tests and observations will be made for the purpose of safety assessment. With 
the exception of urine tests for pregnancy testing, measurement of laboratory test values will 
be performed by the central laboratory. See Table 1, Schedule of Assessments, for the testing 
schedule.  
Information on Liver Safety Monitoring and Assessment is given in Appendix 6. If an 
abnormality is found in the results of liver function tests, liver safety will be evaluated 
according to these procedures. 
5.4.1 
Vital Signs 
Vital signs (body temperature, pulse rate, and blood pressure in sitting position) will be 
collected at each study visit, as shown in Table 1, Schedule of Assessments. The dates and 
results of measurements of vital signs will be recorded in the source document as well as in 
the eCRF. 
5.4.2 
Body Weight 
Body weight will be measured according to Table 1, Schedule of Assessments. The dates and 
results of measurements will be recorded in the eCRF. 
5.4.3 
Adverse Events 
The investigator/sub-investigator will confirm all AEs occurring in the period from the start 
of study drug administration to the end of the final observation. AEs will be handled 
according to the stipulations of Section 5.5, Adverse Events and Other Safety Aspects. 
If an AE related to hepatic function abnormal is found, refer to the procedure in Appendix 6 
entitled “Liver Safety Monitoring and Assessment.”  
If herpes zoster is reported, it will be recorded in the eCRF as adverse event information; a 
Herpes Zoster (shingles) Worksheet will be separately prepared, a copy of which will be 
submitted to the sponsor. For other AEs too, when the sponsor considers necessary and 
requests to submit additional information using a specific form, such a form must be filled 
out and submitted to the sponsor. 
5.4.4 
Laboratory Assessments 
1) Hematology, biochemistry (including fasting lipid profile tests), urinalysis  
As shown in Table 1, Schedule of Assessments, the following hematology, biochemistry, 
fasting lipid profile tests, and urinalysis will be performed at each study visit. 
Measurements will be made by the central laboratory. Dates of blood sampling for lipid 
profile tests will be recorded in the eCRF. 
● 
Hematology 
Hemoglobin, hematocrit, erythrocytes (RBC), leukocytes (WBC), differential WBC 
(neutrophils, lymphocytes, monocytes, eosinophils, basophils), platelet count 


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● 
Biochemistry 
Na, K, Ca, Cl, Mg, HCO3, BUN, phosphorus, glucose, creatinine, ALP, AST (GOT), 
ALT (GPT), γ-GTP, TBL, total protein, albumin, uric acid, CPK, LDH, serum 
amylase, β-D-glucan, eGFR 
● 
Fasting lipid profile tests 
Total cholesterol, LDL, HDL, TGs 
(Blood specimens for these tests should be drawn after the subject has fasted for at 
least 8 hours.) 
● 
Urinalysis 
pH, specific gravity, protein, glucose, keton bodies, bilirubin, occult blood, sediment  
2) Pregnancy test (for females only) 
● 
Urine pregnancy testing will be performed at the study visits every 12 weeks from 
Week 0 onward, as well as at end of treatment/early termination and end of study (at 
time of follow-up). The tests scheduled for the end of study (follow-up) will be 
performed only if the investigator/ sub-investigator decides necessary. 
● 
Urinalysis will be performed at each study center, using the kits provided by the 
central laboratory.  
● 
If a urine pregnancy test is positive at any time, a negative serum pregnancy test 
(with measurements performed by the central laboratory) is required for the subject 
to continue participation in the study. The study may be continued if the possibility 
of pregnancy can clearly be ruled out by other tests. 
● 
The pregnancy tests need not be performed if the possibility of pregnancy can 
clearly be ruled out, such as if the woman is postmenopausal or has not had a 
menstrual period for 1 year or more, or has had a hysterectomy, bilateral 
oophorectomy, etc.  
● 
Tests for pregnancy are not included in safety assessment. 
3) Hepatitis tests 
● 
A subject who has tested positive for either or both HBc and HBs antibodies at 
screening for studies RAJ3 or RAJ4 will be monitored by performing HBV-DNA 
assay at specified visits during the treatment period.  
Results of HBV-DNA assay after the baseline will not be included in safety analysis. 
4) CPK monitoring 
● 
At time of CPK elevation, CPK, CK-MB, troponin T levels, and aldolase levels will 
be measured according to Section 5.4.4.1, CPK Monitoring. As part of the physical 
examination, urinalysis (blood and microscopy) will be performed. 


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5.4.4.1 CPK Monitoring 
If a CPK elevation is observed after administration of the study drug begins, CPK will be 
monitored as follows.  
● 
If CPK is > 3 × ULN after the start of study drug administration and the subject is 
asymptomatic, retest CPK to confirm the CPK value, preferably within approximately 1 
week from the previous blood sampling. In addition, retest CPK weekly, starting from 
the date of the initial CPK elevation to > 3 × ULN, until CPK is ≤ 3 × ULN or until the 
investigator or sub-investigator considers CPK to have achieved a steady state. If the 
retest cannot be performed within 1 week from the collection time of the blood sample 
with the CPK value because of which the monitoring was initiated, suspension or 
interruption of the study drug should be considered until results of the retest are known. 
● 
If CPK is > 3 × ULN already at baseline and is elevated to > 2 × baseline after the start 
of study drug administration and the subject is asymptomatic, retest CPK to confirm the 
value, preferably within approximately 1 week from the previous blood sampling. In 
addition, retest CPK weekly, starting from the date of the initial CPK elevation to > 2 × 
baseline value, until CPK is ≤ 2 × baseline or until the investigator or sub-investigator 
considers CPK to have achieved a steady state. If the retest cannot be performed within 1 
week from the collection time of the blood sample with the CPK value because of which 
the monitoring was initiated, suspension or interruption of the study drug should be 
considered until the results of the retest are known. 
● 
If CPK > 10 × ULN is confirmed after the start of study drug administration, suspend or 
interrupt the administration of the study drug immediately and retest CPK (see Section 
3.4.1, Suspension, Interruption, and Resumption of the Study Drug). 
● 
If a symptomatic CPK elevation (CPK elevation > 1.5 × ULN, accompanied by unusual 
severe myalgia, muscular weakness, and muscle twitching) is reported by the 
investigator or sub-investigator, the study will be discontinued (see Section 3.4, 
Discontinuation Criteria for Individual Subjects). 
At the time of CPK monitoring, the following parameters will also be measured. The answers 
given in the subject questionnaire will be recorded in the eCRF.  
➢ Laboratory tests 
(Parameters to be measured: CK-MB, troponin-T, aldolase) 
➢ A targeted physical examination* and subject questionnaire to assess muscle strength 
and tenderness 
*: As part of the targeted physical examination, urinalysis (blood and microscopy) will 
be performed.  
5.4.4.2 Liver Safety Monitoring and Assessment  
If laboratory testing for a subject enrolled in a study and receiving the study drug reveals > 3 
× ULN elevation in serum aminotransferases (ALT, AST) or TBL elevation to > 2 × ULN, 
the liver function test must be repeated including at least the 4 parameters ALT, AST, ALP, 


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and TBL. The retest is to be performed between 48 hours and 72 hours after notification of 
the test results.  
See Appendix 6 “Liver Safety Monitoring and Assessment” for the assessment of additional 
information and liver function values in the monitoring. 
If a subject enrolled in a study and receiving the study drug reveals > 3 × ULN elevation in 
serum aminotransferases (ALT, AST) concurrently with bilirubin > 2 × ULN, the 
investigator will decide whether the event is SAE. Even if the abnormal change is not 
considered by the investigator or sub-investigator to be SAE, it has to be reported to the 
sponsor or CRO as in the case of SAE. 
5.4.5 
Physical Examination 
A physical examination will be performed at each study visit and during unscheduled visits, 
if necessary, to confirm physical findings, in accordance with Table 1, Schedule of 
Assessments.  
A symptom directed physical exam for RA will be performed at all study visits.  
5.4.6 
12-lead Electrocardiogram (ECG) 
A 12-lead ECG will be obtained at the study visits every 48 weeks from Week 0 onward 
according to Table 1, Schedule of Assessments, as well as at end of treatment/early 
termination. The investigator or sub-investigator will confirm the ECG chart, assess the 
results as “normal,” “abnormal but not to a clinically significant degree,” and “clinically 
significant abnormality” and record the results of the assessment in the CRF. If the finding is 
“abnormal but not to a clinically significant degree” or “clinically significant abnormality,” 
the finding will be recorded in the CRF.  
In addition, the clinical interpretation of the 12-lead ECG performed at Week 0 must be 
completed before the first dose of the study drug.  
5.4.7 
Radiography 
Chest radiography will be obtained at the study visits every 48 weeks from Week 0 onward 
according to Table 1, Schedule of Assessments, as well as at end of treatment/early 
termination. However, chest radiography at end of treatment/early termination need not be 
performed if data obtained within 24 weeks prior to the end of treatment/early termination 
are available. The investigator or sub-investigator will read the chest radiographs, assess the 
result as “normal,” “abnormal but not to a clinically significant degree,” or “clinically 
significant abnormality” and record the results of the assessment in the CRF. If the finding is 
“abnormal but not to a clinically significant degree” or “clinically significant abnormality,” 
the finding will be recorded in the CRF. 
 


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5.5 
Adverse Events and Other Safety Aspects 
5.5.1 
Definition of Adverse Events (AEs) 
An AE is defined as any untoward medical occurrence in a subject administered a study drug 
that does not necessarily have a causal relationship to this treatment. An AE can therefore be 
any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, 
or disease temporally associated with the use of a study drug, whether or not related to the 
study drug.  
All AEs newly observed in the period from the first dose of study drug to end of study (at 
time of follow-up) or spontaneously reported AEs will be recorded in the medical record or 
other source document, as well as in the CRF. If a concurrent disease has clearly worsened to 
an extent that exceeds the usual course after the first dose of the study drug, it will be 
mentioned among the AEs as a worsening of a concurrent disease. If an AE recurs after 
having temporarily disappeared, it will be handled as a new AE.  
An abnormality identified during a medical test (e.g., laboratory parameter, vital sign, ECG 
data, physical examination) should be defined as an AE only if the abnormality meets one of 
the following criteria:  
● 
Induces clinical signs or symptoms 
● 
Requires active intervention 
● 
Requires suspension, interruption, or discontinuation of study medication  
● 
The abnormality or laboratory test value is clinically significant based on the opinion of 
the investigator or other responsible personnel  
The particulars to be noted with respect to the AE are the name of the event, date of onset, 
date of disappearance, severity (at peak time), seriousness, treatment of the study drug, other 
treatment, outcome, causal relationship to the study drug, and rationale for the assessment of 
causal relationship. Recording the rationale for the assessment of causal relationship for all 
AEs is not required; this should be handled at the sponsor’s request. The severity of each 
event should be recorded on a scale of Grade 1 to Grade 5 in the CRF, and the causal 
relationship to the study drug should be recorded as “Probably,” “Possible,” or “Not related” 
(see Section 5.5.3, Criteria for Causal Relationship to the Study Drug, and Section 5.5.4, 
Criteria for Defining the Severity of an Adverse Event). The treatment of the AE (whether it 
was treated with pharmacotherapy or by other means) and the treatment of the study drug 
should be recorded in the medical record or other source document, as well as in the CRF. 
The outcome should be recorded in the medical record or other source document, as well as 
the CRF, as “resolved,” “alleviated,” “unresolved,” “resolved but with late effect,” “death,” 
or “unknown.”  
5.5.2 
Definition of Serious Adverse Events (SAEs) 
An AE is considered “serious” if, in the view of either the investigator or sponsor, it results in 
any of the following outcomes: 
● 
Results in death. 


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● 
Is life threatening (an AE is considered “life-threatening” if, in the view of either the 
investigator or sponsor, its occurrence places the subject at immediate risk of death. It 
does not include an AE that, had it occurred in a more severe form, might have caused 
death).  
● 
Results in persistent or significant disability/incapacity.  
● 
Results in congenital anomaly or birth defect.  
● 
Requires inpatient hospitalization or leads to prolongation of hospitalization 
(Hospitalization for treatment/observation/examination caused by AE is considered to be 
serious).  
● 
Other medically important events 
Medical and scientific judgment should be exercised in deciding whether expedited reporting 
is appropriate in other situations, such as important medical events that may not be 
immediately life-threatening or result in death or hospitalization but may jeopardize the 
subject or may require intervention to prevent any of the other outcomes listed in the 
definition above. These events, including those that may result in disability/incapacity, 
should also usually be considered serious. Examples of such events are allergic 
bronchospasm requiring intensive treatment in an emergency room or at home; blood 
dyscrasias or convulsions that do not result in hospitalization; or development of drug 
dependency or drug abuse. 
In addition, all sponsor’s clinical studies have the requirement that all of the medical events 
described in Appendix 3 “Events Always Considered to be Serious” and Appendix 6 “Liver 
Safety Monitoring and Assessment” be reported by the investigator as SAEs even if they do 
not meet the aforementioned conditions.  
5.5.3 
Criteria for Causal Relationship to the Study Drug 
AEs that fall under either “Possible” or “Probable” should be defined as “AEs whose 
relationship to the study drugs could not be ruled out.” 
Causal Relationship 
to Study Drug 
Related Assessment Criteria 
Not related 
A clinical event, including laboratory test abnormality, with a temporal 
relationship to drug administration which makes a causal relationship 
improbable, and/or in which other drugs, chemicals or underlying disease 
provide plausible explanations. 
Possible 
A clinical event with a reasonable time sequence to administration of the 
drug, to which one of the following applies:  
• Could also be explained by concurrent/underlying disease or other drugs 
• Information on drug withdrawal is lacking or unclear  
Probable 
A clinical event with a reasonable time sequence to administration of the 
drug, to which one of the following applies:  
• Recurs upon re-administration of the drug, or disappears or is alleviated 
when the drug is withdrawn 
• Cannot be explained by concurrent/underlying disease or other drugs, or is 
unlikely to be attributable to them 
 


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5.5.4 
Criteria for Defining the Severity of an Adverse Event  
The AE grades will be based on NCI-CTCAE [Japan Clinical Oncology Group (JCOG), 
2011]. Items unspecified by these criteria will be assessed according to the following criteria 
and recorded.  
Grade 
Assessment Criteria 
Grade 1 (Mild) 
Mild; asymptomatic or mild symptoms, clinical or diagnostic 
observations only; intervention not indicated. 
Grade 2 (Moderate) 
Moderate; minimal; local or noninvasive intervention indicated; 
limiting age-appropriate instrumental ADL. 
Grade 3 (Severe) 
Severe or medically significant but not immediately life-threatening; 
hospitalization or prolongation of hospitalization indicated; disabling; 
limiting self-care ADL. 
Grade 4 (Life threatening or 
incapacitating) 
Life-threatening consequences; urgent intervention indicated. 
Grade 5 (Death) 
Death related to AE. 
5.5.5 
Reporting of Serious Adverse Events (SAEs)  
In the case of an SAE, the investigator/sub-investigator must report the SAE to the head of 
the study center and also contact the sponsor by telephone, e-mail, or fax immediately 
(within 24 hours of awareness) [in case of Japan: in addition to reporting to the head of the 
study center]. 
The investigator should complete and submit an SAE report containing all information that is 
required by the regulatory authorities to the sponsor or CRO [in case of Japan: and to the 
head of the study center] by e-mail or fax immediately (within 24 hours of awareness). If e-
mail transmission or faxing of an SAE report is not possible, or is not possible within 24 
hours, the sponsor or delegated CRO should be informed by phone.  
For contact details, see SECTION II, CONTACT DETAILS OF KEY SPONSOR’S 
PERSONNEL.  
Send the SAE report to the below FAX number. 
 
Contact Information for the Sponsor 
 
TEL: 
, FAX: 
 
 
Contact Information for the CRO 
Japan: 
 
TEL: 
 FAX: 
 
Korea: 


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TEL: 
, FAX: 
 
Taiwan: 
 
TEL: 
, FAX: 
 
 
5.5.6 
Follow-up to Adverse Events 
All AEs occurring during or after the subject has discontinued the study are to be followed up 
until resolved or judged to be no longer clinically significant, or until they become chronic to 
the extent that they can be fully characterized.  
If during AE follow-up, the AE progresses to an “SAE,” or if a subject experiences a new 
SAE, the investigator must immediately report the information to the sponsor/delegated CRO.  
Even if the subject does not return to normal or to his or her previous state, the follow-up can 
be considered finished when the following procedures have been taken.  
1. The investigator judges that the follow-up of the subject concerned is no longer 
necessary based on the progress made during the follow-up,  
2. The reason for such a judgment is entered as a comment in the CRF for the follow-up, 
and  
3. The sponsor judges that the reason is acceptable with regard to the safety of the subject 
concerned.  
 
Refer to Appendix 6 “Liver Safety Monitoring and Assessment” for the details of follow-up 
of DILI (medical history, concomitant medications, history of alcohol intake and narcotic 
use). 
5.5.7 
Procedure in Case of Pregnancy  
If a woman becomes pregnant or is proven to be pregnant during the study dosing period of 
within 28 days from end of treatment or early termination, the investigator should report the 
information to the sponsor or CRO in the same manner as for an SAE. The expected date of 
delivery, estimated fertility date, pregnancy result and neonatal data, etc., should be included 
in this information.  
The investigator or other responsible personnel will handle the pregnancy in the same manner 
as an SAE and will follow the medical status of the mother, as well as the fetus, and report 
the outcome to the sponsor.  
When the outcome of the pregnancy falls under the criteria for SAEs [spontaneous abortion, 
induced abortion, stillbirth, death of newborn, congenital anomaly (including anomaly in a 
miscarried fetus)] and when information on newborn falls under the criteria for SAEs 


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(including death, congenital anomaly, and other, the investigator should respond in 
accordance with the report procedure for SAEs.  
Additional information regarding the outcome of a pregnancy (which is categorized as an 
SAE) is mentioned below.  
● 
“Spontaneous abortion” includes abortion and missed abortion.  
● 
Death of a newborn within 1 month after birth should be reported as an SAE regardless 
of its relationship with the study drug  
● 
If a newborn dies more than 1 month after the birth, it should be reported if a relationship 
between the death and intrauterine exposure to the study drug is judged as “possible” by 
the investigator or other responsible personnel  
● 
In the case of a delivery of a living newborn, the “normality” of the newborn is evaluated 
at the birth.  
● 
“Normality” of a miscarried fetus is evaluated by visual examination unless test results 
that indicate a congenital anomaly are obtained prior to miscarriage.  
If a male subject impregnates his partner during the conduct of the clinical study, the subject 
should report the pregnancy to the investigator or other responsible personnel. The 
investigator must report the pregnancy to the sponsor or CRO.  
 
5.5.8 
Supply of New Information Affecting the Conduct of the Study  
In Japan: 
1. When information is obtained regarding serious and unexpected adverse drug reactions 
(or other) that are specified in Article 80-2 Paragraph 6 and Article 273 of the Law for 
Ensuring the Quality, Efficacy, and Safety of Drugs and Medical Devices (or adverse 
drug reactions during the post-marketing clinical study), the sponsor should inform all 
the investigators involved in the clinical study, the head of the study center, and the 
regulatory authorities of such information.  
Upon receiving such a report, the head of the study center will decide whether the 
clinical study should be continued after hearing the opinions of the IRB. The investigator 
will supply the new information to the subjects, in compliance with Section 8.2.3.2, 
Supply of New and Important Information Influencing the Subject’s Consent and 
Revision of the Written Information.  
2. In addition to 1 above, the head of the study center should submit any reports received 
from the sponsor or investigator to the IRB regarding revision of the investigator’s 
brochure (This is not applicable during a post-marketing clinical study) or the protocol, 
revision of the written information, particulars related to the quality, efficacy, or safety 
of the study drug, important information on properly conducting the study, or other 
revision of materials for discussion by the IRB.  
 
In Korea and Taiwan: 


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When the sponsor gains new information suggesting adverse impact on the subjects’ safety, 
safe conduct of the clinical study, or the IRB/IEC approval for study continuation, the 
sponsor will immediately notify all investigators, all study sites, and relevant regulatory 
authorities. 
The sponsor must immediately report SAEs to all participating principal investigators, study 
sites (and the IRBs/IECs if appropriate) in compliance with local requirements and the 
relevant regulatory authorities. 
When information necessary for conducting the clinical study properly (including “Dear 
Doctor Letters” but not limited to that) becomes available and leads to a protocol amendment, 
the sponsor should inform the regulatory authorities, as well as all investigators and medical 
institutions involved in the clinical study, who will then inform the IRB/IEC of such 
information, and when needed, should amend the Written Information. 
 
5.5.9 
Deviations from the Protocol and Other Actions Taken to Avoid Life-
Threatening Risks to Subjects  
The investigator or other responsible personnel must not deviate from or amend the protocol, 
without obtaining prior written agreement with the sponsor and prior written approval based 
on the review by the IRB/IEC.  
In Japan: 
However, when the investigator does not follow the protocol for medically inevitable reason 
and in order to avoid urgent risks for subjects, the investigator should take the following 
actions:  
1. Describe the content of the deviation or amendment and the reason for it in a written 
notice and immediately send the document stating the deviation or amendment and the 
reasons to the sponsor and the head of the study center. Keep a copy of the notice.  
2. Consult with the sponsor at the earliest possibility for cases in which it is necessary to 
amend the protocol in order to avoid risk to the subjects. Obtain approval for a draft of 
the amended protocol from the IRB and the head of the study center as well as written 
agreement with the sponsor. 
 
In Korea and Taiwan: 
When the investigator does not follow the protocol in order to avoid urgent risks for subjects, 
the investigator should report to sponsor, IRB/IEC, and regulatory authority (if applicable) in 
compliance with local requirements. 
 
5.6 
Test Drug Concentration 
Not applicable. 
 


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5.7 
Other Measurements, Assessments, or Methods 
5.7.1 
Pharmacodynamic Parameters 
For the assessment of pharmacodynamics, lymphocyte subset determination is performed in 
this study (Section 5.3.2, Pharmacodynamics Assessments).  
Blood samples for the lymphocyte subset determination are drawn using 2 mL vacutainer 
tube containing EDTA-2K in Japan, and 3 mL vacutainer tube containing EDTA-2K in 
Korea and Taiwan. For the procedures of collection, storage, and dispatch of blood samples, 
refer to the explanation of test procedures supplied with the test kit. 
 
5.8 
Total Amount of Blood 
The total amount of blood drawn for samples will differ from subject to subject in this study 
because duration of participation in the study will differ depending upon the subject.  
The volume of blood drawn per sample and the total annual sample volume are shown in the 
table below. In addition, blood samples are collected for ESR determination performed at 
each study center; the volume will differ from center to center (approximately 1 to 2 mL per 
sample). See Table 1, Schedule of Assessments, for details regarding the blood-sampling 
schedule.  
Blood samples will be taken at other times as necessary to follow up on laboratory test values 
obtained.  


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[Subjects who transferred from RAJ1] 
Assessment 
Volume of 
sample 
Total annual sample volume (No. of draws) 
First year 
2nd year and later 
Hematology 
2 mL 
28 mL (14 times) 
8 mL (4 times) 
Biochemistry 
(including CRP and lipid 
profile tests)  
14 mL 
196 mL (14 times) 
56 mL (4 times) 
Lymphocyte subsets 
2 mL 
4 mL (2 times) 
2 mL (1 time) 
Total 
18 mL 
228 mL 
66 mL 
[Subjects who transferred from RAJ3 or RAJ4] 
Assessment 
Volume of 
sample 
Total annual sample volume (No. of draws) 
First year 
2nd year and later 
Hematology 
Japan: 2 mL 
Korea: 3 mL 
Taiwan: 3 mL 
Japan: 10 mL 
(5 times) 
Korea: 15 mL 
(5 times) 
Taiwan: 15 mL 
(5 times) 
Japan: 8 mL (4 times) 
Korea: 12 mL 
(4 times) 
Taiwan: 12 mL 
(4 times) 
Biochemistry 
(including CRP and lipid 
profile tests)  
Japan: 14 mL 
Korea: 15.5 mL 
Taiwan: 13.5 
mL 
Japan: 70 mL 
(5 times) 
Korea: 77.5 mL 
(5 times) 
Taiwan: 67.5  mL 
(5 times) 
Japan: 56 mL 
(4 times) 
Korea: 62 mL 
(4 times) 
Taiwan: 54 mL 
(4 times) 
Lymphocyte subsets 
Japan: 2 mL 
Korea: 3 mL 
Taiwan: 3 mL  
Japan: 4 mL (2 times) 
Korea: 6 mL 
(2 times) 
Taiwan: 6 mL 
(2 times) 
Japan: 2 mL (1 time) 
Korea: 3 mL (1 time) 
Taiwan: 3 mL 
(1 time) 
Total 
Japan: 18 mL 
Korea: 21.5 mL 
Taiwan: 
19.5 mL 
Japan: 84 mL 
Korea: 98.5 mL 
Taiwan: 88.5 mL 
Japan: 66 mL 
Korea: 77 mL 
Taiwan: 69 mL 
* Additional 5 mL of blood per sample needs to be drawn in Japan and Taiwan, and 8.5 mL 
in Korea at the scheduled visits after initiation of study drug administration if HBV-DNA 
assay is performed. 
* Additional 4 mL of blood per sample needs to be drawn in Japan, and 5 mL in Korea and 
Taiwan if determination of CK-MB, troponin T, and aldolase is performed. 
 
6 
TERMINATION OF THE CLINICAL STUDY 
1. When the sponsor is aware of information on matters concerning the quality, efficacy, 
and safety of the study drugs, as well as other important information that may affect 
proper conduct of the clinical study, the sponsor may discontinue the clinical study and 
send a written notice of the discontinuation along with the reasons to the investigator 
[unique to Japan: and the head of the study center].  


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2. If the investigator wishes to discontinue the study in the particular study center while the 
study is still in progress, the investigator should contact the sponsor [unique to Japan: 
and the head of the study center] immediately to inform them of the discontinuation and 
the reason for it.  
 
7 
STATISTICAL METHODOLOGY 
A detailed elaboration of the statistical analysis will be included in a separate statistical 
analysis plan based on the opinions and advice from a medical expert. After review, it will be 
finalized prior to data lock. For the analyses of efficacy and pharmacodynamics variables in 
this extension study, values at the baseline in the previous studies (RAJ1, RAJ3, and RAJ4) 
will be used as the baseline values. However, changes from baseline values of this extension 
study will also be examined where appropriate. For the evaluation of safety, Week 0 of this 
extension study (015K-CL-RAJ2) will be referred to as the baseline; however, changes from 
baseline values of the previous studies (RAJ1, RAJ3, and RAJ4) will also be examined where 
appropriate. 
 
7.1 
Sample Size 
Approximately 800 treated patients 
[Rationale for the sample size] 
The sample size estimation is based on the number of subjects who have completed the 
preceding study of ASP015K (Study 015K-CL-RAJ1) and participate in this extension study 
(201 subjects), the planned number of subjects in Study 015K-CL-RAJ3 excluding those in 
the reference group (300 subjects), and the planned number of subjects in Study 015K-CL-
RAJ4 (510 subjects). 
 
7.2 
Analysis Set 
The study analyses will be performed on the following analysis sets. Final judgments on 
inclusion/exclusion of subjects from the analyses will be made following case reviews based 
on the opinions and advice from a medical expert. 
7.2.1 
Full Analysis Set (FAS) 
The FAS is defined as all subjects who receive at least one dose of study drug and have 
measurements for any of the efficacy endpoints. 
7.2.2 
Safety Analysis Set (SAF) 
The SAF is defined as all subjects who received at least one dose of the study drug. 


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7.2.3 
Pharmacodynamics Analysis Set (PDAS) 
The PDAS is defined as all subjects who receive at least one dose of the study drug and from 
whom a pharmacodynamics sample is collected at one or more points of time. 
 
7.3 
Demographics and Other Baseline Characteristics 
Demographics and other baseline characteristics will be summarized for the SAF. 
Descriptive statistics will include sample size, mean, standard deviation, minimum, median 
and maximum for continuous variables, and frequency and percentage for categorical 
variables. Unless otherwise specified, data will be tallied by each preceding study (RAJ1, 
RAJ3, and RAJ4) and for the entire population of RAJ2. When needed, analyses will take 
into consideration the treatment groups in the preceding studies as well as the regions (i.e. 
Japan, Korea, and Taiwan). 
 
7.4 
Analysis of Efficacy 
Efficacy analysis will be conducted on the FAS. The efficacy results will be summarized 
with sample size, mean, standard deviation, minimum, median and maximum by time point 
for continuous variables, and frequency and percentage for categorical variables. Subgroup 
analyses for sex and age categories may be explored. Unless otherwise specified, data will be 
tallied by each preceding study (RAJ1, RAJ3, and RAJ4) and for the entire population of 
RAJ2. When needed, analyses will take into consideration the treatment groups in the 
preceding studies as well as the regions (i.e. Japan, Korea, and Taiwan). 
 
7.5 
Analysis of Safety 
Unless otherwise specified, data will be tallied by each preceding study (RAJ1, RAJ3, and 
RAJ4). When needed, analyses will take into consideration the treatment groups in the 
preceding studies as well as the regions (i.e. Japan, Korea, and Taiwan). 
7.5.1 
Adverse Events 
AEs will be coded using the MedDRA. The incidence of AEs, SAEs, AEs leading to 
treatment discontinuation, and AEs whose relationship to the study drugs could not be ruled 
out will be summarized by system organ class and preferred term. The incidence of AEs by 
severity will also be summarized. All AEs will be listed. 
7.5.2 
Laboratory Measurements 
Descriptive statistics will be used to summarize clinical laboratory measurements and change 
from baseline if quantitative, by time point. Laboratory data will be displayed in listings. 


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7.5.3 
Vital Signs 
Descriptive statistics will be used to summarize vital sign measurements and change from 
baseline by time point. 
7.5.4 
12-lead ECG 
The frequency of each category of 12-lead ECG results will be summarized by time point. 
7.5.5 
Body Weight 
Descriptive statistics will be used to summarize the body weight measurements by time point. 
 
7.6 
Other Analyses 
Any other analyses, including disposition of subjects, exposure to study drug and etc., will be 
specified in a statistical analysis plan (SAP). 
7.6.1 
Analysis of Pharmacodynamics 
Analysis of pharmacodynamics will be conducted on the PDAS. Descriptive statistics will be 
used to summarize the pharmacodynamics measurements and change from baseline by time 
point. Unless otherwise specified, data will be tallied by each preceding study (RAJ1, RAJ3, 
and RAJ4) and for the entire population of RAJ2. When needed, analyses will take into 
consideration the treatment groups in the preceding studies as well as the regions (i.e. Japan, 
Korea, and Taiwan). 
 
7.7 
Interim Analysis (and Early Discontinuation of the Clinical Study) 
Not applicable. However, while the study is ongoing, safety data review and evaluation of 
safety will be performed according to the operating procedures developed separately by the 
Data and Safety Monitoring Board (DSMB; see Section 10.1). 
 
7.8 
Handling of Missing Data, Outliers, Visit Windows, and Other 
Information 
Final judgments on handling of missing data, outliers, visit windows, and other information 
will be made at the Case Review Meeting based on the opinions and advice from a medical 
expert prior to data lock and included in the SAP. 
The acceptable time ranges of the efficacy and safety examinations, observations, etc. from 
the date of initial study treatment (Day 1) are defined as follows. If there are multiple data 
available over the same period of time, the data obtained on the day closest to the reference 
date will be utilized; the later date will be applied if the number of days from the reference 
date is equal. Missing data at the end or discontinuation of treatment will be imputed using 
the LOCF method. 


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Since the study period of this study differs depending on the subject, the timing for the 
required visits to the study center will also differ from subject to subject. Only subjects who 
transferred from study RAJ1, but not those who transferred from studies RAJ3 or RAJ4, are 
required to come for visits at Week 2, Week 4, Week 8, Week 16, Week 20, Week 28, Week 
32, Week 40, and Week 44. Therefore, these time points defined in the analysis are set only 
for the subjects from study RAJ1. 
7.8.1 
Handling of Schedule of Assessments of Efficacy Variables 
For data obtained after the end of treatment, the data obtained within +2 days after the last 
dose will be included in analysis, except for the data at the end of the study (at time of 
follow-up). 
(1) 
RA disease activity (TJC, SJC, PGA, SGA, subject's assessment of pain), CRP, ESR 
Time points defined in analysis 
Reference date* 
Acceptable time range 
Week 0 
Day 1 
Day 1 
Week 2 
Day 15 
Day 12 to Day 18 
Week 4 
Day 29 
Day 22 to Day 36 
Week 8 
Day 57 
Day 50 to Day 64 
Week 12 
Day 85 
Day 78 to Day 92 
Week 16 
Day 113 
Day 106 to Day 120 
Week 20 
Day 141 
Day 134 to Day 148 
Week 24 
Day 169 
Day 162 to Day 176 
Week 28 
Day 197 
Day 190 to Day 204 
Week 32 
Day 225 
Day 218 to Day 232 
Week 36 
Day 253 
Day 246 to Day 260 
Week 40 
Day 281 
Day 274 to Day 288 
Week 44 
Day 309 
Day 302 to Day 316 
Week 48 
Day 337 
Day 330 to Day 344 
Week 60 
Day 421 
Day 407 to Day 435 
Week 72 
Day 505 
Day 491 to Day 519 
Week 84 
Day 589 
Day 575 to Day 603 
Week 96 
Day 673 
Day 659 to Day 687 
Week 108 
Day 757 
Day 743 to Day 771 
Week 120 
Day 841 
Day 827 to Day 855 
Week 132 
Day 925 
Day 911 to Day 939 
Week 132 + 12 × x 
Day 7 × (132 + 12 × x) + 
1 
Day 7 × (132 + 12 × x) − 13 to 
Day 7 × (132 + 12 × x) + 15 
End/discontinuation of treatment 
Day of the last dose 
Day 2 to 2 days after the last dose 
End of the study  
(at time of follow-up) 
28 days after the last 
dose 
21 to 35 days after the last dose 
*: Day 1 represents the first day of study treatment. 


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(2) 
Patient Questionnaires (HAQ-DI, FACIT-Fatigue) 
The schedule for FACIT-Fatigue applies only to subjects who transferred from study RAJ1. 
Time points defined in analysis 
Reference date* 
Acceptable time range 
Week 0 
Day 1 
Day 1 
Week 2 
Day 15 
Day 12 to Day 18 
Week 4 
Day 29 
Day 22 to Day 36 
Week 8 
Day 57 
Day 50 to Day 64 
Week 12 
Day 85 
Day 78 to Day 92 
Week 16 
Day 113 
Day 106 to Day 120 
Week 20 
Day 141 
Day 134 to Day 148 
Week 24 
Day 169 
Day 162 to Day 176 
Week 28 
Day 197 
Day 190 to Day 204 
Week 32 
Day 225 
Day 218 to Day 232 
Week 36 
Day 253 
Day 246 to Day 260 
Week 40 
Day 281 
Day 274 to Day 288 
Week 44 
Day 309 
Day 302 to Day 316 
Week 48 
Day 337 
Day 330 to Day 344 
Week 60 
Day 421 
Day 407 to Day 435 
Week 72 
Day 505 
Day 491 to Day 519 
Week 84 
Day 589 
Day 575 to Day 603 
Week 96 
Day 673 
Day 659 to Day 687 
Week 108 
Day 757 
Day 743 to Day 771 
Week 120 
Day 841 
Day 827 to Day 855 
Week 132 
Day 925 
Day 911 to Day 939 
Week 132 + 12 × x 
Day 7 × (132 + 12 × x) + 
1 
Day 7 × (132 + 12 × x) − 13 to 
Day 7 × (132 + 12 × x) + 15 
End/discontinuation of treatment 
Day of the last dose 
Day 2 to 2 days after the last dose 
End of the study  
(at time of follow-up)** 
28 days after the last 
dose 
21 to 35 days after the last dose 
*: Day 1 represents the first day of study treatment. 
**: The assessment at the end of the study (at the time of follow-up) will be scheduled only for HAQ-DI. 


Sponsor: Astellas Pharma Inc. 
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(3) 
Patient Questionnaires (SF-36v2®) 
Time points defined in analysis 
Reference date* 
Acceptable time range 
Week 0 
Day 1 
Day 1 
Week 4** 
Day 29 
Day 22 to Day 36 
Week 8** 
Day 57 
Day 50 to Day 64 
Week 12** 
Day 85 
Day 78 to Day 92 
Week 16** 
Day 113 
Day 106 to Day 120 
Week 20** 
Day 141 
Day 134 to Day 148 
Week 24 
Day 169 
Day 162 to Day 176 
Week 28** 
Day 197 
Day 190 to Day 204 
Week 32** 
Day 225 
Day 218 to Day 232 
Week 36** 
Day 253 
Day 246 to Day 260 
Week 40** 
Day 281 
Day 274 to Day 288 
Week 44** 
Day 309 
Day 302 to Day 316 
Week 48 
Day 337 
Day 330 to Day 344 
Week 60** 
Day 421 
Day 407 to Day 435 
Week 72 
Day 505 
Day 491 to Day 519 
Week 84** 
Day 589 
Day 575 to Day 603 
Week 96 
Day 673 
Day 659 to Day 687 
Week 108** 
Day 757 
Day 743 to Day 771 
Week 120 
Day 841 
Day 827 to Day 855 
Week 120 + 12 × x** 
Day 7 × (120 + 12 × x) + 
1 
Day 7 × (120 + 12 × x) − 13 to 
Day 7 × (120 + 12 × x) + 15 
End/discontinuation of treatment 
Day of the last dose 
Day 2 to 2 days after the last dose 
*: Day 1 represents the first day of study treatment. 
**: Scheduled only for subjects who transferred from study RAJ1. For subjects who transferred from 
studies RAJ3 or RAJ4, the survey is administered every 24 weeks after Week 120. Starting at the first 
visit after the revision of the study protocol, the survey will be administered to subjects who transferred 
from study RAJ1 also every 24 weeks. 
(4) 
Patient Questionnaires (WPAI [subjects from RAJ3 or RAJ4]) 
Scheduled only for subjects who transferred from studies RAJ3 or RAJ4. 
Time points defined in analysis 
Reference date* 
Acceptable time range 
Week 0 
Day 1 
Day 1 
Week 24 
Day 169 
Day 162 to Day 176 
Week 48 
Day 337 
Day 330 to Day 344 
Week 72 
Day 505 
Day 491 to Day 519 
Week 96 
Day 673 
Day 659 to Day 687 
Week 120 
Day 841 
Day 827 to Day 855 
Week 120 + 24 × x 
Day 7 × (120 + 24 × x) + 
1 
Day 7 × (120 + 24 × x) − 13 to 
Day 7 × (120 + 24 × x) + 15 
End/discontinuation of treatment 
Day of the last dose 
Day 2 to 2 days after the last dose 
*: Day 1 represents the first day of study treatment. 
 


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7.8.2 
Handling of Schedule of Assessments of Pharmacodynamics Variables 
For data obtained after the end of study treatment, the data obtained within +2 days after the 
last dose will be included in analysis, except for the data at the end of the study (at time of 
follow-up). 
(1) 
Lymphocyte subsets 
Time points defined in 
analysis 
Reference date* 
Acceptable time range 
Week 0 
Day 1 
Day 1 
Week 48 
Day 337 
Day 330 to Day 344 
Week 96 
Day 673 
Day 659 to Day 687 
Week 96 + 48 × x 
Day 7 × (96 + 48 × x) + 
1 
Day 7 × (96 + 48 × x) − 13 to Day 
7 × (96 + 48 × x) + 15 
End/discontinuation of treatment 
Day of the last dose 
Day 2 to 2 days after the last dose 
End of the study  
(at time of follow-up) 
28 days after the last 
dose 
21 to 35 days after the last dose 
*: Day 1 represents the first day of study treatment. 
7.8.3 
Handling of Schedule of Assessments of Safety Variables 
For data obtained after the end of study treatment, the data obtained within +2 days after the 
last dose will be included in analysis, except for the data at the end of the study (at time of 
follow-up). 


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(1) 
Vital Signs 
Time points defined in 
analysis 
Reference date* 
Acceptable time range 
Week 0 
Day 1 
Day 1 
Week 2 
Day 15 
Day 12 to Day 18 
Week 4 
Day 29 
Day 22 to Day 36 
Week 8 
Day 57 
Day 50 to Day 64 
Week 12 
Day 85 
Day 78 to Day 92 
Week 16 
Day 113 
Day 106 to Day 120 
Week 20 
Day 141 
Day 134 to Day 148 
Week 24 
Day 169 
Day 162 to Day 176 
Week 28 
Day 197 
Day 190 to Day 204 
Week 32 
Day 225 
Day 218 to Day 232 
Week 36 
Day 253 
Day 246 to Day 260 
Week 40 
Day 281 
Day 274 to Day 288 
Week 44 
Day 309 
Day 302 to Day 316 
Week 48 
Day 337 
Day 330 to Day 344 
Week 60 
Day 421 
Day 407 to Day 435 
Week 72 
Day 505 
Day 491 to Day 519 
Week 84 
Day 589 
Day 575 to Day 603 
Week 96 
Day 673 
Day 659 to Day 687 
Week 108 
Day 757 
Day 743 to Day 771 
Week 120 
Day 841 
Day 827 to Day 855 
Week 132 
Day 925 
Day 911 to Day 939 
Week 132 + 12 × x 
Day 7 × (132 + 12 × x) + 
1 
Day 7 × (132 + 12 × x) − 13 to 
Day 7 × (132 + 12 × x) + 15 
End/discontinuation of treatment 
Day of the last dose 
Day 2 to 2 days after the last dose 
End of the study  
(at time of follow-up) 
28 days after the last 
dose 
21 to 35 days after the last dose 
*: Day 1 represents the first day of study treatment. 


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(2) 
Laboratory Tests (Hematology, Biochemistry [including Fasting Lipid Profile Test], 
Urinalysis) 
Time points defined in analysis 
Reference date* 
Acceptable time range 
Week 0 
Day 1 
Day 1 
Week 2 
Day 15 
Day 12 to Day 18 
Week 4 
Day 29 
Day 22 to Day 36 
Week 8 
Day 57 
Day 50 to Day 64 
Week 12 
Day 85 
Day 78 to Day 92 
Week 16 
Day 113 
Day 106 to Day 120 
Week 20 
Day 141 
Day 134 to Day 148 
Week 24 
Day 169 
Day 162 to Day 176 
Week 28 
Day 197 
Day 190 to Day 204 
Week 32 
Day 225 
Day 218 to Day 232 
Week 36 
Day 253 
Day 246 to Day 260 
Week 40 
Day 281 
Day 274 to Day 288 
Week 44 
Day 309 
Day 302 to Day 316 
Week 48 
Day 337 
Day 330 to Day 344 
Week 60 
Day 421 
Day 407 to Day 435 
Week 72 
Day 505 
Day 491 to Day 519 
Week 84 
Day 589 
Day 575 to Day 603 
Week 96 
Day 673 
Day 659 to Day 687 
Week 108 
Day 757 
Day 743 to Day 771 
Week 120 
Day 841 
Day 827 to Day 855 
Week 132 
Day 925 
Day 911 to Day 939 
Week 132 + 12 × x 
Day 7 × (132 + 12 × x) + 
1 
Day 7 × (132 + 12 × x) − 13 to 
Day 7 × (132 + 12 × x) + 15 
End/discontinuation of treatment 
Day of the last dose 
Day 2 to 2 days after the last dose 
End of the study  
(at time of follow-up) 
28 days after the last 
dose 
21 to 35 days after the last dose 
*: Day 1 represents the first day of study treatment. 
(3) 
12-lead ECG, Chest Radiography 
Time points defined in analysis 
Reference date* 
Acceptable time range 
Week 0** 
Day 1 
Day 1 
Week 48 
Day 337 
Day 330 to Day 344 
Week 96 
Day 673 
Day 659 to Day 687 
Week 96 + 48 × x 
Day 7 × (96 + 48 × x) + 
1 
Day 7 × (96 + 48 × x) − 13 to Day 
7 × (96 + 48 × x) + 15 
End/discontinuation of 
treatment*** 
Day of the last dose 
Day 2 to 2 days after the last dose 
*: Day 1 represents the first day of study treatment. 
**: Regarding chest radiography, it is allowed to use data obtained within 28 days prior to the Week 0 
visit. 
***: Chest radiography at the end/discontinuation of treatment is unnecessary if one has been taken 
within 24 weeks from the day of discontinuation. 


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(4) 
Body weight 
Time points defined in analysis 
Reference date* 
Acceptable time range 
Week 0 
Day 1 
Day 1 
Week 2 
Day 15 
Day 12 to Day 18 
Week 4 
Day 29 
Day 22 to Day 36 
Week 8 
Day 57 
Day 50 to Day 64 
Week 12 
Day 85 
Day 78 to Day 92 
Week 24 
Day 169 
Day 162 to Day 176 
Week 36 
Day 253 
Day 246 to Day 260 
Week 48 
Day 337 
Day 330 to Day 344 
Week 60 
Day 421 
Day 407 to Day 435 
Week 72 
Day 505 
Day 491 to Day 519 
Week 84 
Day 589 
Day 575 to Day 603 
Week 96 
Day 673 
Day 659 to Day 687 
Week 108 
Day 757 
Day 743 to Day 771 
Week 120 
Day 841 
Day 827 to Day 855 
Week 132 
Day 925 
Day 911 to Day 939 
Week 132 + 12 × x 
Day 7 × (132 + 12 × x) + 
1 
Day 7 × (132 + 12 × x) − 13 to 
Day 7 × (132 + 12 × x) + 15 
End/discontinuation of treatment 
Day of the last dose 
Day 2 to 2 days after the last dose 
End of the study  
(at time of follow-up) 
28 days after the last 
dose 
21 to 35 days after the last dose 
*: Day 1 represents the first day of study treatment. 
 
8 
OPERATIONAL AND ADMINISTRATIVE CONSIDERATIONS 
8.1 
Procedure for Clinical Study Quality Control 
8.1.1 
Data Collection 
The investigator is responsible to ensure that all data in the eCRFs and queries are accurate 
and complete and that all entries are verifiable with source documents. These source 
documents should be appropriately maintained by the study center. 
The investigator, sub-investigator, or collaborator will enter data collected using an EDC 
system. The investigator, sub-investigator, and collaborator will enter the data within 5 
working days from the day of their occurrence (e.g., day of the subject’s visit, day of receipt 
of information) as a general rule. 
In case of an AE, the name of the AE is to be entered within 5 working days from the day on 
which the event was confirmed, and in case of concurrent medications/therapies, the name of 
the medication or therapy is to be entered within 5 working days from the day on which the 
concurrent use was started or became known. Other information to be entered into the eCRF 
is to be entered without delay as soon as they become known. 
The monitor should verify the data in the eCRFs with source documents and confirm that 
there are no inconsistencies between them. 


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For screening failures, the minimum demographic data (sex and informed consent date as 
well as study region and birth date of subjects who transferred from studies RAJ3 or RAJ4) 
and reason for screening failure will be collected from SFL. 
Laboratory tests and pharmacodynamics measurements are performed at a central laboratory. 
At predefined intervals during the study, the Data Science Department of the sponsor will 
obtain the laboratory test results and measurement results of pharmacodynamics parameters 
and records with verified quality from the central laboratory. 
8.1.2 
Specification of Source Documents 
Source data must be available at the study center to document the existence of the study 
subjects and substantiate the integrity of study data collected. Source data must include the 
original documents relating to the study as well as those relating to the medical treatment and 
medical history of the subject. 
The following information should be included in the source medical records: 
● 
Demographic data [birth date (subjects who transferred from studies RAJ3 or RAJ4), 
study region (subjects who transferred from studies RAJ3 or RAJ4), sex, height, and 
body weight] 
● 
Inclusion and exclusion criteria details 
● 
Participation in study and signed and dated informed consent forms 
● 
Visit dates 
● 
Medical history and physical examination details 
● 
Key efficacy and safety data 
● 
AEs and symptomatic treatment 
● 
Results of relevant examinations (e.g., ECG charts, X-ray films etc.) 
● 
Laboratory test slips/reports 
● 
Dispensing and return of study drug details 
● 
Reason for premature discontinuation 
● 
Records of RA diagnosis and evaluation, patient questionnaires (e.g., HAQ-DI, SF-
36v2®, FACIT-Fatigue, WPAI) 
● 
Patient questionnaire administered during CPK monitoring 
● 
Herpes Zoster (shingles) Worksheet 
If the following data are not included in medical records, the entries in the eCRFs are treated 
as source data. 
● 
Dates of AE occurrence and resolution, its severity, seriousness, outcome, causality to 
the study drug, and rationale for the causality 
● 
Route of administration, treatment dates, and reason for use for previous and 
concomitant drugs 
● 
Type, treatment dates, and reason for use for previous and concomitant therapies 
● 
Presence or absence of abnormal 12-lead ECG readings, abnormal findings 
● 
Date, reason, and background/details for discontinuation 
● 
Other comments 


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8.1.3 
Clinical Study Monitoring 
The sponsor or delegated CRO is responsible for monitoring the clinical study to ensure that 
subject's human rights, safety, and well-being are protected, that the study is properly 
conducted in adherence to the current protocol and GCP, and study data reported by the 
investigator/sub-investigator are accurate and complete and that they are verifiable with 
study-related records such as source documents. The sponsor is responsible for assigning 
study monitor(s) to this study for proper monitoring. They will monitor the study in 
accordance with planned monitoring procedures. 
8.1.4 
Direct Access to Source Data/Documents 
The investigator and the study center must accept monitoring and auditing by the sponsor or 
delegated CRO as well as inspections from the IRB/Independent Ethic Committee (IEC) and 
relevant regulatory authorities. In these instances, they must provide all study-related records, 
such as source documents (see Section 8.1.2, Specification of Source Documents) when they 
are requested by the sponsor monitors and auditors, the IRB/IEC, or regulatory authorities. 
The confidentiality of the subject's identities shall be well protected consistent with local and 
national laws/regulations when the source documents are subject to direct access. 
8.1.5 
Data Management 
Data management will be coordinated by the Data Science Department of the sponsor in 
accordance with the SOPs for data management. All study specific processes and definitions 
will be documented by Data Management. CRF retrieval and correction process will be 
referenced in the CRF instructions. Coding of medical terms will be performed using 
MedDRA. 
 
8.2 
Ethics and Protection of Subject Confidentiality 
8.2.1 
Institutional Review Board (IRB)/Independent Ethic Committee (IEC) 
Prior to a conclusion of study contracts for the present study, the protocol and documents 
used to obtain patient consent shall be reviewed and approved by the IRBs/IECs of each 
study center in order to ensure that subject's human rights, safety, and well-being are 
protected. 
8.2.2 
Ethical Conduct of the Study 
The investigator(s) and all parties involved in this study should conduct the study in 
adherence to GCP, ICH Guidelines, and the applicable laws/regulations. 
8.2.3 
Informed Consent of Subjects 
8.2.3.1 Subject Information and Consent 
Prior to execution of the clinical study, the investigator should prepare the written informed 
consent form and other written information in collaboration with the sponsor and revise the 
information whenever necessary. The written and revised informed consent form and any 


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other written information should be submitted to the sponsor and be subject to prior approval 
by the IRB/IEC. 
● 
The investigator or other responsible personnel is responsible for explaining the nature 
and purpose of the study as well as other study-related matters to subjects, using the 
written information, and for obtaining their full understanding and written consent to 
participate in the study of their own free will. 
● 
The investigator or other responsible personnel who provided explanations (including 
collaborators who gave supportive information, if applicable) and the subject should sign, 
[unique to Japan: seal,] and date the written information. 
● 
Informed consent must be obtained by the time that the first observations/examinations 
of the present study, before the initial administration, are performed. 
● 
The investigator or other responsible personnel must give a copy of the signed [unique to 
Japan: or sealed] consent form to the subject with the written information and store the 
original appropriately in accordance with the rules at the study center concerned. 
● 
The investigator or other responsible personnel should note the following when 
obtaining consent from subjects: 
➢ No subject may be subjected to undue influence, such as compulsory enrollment into 
a study. 
➢ The language and expressions used in the written information should be as plain and 
understandable as possible for subjects. Subjects should be given the opportunity to 
ask questions and receive satisfactory answers to the inquiry, and should have 
adequate time to decide whether or not to participate in the study. Written information 
should not contain any language or contents that causes the subject to waive or 
appears to waive any legal rights, or that releases/mitigates or appears to 
release/mitigate the study center, the investigator/sub-investigator, collaborators, or 
the sponsor from liability for negligence. 
The signed consent forms will be retained by the investigator and made available (for review 
only) to the study monitor and auditor upon request. 
8.2.3.2 Supply of New and Important Information Influencing the Subject’s Consent 
and Revision of the Written Information 
1. The investigator or other responsible personnel will immediately inform the subject 
orally whenever new information becomes available that may be relevant to the subject's 
consent or may influence the subject's willingness to continue participation in the study 
(e.g., report of serious adverse drug reactions). The communication should be 
documented in the subject's medical records, and it should be confirmed whether the 
subject is willing to remain in the study or not. 
2. If the investigator recognizes the necessity to revise the written information in the terms 
and conditions applicable to paragraph 1, the written information should be revised 
immediately based upon the newly available information, and be re-approved by the 
IRB/IEC. 


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3. The investigator or other responsible personnel should obtain written informed consent 
to continue participation in the study with the revised written information defined in 
paragraph 2, even if subjects are already informed of the relevant information orally. The 
investigator or other responsible personnel who provided explanations (including 
collaborators who gave supportive information, if applicable) and the subject should sign 
[unique to Japan: or seal] and date the informed consent form, or write down his/her 
name, place a personal seal, and date the form. The investigator or other responsible 
personnel should give a copy of the signed or sealed informed consent form to the 
subject who had given consent with the written information and store the original 
appropriately as done for the previous informed consent. 
8.2.4 
Subject Confidentiality 
Individual subject medical information obtained as a result of this study is considered 
confidential and disclosure to third parties is prohibited. Such medical information may be 
given only after approval of the subject to the subject's physician or to other appropriate 
medical personnel responsible for the subject's well-being. 
The sponsor, its board members or its employee shall not disclose any confidential 
information on subjects obtained during the performance of their duties in the clinical study 
without justifiable reasons. 
All individuals and organizations involved in the study must pay very careful attention to 
protect subjects’ privacy with appropriate measures, for example, by prohibiting the use of 
any private information that may identify a subject (e.g., name or address). These details 
shall be processed in accordance with the applicable laws such as Personal Information 
Protection Law and regulatory requirement(s).  
Even though any individuals involved in the study, including the study monitors and auditors, 
may get to know matters related to subject's privacy due to direct access to source documents, 
or from other sources, they may not leak the content to third parties. 
 
8.3 
Administrative Matters 
8.3.1 
Arrangement for Use of Information and Publication of the Clinical Study 
Information concerning the study drug, patent applications, processes, unpublished scientific 
data, the Investigator's Brochure and other pertinent information is confidential and remains 
the property of the sponsor. Details should be disclosed only to the persons involved in the 
approval or conduct of the study. The investigator or other responsible personnel may use 
this information for the purpose of the study only. It is understood by the investigator that the 
sponsor will use the information obtained during the clinical study in connection with the 
clinical development of the study drug and therefore may disclose it as required to other 
clinical investigators or to regulatory agencies. In order to allow for the use of the 
information derived from this clinical study, the investigator understands that he/she has an 
obligation to provide the sponsor with all data obtained during the study. 


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The study will be considered for publication or presentation at (scientific) symposia and 
congresses. The investigator or other responsible personnel will be entitled to publish or 
disclose the data generated at their respective study center only after having all transcripts, 
texts of presentations, and abstracts related to the study reviewed by sponsor at least 90 days 
prior to the intended submission for publication or any other disclosure. This is necessary to 
prevent proprietary information and/or knowledge protected by a patent from undue 
premature disclosure. In addition, this is in no way intended to restrict publication of facts or 
opinions formulated by the investigator or other responsible personnel. The sponsor will 
inform the investigator in writing of any objection or question arising within 30 days of 
receipt of the proposed publication material. After agreement between investigator or other 
responsible personnel and sponsor, the manuscript is free for publication. 
8.3.2 
Retaining Documents and Records Related to the Clinical Study 
The sponsor will provide the investigator or other responsible personnel and/or study center 
with the following: 
● 
Study protocol (and amendments, where applicable) 
● 
Investigator's Brochure (and amendments, where applicable) 
● 
eCRFs and other related documents, SAE report 
● 
Study drug with all necessary documentation 
● 
Study contract 
In order to start the study, the investigator and/or study center is required to provide the 
following documentation to the sponsor: 
● 
Signed Investigator's Statement in this protocol and eCRF 
● 
Current curricula vitae (CVs) of all investigators 
● 
List of sub-investigators and collaborators 
● 
IRB/IEC approval of the protocol, protocol supplement (if applicable) including a 
membership list with names and qualification (copy) 
● 
Instruction and decision of the head of the study center (if applicable) 
● 
Study contract and memorandum 
● 
Laboratory normal reference ranges (including modification and amendment) 
At the end of the study, the sponsor is responsible for the collection of: 
● 
Unused CRFs (laboratory test slips) and other study documentation, 
● 
Unused study drug (if applicable) 
The investigator will archive all study data (e.g., subject identification code list, source 
documents, CRFs (laboratory test slips), and investigator's file) and relevant correspondence. 
These documents are to be kept on file for the appropriate term determined by local 
regulation. The sponsor will archive and retain all documents pertaining to the study 
according to local regulations. 
The sponsor will notify the investigator or other responsible personnel if the NDA/ marketing 
authorization application (MAA)/NDA is approved or if the IND/IMPD/NDA is discontinued. 


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The investigator or other responsible personnel agrees to obtain the sponsor's agreement prior 
to disposal, moving, or transferring of any study-related records. The sponsor will archive 
and retain all documents pertaining to the study according to local regulations. 
Data generated by the methods described in the protocol will be recorded in the subjects' 
medical records and/or study progress notes. All data will be entered into CRFs supplied for 
each subject. 
In Japan: 
The records to be retained at the study centers are the ones listed as essential documents in 
GCP. These records shall be retained by the head of the study center or the record keeper 
designated by the head until notice issued by the sponsor on completion of the retention 
period is received. These documents are also subject to direct access and should be provided 
upon request from the sponsor or regulatory authorities. 
 
The following are the major documents to be retained at the study center. 
Source documents (clinical data, documents, and records for preparing the eCRF) 
1. Hospital records, medical records, test records, memoranda, or check lists for evaluation, 
administration records, data recorded by automatic measuring instruments, reproductions 
or transcripts verified as precise copies, microfiche, negative films, microfilms/magnetic 
media, X-ray films, subject files and study-related records kept at either a pharmacy, a 
laboratory, or medical technical office, as well as subject registration forms, laboratory 
test slips including central measurement, worksheets/forms specified by the sponsor [e.g., 
patient questionnaire administered during CPK monitoring, Herpes Zoster (shingles) 
Worksheet], records of clinical coordinators, and records related to the clinical study 
selected from those verified in other departments or hospitals. 
2. Contracts, written informed consent forms, written information, and other documents or 
their copies prepared by the study personnel. 
A letter of request for clinical study (including a request for continuation/amendment), 
letter of request for review, notice of clinical study contract, clinical study contract, 
notification of discontinuation or completion of clinical study, written information for 
informed consent (including revisions), signed and dated written informed consent 
(including revisions), CVs of investigators, list of sub-investigators, list of signatures and 
print of seals (copy), and electronic media storing the eCRF data, etc. 
3. The protocol, documents obtained from the IRB related to the adequacy of conducting 
the clinical study by the head of the study centers, documents obtained from the IRB 
related to the adequacy of conducting a clinical study whose period exceeds one year or 
the adequacy of continuously conducting the clinical study from which information on 
adverse drug reactions is obtained, and other documents obtained. 
An agreed-upon protocol (including revisions), Investigator's Brochure (including 
revisions), SAP for the investigator, materials and information supplied by the sponsor 
(e.g., AE report), matters reported by the investigator (revisions of the protocol, AE 


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reports, etc.), SOP for the IRB/IEC, the list of names of the IRB/IEC members, materials 
for IRB/IEC review (including continuous deliberation), IRB/IEC review records 
(including continuous deliberation), and the review result report of the IRB/IEC 
(including continuous deliberation), etc. 
4. Records of control for study drugs and other duties related to the clinical study 
Procedure for controlling the study drugs, drug inventory and accountability record, 
vouchers for the receipt and return of the study drugs, and other records of the 
prescriptions for concomitant medications 
5. The documents of the Independent DSMB (minutes, SOP and others) shall be retained 
by the sponsor. 
 
Unique to Korea and Taiwan: The investigator and the study center will retain the documents 
and records related to the clinical study in compliance with the applicable laws and 
regulations. The investigator and the study center should take measures to prevent loss or 
disposal of these records during the period when the records must be retained. 
 
8.3.3 
Protocol Amendment and/or Revision 
Any changes to the study that arise after approval of the protocol must be documented as 
protocol amendments and/or revisions. Depending on the nature of the amendment and/or 
revisions, either IRB/IEC (if applicable) approval or notification is required. The changes 
will become effective only after the approval of the sponsor, the investigator, and the 
IRB/IEC (if applicable) [unique to Japan: followed by the approval of the head of the study 
center]. 
8.3.4 
Insurance of Subjects and Others 
If a subject suffers any study-related injury, the sponsor will compensate appropriately 
according to the severity and duration of the damage. However, if it was caused intentionally 
or was due to gross negligence by the study center, the sponsor will consult with the study 
center about handling the injury, based on the agreed study contract. 
Compensation for study-related injury is provided by the following procedures: 
1. If a subject incurs an injury as a result of participation in the clinical study, the study 
center should provide medical treatment and other necessary measures. The 
sponsor/delegated CRO should be notified of the injury. 
2. When the subject claims compensation from the study center for the above study-related 
injury, or such compensation may be claimed, the study center should immediately 
communicate the fact to the sponsor/delegated CRO. Both parties should work together 
towards compensation settlement. 
3. The sponsor shall pay compensation or indemnification and bear expenses necessary for 
the settlement as provided in the clinical contract. 


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4. The sponsor shall make an arranging for insurance and take measures necessary to 
ensure the compensation or indemnification mentioned above. 
8.3.5 
Signatory Investigator for Clinical Study Report 
ICH E3 guidelines recommend and EU Directive 2001/83/EC requires that a final study 
report which forms part of a marketing authorization application be signed by a coordinating 
(principal) investigator. The coordinating investigator will have the responsibility to review 
the final study results to confirm to the best of his/her knowledge it accurately describes the 
conduct and results of the study. A coordinating investigator will be selected from the 
participating investigators by the sponsor prior to database lock. 
 
9 
QUALITY ASSURANCE 
The sponsor is implementing and maintaining quality assurance and quality control systems 
with written SOPs to ensure that studies are conducted and data are generated, documented 
(record), and reported in compliance with the protocol, GCP, and applicable regulatory 
requirement(s). 
The Sponsor or Sponsor's designee may arrange to inspect/audit the clinical study at any or 
all study centers. The auditor is independent from the clinical monitoring and project 
management team at the Sponsor. The audit may include on-site review of study-related 
documents/records, eCRFs, and source documents. Direct access to these documents will be 
required by the auditors. 
 
10 
STUDY ORGANIZATION 
10.1 
Independent Data and Safety Monitoring Board (DSMB) 
An independent DSMB will review safety data, make a decision from the safety perspective 
on whether to continue or stop the study or modify the protocol, and provide the sponsor with 
recommendations. The DSMB should follow the procedures separately defined in details, 
including the frequency of meetings and data review. 
 
10.2 
Other Evaluation Committee(s) 
Not applicable. 
 
10.3 
Other Study Organization 
See the Appendix. 
 


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10.4 
Registration of Subjects 
[Subjects who transferred from study RAJ1] 
The investigator or sub-investigators are responsible for conducting survey on demographics 
of the candidate subjects and obtaining their written consent. The investigator or sub-
investigators should confirm whether inclusion/exclusion criteria are met, and make 
necessary entries in the case registration form on the web-based registration system. The 
registration center will confirm the fulfillment of inclusion/exclusion criteria based on the 
case registration information received and inform the study centers of the case inclusion or 
exclusion via the web-based registration system. The investigator or sub-investigators will 
dispense the study drug to the subject who is considered “eligible” for the study registration. 
 
Flow Chart of Subject Registration (for subjects who transferred from study RAJ1): 
 
Investigator 
or 
sub-investigator 
 
Subject registration center 
 
Obtaining informed 
consent 
 
 
 
↓ 
 
Week 0: 
Confirm the eligibility 
 
↓ 
 
 
 
Enter subject 
information 
 
 
web 
 
 
 
 
Confirm inclusion/ 
exclusion of the subject 
Register the subject  
 
 
 
Verify the registration 
confirmation form 
Dispense the study 
drug 
 
 
 
web 
 
 
 
<Subject registration center> 
In Japan: 
URL:
 
Service available: Everyday (365 days, 24 hours) 
Help desk TEL: 
, FAX: 
 
(Monday to Friday: 9:00-18:00, except national holidays, and 29 December to 4 
January) 
 


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[Subjects who transferred from studies RAJ3 or RAJ4] 
The investigator or sub-investigators are responsible for conducting survey on demographics 
of the candidate subjects and obtaining their written consent. The investigator or sub-
investigator should confirm whether inclusion/exclusion criteria are met, and make necessary 
entries in the case registration form on the web-based registration system for the Week 52 
visit of the studies RAJ3 or RAJ4. After the registration is confirmed, the investigator or sub-
investigator will dispense the study drug to the subject who has completed tests and 
observations scheduled for Week 0. 


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11 
REFERENCES 
Aletaha D, Smolen J. The Simplified Disease Activity Index (SDAI) and the Clinical Disease Activity 
Index (CDAI): A review of their usefulness and validity in rheumatoid arthritis. Clin Exp 
Rheumatol 2005;23(Suppl. 39):S100-S108. 
American College of Rheumatology Subcommittee on Rheumatoid Arthritis Guidelines. Guidelines 
for the management of rheumatoid arthritis:2002 Update. Arthritis Rheum 2002;46(2):328-46. 
Felson DT, Anderson JJ, Boers M, Bobmardier C, Furst D, Goldsmith C, et al. American College of 
Rheumatology preliminary definition of improvement in rheumatoid arthritis. Arthritis Rheum 
1995; 38:727-735. 
Felson DT, Smolen JS, Wells G, Zhang B, Tuyl LHD van, Funovitis J, et al. American College of 
Rheumatology/European League Against Rheumatism Provisional Definition of Remission in 
Rheumatoid Arthritis for Clinical Trials. Arthritis Rheum 2011;63:573-586. 
Fransen J, Riel PLCM van. The Disease Activity Score and the EULAR response criteria. Clin Exp 
Rheumatol 2005;23(Suppl 39):S93-9. 
Fransen J, Welsing P, Keijzer Rd, Riel P van. Disease Activity Scores using C-reactive protein: CRP 
may replace ESR in the assessment of RA disease activity. Ann Rheum 2003;62:151. 
Fries JF, Spitz PW, Young DY. The dimensions of health outcomes: The health assessment 
questionnaire, disability and pain scales. J Rheumatol 1982;9:789-793. 
Hochberg MC, Chang RW, Dwosh I, Lindsey S, Pincus T, Wolfe F. The American College of 
Rheumatology 1991 Revised Criteria for the Classification of Global Functional Status in 
Rheumatoid Arthritis. Arthritis Rheum 1992;35:498-502. 
Kremer JM, Bloom BJ, Breedveld FC, Coombs JH, Fletcher MP, Gruben D, et al. The safety and 
efficacy of a JAK inhibitor in patients with active rheumatoid arthritis. Arthritis Rheum. 
2009;60:1895-1905. 
Mallya RK, de Beer FC, Berry H, Hamilton EDB, Mace BEW, Pepys MB. Correlation of clinical 
parameters of disease activity in rheumatoid arthritis with serum concentration of C-reactive 
protein and erythrocyte sedimentation rate. J Rheumatol 1982;9(2):224-8. 
O’Dell JR. Therapeutic strategies for rheumatoid arthritis. N Engl J Med. 2004;350:2591-602. 
O’Shea JJ. Targeting the Jak/STAT pathway for immunosuppression. Ann Rheum Dis. 2004; 
63(Suppl II):ii67-71. 
Papageorgiou AC, Wikman LEK. Is JAK3 a new drug target for immunomodulation-based therapies? 
Trends Pharmacol Sci. 2004;25(11):558-62. 
Prevoo MLL, Hof MA van’t, Kuper HH, Leeuwen MA van, Putte LBA van de, Riel PLCM van. 
Modified disease activity scores that include twenty-eight-joint counts. Arthritis Rheum 
1995;38:44-48. 
Ramey DR, Raynauld JP, Fries JF. The health assessment questionnaire 1992: status and review. 
Arthritis Care & Research 1992;5:119-129. 


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Reilly MC, Zbrozek AS, Dukes EM. The validity and reproducibility of a work productivity and 
activity impairment instrument. PharmacoEconomics 1993; 4(5):353-65. 
Saag KG, Teng GG, Patkar NM, Anuntiyo J, Finney C, Curtis JR, et al. American College of 
Rheumatology 2008 recommendations for the use of non-biologic and biologic disease-
modifying antirheumatic drugs in rheumatoid arthritis. Arthritis Rheum. 2008;59(6):762-84. 
Smolen JS, Breedveld FC, Schiff MH, Kalden JR, Emery P, Eberl G, et al. A simplified disease 
activity index for rheumatoid arthritis for use in clinical practice. Rheumatology 2003;42:244-
257. 
Steinbrocker O, Traeger CH, Batterman RC. Therapeutic criteria in rheumatoid arthritis. J Am Med 
Assoc. 1949;140(8):659-62. 
Van der Heijde DM, Hof MA van’t, Riel PL van, Theunisse LA, Lubberts EW, Leeuwen MA van, 
Rijswijk MH van, Putte LB van de. Judging disease activity in clinical practice in rheumatoid 
arthritis: first step in the development of a disease activity score. Ann Rheum Dis 1990;49:916-
920. 
Van Gestel AM, Prevoo MLL, Hoff MA van’t, Rijswijk MH van, Putte LBA van de, Riel PLCM van. 
Development and validation of the European League Against Rheumatism response criteria for 
rheumatoid arthritis. Arthritis Rheum 1996;39:34-40. 
Van Gestel AM, Haagsma, CJ, Riel PLCM vav. Validation of RA improvement criteria that include 
simplified joint counts. Arthritis Rheum 1998;41:1845-1850. 
Ware JE. SF-36 Health Survey update. The Use of Psychological Testing for Treatment Planning and 
Outcomes Assessment. 2004;3:693-718. 
Wolfe F. Comparative usefulness of C-reactive protein and erythrocyte sedimentation rate in patients 
with rheumatoid arthritis. J Rheumatol 1997;24:1477-85. 
Enbrel® Drug Interview Form (Revised June 2013 Ver. 21) 
Clinical Practice Manual for the Treatment of RA (Revised edition): Diagnostic manual and treatment 
guidelines based on EBM. 2004 
Simponi® Drug Interview Form (September 2013 Ver. 5) 
Xeljanz® Drug Interview Form (Revised July 2013 Ver. 3) 
Takeuchi T. [The significance of assessing the work productivity in the practice of rheumatoid 
arthritis – For higher treatment goals–]. Rheumatology. 2011;46:288-296. Japanese. 
Tanaka Y. [New target molecules in treatment for rheumatoid arthritis – Will signal-inhibiting low-
molecular-weight compounds surpass biologics? –]. Inflammation and Immunity. 2009;17:214-
218. Japanese. 
Nakajima A. [Drug therapy for rheumatoid arthritis: Indications, contraindications, and methods of 
use – Antirheumatic drugs (DMARDs)]. Internal Medicine. 2009;103:655-659. Japanese. 
Japan Clinical Oncology Group (JCOG), Japanese Society of Clinical Oncology (JSCO). Common 
Terminology Criteria for Adverse Events (CTCAE) v4.0, Japanese translation, JCOG/JSCO 
Version; 1 February, 2010. Available from: http://www.jcog.jp/index.htm 


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Humira® Drug Interview Form (Revised July 2013 Ver. 12) 
Yamaoka K, Tanaka Y. [Rheumatoid arthritis treatment with Jak3 inhibitors]. Rheumatology. 
2008;40:526-530. Japanese. 
 


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12 
APPENDICES 
APPENDIX <1>: LIST OF PROHIBITED CONCOMITANT 
MEDICATION 
✓ Biologic DMARDs 
Etanercept, anakinra, adalimumab, golimumab, infliximab, tocilizumab, abatacept, 
rituximab, certolizumab pegol, denosumab, sarilumab 
✓ Non-biologic DMARDs* 
Subjects who transferred from study RAJ1 
MTX, salazosulfapyridine, gold, D-penicillamine, leflunomide, lobenzarit, actarit, 
tacrolimus, mizoribine, bucillamine, iguratimod, tofacitinib, baricitinib 
Subjects who transferred from study RAJ3 
Non-biologic DMARDs other than those used concomitantly in study RAJ3 
Subjects who transferred from study RAJ4 
Salazosulfapyridine, gold, D-penicillamine, leflunomide, lobenzarit, actarit, tacrolimus, 
mizoribine, bucillamine, iguratimod, tofacitinib, baricitinib 
*: Topical drugs other than those for the treatment of RA may be used concomitantly.  
✓ Other drugs used in the treatment of RA  
Cyclosporine, cyclophosphamide, azathioprine, minocycline, etc.  
✓ Corticosteroids** 
Prednisolone, hydrocortisone, hydrocortisone succinate, methylprednisolone, 
methylprednisolone succinate, triamcinolone, triamcinolone acetonide, dexamethasone, 
betamethasone, etc.  
**: It is prohibited to use oral corticosteroids at doses that exceed the amount used from the initiation of 
studies RAJ1, RAJ3, or RAJ4 to the initiation of administration of the study drug in this extension study 
at a daily dose of prednisolone equivalent. Intra-articular, intravenous, intramuscular, or endorectal 
administration is prohibited. However, suppositories for anal diseases may be used concomitantly.  
✓ Oral morphine*** 
Morphine hydrochloride, morphine sulfate 
***: Oral morphine at doses exceeding 30 mg/day (or equivalent amount of opioid analgesics)  
✓ CYP3A substrates with narrow therapeutic range  
Dihydroergotamine, ergotamine, fentanyl, pimozide, quinidine, temsirolimus, 
disopyramide, etc  


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✓ Live or live attenuated virus vaccines  
Freeze-dried live attenuated measles vaccine, freeze-dried live attenuated mumps 
vaccine, freeze-dried BCG vaccine, freeze-dried live attenuated varicella vaccine, 
freeze-dried live attenuated rubella vaccine, live oral poliomyelitis vaccine, etc.  
✓ Articular cartilage protective agents  
Purified sodium hyaluronate (intra-articular injection), chondroitin sulfate (excluding 
eye drops)  
 


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APPENDIX <2>: LABORATORY TESTS  
 
Visit* 
Collecting tube 
(unique to Japan**) 
Parameters to be analyzed 
Hematology 
[Subjects who transferred 
from RAJ1] 
Week 0, Week 2, Week 4, 
Week 8, Week 12, Week 16, 
Week 20, Week 24, Week 28, 
Week 32, Week 36, Week 40, 
Week 44, Week 48, Week 60, 
Week 72, Week 84, Week 96, 
Week 108, Week 120, Week 
132/end of treatment/early 
termination, end of study (at 
time of follow-up), 
Unscheduled Visits 
[Subjects who transferred 
from RAJ3 or RAJ4] 
Week 0, Week 12, Week 24, 
Week 36, Week 48, Week 60, 
Week 72, Week 84, Week 96, 
Week 108, Week 120, Week 
132/end of treatment/early 
termination, end of study (at 
time of follow-up), 
Unscheduled Visits 
2 mL vacutainer tube 
containing EDTA-2K  
Hemoglobin, hematocrit, 
RBC, WBC, differential 
WBC, platelet count  
Biochemistry 
[Subjects who transferred 
from RAJ1] 
Week 0, Week 2, Week 4, 
Week 8, Week 12, Week 16, 
Week 20, Week 24, Week 28, 
Week 32, Week 36, Week 40, 
Week 44, Week 48, Week 60, 
Week 72, Week 84, Week 96, 
Week 108, Week 120, Week 
132/end of treatment/early 
termination, end of study (at 
time of follow-up), 
Unscheduled Visits 
[Subjects who transferred 
from RAJ3 or RAJ4] 
Week 0, Week 12, Week 24, 
Week 36, Week 48, Week 60, 
Week 72, Week 84, Week 96, 
Week 108, Week 120, Week 
132/end of treatment/early 
termination, end of study (at 
time of follow-up), 
Unscheduled Visits 
9 mL vacutainer tube 
containing separating 
medium 
For glucose: 2 mL 
vacutainer tube containing 
NaF+EDTA-2Na 
For β-D glucan: 3 mL 
container for blood 
endotoxin/β-D-glucan 
Na, K, Ca, Cl, Mg, HCO3, 
BUN, phosphorus, glucose, 
creatinine, ALP, AST 
(GOT), ALT (GPT), γ-GTP, 
TBL, total protein, albumin, 
uric acid, CPK, LDH, serum 
amylase, β-D-glucan, eGFR 
Biochemistry 
(during CPK 
monitoring) 
At the time of CPK 
monitoring 
4 mL vacutainer tube 
containing the separating 
medium 
CK-MB, troponin T, 
aldolase 


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Fasting lipid 
profile test 
[Subjects who transferred 
from RAJ1] 
Week 0, Week 2, Week 4, 
Week 8, Week 12, Week 16, 
Week 20, Week 24, Week 28, 
Week 32, Week 36, Week 40, 
Week 44, Week 48, Week 60, 
Week 72, Week 84, Week 96, 
Week 108, Week 120, Week 
132/end of treatment/early 
termination, end of study (at 
time of follow-up), 
Unscheduled Visits 
[Subjects who transferred 
from RAJ3 or RAJ4] 
Week 0, Week 12, Week 24, 
Week 36, Week 48, Week 60, 
Week 72, Week 84, Week 96, 
Week 108, Week 120, Week 
132/end of treatment/early 
termination, end of study (at 
time of follow-up), 
Unscheduled Visits 
(Included among 
biochemical tests)  
  
Total cholesterol, LDL, 
HDL, TGs 
Hepatitis DNA 
test 
[Subjects who transferred 
from RAJ3 or RAJ4] 
Week 0, Week 12, Week 24, 
Week 36, Week 48, Week 60, 
Week 72, Week 84, Week 96, 
Week 108, Week 120, Week 
132/end of treatment/early 
termination, end of study (at 
time of follow-up), 
Unscheduled Visits 
5 mL vacutainer tube 
containing the separating 
medium 
HBV-DNA assay 
Urinalysis 
 
[Subjects who transferred 
from RAJ1] 
Week 0, Week 2, Week 4, 
Week 8, Week 12, Week 16, 
Week 20, Week 24, Week 28, 
Week 32, Week 36, Week 40, 
Week 44, Week 48, Week 60, 
Week 72, Week 84, Week 96, 
Week 108, Week 120, Week 
132/end of treatment/early 
termination, end of study (at 
time of follow-up), 
Unscheduled Visits 
[Subjects who transferred 
from RAJ3 or RAJ4] 
Week 0, Week 12, Week 24, 
Week 36, Week 48, Week 60, 
Week 72, Week 84, Week 96, 
Week 108, Week 120, Week 
132/end of treatment/early 
termination, end of study (at 
time of follow-up), 
Unscheduled Visits 
For urinalysis: 10 mL 
light-blocking urine 
collection tubes 
For urine microscopic 
analysis: 10 mL urine 
collection tubes 
pH, specific gravity, protein, 
glucose, keton bodies, 
bilirubin, occult blood, 
sediment 


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Pregnancy testing 
Week 0, Week 12, Week 24, 
Week 36, Week 48, Week 60, 
Week 72, Week 84, Week 96, 
Week 108, Week 120, Week 
132/end of treatment/early 
termination, end of study (at 
time of follow-up), 
Unscheduled Visits 
Urine pregnancy testing kit 
(in-hospital testing)  
As necessary, serum 
pregnancy testing 
(included among 
biochemistry tests)  
Human chorionic 
gonadotropin (hCG) 
 
 
Acute phase 
reactants 
[Subjects who transferred 
from RAJ1] 
Week 0, Week 2, Week 4, 
Week 8, Week 12, Week 24, 
Week 28, Week 32, Week 36, 
Week 40, Week 44, Week 48, 
Week 60, Week 72, Week 84, 
Week 96, Week 108, Week 
120, Week 132/end of 
treatment/early termination, 
end of study (at time of 
follow-up), Unscheduled 
Visits 
[Subjects who transferred 
from RAJ3 or RAJ4] 
Week 0, Week 12, Week 24, 
Week 36, Week 48, Week 60, 
Week 72, Week 84, Week 96, 
Week 108, Week 120, Week 
132/end of treatment/early 
termination, end of study (at 
time of follow-up), 
Unscheduled Visits 
(Included among 
biochemistry tests) 
CRP 
In-hospital testing 
ESR 
Pharmacodynami
cs 
Week 0, Week 48, Week 96 
/end of treatment/early 
termination, end of study (at 
time of follow-up), 
Unscheduled Visits 
2 mL vacutainer tube 
containing EDTA-2K 
Lymphocyte subsets 
* Necessary hospital visits will differ from subject to subject because the duration of participation in this study 
will differ depending upon the subject. After Week 132, tests will be performed every 12 weeks (only the 
pharmacodynamics tests will be performed every 48 weeks after Week 96.) 
** Types of collecting tube used at Korea and Taiwan are described in the laboratory handling manual. 
 


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APPENDIX <3>: EVENTS ALWAYS CONSIDERED TO BE SERIOUS  
If any of the following events occurs during the study, it should be regarded as a SAE and 
must be reported in accordance with Section 5.5.5, Reporting of Serious Adverse Events 
(SAEs).  
● 
Acute hepatic failure 
● 
Renal failure acute 
● 
Acute respiratory failure 
● 
Agranulocytosis 
● 
Anaphylactic reaction, anaphylactic shock 
● 
Malignant tumor 
● 
Aplastic anaemia 
● 
Endotoxic shock (confirmed or suspected) 
● 
Confirmed or suspected transmission of infectious agents by marketed product 
● 
Congenital anomalies 
● 
Hepatic necrosis 
● 
Malignant hypertension 
● 
Pulmonary fibrosis 
● 
Pulmonary hypertension 
● 
Sclerosing syndromes 
● 
Convulsion (only central neurological seizure) 
● 
Torsades de pointes 
● 
Toxic epidermal necrolysis 
● 
Ventricular fibrillation 
Note: Hy’s Law cases are considered as SAEs. 
See Appendix 6 “Liver Safety Monitoring and Assessment.” 
 


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APPENDIX <4>: CRITERIA FOR THE CLASSIFICATION OF 
GLOBAL FUNCTIONAL STATUS IN RA (1991 
REVISED CRITERIA)  
[Classification of Global Functional Status in RA: Class] 
Class I 
Complete functional capacity with ability to carry on all usual duties without handicaps 
Class II 
 
Functional capacity adequate to conduct normal activities despite handicap or 
discomfort or limited mobility of one or more joints 
Class III 
Functional capacity adequate to perform only few or none of the duties of usual 
occupation or of self-care 
Class IV 
Largely or wholly incapacitated with patient bedridden or confined to wheelchair, 
permitting little or no self-care 
[Hochberg et al, 1992] 
 
APPENDIX <5>: CLASSIFICATION OF DISEASE 
STAGE/PROGRESSION OF RA  
Stage I: Early 
1. 
X-rays do not show destruction of bone.  
2. 
X-rays may show radiological osteoporosis.  
Stage II: Intermediate 
1. 
X-rays show osteoporosis which may or may not be accompanied by 
mild destruction of subchondral bone. Mild bone destruction may be 
observed.  
2. 
Joint mobility may be limited, but there is no joint deformation.  
3. 
Muscle atrophy surround the joint is present.  
4. 
Lesions in extra-articular soft tissue, such as nodules and 
tenosynovitis, may be present.  
Stage III: 
Advanced/Progressive 
1. 
In addition to osteoporosis, X-rays show destruction of bone and 
cartilage.  
2. 
Joint deformities such as subluxation, ulnar displacement, or 
hyperextension are present, unaccompanied by fibrous or bony 
ankylosis. 
3. 
Exaggerated muscle atrophy is present.  
4. 
Lesions in extra-articular soft tissue, such as nodules and 
tenosynovitis, may be present.  
Stage IV: Late Stage 
1. 
Fibrous or bony ankylosis is present.  
2. 
Other symptoms meet criteria for Stage III.  
[Steinbrocker O. 1949] 
 


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APPENDIX <6>: LIVER SAFETY MONITORING AND ASSESSMENT 
If laboratory testing for a subject enrolled in a study and receiving the study drug reveals > 3 
× ULN elevation in serum aminotransferases (ALT, AST) or TBL elevation to > 2 × ULN, 
the investigator/sub-investigator should repeat the liver function test including at least the 4 
parameters ALT, AST, ALP, and TBL. The retest is to be performed between 48 hours and 
72 hours after notification of the test results. For studies for which a central laboratory is used, 
alerts will be generated by the central lab regarding moderate and marked liver abnormality 
to inform the investigator or other responsible personnel, and sponsor. Subjects should be 
asked if they have any symptoms suggestive of hepatobiliary dysfunction by the investigator 
or sub-investigator.  
 
Definition of Hepatic Function Abnormal 
Confirmed hepatic function abnormal will be characterized as moderate (hepatocellular 
failure type or cholestasis type) or marked (mixed type) based on the ULN as follows:  
 
 
 
ALT or AST 
 
Total bilirubin 
Moderate 
Hepatocellular failure type 
or 
cholestasis type 
 
>3 × ULN 
or 
>2 × ULN 
 
 
 
 
 
Marked 
Mixed type 
 
>3 × ULN 
and 
>2 × ULN 
 
In addition, the subject with any of the following should be considered to have marked 
(severe) hepatic function abnormal.  
● 
ALT or AST > 8 × ULN 
● 
ALT or AST > 5 × ULN for more than 2 weeks 
● 
ALT or AST > 3 × ULN and INR > 1.5 
● 
ALT or AST > 3 × ULN with the appearance of fatigue, nausea, vomiting, right upper 
quadrant pain or tenderness, pyrexia, rash and/or eosinophilia (> 5%). 
 
If the investigator or sub-investigator may determine that abnormal liver function results, 
other than as described above, quality as moderate or marked abnormalities, he/she should 
conduct additional monitoring and follow-up.  
 


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Follow-up Procedures 
Confirmed moderate and marked hepatic function abnormal should be thoroughly 
characterized by obtaining appropriate expert consultations, detailed pertinent history, 
physical examination, and laboratory tests by the investigator or sub-investigator. The 
investigator should complete the liver abnormality case report form (LA-CRF) or an 
appropriate document. Subjects with confirmed abnormal liver function testing should be 
followed as described below by the investigator or sub-investigator.  
If moderate liver abnormality is confirmed, re-testing should be performed every 2 to 3 times 
a week. If the abnormal test values stabilize or the patient is asymptomatic after the study 
drug is withdrawn, re-testing should be performed at a frequency of once a week or less.  
Marked hepatic function abnormal, in the absence of another etiology, may be considered an 
important medical event and reported as a SAE by the investigator. The sponsor should be 
contacted and informed of all subjects for whom marked hepatic function abnormal possibly 
attributable to study drug is observed.  
To further assess the findings of hepatic function abnormal, the investigator or sub-
investigator is expected to:  
● 
Obtain a more detailed history of symptoms and prior or concurrent diseases. Symptoms 
and new-onset diseases should be recorded as “AEs” on the AE page of CRF. Illnesses 
and conditions such as hypotensive events, and decompensated cardiac disease that may 
lead to secondary liver abnormalities should be noted. Non-alcoholic steatohepatitis 
(NASH) is seen in obese hyperlipoproteinemic and/or diabetic patients and may be 
associated with fluctuating serum aminotransferase (ALT, AST) levels. The investigator 
or sub-investigator should ensure that the medical history form captures any illness that 
pre-dates study enrollment that may be relevant in assessing hepatic function.  
● 
Obtain a history of concomitant drug use (including non-prescription medication, 
complementary and alternative medications), alcohol intake, drug abuse, and special 
diets. Medications, including dose, should be entered on the concomitant medication 
page of CRF. Information on alcohol, other substance use, and diet should be entered 
into the LA-CRF or an appropriate document.  
● 
Obtain a history of exposure to environmental chemical agents.  
● 
Based on the subject’s history, other testing may be appropriate, including:  
 Acute viral hepatitis subtypes (A, B, C, D, E, or other infectious agents)  
 Ultrasound or other imaging to assess biliary tract disease  
 Other laboratory tests including INR and direct bilirubin 
● 
Consider gastroenterology or hepatology consultations.  
● 
Enter results for any additional testing and possible etiology into the LA-CRF or an 
appropriate document.  
 


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Study Discontinuation 
In the absence of an explanation for liver function test raised, such as viral hepatitis, pre-
existing or acute liver disease or exposure to other agents associated with liver injury, the 
subject may be discontinued from the study by the investigator. The investigator may 
determine that it is not in the subject’s best interest to continue study enrollment. 
Discontinuation of treatment should be considered if any of the following applies:  
● 
ALT or AST > 8 × ULN 
● 
ALT or AST > 5 × ULN for more than 2 weeks 
● 
ALT or AST > 3 × ULN and (TBL > 2 × ULN or INR > 1.5) 
● 
ALT or AST > 3 × ULN with the appearance of fatigue, nausea, vomiting, right upper 
quadrant pain or tenderness, fever, rash, and/or eosinophilia (> 5%). 
 
In addition, if close monitoring of a subject with moderate or marked hepatic function 
abnormal is not possible, the study drug should be discontinued by the investigator.  
 
Reference  
See “Guidance for Industry on Drug-Induced Liver Injury: Premarketing Clinical Evaluation,” 
published by the FDA in July 2009.  
 


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APPENDIX <7>: STUDY PROTOCOL VER. 1.3 (EXCERPT) 
This study has been conducted as an extension study of the Phase IIb Study (RAJ1). After 
completion of study RAJ1, Phase III studies (studies RAJ3 and RAJ4) were planned based on 
the results of study RAJ1. In association with these studies, the dosages of the study drug in 
this study were reconsidered, and the protocol was revised to make it possible for subjects 
who have completed the Phase III studies to also participate in the study. 
The study protocol before the revision (ver. 1.3, supplements 1 to 6 of protocol ver. 1.3) is 
shown below. 
SYNOPSIS 
Title of Study 
Phase IIb Extension Study of ASP015K – Open-Label Extension Study in 
Rheumatoid Arthritis Patients Who Have Completed Phase IIb Study of 
ASP015K –  
 (Protocol Number: 015K-CL-RAJ2) 
Study Objectives 
This is an extension study conducted in RA patients who have completed the 
Phase IIb Study of ASP015K [015K-CL-RAJ1] (hereinafter referred to as study 
RAJ1) to investigate the safety and efficacy of long-term administration of 
ASP015K.  
Another objective of this study is to devise rescue measures for providing the 
active drug to patients who participated in the Phase IIb Study of ASP015K, as 
described in “Guidelines on methodology for clinical assessment of antirheumatic 
drugs” (PFSB Notification No. 0217001, dated 17 February, 2006).  
Design and Methodology 
 
This study is an extension of study RAJ1 conducted as an open-label multicenter 
study in RA patients who completed study RAJ1.  
 
Patients who meet all of the inclusion criteria and do not fall under any of the 
exclusion criteria will be registered and will receive oral ASP015K 50 mg QD 
after breakfast as the starting dose. Subjects who have no safety problems but 
show lack of efficacy may later increase the dose to 100 mg/day. After the dosage 
increase, the dosage may be reduced from 100 mg/day to 50 mg/day at the 
discretion of the investigator or sub-investigator. The dose level will be 
redetermined after the results of the dose finding study (study RAJ1) have been 
obtained.  
 
Because this study will end at the point in time where the Phase III study begins, 
the duration of treatment with the study drug will differ depending upon the 
subject (planned maximum duration of treatment: 132 weeks). To prevent 
purposeless continuation of dosing without effect, the investigator or sub-
investigator will assess each subject for efficacy and safety at each visit, confirm 
the appropriateness of continued administration for each individual, and decide 
whether or not to continue dosing.  
Selection Criteria 
<Inclusion Criteria> 
Subject is eligible for the study if all of the following apply:  
1. Subject has received a full explanation of the study drug and this study in 
advance, and written informed consent to participate in the study has been 
obtained from the subject himself/herself.  
2. Subject has completed treatment with the study drug in study RAJ1 as 
specified in the protocol and has also completed the tests and assessment 
performed at the study visit in Week 16.  
3. The subject himself/herself wishes to continue taking the study drug, and the 
investigator or sub-investigator deems continued administration to be 
necessary or appropriate.  


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4. Subject must be willing and able to comply with the study requirements.  
 
<Exclusion Criteria> 
Subject will be excluded from participation if any of the following apply:  
1. Subject has developed an adverse reaction related to the study drug in study 
RAJ1 and the risks of continuing treatment with this drug are expected to 
outweigh the benefits.  
2. There were abnormal findings in the x-ray taken at Week 0, and an acute or 
chronic infection, tuberculosis infection, or malignant tumor is suspected.  
3. Subject has received live or live attenuated virus vaccination within 30 days 
prior to the first dose of study drug. 
4. Subject is a hepatitis B virus or hepatitis C virus carrier or has a history of a 
positive test for HIV infection. 
5. Subject has concurrent autoimmune disease (except Sjogren’s syndrome) 
other than RA or a history of it. 
6. Subject has a clinically significant infection or disease (requiring 
hospitalization or parenteral therapy).  
7. Subject has a history of any malignant tumor, except for successfully treated 
basal or squamous cell carcinoma of the skin or in-situ carcinoma of the 
cervix, or subject has a concurrent malignant tumor. 
8. Subject has taken one of the following drugs between the end of the 
assessments at Week 12 of study RAJ1 and the start of treatment with the 
study drug in this extension study.  
• Biologic DMARD (biologic for the treatment of RA): Etanercept, 
adalimumab, golimumab, infliximab, tocilizumab, abatacept, rituximab  
• Non-biologic DMARD: MTX, salazosulfapyridine, gold, D-penicillamine, 
leflunomide, lobenzarit, actarit, tacrolimus, mizoribine, bucillamine, 
iguratimod, tofacitinib (However, topical drugs other than those for the 
treatment of RA may be used concomitantly.)  
• Other drugs used in the treatment of RA: Cyclosporine, 
cyclophosphamide, azathioprine, minomycin, etc.  
9. Subject has received plasma exchange therapy between the end of the 
assessments at Week 12 of study RAJ1 and the start of treatment with the 
study drug in this extension study.  
10. Subject has received any of the following CYP3A substrates with narrow 
therapeutic range within 14 days prior to starting treatment with the study 
drug:  
Dihydroergotamine, ergotamine, fentanyl, pimozide, quinidine, and 
temsirolimus  
11. Subject has any of the following laboratory values at the study visit in Week 
12 of study RAJ1:  
• Hemoglobin < 10 g/dL  
• WBC count < 3000/μL 
• Absolute neutrophil count (ANC) < 2000/μL 
• Absolute lymphocyte count < 800/μL 
• Platelet count < 100000/μL  
• ALT ≥ 2 × ULN 
• AST ≥ 2 × ULN 
• TBL ≥ 1.5 ×ULN 
• Estimated glomerular filtration rate (GFR) ≤ 40 mL/min, as measured by 
the Modification of Diet in Renal Disease (MDRD) method 
• CPK > 1.5 ×ULN 
• β-D-glucan ≥ 11 pg/mL 
12. Subject has symptomatic CPK elevation (CPK > 1.5 × ULN with myalgia, 
muscular weakness, or severe unusual muscle twitching) at the study visit in 
Week 12 of study RAJ1.  


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13. Subject is found to have symptoms of myopathy such as myalgia, muscular 
weakness, and severe unusual muscle twitching regardless of CPK level that 
persist for at least 2 weeks or that worsen rapidly in less than 2 weeks, at 
study visit in Week 12 of study RAJ1.  
14. Subject has concurrent cardiac failure with NYHA classification of Class III 
or higher, or a history of it.  
15. Subject has concurrent long QT syndrome or history of it. Subject exhibits 
QT interval prolonged at the study visit in Week 0. 
16. Subject has any ongoing severe, progressive, or uncontrolled renal, hepatic, 
hematological, gastrointestinal, metabolic, endocrine, pulmonary, cardiac, 
neurological, or infectious disease, or any ongoing illness which would make 
the subject unsuitable for the study as determined by the investigator/sub-
investigator. 
17. Subject has any condition possibly affecting oral absorption (e.g., 
gastrectomy or clinically significant diabetic gastroenteropathy). 
18. Subject has received surgical treatment and the investigator/sub-investigator 
judges there to be residual effects of surgical stress. Or, the subject plans to 
have surgical treatment that will require hospitalization during the study 
period or surgery on the joints. 
19. The subject is a woman who is pregnant or might be pregnant, is nursing, 
wishes to conceive within 60 days after end of treatment drug, or for whom 
the possibility of pregnancy cannot be ruled out as a result of the pregnancy 
test given at Week 0.  
20. The subject is a man who cannot practice proper contraception with a 
condom from the time informed consent is given until 90 days after end of 
treatment, or the subject is a woman who could become pregnant and cannot 
practice proper contraception with a condom from the time informed consent 
is given until 60 days after end of treatment.  
21. The subject has been judged unsuitable to participate in the study for other 
reasons by the investigator/sub-investigator.  
Discontinuation Criteria 
The investigator/sub-investigator should discontinue administration of the study 
drug if any of the following occurs: 
1. Subject develops an AE, where continued administration of the study drug is 
deemed not in the subject’s best interest by the investigator and/or the sub-
investigator. 
2. Any of the following laboratory values as confirmed by a re-test within 72 
hours of the initial observation: 
• Hemoglobin < 8.0 g/dL 
• WBC count < 2000/μL 
• ANC < 1000/μL 
• Absolute lymphocyte count < 500/μL 
• Platelet count < 50000/μL 
• CPK > 2000 IU/L 
3. Symptomatic CPK elevation, defined as CPK > 1.5 × ULN with myalgia, 
muscular weakness, or severe unusual muscle twitching. 
4. Any event of myopathy defined as myalgia, muscular weakness, and severe 
unusual muscle twitching regardless of CPK level that persists for at least 2 
weeks or that worsens rapidly within 2 weeks. 
5. If a β-D-glucan test shows a value of 11 pg/mL or higher during the treatment 
period. (However, if further testing shows there to be no problem, 
administration of the study drug can be continued.).  
6. Subject withdraws consent. 
7. The study drug is not sufficiently effective (ACR20 response rate based on 
baseline value for study RAJ1 is not reached in 12 weeks of continuous 
treatment) and a change in treatment method is deemed by the physician to be 
in the subject’s best interest.  


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8. Subject uses or requires a prohibited concomitant medication during the 
study. Subject uses or requires a prohibited concomitant therapy during the 
study. 
9. Subject has been an interruption in treatment with the study drug (drug 
holiday) exceeding the following criteria: 
• The maximum possible drug holiday will be for 4 consecutive weeks or less. 
• Up to 2 drug holidays per year may be taken. Moreover, they must be 
separated by an interval of 16 weeks or more.  
10. Subject has missed doses of the study drug in excess of the following criteria 
(excepting suspension of dosing at the physician’s discretion):  
• Subject has missed 7 or more daily doses in the 4 weeks prior to the study 
visit, up to Week 48 visit (excluding the Week 2 visit).  
• Subject has missed 21 or more daily doses in the 12 weeks prior to the 
study visit in or after Week 60.  
11. Subject is deemed lost to follow-up by the investigator/sub-investigator 
(subject can no longer come to the study center; subject can no longer be 
contacted, etc.).  
12. It comes to light after the administration of the first dose of study drug that 
the inclusion criteria were not met at the time of case enrollment or that 
criteria for exclusion were met. It comes to light that there was some other 
major deviation from the protocol.  
13. Investigator or sub-investigator decides it is in the subject’s best interest to 
discontinue.  
14. The sponsor has requested that administration of the study drug be 
discontinued because of a safety problem in a particular subject, or the 
sponsor has decided to discontinue the study altogether. 
 
The Appendix 6 entitled “Liver Safety Monitoring and Assessment” describes 
liver function tests raised providing grounds for considering discontinuation. 
Refer to this if liver function tests raised is observed. 
Test Drug 
Mode of Administration: 
Dose: 
Duration of Treatment: 
Test drug: ASP015K 10 mg and 30 mg tablets 
Dose: (starting dose) 50 mg/day, (escalated dose) 100 mg/day 
The starting dose will be 50 mg/day.  
The dose may be increased to 100 mg QD will be permitted at the point in 
time as the following 2 conditions are met.  
1) When the DAS28-ESR score is 3.2 or higher (corresponding to 
moderate disease activity or high disease activity) on the study visit 
day specified in the protocol (at 2 or more consecutive visit days up to 
Week 12) 
2) When the investigator or sub-investigator judges there to be no 
problem with safety for the subject in the assessment performed on the 
study visit day on which the DAS28-ESR of 3.2 score or higher was 
exhibited  
Moreover, after dose escalation, the dose may again be reduced from 
100 mg/day to 50 mg/day at the discretion of the investigator or sub-
investigator on the visit day specified in the protocol. The investigator or 
sub-investigator will decide whether or not to reduce the dosage on the 
basis of the following criterion. 
• If an AE with an NCI-CTCAE grade classification of Grade 2 or higher 
has developed.  
Mode of administration: To be orally administered QD after breakfast. The first 
dose should be given at each study center on the day of the Week 0 visit 
after all of the necessary assessments and tests have been completed.  
Duration of treatment: Because this study will end at the point in time where the 
Phase III study begins, the duration of treatment will differ depending 
upon the subject (planned maximum duration of treatment: 132 weeks). To 


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prevent purposeless continuation of dosing without effect, the investigator 
or sub-investigator will assess each subject for efficacy and safety at each 
visit, confirm the appropriateness of continued administration for each 
individual, and decide whether or not to continue dosing. 
Comparative drug 
Mode of Administration: 
Dose: 
Duration of Treatment: 
Not applicable. 
Concomitant Treatment 
(1) The following concomitant medications and complimentary alternative 
treatments are prohibited as described. 
➢ Administration or use of the following drugs and therapies will be prohibited 
from the end of the assessments in Week 12 of study RAJ1 until the start of 
administration of the study drug in this extension study, as well as 
throughout the treatment period.  
1) Biologic DMARDs: etanercept, adalimumab, golimumab, infliximab, 
tocilizumab, abatacept, rituximab, certolizumab pegol  
2) Non-biologic DMARDs: MTX, salazosulfapyridine, gold, D-penicillamine, 
leflunomide, lobenzarit, actarit, tacrolimus, mizoribine, bucillamine, 
iguratimod, tofacitinib (However, topical drugs other than those for the 
treatment of RA may be used concomitantly.) 
3) Other drugs used in the treatment of RA: cyclosporine, cyclophosphamide, 
azathioprine, minomycin, etc.  
4) Plasma exchange therapy  
 
➢ Administration or use of the following medications and therapies will be 
prohibited from the end of the assessments in Week 12 of study RAJ1 until 
the start of study drug administration in this extension study, as well as 
throughout the treatment period and follow-up period.  
5) Live or live attenuated virus vaccines 
 
➢ Administration of the following medications is prohibited within 14 days 
prior to the start of treatment with the study drug, as well as throughout the 
treatment period and follow-up period.  
6) CYP3A substrates with narrow therapeutic range: dihydroergotamine, 
ergotamine, fentanyl, pimozide, quinidine, and temsirolimus.  
 
➢ Concomitant use of the following drugs and therapies will be prohibited 
throughout the treatment period.  
7) Oral corticosteroids in doses that exceed the amount used from the start of 
study RAJ1 to the start of administration of the study drug in this extension 
study, in daily dose of prednisolone or equivalent 
8) Intra-articular, intravenous, intramuscular, or endorectal corticosteroids 
(However, suppositories for anal diseases may be used concomitantly.) 
9) Oral morphine in doses exceeding 30 mg per day (or equivalent amount of 
opioid analgesics) 
10) Intra-articular administration of articular cartilage protective agents 
11) Drainage of fluid accumulated in joint, local anesthesia of joint, and nerve 
block  
12) St. John’s wort and food products (including beverages) containing it 
 
➢ Concomitant use of the following medications and therapies is prohibited 
throughout the treatment period and follow-up period.  
13) Other study drugs, study drugs from post-marketing clinical studies, or 
medical devices being studied in clinical studies  
14) Surgeries requiring hospitalization or surgical treatment of the joints.  
 


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(2) Limited concomitant medications 
During the treatment period, the following medications may be used 
concomitantly at the discretion of the investigator or sub-investigator if they meet 
the following conditions for concomitant use (Both new administration and 
change in dosage/administration are permitted).  
1) NSAIDs 
2) Oral morphine ( 30 mg/day, or equivalent amount of opioid analgesics)  
3) Acetaminophen 
– Conditions for concomitant use – 
• No changes in the dosage/administration of the drug are allowed within the 
period of 12 weeks. However, this shall exclude cases where the 
medication has caused an AE. Moreover, if, after discontinuation of the 
concomitant medication, it becomes apparent that the suspected medication 
was not the offending drug that caused the AE, administration may be 
resumed with the dose prior to discontinuation as the maximum dose.  
• The limited concomitant medications may not be used within 12 hours prior 
to the joint assessment performed at each study visit.  
 
(3) Rescue medications 
The following medications may be used only when needed to treat AEs or 
worsening of the primary disease. However, these medications may not be taken 
within 24 hours prior to the joint assessment at each study visit.  
1) NSAIDs: Single use as needed, for a period of 3 days or less 
2) Analgesics other than NSAIDs (acetaminophen, all-in-one cold and flu 
medications, etc.): For 7 consecutive days or less 
3) Intra-articular administration of corticosteroids, intra-articular 
administration of articular cartilage protective agents, drainage of fluid 
accumulated in joint, local anesthesia of joint, and nerve block: Performed 
once every 24 weeks (on up to 2 joints), starting at or after the Week 12 
study visit. 
However, joints on which intra-articular drug administration or rescue procedure 
has been performed will be assessed as showing disease activity (pain 
[tenderness]/swelling) after administration of the medication/therapy. 
Endpoints (Safety) 
• AEs 
• Vital signs (body temperature, pulse and blood pressure in sitting position ) 
• 12-lead ECG 
• Laboratory Assessments 
Endpoints (Efficacy) 
The following items at each study visit 
• ACR 20 response rate 
• ACR 50 response rate 
• ACR 70 response rate 
• TJC (68 joints)  
• SJC (66 joints) 
• DAS28-CRP and DAS28-ESR 
• Percentage of subjects achieving DAS28-CRP score for remission 
• Percentage of subjects achieving ACR/EULAR score for remission 
ACR/EULAR remission is defined as meeting all 4 of the following criteria:  
o 
Tender Joint Count ≤ 1 
o 
Swollen Joint Count ≤ 1 
o 
CRP ≤ 1 mg/dL  
o 
SGA ≤ 1 cm (0-100 mm on a VAS scale)  
• Percentage of subjects with a SDAI score of ≤ 3.3 (SDAI remission) 
• PGA (VAS) 
• SGA (VAS) 
• Subject’s assessment of pain (VAS) 
• FACIT-Fatigue score (excluding scores from Week 2 study visit and at end of 


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- CONFIDENTIAL - 
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Page 124 of 128 
study [at time of follow-up]) 
• HAQ-DI 
• SF-36v2® score (excluding scores from Week 2 study visit and at end of study 
[at time of follow-up]) 
• Percentage of subjects in EULAR response criterion of “Good Response” 
• Percentage of subjects in EULAR response criterion of “Moderate Response”  
• Percentage of subjects in EULAR response criterion of “Good Response” or 
“Moderate Response”  
• Incidence of subject withdrawal due to lack of efficacy 
Statistical Methods 
• In the assessment of efficacy and safety, the following will be calculated for 
continuous variables: number of subjects, mean, standard deviation, minimum, 
median, and maximum; categorical variables will be expressed as frequency 
and percentage.  
• AEs will be coded using the MedDRA. AEs occurring after administration of 
the study drug will be tallied for the entire study period and for each 3-month 
sub-period.  
• Laboratory test values (actual measured values and change from baseline), vital 
signs (actually measured values and diagram of change from baseline), and 
results of ECG assessment will be tallied at each time point.  
• Incidence of subject withdrawal due to lack of efficacy will be tallied for the 
entire study period and each 3-month sub-period. Other efficacy variables will 
be tallied at each time point.  
 


Sponsor: Astellas Pharma Inc. 
ISN/Protocol <015K-CL-RAJ2> 
 
- CONFIDENTIAL - 
29 March 2019 (Ver. 7.0) 
Astellas 
Page 125 of 128 
FLOW CHART AND SCHEDULE OF ASSESSMENTS 
Flow Chart 
 
 
 
 
 
 
NOTE) The study visit in Week 0 in this extension study will coincide with the day of the visit in Week 16/end 
of study (follow-up) in study RAJ1.  
 
Start and End of Study 
Start of Study: 
Point in time where informed consent is obtained from the first 
subject  
End of Study: 
Point in time where final assessment specified in protocol has 
been performed in the last subject  
Treatment Period: 
Period from the start of treatment to the end of the tests and 
assessments 
 
 
• Obtain 
informed 
consent 
• Complete 
study RAJ1 
Treatment Period 
Until the start of 
Phase III Study. 
Duration of treatment 
with study drug will 
differ depending on 
the subject 
(maximum planned 
duration of treatment: 
132 weeks) 
Follow-up 
Period:  
For 4 weeks after 
end of treatment 
Day 1 
(Week 0NOTE)): 
• Confirmation 
of inclusion/ 
exclusion 
criteria 
• Case 
registration 


Sponsor: Astellas Pharma Inc. 
ISN/Protocol <015K-CL-RAJ2> 
 
- CONFIDENTIAL - 
 
29 March 2019 (Ver. 7.0) 
Astellas 
Page 126 of 128 
Table 1. 
Schedule of Assessments 
Schedule 
Week 
0b 
Treatment Periodc 
Follow-up 
Period 
Unscheduled 
Visit 
Visit Timing 
Week 
2 
Week 
4 
Week 
8 
Week 
12 
Week 
16 
Week 
20 
Week 
24 
Week 
28 
Week 
32 
Week 
36 
Week 
40 
Week 
44 
Week 
48 
Week 
60 
Week 
72 
Week 
84 
Week 
96 
Week 
108 
Week 
120  
Week 
132/ 
end of 
treatment
/early 
terminationd 
End of study 
(Follow-up) e 
 
Visit Day r 
1 
15 
29 
57 
85 
113 
141 
169 
197 
225 
253 
281 
309 
337 
421 
505 
589 
673 
757 
841 
-p 
28 days 
after end of 
treatment 
 
Allowable range 
from specified 
date 
- 
±3 
±7 
±7 
±7 
±7 
±7 
±7 
±7 
±7 
±7 
±7 
±7 
±7 
±14 
±14 
±14 
±14 
±14 
±14 
-p 
±7 
 
Assessment 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Informed consenta 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Inclusion/exclusion 
criteria 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Demographics/ 
medical history 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Weight  
X 
X 
X 
X 
X 
 
 
X 
 
 
X 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Xq 
Physical 
examination f 
X* 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Xq 
Vital signs 
X* 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Xq 
Laboratory test 
(blood/urine) g 
X* 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Xq 
Fasting lipid profile 
test h 
X* 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Xq 
CRP and ESR i 
X* 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Xq 
Pregnancy test j 
X* 
 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Xq 
12-Lead ECG k 
X 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
X 
 
 
X 
 
Xq 
Chest X-ray l 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Xq 
Disease activity 
assessment m 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
TJC/SJC 
X* 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Xq 
PGA and SGA 
(VAS) 
X* 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Xq 


Sponsor: Astellas Pharma Inc. 
ISN/Protocol <015K-CL-RAJ2> 
 
- CONFIDENTIAL - 
 
29 March 2019 (Ver. 7.0) 
Astellas 
Page 127 of 128 
Schedule 
Week 
0b 
Treatment Periodc 
Follow-up 
Period 
Unscheduled 
Visit 
Visit Timing 
Week 
2 
Week 
4 
Week 
8 
Week 
12 
Week 
16 
Week 
20 
Week 
24 
Week 
28 
Week 
32 
Week 
36 
Week 
40 
Week 
44 
Week 
48 
Week 
60 
Week 
72 
Week 
84 
Week 
96 
Week 
108 
Week 
120  
Week 
132/ 
end of 
treatment
/early 
terminationd 
End of study 
(Follow-up) e 
 
Visit Day r 
1 
15 
29 
57 
85 
113 
141 
169 
197 
225 
253 
281 
309 
337 
421 
505 
589 
673 
757 
841 
-p 
28 days 
after end of 
treatment 
 
Allowable range 
from specified 
date 
- 
±3 
±7 
±7 
±7 
±7 
±7 
±7 
±7 
±7 
±7 
±7 
±7 
±7 
±14 
±14 
±14 
±14 
±14 
±14 
-p 
±7 
 
Assessment 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
FACIT-Fatigue, 
SF-36® 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Xq 
HAQ-DI 
X* 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Xq 
Assessment of AEs 
and SAEs n 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
X 
X 
Confirm study drug 
prescriptions/ 
remaining drug 
residueso 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
Record concomitant 
medications and 
therapies 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
a. 
Be sure to obtain informed consent before beginning any of the procedures involved in the study. In principle, informed consent should be obtained at the 
Week 12 visit in study RAJ1.  
b. 
Assessments and tests performed at Week 0 should be performed on the same day as the Week 16 at end of study (day of follow-up) in study RAJ1. For 
items marked with the * symbol, the results of the assessments and tests performed at Week 16/end of study (at time of follow-up) in study RAJ1 may be 
used. 
c. 
From the time of the Week 48 visit onward, the subject should be contacted once a month to confirm the status of compliance with study drug dosing and 
the safety of the subject. Moreover, because this study will end at the point in time where the Phase III Study begins, the duration of the treatment period 
will differ depending upon the subject. Accordingly, the timing for the required visits to the study center will also differ from subject to subject. When 
administration of the study drug has ended, the assessments and tests scheduled to be performed at end of treatment and end of study (at time of follow-up) 
will be performed.  
d. 
The assessments and tests to be performed at end of treatment should be performed promptly after administration of the study drug has ended. If 
administration of the study drug has been terminated early, the assessments and tests specified to be performed at end of treatment/early termination should 


Sponsor: Astellas Pharma Inc. 
ISN/Protocol <015K-CL-RAJ2> 
 
- CONFIDENTIAL - 
 
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Astellas 
Page 128 of 128 
be performed within 2 days of the last dose of the study drug if possible. Moreover, even subjects who have had early termination during the scheduled 
treatment period should in principle visit the study center at end of study (at time of follow-up).  
e. 
The assessments and tests scheduled for end of study (at time of follow-up) should be performed 28 days after the visit at end of treatment. 
f. 
Confirmation of physical findings by questioning the subject during the physical examination should be performed at all study visits. A symptom directed 
physical examination for RA should also be performed at all study visits. See NOTE m with regard to the confirmation of RA symptoms.  
g. 
Hematology: Hemoglobin, hematocrit, RBC, WBC, WBC with differential, platelet count; Biochemistry: Na, K, Ca, Cl, Mg, HCO3, BUN, phosphorus, 
glucose, creatinine, ALP, AST (GOT), ALT (GPT), γ-GTP, TBL, total protein, albumin, uric acid, CPK, LDH, serum amylase, β-D-glucan (see Section 
5.4.4.1 for procedure at time of CPK elevation); Urinalysis: pH, specific gravity, protein, glucose, keton bodies, bilirubin, occult blood, and sediment  
h. 
Subject must fast for at least 8 hours prior to blood sampling for lipid profile (total cholesterol, low density lipoprotein [LDL], high density lipoprotein 
[HDL] and triglycerides [TGs]).  
i. 
CRP and ESR tests will be performed at each study visit. CRP test will be performed by the Central Laboratory; ESR test should be performed by each 
study center.  
j. 
A urine pregnancy test should be performed at the study visits every 12 weeks from Week 0 onward, as well as at end of treatment/early termination and 
end of study (at time of follow-up). If a urine pregnancy test is positive at any time, a negative serum pregnancy test is required for the subject to continue 
participation in the study. The pregnancy tests need not be performed if the possibility of pregnancy can clearly be ruled out, such as if the woman is 
postmenopausal and has not had a menstrual period for 1 year or more, or has had a hysterectomy, bilateral oophorectomy, etc.  
k. 
The 12-lead ECG exams must be performed at the study visits every 48 weeks from Week 0 onward, as well as at end of treatment/early termination. If a 
cardiovascular AE is observed, a 12-lead ECG may be performed at any time as necessary, even in an unscheduled visit. Clinical interpretation of the 
results of the 12-lead ECG at Week 0 must be completed prior to the first dose of the study drug. 
l. 
A chest X-ray will be taken during the study visit in Week 0. If a respiratory AE is observed, a chest X-ray may be taken at any time as necessary, even in 
an unscheduled visit. 
m. 
Assessment of disease activity: Physician – TJC (68 joints), SJC (66 joints), PGA (VAS); Subject – SGA (VAS), subject’s assessment of pain (VAS), 
Health Assessment Questionnaire – Disease Index (HAQ-DI), FACIT-Fatigue, and SF-36®. 
n. 
AEs must be collected from the time of the administration of the first dose of study drug to the end of all assessments at end of study (at time of follow-up).  
o. 
After all of the assessments and tests scheduled for Week 0 have been completed, the subjects will receive the first dose of the study drug at each study 
center.  
p. 
If the study is terminated before the Week 48 visit, the specified date for the study visit at end of treatment will be the date of the previous study visit + 28 
days (allowable range 7 days). If the study is terminated in or after the Week 48 visit, the specified date for the study visit at end of treatment will be the 
date of the previous visit 84 days (allowable range 14 days).  
q. 
For unscheduled visits, these assessments and tests should be performed only if clinically indicated as determined by the investigator.  
r. 
In principle, the subject should visit the study center on the specified date. If it is not possible for subjects to visit the study center on the specified date, the 
date of the visit should be adjusted to the date closest to the reference date as possible.  
 
( GPF 2.02 ) 

SAP_001.pdf: 
−Open-Label Extension Study in Rheumatoid Arthritis 
Patients Who Have Completed Phase IIb Study or Phase 
III Study of ASP015K−
ISN/Protocol 015K-CL-RAJ2
ClinicalTrials.gov Identifier: NCT01638013
Date of Statistical Analysis Plan: Final Version, dated 12
November 2019
Sponsor: Astellas Pharma Inc. (API)
2-5-1 Nihonbashi-Honcho, Chuo-ku, Tokyo


Sponsor: Astellas Pharma Inc.
SAP Final Version
ISN/Protocol 015K-CL-RAJ2
12-Nov-2019
Astellas
Page 1 of 94
STATISTICAL ANALYSIS PLAN
Final Version, dated 12-Nov 2019
Extension Study of ASP015K
Open-Label Extension Study in Rheumatoid Arthritis Patients Who Have Completed Phase 
IIb Study or Phase III Study of ASP015K
ISN: 015K-CL-RAJ2
Astellas Pharma Inc. (API)
This confidential document is the property of the sponsor.  No unpublished information 
contained in this document may be disclosed without prior written approval of the sponsor.


Sponsor: Astellas Pharma Inc.
SAP Final Version
ISN/Protocol 015K-CL-RAJ2
12-Nov-2019
Astellas
Page 2 of 94
Table of Contents
I.
LIST OF ABBREVIATIONS AND KEY TERMS··········································· 5
1
INTRODUCTION·················································································· 8
2
FLOW CHART AND VISIT SCHEDULE···················································· 9
3
STUDY OBJECTIVE(S) AND DESIGN······················································14
3.1
Study Objective(s) ············································································14
3.2
Study Design···················································································14
3.3
Randomization·················································································14
4
SAMPLE SIZE ····················································································15
5
ANALYSIS SETS ·················································································15
5.1
Full Analysis Set (FAS) ······································································15
5.2
Safety Analysis Set (SAF) ···································································15
5.3
Pharmacodynamic Analysis Set (PDAS)···················································15
6
ANALYSIS VARIABLES ·······································································16
6.1
Efficacy Endpoints············································································16
6.1.1
Categorical Variables ···································································16
6.1.2
Continuous Variables ···································································19
6.2
Safety Variables···············································································19
6.3
Pharmacokinetic Variables···································································19
6.4
Pharmacodynamic Variables ································································19
6.5
Other Variables················································································21
7
STATISTICAL METHODOLOGY ···························································22
7.1
General Considerations·······································································22
7.2
Study Population ··············································································25
7.2.1
Disposition of Subjects ·································································25
7.2.2
Demographic and Other Baseline Characteristics ···································26
7.2.3
Concomitant Medications ······························································28
7.3
Study Drugs····················································································29
7.3.1
Exposure··················································································29
7.3.2
Treatment Compliance··································································30
7.4
Analysis of Efficacy ··········································································30
7.4.1
Analysis of Efficacy Endpoint(s)······················································31


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7.4.2
Analysis by Treatment Sequence Set of preceding study···························31
7.4.3
Analysis of Efficacy in Initial/Maximum Dose Level ······························32
7.4.4
Influence of Dose Escalation···························································32
7.4.5
Subgroup Analysis ······································································32
7.5
Analysis of Safety·············································································33
7.5.1
Adverse Events ··········································································33
7.5.2
Clinical Laboratory Evaluation ························································37
7.5.3
Vital Signs················································································42
7.5.4
Electrocardiograms (ECGs)····························································42
7.5.5
Chest radiography ·······································································43
7.5.6
Pregnancies···············································································43
7.6
Analysis of PK·················································································43
7.7
Analysis of PD·················································································43
7.8
Subgroups of Interest ·········································································44
7.8.1
Subgroup analysis of the selected efficacy endpoint (ACR20-CRP) and 
treatment emergent adverse events····················································44
7.8.2
Subgroup analysis by Study Region (Japan, Korea, Taiwan)······················45
7.9
Other Analyses ················································································46
7.10
Interim Analysis (and Early Discontinuation of the Clinical Study)····················46
7.11
Handling of LLOQ, Missing Data, Outliers, Visit Windows, and Other 
Information ····················································································46
7.11.1
LLOQ·····················································································46
7.11.2
Missing Data ·············································································46
7.11.3
Outliers ···················································································48
7.11.4
Visit Windows ···········································································48
7.11.5
Handling of Schedule of Assessments of Efficacy Variables ······················49
7.11.6
Handling of Schedule of Assessments of Safety Variables ························52
7.11.7
Handling of Schedule of Assessments of Pharmacodynamic Variables ··········55
8
DOCUMENT REVISION HISTORY·························································56
9
REFERENCES ····················································································56
10
APPENDICES ·····················································································57
10.1
Appendix 1: Overview of Efficacy Endpoints·············································57
10.2
Appendix 2: Overview of AE analysis ·····················································66


Sponsor: Astellas Pharma Inc.
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Page 4 of 94
10.3
Appendix 3: Overview of Clinical Laboratory Evaluation, Vital Signs, and 
Electrocardiograms (ECGs) analyses·······················································69
10.4
Appendix 4: Computation of HAQ-DI Score··············································71
10.5
Appendix 5: Computation of SF-36v2® Score·············································74
10.6
Appendix 6: Computation of FACIT-Fatigue Scale Score·······························85
10.7
Appendix 7: Computation of WPAI Scale Score··········································87
10.8
Appendix 8: AE of Special Interest·························································88
10.9
Appendix 9: Standard Toxicity Grading for Laboratory Tests According to 
National Cancer Institute Common Terminology Criteria for Adverse Events 
(NCI-CTCAE) v4.0···········································································89
10.10
Appendix 10: Key Contributors and Approvers···········································93


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I.
LIST OF ABBREVIATIONS AND KEY TERMS
List of Abbreviations
Abbreviations
Description of abbreviations
ACR
American College of Rheumatology
AE
Adverse event
ALP
Alkaline phosphatase
ALT
Alanine aminotransferase (GPT) 
AST
Aspartate aminotransferase (GOT) 
ASP015K
Astellas Pharmaceuticals compound 015K
BUN
Blood urea nitrogen
CDAI
Clinical Disease Activity Index
CI
Confidence Intervals
CK/CPK
Creatine kinase/creatine phosphokinase
CK-MB
Creatine kinase MB isozyme
CRF
Case report form
CRO
Contract research organization
CRP
C-reactive protein
CSR
Clinical Study Report
DAS
Disease activity score
DMARD
Disease-modifying antirheumatic drug
DSMB
Data and Safety Monitoring Board
ECG
Electrocardiogram
eCRF
Electronic case report form
ESR
Erythrocyte sedimentation rate 
EU
European Union
EULAR
European League Against Rheumatism
FACIT-Fatigue
Functional Assessment of Chronic Illness Therapy-Fatigue
FAS
Full analysis set
FDA
Food and Drug Administration
GCP
Good Clinical Practice
GFR
Glomerular filtration rate
γ-GTP
γ-glutamyl transpeptidase (GGT)
H
High
HAQ-DI
Health Assessment Questionnaire – Disability Index 
ICH 
International Conference on Harmonization of Technical Requirements for 
Registration of Pharmaceuticals for Human Use 
INR
International normalized ratio 
ISN
International study number 
L
Low
LDL
Low-density lipoprotein
LLN 
Lower Limit of Normal
LLOQ
Lower limit of quantification
LOCF
Last observation carried forward 
MedDRA
Medical Dictionary for Regulatory Activities 
MTX
Methotrexate 
N
Normal


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Abbreviations
Description of abbreviations
NCI-CTCAE
National Cancer Institute Common Terminology Criteria for Adverse Events 
PD
Pharmacodynamic
PDAS
Pharmacodynamic Analysis Set
PGA
Physician's Global Assessment of Arthritis 
PK
Pharmacokinetic
PT
Preferred Term
PY
Patient-years
QD
Once a day
RA
Rheumatoid arthritis 
RBC
Red blood cell 
RCS
Role/social component score of the SF-36v2®
RF
Rheumatoid Factor
SAE
Serious adverse event 
SAF
Safety analysis set 
SAP
Statistical Analysis Plan
SAS 
Statistical Analysis Software
SDAI
Simplified Disease Activity Index 
SF-36v2®
Short form health survey – 36 questions, version 2: SF-36 v2®
SFL
Screening Failure Log 
SGA
Subject's Global Assessment of Arthritis
SGAP
Subject's Global Assessment of Arthritis Pain
SI
International System of Units
SJC
Swollen joint count 
SOC
System Organ Class
SOP
Standard operating procedure
TBL
Total bilirubin
TEAE
Treatment emergent adverse event
TJC
Tender joint count
TLF
Tables, Listings and Figures
TNF
Tumor necrosis factor
ULN
Upper limit of normal
VAS
Visual analog scale
WBC
White blood cell
WHO-DD
World Health Organization Drug Dictionary
WPAI
Work Productivity and Activity Impairment Questionnaire


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List of Key Terms
Terms
Definition of terms
Adverse event
An adverse event is as any untoward medical occurrence in a subject 
administered a study drug and which does not necessarily have a causal 
relationship with this treatment.
Baseline
The last measured values/findings prior to dosing.
There are 2 types of baseline as follow.
baseline of preceding study: baseline of RAJ1, RAJ3 or RAJ4 study.
Week 0: baseline of RAJ2
Study discontinuation
The act of concluding participation, prior to completion of all protocol-
required elements, in a study by an enrolled subject. Four categories of 
discontinuation are distinguished: a) dropout: Active discontinuation by a 
subject (also a noun referring to such a discontinued subject); b) 
discontinuation initiated by the investigator or other responsible personnel
(e.g., for cause); c) loss to follow-up: cessation of participation without 
notice or action by the subject; d) sponsor-initiated discontinuation.
Note that subject discontinuation does not necessarily imply exclusion of 
subject data from analysis.
Enroll
To register or enter into a clinical study; transitively and intransitively.
Informed consent precedes enrollment.
Follow-up period
The follow-up period begins at the completion of all 
assessments/measurements at end of treatment/early termination and ends 
upon completion of all assessments/measurements at end of study (at time 
of follow-up).
Serious adverse event
Any adverse event that is judged “serious” by the investigator/sub-
investigator or the sponsor and results in any of the following outcomes: 
death, a life-threatening condition, persistent or significant 
disability/incapacity or substantial disruption of the ability to conduct 
normal life functions, congenital anomaly/birth defect, hospitalization or 
prolongation of hospitalization, and other medically significant occurrences.
Screening failure
A subject from whom informed consent was obtained but who did not fulfill 
protocol inclusion and/or exclusion criteria and did not receive the study 
drug 
Study period
Period of time from obtaining informed consent from subjects to the end of 
the final evaluation/observation specified in the protocol
Subject
An individual who participates in a clinical study, as a recipient of either the 
test drug(s) or comparative drug(s)
Suspension
Suspension is defined as a temporary discontinuation of study drug administration 
for 7 days or less. 
If administration of the study drug is suspended repeatedly, the discontinuation of 
the clinical study for the particular subject should be considered in consultation with 
the sponsor. 
Interruption
Interruption is defined as a temporary discontinuation of study drug administration 
for a period exceeding 7 days.
Variable
Any quantity that varies; any attribute, phenomenon or event that can have 
different qualitative or quantitative values


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1
INTRODUCTION
This Statistical Analysis Plan (SAP) contains a more technical and detailed elaboration of the 
principal features of the analysis described in the protocol, and includes detailed procedures 
for executing the statistical analysis of the primary and secondary endpoints and other data. 
The SAP is finalized and signed prior to data lock. 
This statistical analysis is coordinated by the responsible biostatistician of GD, API. Any 
changes from the analyses planned in the SAP will be justified in the Clinical Study Report 
(CSR).


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2
FLOW CHART AND VISIT SCHEDULE
Flow Chart
NOTE 1: The study visit at Week 0 of this study
Will coincide with the day of the visit at Week 16/end of the study (follow-up) of study 
RAJ1,
Will coincide with the day of the visit at Week 52 of studies RAJ3 or RAJ4, or fall within 28 
days from the day of the visit at Week 52 of studies RAJ3 or RAJ4.
NOTE 2:
Subjects who transferred from study RAJ1 will be registered at Week 0 of the present 
extension study.
Subjects who plan to transfer from studies RAJ3 or RAJ4 will be registered at Week 52 of 
studies RAJ3 or RAJ4 to proceed to study RAJ2.
Start and End of Study
Start of Study: Point in time where informed consent is obtained from the first subject
End of Study: Point in time where final assessment specified in protocol has been performed 
in the last subject
Treatment period: Period from the initiation of administration of the study drug to completion 
of the tests and assessments stipulated at the end of treatment
●Obtain 
informed 
consent
●Complete 
studies RAJ1, 
RAJ3, or RAJ4
Treatment Period
Until approval.
Duration of treatment 
will differ depending 
on the subject.
Follow-up 
Period:
For 4 weeks 
after end of 
treatment
Day 1
(Week 0NOTE 1)):
●Confirmation of 
inclusion/exclusion 
criteria
●Case registrationNOTE 2)


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Schedule of Assessments
Schedule
Week 0b
Treatment Periodc
Follow-up 
Period
Unscheduled 
Visit
Visit Timing
Week 2v
Week 4v
Week 8v
Week 12
Week 16v
Week 20v
Week 24
Week 28v
Week 32v
Week 36
Week 40v
Week 44v
Week 48
Week 60
Week 72
Week 84
Week 96
Week 108
Week 120
Week 132w
End of 
treatment/ 
early 
terminationd
End of study 
(Follow-up)e
Visit Dayu
1
15
29
57
85
113
141
169
197
225
253
281
309
337
421
505
589
673
757
841
925
–s
28 days after 
end of 
treatment
Allowable range 
from specified date
–
±3
±7
±7
±7
±7
±7
±7
±7
±7
±7
±7
±7
±7
±14
±14
±14
±14
±14
±14
±14
–s
±7
Assessment
Informed consenta
X
Inclusion/exclusion 
criteria
X
Demographics/medica
l history
X
Weight
X*
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Xt
Physical examinationf
X*
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Xt
Vital signs
X*
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Xt
Laboratory test
(blood/urine)g
X*
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Xt
Fasting lipid profile 
testh
X*
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Xt
Blood sampling for 
pharmacodynamics
(lymphocyte subsets)m
X*
X
X
X
X
Xt
CRP and ESRi
X*
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Xt
Pregnancy testj
X*
X
X
X
X
X
X
X
X
X
X
X
X
X
Xt
12-Lead ECGk
X*
X
X
X
Xt
Chest radiographyl
X*
X
X
Xx
Xt
Disease activity 
assessmentn
TJC/SJC
X*
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Xt
PGA and SGA 
(VAS)
X*
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Xt
SF-36v2® (from 
study RAJ1)o
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Xt
SF-36v2® (from 
studies 
RAJ3/RAJ4)o
X*
X
X
X
X
X
X
Xt
HAQ-DI
X*
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Xt


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Schedule
Week 0b
Treatment Periodc
Follow-up 
Period
Unscheduled 
Visit
Visit Timing
Week 2v
Week 4v
Week 8v
Week 12
Week 16v
Week 20v
Week 24
Week 28v
Week 32v
Week 36
Week 40v
Week 44v
Week 48
Week 60
Week 72
Week 84
Week 96
Week 108
Week 120
Week 132w
End of 
treatment/ 
early 
terminationd
End of study 
(Follow-up)e
Visit Dayu
1
15
29
57
85
113
141
169
197
225
253
281
309
337
421
505
589
673
757
841
925
–s
28 days after 
end of 
treatment
Allowable range 
from specified date
–
±3
±7
±7
±7
±7
±7
±7
±7
±7
±7
±7
±7
±7
±14
±14
±14
±14
±14
±14
±14
–s
±7
Assessment
WPAIp (from 
studies RAJ3/RAJ4)
X*
X
X
X
X
X
X
Xt
Assessment of AEs 
and SAEsq
X
X
X
X
X
Confirm study drug 
prescription/remaining 
drugr
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Record concomitant 
medications and 
therapies
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
a.
Be sure to obtain informed consent before beginning any of the procedures involved in the study. Regarding subjects from study RAJ1, informed consent 
should be obtained at the Week 12 visit of study RAJ1 in principle. Informed consent from subjects who transferred from studies RAJ3 or RAJ4 should be 
obtained before completion of all assessments at Week 52 of studies RAJ3 or RAJ4.
b.
[Subjects who transferred from study RAJ1] The assessments and tests at Week 0 should be performed on the day of the visit at Week 16/end of study 
(follow-up) of study RAJ1. For items marked with the * symbol, the results of the assessments and tests performed at Week 16/end of study (at time of 
follow-up) in study RAJ1 may be used.
[Subjects who transferred from studies RAJ3 or RAJ4] The assessments and tests at Week 0 should be performed on the day of the Week 52 visit of studies 
RAJ3 or RAJ4 or within 28 days after the Week 52 visit. If the assessments and tests at Week 0 are performed on the day of the Week 52 visit, results of the
assessments and tests at Week 52 of studies RAJ3 or RAJ4 may be used regarding the items marked with the * symbol. If they are not performed on the 
same day as the Week 52 visit, results of the assessments and tests of studies RAJ3 or RAJ4 during the follow-up period may be used. Only regarding chest 
radiography, it is allowed to use data obtained within 28 days prior to the Week 0 visit if available.
c.
The subject should be contacted once a month to confirm the status of compliance with study drug dosing and the safety of the subject (subjects who 
transferred from study RAJ1 are to be contacted once a month from the time of the Week 48 visit onward). Because this study will end at the point in time 
when ASP015K is approved, the duration of treatment with the study drug will differ depending on the subject. Accordingly, the timing for the required 
visits to the study center will also differ from subject to subject. When administration of the study drug has ended, the assessments and tests scheduled to be 
performed at the end of treatment and end of study (at time of follow-up) will be performed.
d.
The assessments and tests to be performed at the end of treatment should be performed promptly after administration of the study drug has ended. If 
administration of the study drug has been terminated early, the assessments and tests specified to be performed at the end of treatment/early termination 


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should be performed within 2 days of the last dose of the study drug if possible. Moreover, even subjects who have had early termination during the 
scheduled treatment period should visit the study center at the end of study (at time of follow-up).
e.
The assessments and tests scheduled for end of study (at time of follow-up) should be performed 28 days after the visit at the end of treatment.
f.
Confirmation of physical findings by questioning the subject during the physical examination should be performed at all study visits. A symptom directed 
physical examination for RA should also be performed at all study visits. See NOTE n with regard to the confirmation of RA symptoms.
g.
Hematology: Hemoglobin, hematocrit, RBC, WBC, WBC with differential, platelet count; Biochemistry: Na, K, Ca, Cl, Mg, HCO3, BUN, phosphorus, 
glucose, creatinine, ALP, AST (GOT), ALT (GPT), γ-GTP, TBL, total protein, albumin, uric acid, CPK, LDH, serum amylase, β-D-glucan, eGFR (see 
Section 5.4.4.1 for procedure at time of CPK elevation); Urinalysis: pH, specific gravity, protein, glucose, keton bodies, bilirubin, occult blood, and 
sediment
h.
Subject must fast for at least 8 hours prior to blood sampling for lipid profile (total cholesterol, LDL, HDL and triglycerides [TGs]).
i.
CRP and ESR tests will be performed at each study visit. CRP test will be performed by the Central Laboratory; ESR test should be performed by each study 
center.
j.
A urine pregnancy test should be performed at the study visits every 12 weeks from Week 0 onward, as well as at the end of treatment/early termination and 
end of study (at time of follow-up). If a urine pregnancy test is positive at any time, a negative serum pregnancy test is required for the subject to continue 
participation in the study. The pregnancy tests need not be performed if the possibility of pregnancy can clearly be ruled out, such as if the woman is 
postmenopausal and has not had a menstrual period for 1 year or more, or has had a hysterectomy, bilateral oophorectomy, etc.
k.
The 12-lead ECG exams must be performed at the study visits every 48 weeks from Week 0 onward, as well as at the end of treatment/early termination. If a 
cardiovascular AE is observed, a 12-lead ECG may be performed at any time as necessary, even in an unscheduled visit. Clinical interpretation of the results 
of the 12-lead ECG at Week 0 must be completed prior to the first dose of the study drug.
l.
[Subjects who transferred from study RAJ1] Chest radiography is taken at the Week 0 visit.
[Subjects who transferred from studies RAJ3 or RAJ4] Chest radiography is taken at the Week 0 visit, or data obtained within 28 days prior to the Week 0 
visit may be used.
If a respiratory AE is observed, a chest radiography may be taken at any time as necessary, even in an unscheduled visit.
m.
Blood samples for pharmacodynamics (lymphocyte subset assay) are collected before the first dose of the study drug on the day of the Week 0 visit.
n.
Assessment of disease activity: Physician – TJC (68 joints), SJC (66 joints), PGA (VAS); Subject – SGA (VAS), subject's assessment of pain (VAS), 
HAQ-DI, WPAI, and SF-36V2®.
o.
SF-36v2® is administered every 4 weeks until Week 48 and every 24 weeks after Week 48 to subjects from study RAJ1 and every 24 weeks throughout the 
study period to subjects from studies RAJ3 or RAJ4.
p.
WPAI is administered only to subjects who transferred from studies RAJ3 or RAJ4.
q.
AEs must be collected from the time of the administration of the first dose of study drug to the end of all assessments at the end of study (at time of follow-
up).
r.
After all of the assessments and tests scheduled for Week 0 have been completed, the subjects will receive the first dose of the study drug at each study 
center.
s.
[Subjects who transferred from study RAJ1] If the study is terminated before the Week 48 visit, the specified date for the study visit at the end of treatment 
will be the date of the previous visit + 28 days (allowable range, ± 7 days). If the study is terminated in or after the Week 48 visit, the specified date for the 


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study visit at the end of treatment will be the date of the previous visit + 84 days (allowable range, ± 14 days).
[Subjects who transferred from studies RAJ3 or RAJ4] The specified date for the study visit at the end of treatment will be the date of previous study visit + 
84 days (allowable range, ± 14 days).
t.
For unscheduled visits, these assessments and tests should be performed only if clinically indicated as determined by the investigator.
u.
In principle, the subject should visit the study center on the specified date. If it is not possible for subjects to visit the study center on the specified date, the 
date of the visit should be adjusted to the date closest to the reference date as possible.
v.
Only subjects who transferred from study RAJ1 should make study visits at Weeks 2, 4, 8, 16, 20, 28, 32, 40, and 44.
w.
At visits after Week 132, the tests and assessments shall be performed in the same manner as scheduled for Weeks 96 to 132. 
x.
Chest radiography at the end of treatment/early termination is not necessary if one has been taken within 24 weeks from the day of the end of treatment/early 
termination.


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3
STUDY OBJECTIVE(S) AND DESIGN
3.1
Study Objective(s)
This is an extension study conducted in RA patients who have completed the Phase IIb Study 
of ASP015K [015K-CL-RAJ1 (hereinafter referred to as study RAJ1)], Phase III Study of 
ASP015K [015K-CL-RAJ3 (RAJ3)], or Phase III Study of ASP015K [015K-CL-RAJ4 
(RAJ4)] to investigate the safety and efficacy of long-term administration of ASP015K.
Another objective of this study is to devise rescue measures for providing the active drug to 
patients who participated in the Phase IIb Study or Phase III Study of ASP015K, as described 
in the “Guidelines on methodology for clinical assessment of antirheumatic drugs” 
(PFSB/ELD Notification No. 0217001, dated 17 February, 2006).
3.2
Study Design
This study is an extension study conducted as an open-label, multicenter study in RA patients 
who have completed studies RAJ1, RAJ3, or RAJ4.
Patients who meet all the inclusion criteria and do not fall under any of the exclusion criteria 
will receive oral ASP015K 100 mg QD after breakfast as the starting dose. Subjects who 
have no safety problems but show lack of efficacy may later increase the dose to 150 mg/day. 
After the increase, the dosage may be reduced from 100 mg/day or 150 mg/day to 50 mg/day 
at the discretion of the investigator or sub-investigator. The starting dose for subjects who 
transferred from study RAJ1 is 50 mg/day. For subjects who transferred from study RAJ1 
and are continuing to receive 50 mg/day, treatment extension using a dose of 50 mg/day 
should be allowed when the investigator or sub-investigator considers a dose increase to be 
inappropriate in terms of safety and treatment extension with a dose of 50 mg/day to provide 
greater therapeutic benefit for the treatment of RA.
Because this study will end at the point in time when ASP015K is approved, the duration of 
treatment with the study drug will differ depending on the subject. To prevent purposeless 
continuation of dosing without effect, the investigator or sub-investigator will assess each 
subject for efficacy and safety at each visit, confirm the appropriateness of continued 
administration for each individual, and decide whether or not to continue dosing.
3.3
Randomization
Not applicable.


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4
SAMPLE SIZE
Approximately 800 treated patients
[Rationale for the sample size]
The sample size estimation is based on the number of subjects who have completed the 
preceding study of ASP015K (Study 015K-CL-RAJ1) and participate in this extension study 
(201 subjects), the planned number of subjects in Study 015K-CL-RAJ3 excluding those in 
the reference group (300 subjects), and the planned number of subjects in Study 015K-CL-
RAJ4 (510 subjects).
5
ANALYSIS SETS
In accordance with International Conference on Harmonization (ICH) recommendations in 
guidelines E3 and E9, the following analysis sets will be used for the analyses.
5.1
Full Analysis Set (FAS)
The FAS is defined as all subjects who receive at least one dose of study drug and have 
measurements for any of the efficacy endpoints.
5.2
Safety Analysis Set (SAF)
The SAF is defined as all subjects who received at least one dose of the study drug.
5.3
Pharmacodynamic Analysis Set (PDAS)
The PDAS is defined as all subjects who receive at least one dose of the study drug and from 
whom a pharmacodynamics sample is collected at one or more points of time.


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6
ANALYSIS VARIABLES
6.1
Efficacy Endpoints
6.1.1
Categorical Variables
●
Percentage of subjects achieving ACR 20/50/70-CRP response at each analysis visit
●
Percentage of subjects achieving ACR 20/50/70-ESR response at each analysis visit
Definition ACR20 response rate:
It is defined as percentage of subjects achieving ACR 20 response at each study visit, 
based on C-reactive protein (CRP). ACR20 is a binary variable, with levels responder and 
non-responder.
Responder : 
A subject will be defined as an ACR20-CRP responder at any time point (e.g. Week 12)
if the subject meets ALL the following American College of Rheumatology (ACR) 
response criteria:
•
At least 20% reduction from baseline at the time point (e.g. Week 12) in the number of 
68 tender joint count (TJC-68)
AND
•
At least 20% reduction from baseline at the time point (e.g. Week 12) in the number of 
66 swollen joint count (SJC-66)
AND
•
At least 20% reduction from baseline at the time point (e.g. Week 12) in ANY 3 or more 
of the 5 following ACR components 
○
Subject's global assessment of arthritis pain (SGAP) (assessed using a 100 mm VAS 
; score of 0 indicates no pain, and score of 100 indicates very severe pain)
○
Subject's global assessment of arthritis (SGA) (assessed using a 100 mm VAS; score 
of 0 indicates no disease activity, and score of 100 mm indicates very severe disease 
activity)
○
Physician's global assessment of arthritis (PGA) (assessed using a 100 mm VAS; 
score of 0 indicates no disease activity, and score of 100 mm indicates very severe 
disease activity)
○
Health Assessment Questionnaire – Disease Index (HAQ-DI; score ranges from 0 to 
3 with higher scores indicating greater disability)
○
CRP  (Higher values indicate greater inflammation)
Values at the baseline in the preceding studies (RAJ1, RAJ3, and RAJ4) will be used as the 
baseline values. A negative percent change indicates a reduction from baseline (i.e., a 
favorable outcome). If the baseline value is 0 in some of ACR components, then that 


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component is not included in ACR calculation at any visit and ACR response is calculated 
based on remaining non-missing components. 
Non-responder: A subject will be defined as an ACR20-CRP non-responder at the time point
(e.g. Week 12), if the subject does not meet the ACR20-CRP responder criteria. 
Note: ACR 20/50/70-ESR response is similar to the above by replacing CRP with ESR.
●
Percentage of subjects achieving DAS28-CRP score <2.6 at each analysis visit
●
Percentage of subjects achieving DAS28-ESR score <2.6 at each analysis visit
●
Percentage of subjects achieving DAS28-CRP score <=3.2 at each analysis visit
●
Percentage of subjects achieving DAS28-ESR score <=3.2 at each analysis visit
Calculation DAS28-CRP/ESR response:
DAS28-CRP/ESR response is consist of following parameters, and calculated according to 
below description.
o
TJC (28 joints)
o
SJC (28 joints)
o
CRP or ESR
o
SGA
Note: CRP values measured in mg/dL will be converted to mg/L for analysis purposes as:  
value in mg/L = value in mg/dL × 10; SGA is measured on 100 mm VAS. If any component 
is a missing value, then DAS28-CRP/ESR will be a missing value. If ESR is 0 then DAS28-
ESR is missing.
●
Percentage of subjects in DAS28-CRP EULAR response criterion of "Good Response" 
at each analysis visit
●
Percentage of subjects in DAS28-ESR EULAR response criterion of "Good Response" 
at each analysis visit 
●
Percentage of subjects in DAS28-CRP EULAR response criterion of "Good Response" 
or "Moderate Response" at each analysis visit 
●
Percentage of subjects in DAS28-ESR EULAR response criterion of "Good Response" 
or "Moderate Response" at each analysis visit
[When CRP is used]
DAS28 = 0.56√(TJC) + 0.28√(SJC) + 0.36 ln (CRP + 1) + 0.014 × SGA + 0.96
[When ESR is used]
DAS28 = 0.56√(TJC) + 0.28√(SJC) + 0.70 ln ESR + 0.014 × SGA


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Definition EULAR response:
DAS28 after treatment
DAS28 improvement (DAS28 before treatment - DAS28 after treatment)
> 1.2
> 0.6 and <=  1.2
<= 0.6
<= 3.2
Good response
Moderate response
No response
> 3.2 and <=  5.1
Moderate response
Moderate response
No response
> 5.1
Moderate response
No response
No response
●
Percentage of subjects achieving ACR/EULAR score for remission at each analysis visit
If all of the following 4 parameters are fulfilled, it is defined as remission: 
o
TJC (68 joints) <= 1
o
SJC (66 joints) <= 1
o
CRP <= 1 mg/dL
o
SGA <= 1 cm (on a VAS of 0-100 mm)
Note: All 4 conditions must be fulfilled to be in remission. If any component is a missing 
value, then ACR/EULAR score for remission will be a missing value.
●
Percentage of subjects with a simplified disease activity index (SDAI) score  of <= 3.3 at 
each analysis visit
SDAI score is consist of following parameters, and calculated according to below 
description.
o
TJC (28 joints)
o
SJC (28 joints)
o
SGA (0-10 cm VAS)
o
PGA (0-10 cm VAS)
o
CRP (mg/dL)
SDAI = TJC +SJC +SGA +PGA + CRP
Note: If any component is a missing value, then SDAI score will be a missing value.
●
Percentage of subjects with a CDAI score  of <= 2.8 at each analysis visit
CDAI score is consist of following parameters, and calculated according to below 
description.
o
TJC (28 joints)
o
SJC (28 joints)
o
SGA (0-10 cm VAS)
o
PGA (0-10 cm VAS)
CDAI = TJC +SJC +SGA +PGA 
Note: If any component is a missing value, then CDAI score will be a missing value.
●
Percentage of subjects achieving HAQ-DI (<=0.5) at each analysis visit
●
Percentage of subjects achieving decrease of baseline HAQ-DI of at least 0.22 at each 
analysis visit


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●
Percentage of subjects achieving SF-36v2 of difference >= 5 at each visit
6.1.2
Continuous Variables
●
Raw value and change from baseline in the following assessments:
o
TJC (68 joints)
o
SJC (66 joints)
o
CRP 
o
ESR 
o
SGAP (VAS) (100 mm VAS)
o
SGA (VAS) (100 mm VAS)
o
PGA (VAS) (100 mm VAS)
o
HAQ-DI (See Section 10.5 Appendix 5: Computation of HAQ-DI Score)
o
DAS28-CRP score
o
DAS28-ESR score
o
SF-36v2®
o
SDAI score 
o
CDAI score 
o
FACIT-Fatigue Score (only for subjects who transferred from study RAJ1. See 
Section 10.6 Appendix 6: Computation of FACIT-Fatigue Scale Score)
o
WPAI score (only for subjects who transferred from studies RAJ3 or RAJ4. See 
Section 10.7 Appendix 7: Computation of WPAI Scale Score)
6.2
Safety Variables
●
AEs
●
Vital signs (body temperature, pulse rate and blood pressure in sitting position)
●
Body weight
●
12-lead ECG
●
Chest radiography
●
Laboratory assessments
6.3
Pharmacokinetic Variables
Refer to PK analysis plan.
6.4
Pharmacodynamic Variables
●
Change from baseline for following variables in lymphocyte subset assays 
1. Japan
○CD3+/Lymphocytes (%), CD3+ (cells/uL)
○CD8+/Lymphocytes (%), CD8+ (cells/uL)


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○CD4+/Lymphocytes (%), CD4+ (cells/uL)
○CD19+/Lymphocytes (%), CD19+ (cells/uL)
○CD4/CD8 Ratio
○
(CD16 or CD56)+/Lymphocytes (%), (CD16 or CD56)+ (cells/uL)
○
(CD16+ and CD56+)/CD3- (%), CD16+ and CD56+ (cells/uL)
○(CD16- and CD56+)/CD3- (%), CD16- and CD56+ (cells/uL)
○(CD16+ and CD56-)/CD3- (%), CD16+ and CD56- (cells/uL)
○(CD16- and CD56-)/CD3- (%), CD16- and CD56- (cells/uL)
○CD56 bright/CD3- (%), CD56 bright (cells/uL)
○CD56 dim/CD3- (%), CD56 dim (cells/uL)
2. Korea
○CD3+/Lymphocytes (%), CD3 (cells/uL)
○(CD3+ and CD8+)/CD3+ (%), CD3+ and CD8+ (cells/uL)
○(CD3+ and CD4+)/CD3+ (%), CD3+ and CD4+ (cells/uL)
○(CD16 or CD56)+/CD3- (%), (CD16 or CD56)+ (cells/uL)
○CD19+/CD3- (%), CD19+ (cells/uL)
○CD4/CD8 Ratio
○(CD16+ and CD56+)/CD3- (%), CD16+ and CD56+ (cells/uL)
○(CD16- and CD56+)/CD3- (%), CD16- and CD56+ (cells/uL)
○(CD16+ and CD56-)/CD3- (%), CD16+ and CD56- (cells/uL)
○(CD16- and CD56-)/CD3- (%), CD16- and CD56- (cells/uL)
3. Taiwan
○CD3+/Lymphocytes (%), CD3 (cells/uL)
○(CD3+ and CD8+)/Lymphocytes (%), CD3+ and CD8+ (cells/uL)
○(CD3+ and CD4+)/Lymphocytes (%), CD3+ and CD4+ (cells/uL)
○(CD16 or CD56)+/Lymphocytes (%), (CD16 or CD56)+ (cells/uL)
○CD19+/Lymphocytes (%), CD19+ (cells/uL)
○CD4/CD8 Ratio
○(CD16+ and CD56+)/Lymphocytes (%), CD16+ and CD56+ (cells/uL)
○(CD16- and CD56+)/Lymphocytes (%), CD16- and CD56+ (cells/uL)
○(CD16+ and CD56-)/Lymphocytes (%), CD16+ and CD56- (cells/uL)


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○(CD16- and CD56-)/Lymphocytes (%), CD16- and CD56- (cells/uL)
6.5
Other Variables
●
Date of Last Dose of Study Drug:
If date of last dose of study is unknown, the date will be imputed by date of withdrawal.
●
Duration of RA at baseline of preceding study (years), calculated as: (Date of Screening 
visit of preceding study – Onset Date of RA +1) / 365.25, and then rounded to one 
decimal place. The onset date of RA doesn't have the day (e.g., 2013-03), therefore the 
first day of the month will be used (2013-03-01). 
Missing onset date of RA will be imputed. For example, if month is missing (e.g., 2013), 
then the first day of January will be used (2013-01-01). 
●
Age at Week 0 (years), calculated as: integer part of (Date of Week 0 visit – date of birth 
+1) / 365.25.
●
Duration of exposure during RAJ2 (months)
Duration of exposure during RAJ2 will be calculated in days, using the following 
formula:
(('Date of Last Dose of Study Drug'* - 'Date of First Study Drug Taken at RAJ2'**) + 
1)/30.4375
*: DSLDT [End of Study-page of the CRF].
**: EXSTDT [Date of First Study Drug Taken -page of the CRF]
●
Treatment compliance during RAJ2 (%)
Treatment compliance will be based on number of tablets and calculated as follows: 
Treatment compliance (%) =
[Total number of tablets actually received in the treatment period] 
--------------------------------------------------------------------------------------------x 100
[Total number of tablets planned to receive in the treatment period]
Where total number of tablets planned to receive in the treatment period is calculated as 
below: ∑{(number of tablets per administration#) x (duration of administration##)} in 
ASP015K 50,100, 150 mg. It will be summed up to Date of Last Dose of Study Drug.
#: refer to the table below; differ depending on the protocol version
##: summarized by dose level [ASP015K 50,100, 150 mg], by protocol version [Ver. 1.0, 
On and After Ver. 2.0]
Protocol Version
Ver. 1.0
On and After Ver. 2.0
Dose per administration
50 mg
100 mg
50 mg
100 mg
150 mg
Number of tablets per administration
3 tablets
4 tablets
1 tablets
1 tablets
1 tablets


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And total number of tablets actually received in the treatment period will be calculated 
as: (total number of tablets dispensed) – (total number of tablets returned) – (total 
number of tablets lost) up to Date of Last Dose of Study Drug. After study completion 
and data base is locked, all data will be used to calculate the compliance.
●
Number of prior DMARD biologics, According to the preceding study
●
Prior Biologic DMARD-IR, According to the preceding study
7
STATISTICAL METHODOLOGY
7.1
General Considerations
●
For continuous variables, descriptive statistics will include the number of subjects (n), 
mean, standard deviation (SD), median, minimum, and maximum. 
●
For categorical variables: number and percentages of subjects will be described.
●
For time-to-event variables: number and percentage of subjects with the event using 
Kaplan-Meier method, the cumulative event rate will be estimated and a plot will be 
constructed.
●
All data processing, summarization, and analyses will be performed using SAS Drug 
Development (ver. 4.5), and PC-SAS (ver. 9.4) or higher versions. 
●
Specifications for table, figures, and data listing formats can be found in the TLF 
specifications for this study.
●
For the definition of subgroups of interest can be referred to Section 7.8.
●
Summaries based on FAS and SAF (e.g. disposition, baseline, efficacy data and safety 
data) will be presented by preceding studies and overall, unless specifically stated 
otherwise. 
●
Medical Dictionary for Regulatory Activities (MedDRA) 11.1 will be used as the coding 
dictionary for adverse event and medical history.
●
Confidence interval for binary outcome is continuity corrected in all analysis.
●
For the analyses of efficacy and pharmacodynamics variables in this extension study, 
values at the baseline in the preceding studies (RAJ1, RAJ3, and RAJ4) will be used as 
the baseline values. However, changes from baseline values of this extension study will 
also be examined where appropriate. For the analyses of safety, Week 0 of this extension 
study will be referred to as the baseline; however, changes from baseline values of the 
preceding studies (RAJ1, RAJ3, and RAJ4) will also be examined where appropriate.
●
Change from baseline to post-baseline will be calculated as: post-baseline value -
baseline value. If the baseline value is missing, then that subject is not included in the 
calculation at any visit. 
●
Percent change from baseline to post-baseline will be calculated as: 100 × (change 
/baseline). If the baseline value is 0 or missing, or post-baseline value is missing, then 
percent change from baseline to post-baseline is missing. 
●
The values below the lower limit of quantitation (BQL) for β-D-glucan, hCG, Troponin, 
CK-MB will be treated as it is and these variables are not used for descriptive statistics 


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and displayed in the listings. As for β-D-glucan, it is used for shift-from baseline 
analysis.
●
If CRP value (mg/dL) is the lower or equal limit of quantitation (i.e. <0.01 mg/dL or 
=<0.01 mg/dL) then CRP is regarded as 0.01 mg/dL, and used for the calculation of 
DAS28-CRP, etc. and categorized in <0.01 mg/dL.
●
If ESR value (mm/hr) is the upper limit of quantitation (i.e. >=100 mm/hr) then ESR is 
regarded as 100 mm/hr, and used for the calculation of DAS28-ESR.
●
Treatment Sequence Set of preceding study will be used for the analysis by preceding 
study. This set takes into consideration the initial treatment groups (in RAJ1), a switch 
from placebo to active treatment at Week 12 (in RAJ3), and a switch from placebo to 
active treatment at Week 12 or Week 28 (in RAJ4). For subjects in each preceding study, 
following groups are defined:
Treatment Sequence Set for RAJ1
Treatment Sequence
Code
Treatment Sequence
Label
initial treatment 
group
SEQ J1-1
25mg
ASP015K 25mg
SEQ J1-2
50mg
ASP015K 50mg
SEQ J1-3
100mg
ASP015K 100mg
SEQ J1-4
150mg
ASP015K 150mg
SEQ J1-5
Placebo
Placebo
○
25 mg: subjects who initially treated as ASP015K 25 mg Group
○
50 mg: subjects who initially treated as ASP015K 50 mg Group
○
100 mg: subjects who initially treated as ASP015K 100 mg Group
○
150 mg: subjects who initially treated as ASP015K 150 mg Group
○
Placebo: subjects who initially treated as Placebo Group
Treatment Sequence Set for RAJ3
Treatment Sequence
Code
Treatment Sequence
Label
Week 0- Week 12
Week 12- Week 52
SEQ J3-1
100mg
ASP015K 100 mg
ASP015K 100 mg
SEQ J3-2
150mg
ASP015K 150 mg
ASP015K 150 mg
SEQ J3-3
Placebo to 100mg at 
Week 12
Placebo
ASP015K 100 mg
SEQ J3-4
Placebo to 150mg at 
Week 12
Placebo
ASP015K 150 mg
SEQ J3-5
Etanercept
Etanercept
Etanercept
○
100 mg: subjects who initially treated as ASP015K 100 mg Group
○
150 mg: subjects who initially treated as ASP015K 150 mg Group
○
Placebo to 100 mg at Week 12: subjects who initially treated as Placebo group and 
switched ASP015K 100 mg at Week 12 and at least one dose of ASP015K 100 mg
drug after switched


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○
Placebo to 150 mg at Week 12: subjects who initially treated as Placebo group and 
switched ASP015K 150 mg at Week 12 and at least one dose of ASP015K 150 mg
drug after switched
○
Etanercept: subjects who initially treated as Etanercept Group. Subjects in this group 
do not shift to this study.
Treatment Sequence Set for RAJ4
Treatment 
Sequence 
Code
Treatment 
Sequence Label
Week 0- Week 12
Week 12- Week 28
Week 28- Week 52
SEQ J4-1
100mg
ASP015K 100 mg
ASP015K 100 mg
ASP015K 100 mg
SEQ J4-2
150mg
ASP015K 150 mg
ASP015K 150 mg
ASP015K 150 mg
SEQ J4-3
Placebo to 100mg 
at Week 12
Placebo
ASP015K 100 mg
ASP015K 100 mg
SEQ J4-4
Placebo to 150mg 
at Week 12
Placebo
ASP015K 150 mg
ASP015K 150 mg
SEQ J4-5
Placebo to 100mg 
at Week 28
Placebo
Placebo
ASP015K 100 mg
SEQ J4-6
Placebo to 150mg 
at Week 28
Placebo
Placebo
ASP015K 150 mg
○
100 mg: subjects who initially treated ASP015K 100 mg
○
150 mg: subjects who initially treated ASP015K 150 mg
○
Placebo to 100 mg at Week 12: subjects who initially treated Placebo group and 
switched 100 mg at Week 12 and at least one dose of ASP015K 100 mg drug after 
switched
○
Placebo to 150 mg at Week 12: subjects who initially treated Placebo group and 
switched ASP015K 150 mg at Week 12 and at least one dose of ASP015K 150 mg
drug after switched
○
Placebo to 100 mg at Week 28: subjects who initially treated Placebo group and 
switched ASP015K 100 mg at Week 28 and at least one dose of ASP015K 100 mg
drug after switched
○
Placebo to 150 mg at Week 28: subjects who initially treated Placebo group and 
switched ASP015K 150 mg at Week 28 and at least one dose of ASP015K 150 mg
drug after switched
●
If onset date of AE is Unknown, then missing onset date of AE will be imputed as 
following steps. 
1.
If only the day of the month is missing (e.g., 2013-03), then the first day of the 
month will be used (2013-03-01), 
2.
If both day and month are missing (e.g., 2013), then the first day of January will be 
used (2013-01-01).
3.
If day, month and year are missing, then the first date of study drug will be used.
4.
If imputed onset date of AE is earlier than the first date of study drug, 
[Adverse Events(From RAJ2) -page of the CRF]


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then the onset date of AE will be re-imputed by the same date as the first date of 
study drug at RAJ2.
[Adverse Events(From RAJ1)/(From RAJ3 or RAJ4) -page of the CRF]
then the onset date of AE will be re-imputed by the same date as the first date of 
study drug at the preceding study.
7.2
Study Population
These analyses will be also conducted for overall by Study Region.
7.2.1
Disposition of Subjects
[Analysis Set: All Subjects with Informed Consent]
The following subject data will be summarized and presented:
●
Screened
●
Screen failed
●
Dosed
[Analysis Set: All Dosed Subjects]
The following subject data will be summarized and presented:
●
Subjects who prematurely discontinued from the study period during overall period
●
In addition, subjects who prematurely discontinued from the study period will be 
summarized for primary reason for withdrawal during overall period.
●
Subjects who prematurely discontinued from the study period up to 84 months, each 
interval are as follows:
●
In addition, subjects who prematurely discontinued from the study period will be 
summarized for primary reason for withdrawal up to 84 months
○
0 – 1 month
○
1 <- 3 months
○
3 <- 6 months
○
6 <- 12 months
○
12 <- 24 months
○
24 <- 36 months
○
36 <- 48 months
○
48 <- 60 months
○
60 <- 72 months
○
72 <- 84 months
○
84 months <
●
Subjects who included/excluded of FAS, SAF, and PDAS


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●
In addition, subjects who were excluded from FAS, SAF, and PDAS will be summarized
by reason for exclusion
[Analysis Set: Subject who experienced dose decrease to 50 mg]
The following subject data will be summarized and presented:
●
Subjects who prematurely discontinued from the study period during overall period
●
In addition, subjects who prematurely discontinued from the study period will be 
summarized for primary reason for withdrawal during overall period.
7.2.2
Demographic and Other Baseline Characteristics
7.2.2.1 Demographics
[Analysis Set: FAS, SAF, PDAS]
The following demographic variables will be summarized. 
Demographic Variables
Item
Classification
Age (years) at Week 0
Measurement value
<65, >= 65
Sex
Male, Female
Body Weight (kg) at Week 0
Measurement value
<- 40 kg,
40 kg <- 60 kg,
60 kg <- 80 kg,
> 80 kg
Complications at Week 0
No, Yes
Concomitant Medications at Week 0
No, Yes
Concomitant DMARD at Week 0
No, Yes
Concomitant MTX at Week 0
No, Yes
Concomitant DMARD category at Week 0
MTX, DMARD except for MTX only, 
None
Concomitant Steroid at Week 0
No, Yes
Prednisone dose (mg/day) at Week 0
Measurement value
None, 0 =< 5 mg/day, > 5 mg/day
Study Region
Japan, Korea, Taiwan
7.2.2.2 Baseline Disease Activity
[Analysis Set: FAS, SAF, PDAS]


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The following baseline disease activity variables will be summarized by descriptive statistics. 
The summaries will be presented for values at both “Week 0” and “baseline of preceding 
study”.
○
TJC-68
○
TJC-28
○
SJC-66
○
SJC-28
○
SGAP (100 mm VAS)
○
SGA (100 mm VAS)
○
PGA (100 mm VAS)
○
HAQ-DI (scale 0 - 3)
○
CRP (mg/dL)
○
ESR (mm/hr)
○
DAS28-CRP
○
DAS28–ESR
○
SDAI score 
○
CDAI score 
○
WPAI (only for subjects who transferred from studies RAJ3 or RAJ4)
○
SF-36V2®
In addition, following baseline efficacy categorical variables will be summarized as well. 
○
Baseline CRP (< 1.0, >= 1.0)
○
Baseline DAS28-CRP/ ESR (<= 3.2, 3.2<-5.1, > 5.1)
7.2.2.3 RA History
[Analysis Set: SAF]
The following RA history variables will be summarized. The summaries will be presented for 
values at both "Week 0" and "baseline of preceding study", unless specifically stated 
otherwise.
RA History and Analysis Methods
Item
Classification
ACR 1991 Revised Criteria for Global Functional 
Status in RA
Class I, Class II, Class III, Class IV
Steinbrocker Classification
Stage I, Stage II, Stage III, Stage IV
Duration of RA (years) #
Measurement value
< 5 years, >- 5 years 
< 1 year,
1 year -<5 years,


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#: only for baseline of preceding study
7.2.2.4 Medical Condition
[Analysis Set: SAF]
Medical Conditions at "baseline of preceding study" will be coded using MedDRA (Version 
11.1) and summarized. 
7.2.3
Concomitant Medications
[Analysis Set: SAF]
Previous DMARD medications up to Screening of preceding study will be summarized as 
described in 7.2.2.3.
For subjects who shift from RAJ3/4, concomitant medications (Non-Biologic DMARD/ 
Medications except for Non-Biologic DMARD) will be coded using WHODDE (B2) 
(V2011SEP) and summarized with preferred WHO name, respectively from following CRF 
page. Concomitant medications are defined as any drug medications after the first dose of 
study drug at RAJ2 up to the end of study.
●
Concomitant Medication 2B -page of the CRF
●
Concomitant Medication (Non-Biologic DMARD) -page of the CRF
5 years -< 10 years,
>- 10 years
Prior MTX #
Use
Non-User, User
Maximum Dose (mg/week)
Measurement value
Reactivity
Response, Inadequate Response, 
Unknown
Tolerance
Intolerance, Tolerance, Unknown
MTX Dose (mg/week) at Week 0
Measurement value
None,
0 <- 8  mg/week, 
8 <- 12 mg/week, 
> 12      mg/week
Prior Non-Biologic DMARD 
Except for MTX #
Use
Non-User, User
Prior Anti-TNF DMARD Use
#
Use
Non-User, User
Prior Biologic DMARD #
Use
Non-User, User
Reactivity
Response, Inadequate Response, 
Unknown
Prior Biologic DMARD-IR #
No, Yes
Number of Prior Biologic DMARDs #
0, 1, 2, >= 3
Number of Prior DMARDs (including biologics) #
0, 1, 2, >= 3


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Subjects taking the same medication multiple times will be counted once per medication.
In addition to this, the maximum/ minimum MTX Dose (mg/week) during the study period
will be summarized by descriptive statistics.
7.3
Study Drugs
These analyses will be also conducted for overall by Study Region.
7.3.1
Exposure
[Analysis Set: SAF]
Duration of exposure during RAJ2 will be summarized in two ways.
●
Descriptive statistics will be presented
●
Exposure time for overall period will be categorized according to the following 
categories:
○
0 – 1 month
○
1 <- 3 months
○
3 <- 6 months
○
6 <- 12 months
○
12 <- 24 months
○
24 <- 36 months
○
36 <- 48 months
○
48 <- 60 months
○
60 <- 72 months
○
72 <- 84 months
○
84 months <
Counts and percentages of subjects in each category will be summarized.
In addition to this, the following information on drug exposure will be presented:
●
Number and percent of subject with dose increase/ dose decrease/ drug suspension/ drug
interruption
●
Number of experience for dose increase/ dose decrease/ drug suspension/ drug 
interruption per subject
●
Duration from First Study Drug Taken up to First Dose Change to ASP015K 100 mg 
(from RAJ1) or 150 mg (from RAJ3/RAJ4) 
●
Maximum Dose of Study Drug (ASP015K 50 mg/ 100 mg/ 150 mg)
The following Kaplan-Meier plot of time-to-event from initial dose will be constructed.


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Event
Censor
Time to changing initial 
50mg
RAJ1
Dose increase
Discontinuation
Study 
Completion
Time to changing initial 
100mg
RAJ3/4
Dose increase
Dose decrease
Discontinuation
Study 
Completion
Time to dose increasing 
initial 100mg
RAJ3/4
Dose increase
Study 
Completion
Discontinuation
Dose decrease
Time to dose decrease 
initial 100mg
RAJ3/4
Dose decrease
Study 
Completion
Discontinuation
Dose increase
7.3.2
Treatment Compliance
[Analysis Set: SAF]
Treatment compliance during RAJ2 will be examined for subjects in the SAF whose total 
study drug count and first and last days of treatment are known. These data will be 
summarized as below.
●
Descriptive statistics for treatment compliance during RAJ2 will be presented.
●
Treatment compliance during RAJ2 will be categorized according to the following 
categories:
○
<50%
○
50% - <75% 
○
75% - <90%
○
90% - 100% 
7.4
Analysis of Efficacy
[Analysis Set: FAS]
Details for analysis of efficacy will be described in 10.1 Appendix 1: Overview of Efficacy 
Endpoints. They include categorical, and continuous variables, with "X" indicating that the 


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variable will be analyzed. Basically, analysis of efficacy will be performed by preceding 
studies only, not performed by overall.
7.4.1
Analysis of Efficacy Endpoint(s)
The efficacy variables and analyses are as follows.
●
Categorical variables at each visit will be summarized. 
●
For continuous variables, raw value and change from baseline of preceding study at each 
visit will be summarized by descriptive statistics. In addition, for the selected efficacy 
variables (DAS28-CRP), change from Week 0 at each visit will be summarized similarly.
●
Graphical analysis:
○
ACR20/50/70-CRP/ESR will be plotted for over time. 
○
The mean-standard deviation plot of actual values and changes from baseline of 
preceding study will be presented for DAS28-CRP and DAS28-ESR.
7.4.2
Analysis by Treatment Sequence Set of preceding study
The selected efficacy variables (ACR20-CRP and DAS28-CRP) are summarized by 
Treatment Sequence Set, and by preceding study respectively. In this analysis, time course of 
each efficacy variable will be presented from baseline of preceding study up to end of RAJ2 
study. Following analysis visits of preceding study will be used,
-
Subjects shifted from RAJ1
o
RAJ1 – Week 0
o
RAJ1 – Week 12
o
Week 0 (RAJ1 – Week 16)
-
Subjects shifted from RAJ3/4
o
RAJ3/4 – Week 0
o
RAJ3/4 – Week 12
o
RAJ3/4 – Week 28
o
RAJ3/4 – Week 40
o
RAJ3/4 – Week 52
o
Week 0
●
Categorical variables at each visit will be summarized. 
●
For continuous variables, raw value and change from baseline of preceding study at each 
visit will be summarized by descriptive statistics.
●
Graphical analysis:
○
ACR20-CRP will be plotted from baseline of preceding study. 
○
The mean-standard deviation plot of actual values and changes from baseline of 
preceding study will be presented for DAS28-CRP from baseline of preceding study.


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7.4.3
Analysis of Efficacy in Initial/Maximum Dose Level
The selected efficacy variables (ACR20-CRP and DAS28-CRP) are summarized by 
preceding study. In Initial dose analysis, data obtained after changing initial dose at RAJ2 
(50mg for subjects from RAJ1, 100mg for subjects from RAJ3/4) will not be used for 
efficacy analyses.
●
Categorical variables at each visit will be summarized. 
●
For continuous variables, raw value and change from baseline of preceding study at each 
visit will be summarized by descriptive statistics.
7.4.4
Influence of Dose Escalation
In order to evaluate influence of ASP015K dose escalation to 100 mg from 50 mg for 
subjects who shifted from RAJ1 and dose escalation to 150 mg from 100 mg for subjects 
who shifted from RAJ3 or RAJ4, the selected efficacy variables (ACR20-CRP and DAS28-
CRP) will be analyzed based on the days of first dose increase to 100mg or 150mg until dose 
decrease. Following intervals will be used.
o
< -336
o
-336 - < -252
o
-252 - < -168
o
-168 - < -84
o
-84 - < 0
o
0 - < 84
o
84 - < 168
o
168 - < 252
o
252 - < 336
o
>= 336
If multiple efficacy values are included in one interval, the last one is used.
●
Graphical analysis:
○
ACR20-CRP will be plotted 
○
The mean-standard deviation plot of actual values and changes from baseline of 
preceding study will be presented for DAS28-CRP from baseline of preceding study.
7.4.5
Subgroup Analysis
In order to evaluate homogeneity of treatment effects across subjects with different 
demographic and baseline characteristics, subgroup analysis of the efficacy variables will be 
performed, respectively. The subgroups in Section 7.8 will be analyzed.


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7.5
Analysis of Safety
[Analysis Set: SAF]
Details for analysis of safety will be described in 10.2 Appendix 2: Overview of AE analysis, 
and, 10.3 Appendix 3: Overview of Clinical Laboratory Evaluation, Vital Signs, and 
Electrocardiograms (ECGs) analyses.
7.5.1
Adverse Events
Treatment emergent adverse events (TEAEs) in this study will be defined as below:
●
Any adverse event that started or worsened in severity after the first dose of study drug 
at RAJ2 to the end of the final observation
Any unrecovered adverse event that first occurred during the preceding studies (RAJ1, RAJ3, 
and RAJ4) will be treated as medical conditions and not treated as TEAEs in this study.
A drug-related TEAE is defined as any TEAE with possible, probable or missing relationship 
to study drug as assessed by the investigator. Moreover, any TEAE with missing relationship 
to study drug or reference drug was counted as drug related (probable).
Adverse events will be coded using the MedDRA. 
All adverse events reported during the study period will be presented in subject listings. 
In this study 2 types of analyses for TEAEs will be performed: 
●
TEAE occurrence analysis
●
TEAE per 100 patient-years analysis
TEAE occurrence analysis will be displayed by whole treatment period, unless specifically 
stated otherwise. TEAE per 100 patient-years analysis will be displayed the following
category, and by overall period.
○
0 – 6 months
○
6 <- 12 months
○
12 <- 24 months
○
24 <- 36 months
○
36 <- 48 months
○
48 <- 60 months
○
60 <- 72 months
○
72 <- 84 months
○
84 months <


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7.5.1.1 Adverse events
The coding dictionary for this study will be MedDRA 11.1. It will be used to summarize AEs 
by SOC and PT. Subjects reporting more than one AE for a given MedDRA PT will be 
counted only once for that term. Subjects reporting more than one AE within a SOC will be 
counted only once for the SOC total. Subjects reporting more than one AE will be counted 
only once in the overall AE total.
SOCs will be presented by descending frequency for "Total" (RAJ1 + RAJ3 + RAJ4) column, 
and PTs within SOC will be presented by decreasing frequency in "Total". 
Number and percentage of subjects with TEAE in the following AE categories will be 
summarized by SOC and PT:
An overview table will include the following details:
●
Number and percentage of subjects with TEAE 
●
Number and percentage of subjects with drug related TEAE
●
Number and percentage of subjects with death 
●
Number and percentage of subjects with serious TEAE
●
Number and percentage of subjects with drug related serious TEAE
●
Number and percentage of subjects with Grade 3 or Higher in Severity TEAE
●
Number and percentage of subjects with TEAE leading to permanent discontinuation of 
study drug
●
Number and percentage of subjects with drug related TEAE leading to permanent 
discontinuation of study drug
●
Number and percentage of subjects with serious TEAE leading to permanent 
discontinuation of study drug
●
Number and percentage of subjects with drug related serious TEAE leading to 
permanent discontinuation of study drug
●
Number and percentage of subjects with TEAE leading to dose decrease of study drug
●
Number and percentage of subjects with drug related TEAE leading to dose decrease of 
study drug
●
Number and percentage of subjects with TEAE leading to temporary discontinuation of 
study drug
●
Number and percentage of subjects with drug related TEAE leading to temporary 
discontinuation of study drug
The number and percentage of subjects with TEAEs, as classified by SOC and PT will be 
summarized by preceding studies and overall. Summaries will be provided for:
●
TEAEs
●
Drug related TEAEs, defined as any TEAE with possible, probable or missing 
relationship to study drug as assessed by the investigator. 
Subjects reporting more than one TEAE for a given PT will be counted only once for 
that term in the most related category reported. 


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In addition, the number and percentage of subjects with TEAEs and Drug related TEAEs, as 
classified by SOC and PT will be presented by preceding studies and overall, by Maximum 
Dose of Study Drug.
●
Serious TEAEs 
●
Drug related serious TEAEs
●
TEAEs by severity based on National Cancer Institute Common Terminology Criteria 
for Adverse Events (NCI-CTCAE) Grade (Grade 1 = mild, Grade 2 = moderate, Grade 3 
= severe or medically significant, Grade 4 = life threatening, Grade 5 = death related to 
AE)
Subjects reporting more than one TEAE for a given PT will be counted only once for 
that term in the most severe category reported.  
If a subject has an AE which has a missing severity, then the subject will be counted in 
the severity category of "Missing" (i.e., missing severity will not be imputed). 
●
Drug related TEAEs by severity
●
Grade 3 or higher TEAEs by severity
●
TEAEs by relationship to study drug
Subjects reporting more than one TEAE for a given PT will be counted only once for 
that term in the most related category reported. 
TEAE with missing relationship to study drug missing will be counted as drug related.
Moreover, any TEAE with missing relationship to study drug or reference drug was 
counted as drug related (probable).
●
TEAEs leading to death 
●
TEAEs leading to permanent discontinuation of study drug
●
Drug related TEAEs leading to permanent discontinuation of study drug
●
Serious TEAEs leading to permanent discontinuation of study drug
●
Drug related serious TEAEs leading to permanent discontinuation of study drug
●
TEAE leading to dose decrease of study drug
●
Drug related TEAE leading to dose decrease of study drug
●
TEAE leading to temporary discontinuation of study drug
●
Drug related TEAE leading to temporary discontinuation of study drug
●
Most common TEAEs (> 5% in any preceding study)
●
Most common serious TEAEs (> 5% in any preceding study)
●
TEAEs excluding serious adverse events that equal to or exceed a threshold of 5% in any 
preceding study
●
The number and percentage of subjects with TEAEs of special interest. 
Following adverse events of special interest are defined:
○
Serious Infections
○
Malignancies
○
Herpes Zoster Related Disease (Herpes Zoster and Varicella)
○
Herpes Zoster
○
Varicella


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○
Infections That Require Intravenous Anti-infectious Therapy
Note: Definition will be provided in 10.8 Appendix 8: AE of Special Interest.
In addition, the subgroup analysis of Sex, Age Group, Concomitant Steroid at Baseline, 
Prednisone Dose at Baseline, Body Weight (kg) at Week 0, Concomitant DMARD category 
at Week 0, Maximum Dose of Study Drug and Study Region will be conducted.
7.5.1.2 Adverse Events Per 100 Patient-Years
In order to adjust for differences in subjects' durations in the study and the potential 
differential dropout rates between the preceding studies, TEAEs per 100 patient-years (PYs) 
will be calculated as follows:
Definition 1: 
TEAEs per 100 PYs = 100 × (Number of subjects who had at least 1 incidence / Total PYs)
Total PYs will be calculated by summing individual subjects' durations. 
If subjects had at least 1 predefined AE, then the duration of these subjects are summed as 
from initial dose up to first incidence of predefined AEs.
If subjects had no predefined AE, then the duration of these subjects are summed as from 
initial dose through follow-up. Summed duration will be divided by 365.25 to represent per 
year.
Definition 2: 
TEAEs per 100 PYs = 100 × (Number of TEAEs for all subjects/ Total PYs)
For number of TEAEs for all subjects, multiple occurrences of the same TEAE in the same 
subject will be counted multiple times.
Total PYs will be calculated by summing subjects' durations in this study through the follow-
up period. Each subject's duration will be calculated as:  (last date of follow-up in the study –
date of initial dose of study drug + 1) / 365.25. 
The number of TEAEs and TEAEs per 100 PYs will be provided by Definition 2, for all 
TEAEs (if analyzable) by SOC and PT for each preceding study, and Total. 
Patient-Year analysis for following specified AE will also be conducted by Definition 1 with 
95% confidence interval.
○
Serious Infections
○
Malignancies
○
Herpes Zoster Related Disease (Herpes Zoster and Varicella)
○
Herpes Zoster
○
Varicella
○
Infections That Require Intravenous Anti-infectious Therapy


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Note: Definition will be provided in 10.8 Appendix 8: AE of Special Interest.
Confidence Interval for TEAEs per 100 patient-years will be calculated for AE of special 
Interest based on following formula (assuming Poisson distribution).
○
Upper limit of CI (TEAEs per 100 PYs) : 100×exp(log(A/T) + Z(alpha)*√(1/A))
○
Lower limit of CI (TEAEs per 100 PYs) : 100×exp(log(A/T) - Z(alpha)* √(1/A))
A: Number of subjects who had at least 1 incidence
T: Total PYs
Z(alpha): alpha % point of standard normal distribution
alpha = 0.025
TEAE of special interest per 100 patient-years analysis will be displayed the following 
category.
○
0 – 6 months
○
6 <- 12 months
○
12 <- 24 months
○
24 <- 36 months
○
36 <- 48 months
○
48 <- 60 months
○
60 <- 72 months
○
72 <- 84 months
○
84 months <
In addition, the subgroup analysis of Sex, Age Group, Concomitant Steroid at Baseline, 
Prednisone Dose at Baseline, Body Weight (kg) at Week 0, Concomitant DMARD category 
at Week 0, Maximum Dose of Study Drug and Study Region will be conducted.
7.5.1.3 Subgroup Analyses
In order to assess whether or not AEs vary across specific patient groups, AE occurrence will 
be summarized by SOC and PT for the subgroups specified in Section 7.8.
7.5.2
Clinical Laboratory Evaluation
7.5.2.1 All Laboratory Tests
For clinical laboratory parameters (hematology, biochemistry, fasting lipid profile, and 
urinalysis), raw values at each scheduled visit, change from Week 0 at each post-Week 0 visit, 
shift from Week 0 and shift from reference range will be summarized using descriptive 
statistics or frequency tabulations. For Fasting Lipids Profile, all analysis will be conducted 
using the measured values which are confirmed under fasting condition. In addition, all Lipid 


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Profile values including non-fasting condition will also be summarized for descriptive 
statistics.
For subjects who shift from RAJ3, clinical laboratory test is conducted at central institution at 
each region (Japan, Korea, and Taiwan) in accordance with each procedure and each reagent 
for clinical test. The possibility of harmonization among each region was conducted before 
clinical laboratory test was initiated in Korea and Taiwan. If clinical laboratory evaluation 
could be harmonized, then these measurement data among each region could be regarded as 
the same scale. If harmonization was reported to be difficult, then clinical test would be 
summarized by Study Region (Japan, Korea, and Taiwan). However, among clinical 
laboratory tests not-harmonized, for exploratory analysis, Beta-D-glucan, Glucose, HCO3, 
urine pH, urine gravity will be summarized by whole population. Qualitative Urinalysis test 
will be summarized by Study Region, only (see 7.8.2 Subgroup analysis for Study Region 
(Japan, Korea, and Taiwan).
○
Clinical laboratory tests harmonized 
-
All of the hematology test
-
Biochemistry test except for Beta-D-glucan, Glucose, HCO3
-
All of the fasting lipid profile
-
CRP
○
Clinical laboratory tests not-harmonized 
-
Beta-D-glucan, Glucose, HCO3
-
All of the urinalysis test
* Pregnancy test, CPK monitoring, and Hepatitis test are not applicable to 
harmonization and it will be displayed in listing only.
●
For continuous variables, descriptive statistics of raw values at each scheduled visit will 
be summarized at each time point using SI unit. For the ratio T-Chol to HDL and the 
ratio LDL to HDL, descriptive statistics will be summarized at each post-baseline visit.
●
For continuous variables, descriptive statistics of change from Week 0 value will be 
summarized at each visit using SI unit. 
●
In addition, for the selected laboratory tests (hematology, biochemistry, fasting lipid 
profile), descriptive statistics of raw values and change from baseline of preceding study 
at each visit will be summarized similarly. In this analysis, time course of each safety
variable will be presented from baseline of preceding study up to end of RAJ2 study by 
Treatment Sequence Set. Following analysis visits of preceding study will be used,
-
Subjects shifted from RAJ1
o
RAJ1 – Week 0
o
RAJ1 – Week 12
o
Week 0 (RAJ1 – Week 16)


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-
Subjects shifted from RAJ3/4
o
RAJ3/4 – Week 0
o
RAJ3/4 – Week 12
o
RAJ3/4 – Week 28
o
RAJ3/4 – Week 40
o
RAJ3/4 – Week 52
o
Week 0
●
Shift-from-Week 0 table: Shift from Week 0 to highest value, and Shift from Week 0 to 
lowest value during entire period, for all laboratory variables. If the laboratory value of 
same subject is measured lower from normal range at one visit, and higher from normal 
range at the other visit, that subject will be counted as both low and high from Week 0
during entire period.
●
Graphical analysis:
○
The mean-standard deviation plot of actual values and changes from week 0 will be 
presented for the selected laboratory tests (hematology, biochemistry, fasting lipid 
profile).
7.5.2.2 Laboratory Tests for NCI-CTC Toxicity Grading
Laboratory test results for the selected laboratory tests will be graded programmatically using 
the standardized NCI-CTC toxicity grading criteria (Grade 0, 1, 2, 3, 4) specified in the 10.9 
Appendix 9: Standard Toxicity Grading for Laboratory Tests According to National Cancer 
Institute Common Terminology Criteria for Adverse Events (NCI-CTCAE) v4.0. Shift-from-
Week 0 to worst value during entire period will be provided. Note: AEs in this study are 
graded the investigator using NCI-CTAE Grade (1, 2, 3, 4, 5).
7.5.2.3 Laboratory Tests for Reference Range
Test results for the selected laboratory tests in the table below will be summarized against the 
reference range indicated. Number and percentage for the Highest/Lowest values of each 
subject included in pre-specified reference range for select laboratory during entire period 
will be provided. 


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Select Laboratory Variables and Corresponding Reference Ranges
Select Laboratory Variable
Reference Range
Highest/Lowest
Note
Aspartate Aminotransferase 
(AST)
>= 1 × ULN to < 2 × ULN
>= 2 × ULN to < 3 × ULN
>= 3 × ULN
Highest
Alanine Aminotransferase 
(ALT)
>= 1 × ULN to < 2 × ULN
>= 2 × ULN to < 3 × ULN
>= 3 × ULN
Highest
Alkaline Phosphatase (ALP)
> 2 × ULN to <= 3 × ULN
> 3 × ULN to <= 5 × ULN
> 5 × ULN
Highest
Total Bilirubin
>1.5× ULN
Highest
Total Bilirubin
>= 1 × ULN to < 2 × ULN
>= 2 × ULN to < 3 × ULN
>= 3 × ULN
Highest
Low-Density Lipoprotein 
(LDL)
> 160 mg/dL
Highest
Low-Density Lipoprotein 
(LDL) (maximum value)
< 100 mg/dL
100 to < 130  mg/dL
130 to < 160 mg/dL
160 to < 190 mg/dL
>= 190 mg/dL
Highest
Hemoglobin (HGB)
>=8.0 to < 10.0 g/dL
< 8.0 g/dL
Lowest
Hemoglobin (HGB)
>= (Week 0 value -2) to 
<(Week 0 value -1) g/dL
<( Week 0 value -2) g/dL
Lowest
Hemoglobin (HGB)
∙
Mild to Moderate: decrease 
from Week 0 value >=1 to 
<=2 g/dL,
∙
Severe: decrease from 
Week 0 value >2 to <3 
g/dL or absolute value >7 
and <8 g/dL,
∙
Potentially Life 
Threatening: decrease from 
Week 0 value >=3 or 
absolute value <=7 g/dL
Lowest
Creatine Phosphokinase 
(CPK)
> 500 to <= 2,000 U/L
> 2,000 U/L
Highest
Based on "CPK 
Monitoring" in 
protocol
Creatine Phosphokinase 
(CPK)
> 5 × Week 0 value
Highest
Based on "CPK 
Monitoring" in 
protocol


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Select Laboratory Variable
Reference Range
Highest/Lowest
Note
Creatine Phosphokinase 
(CPK)
> 2× ULN to <= 5 × ULN
> 5 × ULN to <= 10 × ULN
> 10 × ULN
Highest
Based on "CPK 
Monitoring" in 
protocol
Creatinine
> 1.5 × Week 0 value to <= 3.0 
×Week 0 value
> 3.0 × Week 0 value
Highest
Absolute Neutrophil Count 
(ANC)
>= 1,500 to < 2,000 / mm^3
>= 500 to < 1,500 / mm^3
< 500 / mm^3
Lowest
Based on 
"OMERACT 
criteria"
Lymphocytes
>= 200 to < 500 /uL
< 200 /uL
Lowest
Lymphocytes
>= 1,500 to < 2,000 / mm^3
>= 500 to < 1,500 / mm^3
< 500 / mm^3
Lowest
Based on 
"OMERACT 
criteria"
Platelets
>= 2 × 10^4 to < 5 × 10^4 /uL
< 2 × 10^4 /uL
Lowest
Platelets
> 600,000 /uL
Highest
ULN = Upper Limit Normal
Each categories are mutually exclusive.
7.5.2.4 Liver Abnormalities
The following potentially clinically significant criteria in liver function tests for Alkaline 
Phosphatase (ALP), Alanine Transaminase (ALT), total bilirubin, Aspartate Transaminase 
(AST) and their combination are defined. The subject's highest value during the 
investigational period will be used. 
Parameter
Criteria
ALT
> 3xULN
> 5xULN
> 10xULN
> 20xULN
AST
> 3xULN
> 5xULN
> 10xULN
> 20xULN
ALT or AST
> 3xULN


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            > 8xULN
Total Bilirubin
> 2xULN
ALP
> 1.5xULN
ALT and/or AST OR Total Bilirubin(*)
(ALT and/or AST > 3xULN) or 
total bilirubin > 2xULN
ALT and/or AST AND Total Bilirubin(*)
(ALT and/or AST > 3xULN) and total bilirubin 
> 2xULN
(*) Combination of values measured within same sample
The number and percentage of subjects with potentially clinically significant values in liver 
function tests during the investigational period will be presented.
Additionally, confirmed liver abnormities will be characterized as moderate and marked, as 
follow:
Moderate: ALT or AST > 3×ULN OR Total Bilirubin > 2×ULN. 
Marked: ALT or AST > 3×ULN AND Total Bilirubin > 2×ULN. 
Number and percentage of subjects in each category at each scheduled visit will be 
summarized. These combinations of elevated values are based on measured value within the 
same sample.
7.5.2.5 Liver Functions Plots
A matrix scatter plot of liver function test will be plotted showing the maximum ALT, AST, 
ALP and total bilirubin during the study period crossed against each other. Different dots will 
be used for preceding studies.
7.5.3
Vital Signs
Raw values and changes from Week 0 at each scheduled visit will be summarized using 
descriptive statistics.
7.5.4
Electrocardiograms (ECGs)
<12-lead ECG>
●
Raw values (categorical) and changes from Week 0 (shift from Week 0) will be 
summarized, and the summaries will include number and percentage of subjects with 
normal, not clinically significant abnormal and clinically significant abnormal 12 lead 
ECG findings.


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7.5.5
Chest radiography
Chest radiography will be provided as a subject listing only.
7.5.6
Pregnancies
Pregnancies will be provided as a subject listing only.
7.6
Analysis of PK
Refer to PK SAP.
7.7
Analysis of PD
[Analysis Set: PDAS]
For subjects who shift from RAJ3, as described in 7.5.2, harmonization for lymphocytes 
subset variables among each region (Japan, Korea, Taiwan) was reported to be difficult and 
therefore, raw values and changes from baseline of preceding study will be summarized by 
Study Region (Japan, Korea, Taiwan), using descriptive statistics. For CD3, CD8, CD4, 
CD19, CD4/CD8 ratio, (CD16 or CD56)+, CD16+ and CD56+, CD16- and CD56+, CD16+ 
and CD56-, CD16- and CD56-, count values (cells/uL) will be summarized by whole 
population for exploratory analysis.
1. Japan
○CD3+/Lymphocytes (%), CD3+ (cells/uL)
○CD8+/Lymphocytes (%), CD8+ (cells/uL)
○CD4+/Lymphocytes (%), CD4+ (cells/uL)
○CD19+/Lymphocytes (%), CD19+ (cells/uL)
○CD4/CD8 Ratio
○
(CD16 or CD56)+/Lymphocytes (%), (CD16 or CD56)+ (cells/uL)
○
(CD16+ and CD56+)/CD3- (%), CD16+ and CD56+ (cells/uL)
○(CD16- and CD56+)/CD3- (%), CD16- and CD56+ (cells/uL)
○(CD16+ and CD56-)/CD3- (%), CD16+ and CD56- (cells/uL)
○(CD16- and CD56-)/CD3- (%), CD16- and CD56- (cells/uL)
○CD56 bright/CD3- (%), CD56 bright (cells/uL)
○CD56 dim/CD3- (%), CD56 dim (cells/uL)


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2. Korea
○CD3+/Lymphocytes (%), CD3 (cells/uL)
○(CD3+ and CD8+)/CD3+ (%), CD3+ and CD8+ (cells/uL)
○(CD3+ and CD4+)/CD3+ (%), CD3+ and CD4+ (cells/uL)
○(CD16 or CD56)+/CD3- (%), (CD16 or CD56)+ (cells/uL)
○CD19+/CD3- (%), CD19+ (cells/uL)
○CD4/CD8 Ratio
○(CD16+ and CD56+)/CD3- (%), CD16+ and CD56+ (cells/uL)
○(CD16- and CD56+)/CD3- (%), CD16- and CD56+ (cells/uL)
○(CD16+ and CD56-)/CD3- (%), CD16+ and CD56- (cells/uL)
○(CD16- and CD56-)/CD3- (%), CD16- and CD56- (cells/uL)
3. Taiwan
○CD3+/Lymphocytes (%), CD3 (cells/uL)
○(CD3+ and CD8+)/Lymphocytes (%), CD3+ and CD8+ (cells/uL)
○(CD3+ and CD4+)/Lymphocytes (%), CD3+ and CD4+ (cells/uL)
○(CD16 or CD56)+/Lymphocytes (%), (CD16 or CD56)+ (cells/uL)
○CD19+/Lymphocytes (%), CD19+ (cells/uL)
○CD4/CD8 Ratio
○(CD16+ and CD56+)/Lymphocytes (%), CD16+ and CD56+ (cells/uL)
○(CD16- and CD56+)/Lymphocytes (%), CD16- and CD56+ (cells/uL)
○(CD16+ and CD56-)/Lymphocytes (%), CD16+ and CD56- (cells/uL)
○(CD16- and CD56-)/Lymphocytes (%), CD16- and CD56- (cells/uL)
7.8
Subgroups of Interest 
7.8.1
Subgroup analysis of the selected efficacy endpoint (ACR20-CRP) and 
treatment emergent adverse events
The selected efficacy variable (ACR20-CRP) and TEAEs will be summarized for the 
subgroups defined on the basis of the categorized variables listed below:
○
Sex (Male, Female,)
○
Age Group at Week 0 (< 65 years, >= 65 years)
○
Prior Anti-TNF DMARD Use in preceding study (User, Non-user)
○
Prior Biologic DMARD-IR in preceding study (No, Yes)


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○
Duration of RA (years) in preceding study (< 5 years, >= 5 years)
○
Number of Prior DMARDs Used in preceding study (0, 1, 2, >= 3)
○
Number of Prior Biologic DMARDs Used in preceding study (0, 1, 2, >= 3)
○
MTX Dose (mg/week) at Week 0 (None, 0 <- 8 mg/week, 8 <- 12 mg/week, > 
12 mg/week)
○
Concomitant Steroid at Week 0 (No, Yes)
○
Prednisone Dose  (mg/day) at Week 0 (None, 0 <- 5 mg/day, > 5 mg/day)
○
Concomitant non-Biologic DMARD Use at Week 0 (No, Yes)
○
Study Region (Japan, Korea, Taiwan)
○
Baseline DAS28-CRP in preceding study (<= 3.2, 3.2<-5.1, > 5.1), efficacy 
analyses only
○
Baseline DAS28-ESR in preceding study (<= 3.2, 3.2<-5.1, > 5.1), efficacy 
analyses only
○
Baseline CRP in preceding study (< 1.0, >= 1.0) , efficacy analyses only
○
Concomitant DMARD category at Week 0 (MTX, DMARD except for MTX
only, None)
○
Body Weight (kg) at Week 0 (<- 40 kg, 40 kg <- 60 kg, 60 kg <- 80 kg, > 80 
kg)
○
Maximum Dose of Study Drug (50 mg, 100 mg, 150 mg)
7.8.2
Subgroup analysis by Study Region (Japan, Korea, Taiwan)
Following efficacy, safety, and pharmacodynamic variables will be analyzed by Study 
Region (Japan, Korea, Taiwan) in addition to 7.8.1 Subgroup analysis.
○
ACR50
○
ACR70
○
DAS28-CRP
○
DAS28-ESR
○
HAQ-DI
○
SF-36V2®
○
Overview of TEAEs
○
Serious TEAEs
○
Drug related TEAE
○
TEAE leading to permanent discontinuation of study drug
○
The number and percentage of subjects with TEAEs of special interest
-
Serious Infections
-
Malignancies
-
Herpes Zoster Related Disease (Herpes Zoster and Varicella)
-
Herpes Zoster
-
Varicella
-
Infections That Require Intravenous Anti-infectious Therapy
○
Clinical Laboratory Evaluation


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-
For continuous variables, descriptive statistics of raw values, change from 
Week 0 value at each scheduled visit will be summarized at each time 
point using SI unit
-
For categorical variables, frequencies and percentages will be displayed at 
each scheduled visit.
○
Pharmacodynamic variables
-
Described in 7.7
7.9
Other Analyses
Not Applicable.
7.10
Interim Analysis (and Early Discontinuation of the Clinical Study)
Not applicable for efficacy analysis. Review of safety data and safety evaluation will be 
conducted by an independent DSMB during the study in accordance with separate SOP.
7.11
Handling of LLOQ, Missing Data, Outliers, Visit Windows, and 
Other Information
7.11.1
LLOQ
Safety variables
Values below the LLOQ for beta-D-glucan, hCG, Troponin-T, CK-MB  will be treated as it 
is and these variables are not used for descriptive statistics and displayed in the listings. As 
for beta-D-glucan, it is used for shift-from baseline analysis.
PD variables
Values below the LLOQ will be set to 0 for calculation of descriptive statistics. 
7.11.2
Missing Data
Missing Data in ACR20/50/70, DAS28
Table below addresses the handling of missing ACR components and ACR response in
analyses of ACR20/50/70, DAS28, and DAS28-related variables at ET. Note that if subject 
does not have any post-baseline values, then that subject will be defined as a non-responder.


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Imputation Methods for ACR and DAS28 for Components and Response at ET
Imputation Method
Explanation/Instruction
For use in all ACR20/50/70 analyses at ET
1
LOCF 
components
●
LOCF all ACR component value(s) at the last evaluation point
and then calculate ACR response as ET.
For use in all DAS28 and DAS28-based analyses at ET
2
LOCF 
components
●
LOCF all DAS28 CRP component value(s) at the last 
evaluation point and then calculate the DAS28 score as ET.
Missing Data in HAQ-DI
For HAQ-DI, there are 20 items in 8 categories, with each category having 2 or 3 questions. 
A subject must have a score in >= 6 of the 8 categories, otherwise the HAQ-DI cannot be 
computed and will be considered missing for data summarization and analysis purposes. If 
responses to individual questions within a category are missing, they are not imputed. 
Therefore, the score in each category is based on non-missing responses. A category score is 
missing when all responses within a category are missing. 
Missing Data in SF-36v2
For SF-36v2, there are 8 scales (domains). Missing values will be imputed if at least half of 
the items in the domain that included the missing item score(s) are non-missing. In that case, 
the missing value will be imputed with the average score of the non-missing item scores in 
this domain. 
Missing Data in FACIT-Fatigue
For FACIT-Fatigue, there are 13 items. Missing values of any individual item will be 
imputed with the average score obtained from the non-missing items if more than 50% of the 
items are available, i.e., if the number of non-missing items >= 7. 
Missing Data in WPAI
For WPAI Scale Score, each score will be computed on condition that the all of the questions 
for each score will not be non-missing.
Safety Data Imputation Methods
For safety data, LOCF method will be used for the value at ET.


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7.11.3
Outliers
All values will be included in the analyses.
7.11.4
Visit Windows
The acceptable time ranges of the efficacy and safety examinations, observations, etc. from 
the date of initial study treatment (Day 1) are defined as follows. If there are multiple data 
available over the same period of time, the data obtained on the day closest to the reference 
date will be utilized; the later date will be applied if the number of days from the reference 
date is equal. Missing data at the end or discontinuation of treatment will be imputed using 
the LOCF method.
Since the study period of this study differs depending on the subject, the timing for the 
required visits to the study center will also differ from subject to subject. Only subjects who 
transferred from study RAJ1, but not those who transferred from studies RAJ3 or RAJ4, are 
required to come for visits at Week 2, Week 4, Week 8, Week 16, Week 20, Week 28, Week 
32, Week 40, and Week 44. Therefore, these time points defined in the analysis are set only 
for the subjects from study RAJ1.


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7.11.5
Handling of Schedule of Assessments of Efficacy Variables
For data obtained after the end of treatment, the data obtained within +2 days after the last 
dose will be included in analysis, except for the data at the end of the study (at time of 
follow-up).
(1)
RA disease activity (TJC, SJC, PGA, SGA, subject's assessment of pain), CRP, ESR
Time points defined in analysis
Reference date*
Acceptable time range
Week 0
Day 1
Day 1
Week 2
Day 15
Day 12 to Day 18
Week 4
Day 29
Day 22 to Day 36
Week 8
Day 57
Day 50 to Day 64
Week 12
Day 85
Day 78 to Day 92
Week 16
Day 113
Day 106 to Day 120
Week 20
Day 141
Day 134 to Day 148
Week 24
Day 169
Day 162 to Day 176
Week 28
Day 197
Day 190 to Day 204
Week 32
Day 225
Day 218 to Day 232
Week 36
Day 253
Day 246 to Day 260
Week 40
Day 281
Day 274 to Day 288
Week 44
Day 309
Day 302 to Day 316
Week 48
Day 337
Day 330 to Day 344
Week 60
Day 421
Day 407 to Day 435
Week 72
Day 505
Day 491 to Day 519
Week 84
Day 589
Day 575 to Day 603
Week 96
Day 673
Day 659 to Day 687
Week 108
Day 757
Day 743 to Day 771
Week 120
Day 841
Day 827 to Day 855
Week 132
Day 925
Day 911 to Day 939
Week 132 + 12 × x
Day 7 × (132 + 12 × x) + 
1
Day 7 × (132 + 12 × x) − 13 to 
Day 7 × (132 + 12 × x) + 15
End/discontinuation of treatment
Day of the last dose
Day 2 to 2 days after the last dose
End of the study 
(at time of follow-up)
28 days after the last 
dose
21 to 35 days after the last dose
*: Day 1 represents the first day of study treatment.


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(2)
Patient Questionnaires (HAQ-DI, FACIT-Fatigue)
The schedule for FACIT-Fatigue applies only to subjects who transferred from study RAJ1.
Time points defined in analysis
Reference date*
Acceptable time range
Week 0
Day 1
Day 1
Week 2
Day 15
Day 12 to Day 18
Week 4
Day 29
Day 22 to Day 36
Week 8
Day 57
Day 50 to Day 64
Week 12
Day 85
Day 78 to Day 92
Week 16
Day 113
Day 106 to Day 120
Week 20
Day 141
Day 134 to Day 148
Week 24
Day 169
Day 162 to Day 176
Week 28
Day 197
Day 190 to Day 204
Week 32
Day 225
Day 218 to Day 232
Week 36
Day 253
Day 246 to Day 260
Week 40
Day 281
Day 274 to Day 288
Week 44
Day 309
Day 302 to Day 316
Week 48
Day 337
Day 330 to Day 344
Week 60
Day 421
Day 407 to Day 435
Week 72
Day 505
Day 491 to Day 519
Week 84
Day 589
Day 575 to Day 603
Week 96
Day 673
Day 659 to Day 687
Week 108
Day 757
Day 743 to Day 771
Week 120
Day 841
Day 827 to Day 855
Week 132
Day 925
Day 911 to Day 939
Week 132 + 12 × x
Day 7 × (132 + 12 × x) + 
1
Day 7 × (132 + 12 × x) − 13 to 
Day 7 × (132 + 12 × x) + 15
End/discontinuation of treatment
Day of the last dose
Day 2 to 2 days after the last dose
End of the study 
(at time of follow-up)**
28 days after the last 
dose
21 to 35 days after the last dose
*: Day 1 represents the first day of study treatment.
**: The assessment at the end of the study (at the time of follow-up) will be scheduled only for HAQ-
DI.


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(3)
Patient Questionnaires (SF-36v2®)
Time points defined in analysis
Reference date*
Acceptable time range
Week 0
Day 1
Day 1
Week 4**
Day 29
Day 22 to Day 36
Week 8**
Day 57
Day 50 to Day 64
Week 12**
Day 85
Day 78 to Day 92
Week 16**
Day 113
Day 106 to Day 120
Week 20**
Day 141
Day 134 to Day 148
Week 24
Day 169
Day 162 to Day 176
Week 28**
Day 197
Day 190 to Day 204
Week 32**
Day 225
Day 218 to Day 232
Week 36**
Day 253
Day 246 to Day 260
Week 40**
Day 281
Day 274 to Day 288
Week 44**
Day 309
Day 302 to Day 316
Week 48
Day 337
Day 330 to Day 344
Week 60**
Day 421
Day 407 to Day 435
Week 72
Day 505
Day 491 to Day 519
Week 84**
Day 589
Day 575 to Day 603
Week 96
Day 673
Day 659 to Day 687
Week 108**
Day 757
Day 743 to Day 771
Week 120
Day 841
Day 827 to Day 855
Week 120 + 12 × x**
Day 7 × (120 + 12 × x) + 
1
Day 7 × (120 + 12 × x) − 13 to 
Day 7 × (120 + 12 × x) + 15
End/discontinuation of treatment
Day of the last dose
Day 2 to 2 days after the last dose
*: Day 1 represents the first day of study treatment.
**: Scheduled only for subjects who transferred from study RAJ1. For subjects who transferred from 
studies RAJ3 or RAJ4, the survey is administered every 24 weeks after Week 120. Starting at the first 
visit after the revision of the study protocol, the survey will be administered to subjects who transferred 
from study RAJ1 also every 24 weeks.
(4)
Patient Questionnaires (WPAI [subjects from RAJ3 or RAJ4])
Scheduled only for subjects who transferred from studies RAJ3 or RAJ4.
Time points defined in analysis
Reference date*
Acceptable time range
Week 0
Day 1
Day 1
Week 24
Day 169
Day 162 to Day 176
Week 48
Day 337
Day 330 to Day 344
Week 72
Day 505
Day 491 to Day 519
Week 96
Day 673
Day 659 to Day 687
Week 120
Day 841
Day 827 to Day 855
Week 120 + 24 × x
Day 7 × (120 + 24 × x) + 
1
Day 7 × (120 + 24 × x) −13 to 
Day 7 × (120 + 24 × x) + 15
End/discontinuation of treatment
Day of the last dose
Day 2 to 2 days after the last dose
*: Day 1 represents the first day of study treatment.


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7.11.6
Handling of Schedule of Assessments of Safety Variables
For data obtained after the end of study treatment, the data obtained within +2 days after the 
last dose will be included in analysis, except for the data at the end of the study (at time of 
follow-up).
(1)
Vital Signs
Time points defined in 
analysis
Reference date*
Acceptable time range
Week 0
Day 1
Day 1
Week 2
Day 15
Day 12 to Day 18
Week 4
Day 29
Day 22 to Day 36
Week 8
Day 57
Day 50 to Day 64
Week 12
Day 85
Day 78 to Day 92
Week 16
Day 113
Day 106 to Day 120
Week 20
Day 141
Day 134 to Day 148
Week 24
Day 169
Day 162 to Day 176
Week 28
Day 197
Day 190 to Day 204
Week 32
Day 225
Day 218 to Day 232
Week 36
Day 253
Day 246 to Day 260
Week 40
Day 281
Day 274 to Day 288
Week 44
Day 309
Day 302 to Day 316
Week 48
Day 337
Day 330 to Day 344
Week 60
Day 421
Day 407 to Day 435
Week 72
Day 505
Day 491 to Day 519
Week 84
Day 589
Day 575 to Day 603
Week 96
Day 673
Day 659 to Day 687
Week 108
Day 757
Day 743 to Day 771
Week 120
Day 841
Day 827 to Day 855
Week 132
Day 925
Day 911 to Day 939
Week 132 + 12 × x
Day 7 × (132 + 12 × x) + 
1
Day 7 × (132 + 12 × x) − 13 to 
Day 7 × (132 + 12 × x) + 15
End/discontinuation of treatment
Day of the last dose
Day 2 to 2 days after the last dose
End of the study 
(at time of follow-up)
28 days after the last 
dose
21 to 35 days after the last dose
*: Day 1 represents the first day of study treatment.


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(2)
Laboratory Tests (Hematology, Biochemistry [including Fasting Lipid Profile Test], 
Urinalysis)
Time points defined in analysis
Reference date*
Acceptable time range
Week 0
Day 1
Day 1
Week 2
Day 15
Day 12 to Day 18
Week 4
Day 29
Day 22 to Day 36
Week 8
Day 57
Day 50 to Day 64
Week 12
Day 85
Day 78 to Day 92
Week 16
Day 113
Day 106 to Day 120
Week 20
Day 141
Day 134 to Day 148
Week 24
Day 169
Day 162 to Day 176
Week 28
Day 197
Day 190 to Day 204
Week 32
Day 225
Day 218 to Day 232
Week 36
Day 253
Day 246 to Day 260
Week 40
Day 281
Day 274 to Day 288
Week 44
Day 309
Day 302 to Day 316
Week 48
Day 337
Day 330 to Day 344
Week 60
Day 421
Day 407 to Day 435
Week 72
Day 505
Day 491 to Day 519
Week 84
Day 589
Day 575 to Day 603
Week 96
Day 673
Day 659 to Day 687
Week 108
Day 757
Day 743 to Day 771
Week 120
Day 841
Day 827 to Day 855
Week 132
Day 925
Day 911 to Day 939
Week 132 + 12 × x
Day 7 × (132 + 12 × x) + 
1
Day 7 × (132 + 12 × x) − 13 to 
Day 7 × (132 + 12 × x) + 15
Minimum on Treatment
Minimum value during Entire
Period (No limitation for period)
Maximum on Treatment
Maximum value during Entire 
Period (No limitation for period)
End/discontinuation of treatment
Day of the last dose
Day 2 to 2 days after the last dose
End of the study 
(at time of follow-up)
28 days after the last 
dose
21 to 35 days after the last dose
*: Day 1 represents the first day of study treatment.
(3)
12-lead ECG, Chest Radiography
Time points defined in analysis
Reference date*
Acceptable time range
Week 0**
Day 1
Day 1
Week 24****
Day 169
Day 162 to Day 176
Week 48
Day 337
Day 330 to Day 344
Week 72****
Day 505
Day 491 to Day 519
Week 96
Day 673
Day 659 to Day 687
Week 96 + 24 × x****
Day 7 × (96 + 24 × x) + 
1
Day 7 × (96 + 24 × x) − 13 to Day 
7 × (96 + 24 × x) + 15
End/discontinuation of 
treatment***
Day of the last dose
Day 2 to 2 days after the last dose
*: Day 1 represents the first day of study treatment.
**: Regarding chest radiography, it is allowed to use data obtained within 28 days prior to the Week 0 
visit.
***: Chest radiography at the end/discontinuation of treatment is unnecessary if one has been taken 
within 24 weeks from the day of discontinuation.
****: Only Chest radiography is applied for 24 weeks intervals (only for Taiwan).


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(4)
Body weight
Time points defined in analysis
Reference date*
Acceptable time range
Week 0
Day 1
Day 1
Week 2
Day 15
Day 12 to Day 18
Week 4
Day 29
Day 22 to Day 36
Week 8
Day 57
Day 50 to Day 64
Week 12
Day 85
Day 78 to Day 92
Week 24
Day 169
Day 162 to Day 176
Week 36
Day 253
Day 246 to Day 260
Week 48
Day 337
Day 330 to Day 344
Week 60
Day 421
Day 407 to Day 435
Week 72
Day 505
Day 491 to Day 519
Week 84
Day 589
Day 575 to Day 603
Week 96
Day 673
Day 659 to Day 687
Week 108
Day 757
Day 743 to Day 771
Week 120
Day 841
Day 827 to Day 855
Week 132
Day 925
Day 911 to Day 939
Week 132 + 12 × x
Day 7 × (132 + 12 × x) + 
1
Day 7 × (132 + 12 × x) − 13 to 
Day 7 × (132 + 12 × x) + 15
End/discontinuation of treatment
Day of the last dose
Day 2 to 2 days after the last dose
End of the study 
(at time of follow-up)
28 days after the last 
dose
21 to 35 days after the last dose
*: Day 1 represents the first day of study treatment.


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7.11.7
Handling of Schedule of Assessments of Pharmacodynamic Variables
For data obtained after the end of study treatment, the data obtained within +2 days after the 
last dose will be included in analysis, except for the data at the end of the study (at time of 
follow-up).
(1)
Lymphocyte subsets
Time points defined in 
analysis
Reference date*
Acceptable time range
Week 0
Day 1
Day 1
Week 48
Day 337
Day 330 to Day 344
Week 96
Day 673
Day 659 to Day 687
Week 96 + 48 × x
Day 7 × (96 + 48 × x) + 
1
Day 7 × (96 + 48 × x) − 13 to Day 
7 × (96 + 48 × x) + 15
End/discontinuation of treatment
Day of the last dose
Day 2 to 2 days after the last dose
End of the study 
(at time of follow-up)
28 days after the last 
dose
21 to 35 days after the last dose
*: Day 1 represents the first day of study treatment.


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8
DOCUMENT REVISION HISTORY 
Version
Date
Changes
Comment/rationale for change
1.00
18-Jan-2018
NA
Document finalized
9
REFERENCES
ICH Harmonized Tripartite Guideline E 3. Structure and Content of Clinical Study Reports, 
November 1995. (www.ich.org; Guidelines; "Efficacy" Topics)
ICH Harmonized Tripartite Guideline E 9. Statistical Principles for Clinical Trials, February 1998. 
(www.ich.org; Guidelines; "Efficacy" Topics) 


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10
APPENDICES
10.1
Appendix 1: Overview of Efficacy Endpoints
Table below summarizes the analyses of the efficacy variables, with "X" indicating that the variable will be analyzed. All analyses will 
be based on the FAS and presented by preceding studies, unless otherwise specified. No statistical hypothesis testing will be performed.
Overview of Efficacy Endpoints analysis
Analysis Type/Analysis Variable
Component for use
Study for Analysis
Analysis Group
CRP
ESR
None
RAJ1
RAJ3
RAJ4
Categorical Variables
1.1
Percentage of subjects achieving ACR20/50/70 at each visit
X
X
X
X
X
preceding studies
1.2.1
Percentage of subjects achieving ACR20 at each visit
Analysis by Treatment Sequence Set of preceding study
X
X
Treatment 
Sequence Set
1.2.2
Percentage of subjects achieving ACR20 at each visit
Analysis by Treatment Sequence Set of preceding study
X
X
Treatment 
Sequence Set
1.2.3
Percentage of subjects achieving ACR20 at each visit
Analysis by Treatment Sequence Set of preceding study
X
X
Treatment 
Sequence Set
1.3
Percentage of subjects achieving ACR20 at each visit
Analysis of Efficacy in Each Dose Level
X
X
X
X
preceding studies


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Analysis Type/Analysis Variable
Component for use
Study for Analysis
Analysis Group
CRP
ESR
None
RAJ1
RAJ3
RAJ4
1.4.1
Percentage of subjects achieving ACR20 at each interval
Influence of Dose Escalation
X
X
Subjects Who 
Experienced Dose 
Up to 100 mg
1.4.2
Percentage of subjects achieving ACR20 at each interval
Influence of Dose Escalation
X
X
Subjects 
Who 
Experienced Dose 
Up to 150 mg
1.4.3
Percentage of subjects achieving ACR20 at each interval
Influence of Dose Escalation
X
X
Subjects Who 
Experienced Dose 
Up to 150 mg


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Analysis Type/Analysis Variable
Component for use
Study for Analysis
Analysis Group
CRP
ESR
None
RAJ1
RAJ3
RAJ4
1.5.1
Percentage of subjects achieving ACR20 at each visit
subgroup analysis
●
Sex (Male, Female,)
●
Age Group at Week 0 (< 65 years, >= 65 years)
●
Prior Anti-TNF DMARD Use in preceding study (User, Non-
user)
●
Prior Biologic DMARD-IR in preceding study (No, Yes)
●
Duration of RA (years) in preceding study (< 5 years, >= 5 years)
●
Number of Prior DMARDs Used in preceding study (0, 1, 2, >= 
3)
●
Number of Prior Biologic DMARDs Used in preceding study (0, 
1, 2, >= 3)
●
MTX Dose (mg/week) at Week 0 (None, 0 <- 8 mg/week, 8 <- 12 
mg/week, > 12 mg/week)
●
Concomitant Steroid at Week 0 (No, Yes)
●
Prednisone Dose  (mg/day) at Week 0 (None, 0 <- 5 mg/day, > 5 
mg/day)
●
Concomitant non-Biologic DMARD Use at Week 0 (No, Yes)
●
Study Region (Japan, Korea, Taiwan)
●
Baseline DAS28-CRP in preceding study (<= 3.2, 3.2<-5.1, > 
5.1), efficacy analyses only
●
Baseline DAS28-ESR in preceding study (<= 3.2, 3.2<-5.1, > 
5.1), efficacy analyses only
●
Baseline CRP in preceding study (< 1.0, >= 1.0) , efficacy 
analyses only
●
Concomitant DMARD category at Week 0 (MTX, DMARD 
except for MTX only, None)
X
X
X
X
preceding studies
1.5.2
Percentage of subjects achieving ACR50/70 at each visit
subgroup analysis
●
Study Region (Japan, Korea, Taiwan)
X
X
preceding studies
1.7
Percentage of subjects achieving ACR20 at each visit
ACR20 Response plot
X
X
X
X
preceding studies


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Analysis Type/Analysis Variable
Component for use
Study for Analysis
Analysis Group
CRP
ESR
None
RAJ1
RAJ3
RAJ4
1.8.1
Percentage of subjects achieving ACR20 at each visit
ACR20 Response plot
Analysis by Treatment Sequence Set of preceding study
X
X
Treatment 
Sequence Set
1.8.2
Percentage of subjects achieving ACR20 at each visit
ACR20 Response plot
Analysis by Treatment Sequence Set of preceding study
X
X
Treatment 
Sequence Set
1.8.3
Percentage of subjects achieving ACR20 at each visit
ACR20 Response plot
Analysis by Treatment Sequence Set of preceding study
X
X
Treatment 
Sequence Set
2.1
Percentage of subjects achieving DAS28 score <2.6 at each visit
X
X
X
X
X
preceding studies
2.2
Percentage of subjects achieving DAS28 score <=3.2 at each visit
X
X
X
X
X
preceding studies
3
Percentage of subjects achieving "Good Response" using DAS28 
EULAR response criterion at each visit
X
X
X
X
X
preceding studies
4
Percentage of subjects achieving "Good Response" or "Moderate 
Response" using DAS28 EULAR response criterion at each visit
X
X
X
X
X
preceding studies
5
Percentage of subjects in ACR/EULAR remission at each visit
X
X
X
X
preceding studies
6
Percentage of subjects in SDAI <= 3.3 at each visit
X
X
X
X
preceding studies


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Analysis Type/Analysis Variable
Component for use
Study for Analysis
Analysis Group
CRP
ESR
None
RAJ1
RAJ3
RAJ4
7
Percentage of subjects in CDAI <= 2.8 at each visit
X
X
X
X
preceding studies
8.1
Percentage of subjects achieving HAQ-DI (<=0.5) at each visit
X
X
X
X
preceding studies
8.2
Percentage of subjects achieving decrease of baseline HAQ-DI in 
preceding study of at least 0.22 at each visit
X
X
X
X
preceding studies
9
Percentage of subjects achieving SF-36v2 of difference >= 5 at each 
visit
X
X
X
X
preceding studies
Continuous Variables 
10.1.1
Raw value and change from baseline of preceding study in DAS28 
score at each visit
X
X
X
X
X
preceding studies
10.1.2
Raw value and change from Week 0 in DAS28 score at each visit
X
X
X
X
preceding studies
10.2.1
Raw value and change from baseline of preceding study in DAS28 
score at each visit
Analysis by Treatment Sequence Set of preceding study
X
X
Treatment 
Sequence Set
10.2.2
Raw value and change from baseline of preceding study in DAS28 
score at each visit
Analysis by Treatment Sequence Set of preceding study
X
X
Treatment 
Sequence Set


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Analysis Type/Analysis Variable
Component for use
Study for Analysis
Analysis Group
CRP
ESR
None
RAJ1
RAJ3
RAJ4
10.2.3
Raw value and change from baseline of preceding study in DAS28 
score at each visit
Analysis by Treatment Sequence Set of preceding study
X
X
Treatment 
Sequence Set
10.3
Raw value and change from baseline of preceding study in DAS28 
score at each visit
Analysis of Efficacy in Each Dose Level
X
X
X
X
preceding studies
10.4.1
Raw value and change from baseline of preceding study in DAS28 
score at each interval
Influence of Dose Escalation
X
X
Subjects Who 
Experienced Dose 
Up to 100 mg
10.4.2
Raw value and change from baseline of preceding study in DAS28 
score at each interval
Influence of Dose Escalation
X
X
Subjects Who 
Experienced Dose 
Up to 150 mg
10.4.3
Raw value and change from baseline of preceding study in DAS28 
score at each interval
Influence of Dose Escalation
X
X
Subjects Who 
Experienced Dose 
Up to 150 mg
10.5
Raw value and change from baseline of preceding study in DAS28 
score at each visit
subgroup analysis
●
Study Region (Japan, Korea, Taiwan)
X
X
X
preceding studies


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Analysis Type/Analysis Variable
Component for use
Study for Analysis
Analysis Group
CRP
ESR
None
RAJ1
RAJ3
RAJ4
10.6
Raw value and change from baseline of preceding study in DAS28 
score at each visit
Mean-standard deviation plot
X
X
X
X
X
preceding studies
10.7.1
Raw value and change from baseline of preceding study in DAS28 
score at each visit
Mean-standard deviation plot
Analysis by Treatment Sequence Set of preceding study
X
X
Treatment 
Sequence Set
10.7.2
Raw value and change from baseline of preceding study in DAS28 
score at each visit
Mean-standard deviation plot
Analysis by Treatment Sequence Set of preceding study
X
X
Treatment 
Sequence Set
10.7.3
Raw value and change from baseline of preceding study in DAS28 
score at each visit
Mean-standard deviation plot
Analysis by Treatment Sequence Set of preceding study
X
X
Treatment 
Sequence Set
11
Raw value and change from baseline of preceding study in SDAI score 
at each visit
X
X
X
X
preceding studies
12
Raw value and change from baseline of preceding study in CDAI score 
at each visit
X
X
X
X
preceding studies
13
Raw value and change from baseline of preceding study in HAQ-DI at 
each visit
X
X
X
X
preceding studies


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Analysis Type/Analysis Variable
Component for use
Study for Analysis
Analysis Group
CRP
ESR
None
RAJ1
RAJ3
RAJ4
14
Raw value and change from baseline of preceding study in FACIT-
Fatigue at each visit
X
X
RAJ1
15
Raw value and change from baseline of preceding study in WPAI at  
each visit
X
X
X
RAJ3 and RAJ4
16
Raw value and change from baseline of preceding study in SF-36v2 at  
each visit
X
X
X
X
preceding studies
17
Raw value and change from baseline of preceding study in TJC68 at 
each visit 
X
X
X
X
preceding studies
18
Raw value and change from baseline of preceding study in TJC28 at 
each visit 
X
X
X
X
preceding studies
19
Raw value and change from baseline of preceding study in SJC66 at 
each visit 
X
X
X
X
preceding studies
20
Raw value and change from baseline of preceding study in SJC28 at 
each visit
X
X
X
X
preceding studies
21
Raw value and change from baseline of preceding study in CRP at each 
visit 
X
X
X
X
preceding studies
22
Raw value and change from baseline of preceding study in ESR at each 
visit 
X
X
X
X
preceding studies
23
Raw value and change from baseline of preceding study in SGAP (100 
mm VAS) at each visit 
X
X
X
X
preceding studies
24
Raw value and change from baseline of preceding study in SGA (100 
mm VAS) at each visit 
X
X
X
X
preceding studies


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Analysis Type/Analysis Variable
Component for use
Study for Analysis
Analysis Group
CRP
ESR
None
RAJ1
RAJ3
RAJ4
25
Raw value and change from baseline of preceding study in PGA (100 
mm VAS) at each visit 
X
X
X
X
preceding studies


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10.2
Appendix 2: Overview of AE analysis
Tables below summarize AE occurrence analysis, SOC/PT analysis, and Patient-year 
analysis with "X" indicating that the variable will be analyzed. All analyses will be based on 
the SAF and presented by preceding studies and overall, unless otherwise specified.
The overview of AE occurrence analysis
Study for Analysis
Analysis Group
RAJ1
RAJ3
RAJ4
Number and percentage of subjects with TEAE 
X
preceding studies 
and overall
Number and percentage of subjects with drug related TEAE
Number and percentage of subjects with death 
Number and percentage of subjects with serious TEAE
Number and percentage of subjects with drug related serious TEAE
Number and percentage of subjects with Grade 3 or Higher in 
Severity TEAE
Number and percentage of subjects with TEAE leading to 
permanent discontinuation of study drug
Number and percentage of subjects with drug related TEAE 
leading to permanent discontinuation of study drug
Number and percentage of subjects with serious TEAE leading to 
permanent discontinuation of study drug
Number and percentage of subjects with drug related serious TEAE 
leading to permanent discontinuation of study drug
The overview of the number of SOC/PT analysis
  
Study for Analysis
Analysis Group
RAJ1
RAJ3
RAJ4
TEAEs
X
X
X
preceding 
studies and 
overall
TEAEs by maximum dose of study drug
X
X
X
preceding 
studies and 
overall
Drug related TEAEs by maximum dose of study drug
X
X
X
preceding 
studies and 
overall
Drug related TEAEs
X
X
X
preceding 
studies and 
overall
Serious TEAEs 
X
X
X
preceding 
studies and 
overall


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Study for Analysis
Analysis Group
RAJ1
RAJ3
RAJ4
Drug related serious TEAEs
X
X
X
preceding 
studies and 
overall
TEAEs by severity
X
X
X
preceding 
studies and 
overall
Drug related TEAEs by severity
X
X
X
preceding 
studies and 
overall
TEAEs leading to permanent discontinuation of study drug
X
X
X
preceding 
studies and 
overall
Drug related TEAEs leading to permanent discontinuation of study drug
X
X
X
preceding 
studies and 
overall
Serious TEAEs leading to permanent discontinuation of study drug
X
X
X
preceding 
studies and 
overall
Drug related serious TEAEs leading to permanent discontinuation of study 
drug
X
X
X
preceding 
studies and 
overall
Grade 3 or higher TEAEs by severity
X
X
X
preceding 
studies and 
overall
TEAEs by relationship to study drug
X
X
X
preceding 
studies and 
overall
TEAEs leading to death 
X
X
X
preceding 
studies and 
overall
Most common TEAEs (> 5% in any preceding study) 
X
X
X
preceding 
studies and 
overall
Most common serious TEAEs (> 5% in any preceding study) 
X
X
X
preceding 
studies and 
overall
TEAEs excluding serious adverse events that equal to or exceed a threshold 
of 5% in any preceding study
X
X
X
preceding 
studies and 
overall
TEAEs of special interest
●
Serious Infections
●
Malignancies
●
Herpes Zoster Related Disease (Herpes Zoster and Varicella)
●
Herpes Zoster
●
Varicella
●
Infections That Require Intravenous Anti-infectious Therapy
X
X
X
preceding 
studies and 
overall
TEAEs by subgroups
●
Sex (Male, Female,)
●
Age Group at Week 0 (< 65 years, >= 65 years)
●
Prior Anti-TNF DMARD Use in preceding study (User, Non-user)
●
Prior Biologic DMARD-IR in preceding study (No, Yes)
●
Duration of RA (years) in preceding study (< 5 years, >= 5 years)
●
Number of Prior DMARDs Used in preceding study (0, 1, 2, >= 3)
●
Number of Prior Biologic DMARDs Used in preceding study (0, 1, 2, 
>= 3)
●
MTX Dose (mg/week) at Week 0 (None, 0 <- 8 mg/week, 8 <- 12 
X
X
X
preceding 
studies and 
overall


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Study for Analysis
Analysis Group
RAJ1
RAJ3
RAJ4
mg/week, > 12 mg/week)
●
Concomitant Steroid at Week 0 (No, Yes)
●
Prednisone Dose  (mg/day) at Week 0 (None, 0 <- 5 mg/day, > 5
mg/day)
●
Concomitant non-Biologic DMARD Use at Week 0 (No, Yes)
●
Study Region (Japan, Korea, Taiwan)
●
Concomitant DMARD category at Week 0 (MTX, DMARD except 
for MTX only, None)
TEAEs of special interest by subgroups
●
Sex (Male, Female,)
●
Age Group at Week 0 (< 65 years, >= 65 years)
●
Concomitant Steroid at Week 0 (No, Yes)
●
Prednisone Dose  (mg/day) at Week 0 (None, 0 <- 5 mg/day, > 5 
mg/day)
X
X
X
preceding 
studies and 
overall
Patient-year analysis
Study for Analysis
Analysis Group
RAJ1
RAJ3
RAJ4
TEAEs1, 3
X
X
X
preceding studies 
and overall
TEAEs of special interest2
●
Serious Infections
●
Malignancies
●
Herpes Zoster Related Disease (Herpes Zoster and Varicella)
●
Herpes Zoster
●
Varicella
●
Infections That Require Intravenous Anti-infectious Therapy
X
X
X
preceding studies 
and overall
TEAEs of special interest by subgroups 2
●
Sex (Male, Female,)
●
Age Group at Week 0 (< 65 years, >= 65 years)
●
Concomitant Steroid at Week 0 (No, Yes)
●
Prednisone Dose  (mg/day) at Week 0 (None, 0 <- 5 mg/day, > 5 
mg/day)
X
X
X
preceding studies 
and overall
1 According to Definition 2
2 According to Definition 1
3 Patient-years analysis will be displayed by time intervals and by overall period.


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10.3
Appendix 3: Overview of Clinical Laboratory Evaluation, Vital 
Signs, and Electrocardiograms (ECGs) analyses
Table below summarizes the analyses of Clinical Laboratory Evaluation, Vital Signs, and 
Electrocardiograms (ECGs), with "X" indicating that the variable will be analyzed. All 
analyses will be based on the SAF and presented by preceding studies and overall, unless 
otherwise specified.
The overview of Clinical Laboratory Evaluation, Vital Signs, and Electrocardiograms 
(ECGs) analyses
Study for Analysis
Analysis Group
RAJ1
RAJ3
RAJ4
Clinical Laboratory Evaluation
Quantitative Laboratory Test Results in SI Units, Hematology;
Actual and Change from Week 0
X
X
X
preceding studies and 
overall
Quantitative Laboratory Test Results in SI Units, Hematology;
Actual and Change from Week 0
By study region
X
X
X
preceding studies and 
overall
Quantitative Laboratory Test Results in SI Units, Biochemistry;
Actual and Change from Week 0
X
X
X
preceding studies and 
overall
Quantitative Laboratory Test Results in SI Units, Biochemistry;
Actual and Change from Week 0
By study region
X
X
X
preceding studies and 
overall
Quantitative Laboratory Test Results in SI Units, Urinalysis;
Actual and Change from Week 0
X
X
X
preceding studies and 
overall
Quantitative Laboratory Test Results in SI Units, Urinalysis;
Actual and Change from Week 0
By study region
X
X
X
preceding studies and 
overall
Quantitative Laboratory Test Results in SI Units, Fasting Lipids Profile;
Actual and Change from Week 0
X
X
X
preceding studies and 
overall
Quantitative Laboratory Test Results in SI Units, Fasting Lipids Profile;
Actual and Change from Week 0
By study region
X
X
X
preceding studies and 
overall
Quantitative Laboratory Test Results in SI Units, T-Chol/HDL, 
LDL/HDL Ratio;
Actual and Change from Week 0
X
X
X
preceding studies and 
overall
Quantitative Laboratory Test Results in SI Units, T-Chol/HDL, 
LDL/HDL Ratio;
Actual and Change from Week 0
By study region
X
X
X
preceding studies and 
overall
Quantitative Laboratory Test Results in SI Units, Erythrocyte 
Sedimentation Rate (ESR) ;
Actual and Change from Week 0
X
X
X
preceding studies and 
overall
Quantitative Laboratory Test Results in SI Units, Erythrocyte;
Actual and Change from Week 0
By study region
X
X
X
preceding studies and 
overall
Qualitative Laboratory Test Results, Urinalysis;
By study region (Japan)
X
X
X
preceding studies and 
overall
Qualitative Laboratory Test Results, Urinalysis
For subjects shifted from RAJ3, by study region (Korean/Taiwan)
X
RAJ3
Shift-from-Week 0 Table for Laboratory Test Results, Hematology;
Week 0 to Lowest Value up to ET
X
X
X
preceding studies and 
overall
Shift-from-Week 0 Table for Laboratory Test Results, Hematology;
Week 0 to Highest Value up to ET
X
X
X
preceding studies and 
overall


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Study for Analysis
Analysis Group
RAJ1
RAJ3
RAJ4
Shift-from-Week 0 Table for Laboratory Test Results, Biochemistry;
Week 0 to Lowest Value up to ET
X
X
X
preceding studies and 
overall
Shift-from-Week 0 Table for Laboratory Test Results, Biochemistry;
Week 0 to Highest Value up to ET
X
X
X
preceding studies and 
overall
Shift-from-Week 0 Table for Laboratory Test Results, Urinalysis;
Week 0 to Lowest Value up to ET
X
X
X
preceding studies and 
overall
Shift-from-Week 0 Table for Laboratory Test Results, Urinalysis;
Week 0 to Highest Value up to ET
X
X
X
preceding studies and 
overall
Shift-from-Week 0 Table for Laboratory Test Results, Fasting Lipids 
Profile;
Week 0 to Lowest Value up to ET
X
X
X
preceding studies and 
overall
Shift-from-Week 0 Table for Laboratory Test Results, Fasting Lipids 
Profile;
Week 0 to Highest Value up to ET
X
X
X
preceding studies and 
overall
Shift-from-Week 0 Table for Selected Laboratory Variables using NCI-
CTCAE Toxicity Grade (version 4.0) ;
Week 0 to ET
X
X
X
preceding studies and 
overall
Shift-from-Week 0 Table in Pre-Specified Reference Range Laboratory 
test Results by Visit, Selected Laboratory Variables
●
Aspartate Aminotransferase (AST)
●
Alanine Aminotransferase (ALT)
●
Alkaline Phosphatase (ALP)
●
Total Bilirubin Category 1
●
Total Bilirubin Category 2
●
Low-Density Lipoprotein (LDL) Category 1
●
Low-Density Lipoprotein (LDL) Category 2
●
Hemoglobin (HGB) Category 1
●
Hemoglobin (HGB) Category 2
●
Hemoglobin (HGB) Category 3
●
Creatine Phosphokinase (CPK) Category 1
●
Creatine Phosphokinase (CPK) Category 2
●
Creatine Phosphokinase (CPK) Category 3
●
Creatinine
●
Absolute Neutrophil Count (ANC)
●
Lymphocytes Category 1
●
Lymphocytes Category 2
●
Platelets Category 1
●
Platelets Category 2
X
X
X
preceding studies and 
overall
Liver Function Analysis for Overall Period
●
Clinically Significant Values in Liver Function Tests
●
Summary of Moderate and Marked Liver Abnormalities by Visit
X
X
X
preceding studies and 
overall
Liver Functions Plots
X
X
X
preceding studies and 
overall
Vital Signs
Vital Signs;
Actual and Change from Week 0
X
X
X
preceding studies and 
overall
ECG Results
Interpretation of 12- Lead ECG Results, Assessment by Investigator
X
X
X
preceding studies and 
overall
Shift-from-Week 0 Table for 12-Lead ECG 
X
X
X
preceding studies and 
overall


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10.4
Appendix 4: Computation of HAQ-DI Score
The HAQ-DI is composed of 20 items in 8 categories (Dressing and Grooming, Arising, 
Eating, Walking, Hygiene, Reach, Grip, and Activities). Each category has at least two 
questions. Within each category, subjects report the amount of difficulty they have in 
performing the specific question items. 
Classification of HAQ Question and Checkbox for computation of HAQ-DI Score 
Category
Question
Checkbox
1.
Dressing 
and 
Grooming 
1)
Dress yourself, including 
shoelaces and buttons
2)
Shampoo your hair
●
1 "aids or devices" check box: 
o
Devices used for dressing 
(button hook, zipper pull, 
etc.)
●
1 "help from another person"
checkbox: 
o
Dressing and grooming
2.
Arising
1)
Stand up from a straight 
chair
2)
Get in and out of bed
●
1 "aids or devices" checkbox: 
o
Special or built up chair
●
1 "help from another person"
checkbox: 
o
Arising
3.
Eating
1)
Cut your own meat
2)
Lift a full cup or glass to 
your mouth
3)
Open a new milk carton
●
1 "aids or devices" checkbox: 
o
Built up or special utensils
●
1 "help from another person"
checkbox: 
o
Eating
4.
Walking
1)
Walk outdoors on flat 
ground
2)
Climb up five steps
●
4 "aids or devices" checkboxes: 
o
Cane
o
Walker
o
Crutches
o
Wheelchair
●
1 "help from another person"
checkbox: 
o
Walking
5.
Hygiene
1)
Wash and dry your body
2)
Take a tub bath
3)
Get on and off the toilet
●
4 "aids or devices" checkboxes: 
o
Raised toilet seat
o
Bathtub seat
o
Bathtub bar
o
Long-handled appliances in 
bathroom
●
1 "help from another person"
checkbox:
o
Hygiene


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Category
Question
Checkbox
6.
Reach
1)
Reach and get down a 5 
pound object (such as a bag 
of sugar) from above your 
head
2)
Bend down to pick up 
clothing from the floor
●
1 "aids or devices" checkbox: 
o
Long-handled appliances for 
reach
●
1 "help from another person"
checkbox:
o
Reach
7.
Grip
1)
Open car doors
2)
Open previously  opened 
jars 
3)
Turn faucets on and off
●
1 "aids or devices" checkbox:
o
Jar opener (for jars previously 
opened)
●
1 "help from another person"
checkbox:
o
Gripping and opening things
8.
Activities
1)
Run errands and shop
2)
Get in and out of a car
3)
Do chores such as 
vacuuming or yard work
●
1 "help from another person"
checkbox:
o
Errands and chores
For each question, there are four response options ranging from "Without Any Difficulty" to 
"Unable to Do", scored 0 - 3. Details are as follows.
Response
Score
Without Any Difficulty
0
With Some Difficulty      
1
With Much Difficulty     
2
Unable to Do                  
3
The patient must have a score for >= 6 of the 8 categories. If there are less than 6 categories 
completed, a HAQ-DI cannot be computed, whether the missing categories are due to 
missing values or they do not apply to the respondent. Individual questions within a category 
are not imputed. Therefore the maximum score in each category is based on non-missing 
questions, and a category score is missing when all questions within a category are missing.
There are three steps to compute the HAQ-DI score.
1.
For each category, compute the category score by using the highest question score. 
●
For example, in the category "Eating" there are 3 questions, a subject responds with a 1, 
2, and 0, respectively. 


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Category
Question
Subject Reported 
Response
Eating
1)
Cut your own meat
1
2)
Lift a full cup or glass to your 
mouth
2
3)
Open a new milk carton
0
●
The highest score is 2, so the category score is 2 for this subject. 
2.
Adjust for use of "aids or devices" and/or "help from another person" when indicated in 
the checkbox(es)
●
If the category score is < 2 but at least one "aids or devices" or "help from another 
person" box is checked, the category score is set equal to 2. 
●
If the category score is < 2 and none of the "aids or devices" or "help from another 
person" boxes is checked, the category score remains. 
●
If the category score is 2, it remains 2, and if a three, it remains a three. 
3.
Divide the summed category scores by the number of categories answered (must be a 
minimum of 6) to obtain a HAQ-DI score of 0 – 3, with higher scores indicating greater 
disability (3 = worst functioning).


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10.5
Appendix 5: Computation of SF-36v2® Score
The SF-36v2® will be scored for the 8 scales according to the standard SF-36v2® scoring 
algorithm (0-100 scale) explained in the SF-36v2® Japanese Manual (Fukuhara et al., 2011). 
The physical component score (PCS), mental component score (MCS) and role/social 
component score (RCS) will be scored according to the standard SF-36v2® scoring algorithm 
(0-100 scale) explained in the same Manual. A higher score indicates a better health state. 
Prior to the analysis, the responses will be scored according to the following four steps. 
1.
Item recoding for the 10 items which require recoding
2.
Computing raw scale scores by summing across items within the same scale (raw scale 
scores)
3.
Transforming the raw scale scores into a 0-100 scale (transformed scale scores) 
4.
Normalizing the transformed scale scores with a mean of 50 and a standard deviation of 
10 in the general Japanese population (norm-based scale scores)
Questions, coding and scoring of the 8 scales (Physical Functioning, Role-Physical, Bodily 
Pain, General Health, Vitality, Social Functioning, Role-Emotional, Metal Health), PCS and 
MCS are presented below. 
Physical Functioning: Verbatim Items and Scoring Information
Question
Number
Verbatim Items
3.
The following questions are about activities you might do during a typical 
day. Does your health now limit you in these activities? If so, how much?
3a.
Vigorous activities, such as running, lifting heavy objects, participating in 
strenuous sports
3b.
Moderate activities, such as moving a table, pushing a vacuum cleaner, 
bowling, or playing golf
3c.
Lifting or carrying groceries
3d.
Climbing several flights of stairs
3e.
Climbing one flight of stairs
3f.
Bending, kneeling, or stooping
3g.
Walking more than a mile
3h.
Walking several hundred yards
3i.
Walking one hundred yards
3j.
Bathing or dressing yourself
Precoded and Final Values for Items 3a through 3j
Response Choices
Precoded Item Value
Final Item Value
Yes, limited a lot
1
1
Yes, limited a little
2
2
No, not limited at all
3
3


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Role-Physical: Verbatim Items and Scoring Information
Question 
Number
Verbatim Items
4.
During the past 4 weeks, how much of the time have you had any of the 
following problems with your work or other regular daily activities as a 
result of your physical health?
4a.
Cut down the amount of time you spent on work or other activities
4b.
Accomplished less than you would like
4c.
Were limited in the kind of work or other activities
4d.
Had difficulty performing the work or other activities (for example, it took 
extra effort)
Precoded and Final Values for Items 4a through 4d
Response Choices
Precoded Item Value
Final Item Value
All of the time
1
1
Most of the time
2
2
Some of the time
3
3
A little of the time
4
4
None of the time
5
5
Bodily Pain: Verbatim Items and Scoring Information
Question 
Number
Verbatim Items
7.
How much bodily pain have you had during the past 4 weeks?
8.
During the past 4 weeks, how much did pain interfere with your normal 
work (including both work outside the home and housework)?
Precoded and Final Values for Item 7
Response Choices
Precoded Item Value
Final Item Value
None
1
6.0
Very mild
2
5.4
Mild
3
4.2
Moderate
4
3.1
Severe
5
2.2
Very Severe
6
1.0


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Scoring for Item 8 if both Items 7 and 8 are Answered
Response Choices
If Item 8 Precoded 
Item Value
And Item 7 
Precoded 
Item Value
Then Final Item 
Value
Not at all
1
1
6
1
2 through 6
5
A little bit
2
1 through 6
4
Moderately
3
1 through 6
3
Quite a bit
4
1 through 6
2
Extremely
5
1 through 6
1
Scoring for Item 8 if Item 7 is Not Answered
Response Choices
Precoded Item Value
Then Final Item Value
Not at all
1
6.0
A little bit
2
4.75
Moderately
3
3.5
Quite a bit
4
2.25
Extremely
5
1.0
General Health: Verbatim Items and Scoring Information
Question Number
Verbatim Items
1.
In general, would you say your health is :
11.
How TRUE or FALSE is each of the following statements for 
you?
11a.
I seem to get sick a little easier than other people
11b.
I am as healthy as anybody I know
11c.
I expect my health to get worse
11d.
My health is excellent


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Precoded and Final Values for Items 1 and 11a through 11d
Item 1
Response Choices
Precoded Item Value
Final Item Value
Excellent
1
5.0
Very good
2
4.4
Good
3
3.4
Fair
4
2.0
Poor
5
1.0
Items 11a and 11c
Response Choices
Precoded Item Value
Final Item Value
Definitely True
1
1
Mostly True
2
2
Don't Know
3
3
Mostly False
4
4
Definitely False
5
5
Items 11b and 11d
Response Choices
Precoded Item Value
Final Item Value
Definitely True
1
5
Mostly True
2
4
Don't Know
3
3
Mostly False
4
2
Definitely False
5
1
Vitality: Verbatim Items and Scoring Information
Question 
Number
Verbatim Items
9.
These questions are about how you feel and how things have been with 
you during the past 4 weeks. For each question, please give the one answer 
that comes closest to the way you have been feeling. How much of the 
time during the past 4 weeks …
9a.
Did you feel full of life?
9e.
Did you have a lot of energy?
9g.
Did you feel worn out?
9i.
Did you feel tired?


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Precoded and Final Values for Items 9a, 9e, 9g and 9i
Item 9a and 9e
Response Choices
Precoded Item Value
Final Item Value
All of the time
1
5
Most of the time
2
4
Some of the time
3
3
A little of the time
4
2
None of the time
5
1
Items 9g and 9i
Response Choices
Precoded Item Value
Final Item Value
All of the time
1
1
Most of the time
2
2
Some of the time
3
3
A little of the time
4
4
None of the time
5
5
Social Functioning: Verbatim Items and Scoring Information
Question 
Number
Verbatim Items
6.
During the past 4 weeks, to what extent has your physical health or 
emotional problems interfered with your normal social activities with 
family, friends, neighbors, or groups?
10.
During the past 4 weeks, how much of the time has your physical health or 
emotional problems interfered with your social activities (like visiting with 
friends, relatives, etc.)?
Precoded and Final Values for Items 6 and 10
Item 6
Response Choices
Precoded Item Value
Final Item Value
Not at all
1
5
Slightly
2
4
Moderately
3
3
Quite a bit
4
2
Extremely
5
1
Item 10
Response Choices
Precoded Item Value
Final Item Value
All of the time
1
1
Most of the time
2
2
Some of the time
3
3
A little of the time
4
4
None of the time
5
5


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Role-Emotional: Verbatim Items and Scoring Information
Question 
Number
Verbatim Items
5.
During the past 4 weeks, how much of the time have you had any of the 
following problems with your work or other regular daily activities as a 
result of any emotional problems (such as feeling depressed or anxious)?
5a.
Cut down on the amount of time you spent on work or other activities
5b.
Accomplished less than you would like
5c.
Did work or other activities less carefully than usual
Precoded and Final Values for Items 5a through 5c
Item 5a through 5c
Response Choices
Precoded Item Value
Final Item Value
All of the time
1
1
Most of the time
2
2
Some of the time
3
3
A little of the time
4
4
None of the time
5
5
Mental Health: Verbatim Items and Scoring Information
Question 
Number
Verbatim Items
9.
These questions are about how you feel and how things have been with you 
during the past 4 weeks. For each question, please give the one answer that 
comes closest to the way you have been feeling. How much of the time 
during the past 4 weeks …
9b.
Have you been very nervous?
9c.
Have you felt so down in the dumps that nothing could cheer you up?
9d.
Have you felt calm and peaceful?
9f.
Have you felt downhearted and depressed?
9h.
Have you been happy?


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Precoded and Final Values for Items 9b, 9c, 9d, 9f and 9h
Items 9b, 9c and 9f
Response Choices
Precoded Item Value
Final Item Value
All of the time
1
1
Most of the time
2
2
Some of the time
3
3
A little of the time
4
4
None of the time
5
5
Item 9d and 9h
Response Choices
Precoded Item Value
Final Item Value
All of the time
1
5
Most of the time
2
4
Some of the time
3
3
A little of the time
4
2
None of the time
5
1
Reported Health Transition: Verbatim Items and Scoring Information
Question 
Number
Verbatim Items
2.
Compared to one year ago, how would you rate your health in general now?
Precoded and Final Values for Item 2
Item 2
Response Choices
Precoded 
Item Value
Final Item 
Value
Much better now than one year ago
1
1
Somewhat better now than one year ago
2
2
About the same as one year ago
3
3
Somewhat worse now than one year ago
4
4
Much worse now than one year ago
5
5
Use Table below to compute simple algebraic sums of the presented final item scores. 


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Formulas for Scoring and Transforming Scales
SF-36v2 Scale
Sum Final Item Values 
(after recoding items as 
in Tables above)
Lowest and 
Highest Possible 
Raw Scores
Possible Raw 
Score Range
Physical 
Functioning
3a + 3b + 3c + 3d + 3e + 
3f + 3g + 3h + 3i + 3j
10, 30
20
Role-Physical
4a + 4b + 4c + 4d
4, 20
16
Bodily Pain
7 + 8
2, 12
10
General Health
1 + 11a + 11b + 11c + 
11d
5, 25
20
Vitality
9a + 9e + 9g + 9i
4, 20
16
Social Functioning
6 + 10
2, 10
8
Role-Emotional
5a + 5b + 5c
3, 15
12
Mental Health
9b + 9c + 9d + 9f + 9h
5, 25
20
Formula for transformation of raw scale scores to 0-100 scale scores
Transformed Scale =
(Actual raw score – lowest possible raw score)
× 100
(Possible raw score range)
After calculating the transformed scale score, the next step is to compute a z-score 
transformation.  A z-score for each scale is computed by subtracting the 2007 General 
Japanese Population Means for each SF-36v2® scale and dividing the difference by the 
corresponding scale standard deviation (Table 20) from the 2007 General Japanese 
Population Means and Standard Deviations Used to Derive SF-36v2® Z-score. Formulas are 
listed below.
2007 General Japanese Population Means and Standard Deviations Used to Derive SF-36v2® Z-
score
SF-36v2 Scale
Mean
Standard Deviation
Physical Functioning (PF)
89.13446
13.85045
Role-Physical (RP)
89.24007
18.80773
Bodily Pain (BP)
73.77098
22.39818
General Health (GH)
62.91007
18.76562
Vitality (VT)
62.82787
19.46255
Social Functioning (SF)
86.38347
19.40441
Role-Emotional (RE)
87.84637
20.01521
Mental Health (MH)
71.60598
18.62983


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Step 1.Formulas for Z-score Standardization of SF-36v2® Scales
PF_Z
=
(PF – 89.13446) / 13.85045
RP_Z
=
(RP – 89.24007) / 18.80773
BP_Z
=
(BP – 73.77098) / 22.39818
GH_Z
=
(GH – 62.91007) / 18.76562
VT_Z
=
(VT – 62.82787) / 19.46255
SF_Z
=
(SF – 86.38347) / 19.40441
RE_Z
=
(RE – 87.84637) / 20.01521
MH_Z
=
(MH – 71.60598) / 18.62983
Means and standard deviations are from previous Table.
Step 2.Norm-based Transformation of SF-36v2® Z-scores
The next step involves transforming each SF-36v2® z-score to the norm-based (50, 10) 
scoring. This is accomplished by multiplying each z-score from Step 1 by 10 and adding the 
resulting product to 50.  Formulas are listed below.
Norm-Based Physical Functioning (PF)
=
50 + (PF_Z × 10)
Norm-Based Role-Physical (RP)
=
50 + (RP_Z × 10)
Norm-Based Bodily Pain (BP)
=
50 + (BP_Z × 10)
Norm-Based General Health (GH)
=
50 + (GH_Z × 10)
Norm-Based Vitality (VT)
=
50 + (VT_Z × 10)
Norm-Based Social Functioning (SF)
=
50 + (SF_Z × 10)
Norm-Based Role-Emotional (RE)
=
50 + (RE_Z × 10)
Norm-Based Mental Health (MH)
=
50 + (MH_Z × 10)
PCS, MCS and RCS are scored in three steps as explained below:
Step 1.Z-score Standardization of SF-36v2® Scales
The first consists of standardizing each of the 8 SF-36v2® scales using a z-score 
transformation.  This is the same as Step 1 used in the norm-based scoring of the 8 SF-36 
scales.
Step 2.Aggregating Scales in Estimating Aggregate Physical, Mental, and Role/social
Component Scores
After a z-score has been computed for scale, the second step involves computation of 
aggregate scores for the physical,mental and role/social components using the physical and 
mental factor score coefficients from 2002 survey as given in next Table.


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2002 Factor Score Coefficients Used to Derive PCS,MCS, and RCS Scale Scores 
SF-36v2 Scale
PCS
MCS
RCS
Physical Functioning (PF)
0.67908
-0.20472
-0.13048
Role Physical (RP)
0.22298
-0.27243
0.40393
Bodily Pain (BP)
0.37244
0.14644
-0.21786
General Health (GH)
0.36992
0.33933
-0.41710
Vitality (VT)
-0.08420
0.46413
-0.13120
Social Functioning (SF)
-0.30769
0.06727
0.49261
Role Emotional (RE)
-0.14256
-0.15597
0.61022
Mental Health (MH)
-0.33155
0.44572
0.10326
Computation of an aggregate physical component score consists of multiplying each 
SF-36v2® scale z-score by its respective physical factor score coefficient and summing the 
eight products, as shown below.  Similarly, an aggregate mental, and role/social component 
score is obtained by multiplying each SF-36v2® scale z-score by its respective mental factor 
score coefficient and summing the eight products.
Formulas for Aggregating Scales in Estimating Aggregate Physical, Mental, and 
Role/social Component Scores (Standard Form)
AGG_PHYS
=
(PF_Z × 0.67908) + (RP_Z × 0.22298) + (BP_Z × 0.37244) + (GH_Z × 0.36992) + 
(VT_Z × -0.08420) + (SF_Z ×-0.30769) + (RE_Z × -0.14256) + (MH_Z × -0.33155)
AGG_MENT
=
(PF_Z × -0.20472) + (RP_Z × -0.27243) + (BP_Z × 0.14644) + (GH_Z × 0.33933) + 
(VT_Z × 0.46413) + (SF_Z ×0.06727) + (RE_Z × -0.15597) + (MH_Z × 0.44572)
AGG_ROLE
=
(PF_Z × -0.13048) + (RP_Z × 0.40393) + (BP_Z × -0.21786) + (GH_Z × -0.41710) + 
(VT_Z × -0.13120) + (SF_Z × 0.49261) + (RE_Z × 0.61022) + (MH_Z ×0.10326)
Step 3.Formulas for T-score Transformation of Component Scores (Standard Form)
The third step involves transforming each component score to the norm-based (50, 10) 
scoring.  This is accomplished by multiplying each aggregate component scale score by 10 
and adding the resulting product to 50. 
Transformed Physical (PCS)
= 50 + (AGG_PHYS × 10)
Transformed Mental (MCS)
= 50 + (AGG_MENT × 10)
Transformed Role/Social
(RCS)
= 50 + (AGG_ROLE × 10)
Missing Data in an Individual Questionnaire
In the event that data is missing for an individual item from the scales of the SF-36v2® Health 
Status Survey, the average value of the completed items in the corresponding scale will be 
used as an estimate of the missing item.  If more than 50 percent of the items from a scale are 


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missing for an individual questionnaire, the corresponding deficient scale(s) will be excluded 
from analyses.
Items in each scale are given below:
SF-36v2 
Scale
No. 
Items
Items
Minimum No. Non-Missing Items 
for Imputation of Missing Values
PF
10
3a, 3b, 3c, 3d, 3e, 3f, 3g, 3h, 3i, 3j
5
RP
4
4a, 4b, 4c, 4d
2
BP 
2
7, 8
1
GH 
5
1, 11a, 11b, 11c, 11d
3
VT 
4
9a, 9e, 9g, 9i
2
SF 
2
6, 10
1
RE
3
5a, 5b, 5c
2
MH 
5
9b, 9c, 9d, 9f, 9h
3
Example Showing the Mechanics of Imputation Technique:
Suppose for a subject the items 1, 3b, 3e, 3f, 4a, 4b, 11b, 11d, 5a and 5b are missing. First 
group the missing items according to the scale:
●
GH: Items 1, 11b, 11d 
●
PF: Items 3b, 3e, 3f 
●
RP: Items 4a and 4b
●
RE: Items 5a and 5b
GH consists of 5 items and 3 are missing. That is only 2 have non-missing scores. Since at 
least half of the items are not non-missing, missing items 1, 11a and 11d cannot be imputed. 
Therefore for this subject, the General Health scale score will be missing.
PF consists of 10 items. So, for this subject 7 of the items are non-missing. That is, at least 
half of the items are non-missing. Therefore replace the missing Items 3b, 3e and 3f scores 
by the average score of the non-missing items, i.e., replace by (3a + 3c + 3d + 3g + 3h + 3i + 
3j) / 7.
RP consists of 4 items and two are missing. So at least half are non-missing. Therefore 
replace the missing item scores 4a and 4b by (4c+4d) / 2.
RE consists of 3 and two are missing. That is, more than half of the item scores are missing. 
Therefore, missing scores 5a and 5b cannot be imputed for this subject and thus RE scale 
score for this subject will be missing. 


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10.6
Appendix 6: Computation of FACIT-Fatigue Scale Score
Functional Assessment of Chronic Illness Therapy-Fatigue (FACIT-Fatigue) scale shown 
below, uses 13-item symptom-specific questionnaire to assess the burden of self-reported 
fatigue caused by a chronic disease and its impact upon daily activities and function. It's a 
reliable and valid instrument for measuring fatigue in subjects that has garnered interest in 
rheumatologic drug trials or its capacity to demonstrate decreases in fatigue associated with 
pharmacotherapy.


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As each of the 13 items of the FACIT-Fatigue scale ranges from 0 – 4, the range of possible 
scores is 0 – 52, with 0 being the worst possible score and 52 the best. 
To obtain the 0 – 52 score, each negatively worded item response is recoded so that 0 is a bad 
response and 4 is good response. Therefore, specifically, prior to calculation of the FACIT-
Fatigue scale score, all questions with the exception of "I have energy" and "I am able to 
perform usual activities" will have their responses recoded specified as follows so that:
Response
Recoded Score
Not at all
4
A little bit
3
Somewhat
2
Quite a bit
1
Very much
0
For the questions "I have energy" and "I am able to do my usual activities", the following 
5-point Likert-type scale as follows will be used: 
Response
Score
Not at all
0
A little bit
1
Somewhat
2
Quite a bit
3
Very much
4
All responses are added with equal weight to obtain the total score. Lower values of the 
FACIT-Fatigue score denote higher fatigue.


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10.7
Appendix 7: Computation of WPAI Scale Score
Work Productivity and Activity Impairment Questionnaire: WPAI
In this study, the following scoring methods are applied. These scoring methods are based on 
the specific health problem version of WPAI (WPAI:SHP).
Question 
Number
Contents
1.
1. Are you currently employed (working for pay)?
2.
2. During the past seven days, how many hours did you miss from work because of 
problems associated with your rheumatoid arthritis?
3.
3. During the past seven days, how many hours did you miss from work because of any 
other reason, such as vacation, holidays, time off to participate in this study?
4.
4. During the past seven days, how many hours did you actually work?
5.
5. During the past seven days, how much did your rheumatoid arthritis affect your 
productivity while you were working?
6.
6. During the past seven days, how much did your rheumatoid arthritis affect your ability to 
do your regular daily activities, other than work at a job?
Scores:
Multiply scores by 100 to express in percentages.
●
Percent work time missed due to problem: Q2/(Q2+Q4)
●
Percent impairment while working due to problem: Q5/10
●
Percent overall work impairment due to problem:
Q2/(Q2+Q4)+[(1-(Q2/(Q2+Q4))x(Q5/10)]
●
Percent activity impairment due to problem: Q6/10


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10.8
Appendix 8: AE of Special Interest
1.
Serious Infections
AE which belongs to SOC of Infections and infestations (10021881) and regarded as 
serious. 
2.
Malignancies
Following PT terms are included.
Diffuse large B-cell lymphoma (10012818), Bladder cancer (10005003), Breast cancer 
(10006187), Carcinoma in situ (10061450), Colon cancer (10009944), Gastric cancer 
(10017758), Renal cancer (10038389), Squamous cell carcinoma (10041823), Small cell 
lung cancer stage unspecified (10041071), Extraskeletal chondrosarcoma (10015838), 
Lymphoma (10025310), Thyroid cancer (10066474).
3.
Herpes Zoster Related Disease (Herpes Zoster and Varicella)
Following PT terms are included.
Herpes zoster (10019974), Herpes zoster iridocyclitis (10019980), Herpes zoster 
ophthalmic (10019983), Herpes zoster multi-dermatomal (10058428), Herpes zoster 
infection neurological (10061208), Herpes zoster oticus (10063491), Herpes zoster 
disseminated (10065038), Encephalitis post varicella (10014603), Varicella (10046980), 
Varicella post vaccine (10063522).
4.
Herpes Zoster
Following PT terms are included.
Herpes zoster (10019974), Herpes zoster iridocyclitis (10019980), Herpes zoster 
ophthalmic (10019983), Herpes zoster multi-dermatomal (10058428), Herpes zoster 
infection neurological (10061208), Herpes zoster oticus (10063491), Herpes zoster 
disseminated (10065038)
5.
Varicella 
Following PT terms are included.
Encephalitis post varicella (10014603), Varicella (10046980), Varicella post vaccine
(10063522).
6.
Infections That Require Intravenous Anti-infectious Therapy
All PTs which belong to SOC of Infections and Infestations (10021881) for which there 
is an intravenous concomitant medication (antibiotics, antivirals, antifungals, etc.) 
associated with that event for that patient.


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10.9
Appendix 9: Standard Toxicity Grading for Laboratory Tests 
According to National Cancer Institute Common Terminology 
Criteria for Adverse Events (NCI-CTCAE) v4.0
Standard Toxicity Grading for Laboratory Tests According to National Cancer Institute 
Common Terminology Criteria for Adverse Events (NCI-CTCAE) v4.0
Test 
Name
Direction of 
Change /
CTCAE Grade 2
NCI 
Ref.
Tes
t 
Co
de
  Units 
1
AE Term
0
1
2
3
4
Ver
sion
Pa
ge
Unit
s
Alanine 
Aminotran
sferase(AL
T/SGPT)
ALT
n/a
Increase/
Alanine 
aminotransfera
se increased
WNL
>ULN -
<=
3.0×UL
N
>3.0×U
LN -
<=
5.0×UL
N
>5.0×U
LN -
<=
20.0×U
LN
>20.0
×ULN
4.0
107
n/a
Albumin
ALB
g/dL
Decrease/
Hypoalbumine
mia
WNL
>=3 -
<LLN
>=2 -
<3
<2
4.0
116
g/dL
Alkaline 
Phosphatas
e
ALK
P
n/a
Increase/
Alkaline 
phosphatase 
increased
WNL
>ULN -
<=
2.5×UL
N
>2.5×U
LN -
<=
5.0×UL
N
>5.0×U
LN -
<=
20.0×U
LN
>20.0
×ULN
4.0
107
n/a
Amylase
AM
Y
n/a
Increase/
Serum amylase 
increased
WNL
>ULN -
<=
1.5×UL
N
>1.5×U
LN -
<=
2.0×UL
N
>2.0×U
LN -
<=
5.0×UL
N
>5.0×
ULN
4.0
112
n/a
Aspartate 
Aminotran
sferase(AS
T/SGOT)
  
AST
n/a
Increase/
Aspartate 
aminotransfera
se increased
WNL
>ULN -
<=3.0×U
LN
>3.0×U
LN -
<=5.0×
ULN
>5.0×U
LN -
<=20.0
×ULN
>20.0
×ULN
4.0
107
n/a
Calcium 
Corrected 3
CAC
OR
mg/dL
Increase/
Hypercalcemia
WNL
>ULN -
<= 11.5
>11.5 -
<=12.5
>12.5 -
<= 13.5
>13.5
4.0
115
mg/d
L
Calcium
Corrected 3
CAC
OR
mg/dL
Decrease/
Hypocalcemia
WNL
>=8.0 -
<LLN
>=7.0 -
<8.0
>=6.0 -
<7.0
<6.0
4.0
116
mg/d
L
Total 
Cholesterol
TCH
OL
mg/dL
Increase/
Cholesterol 
high
WNL
>ULN -
<=300
>300 -
<= 400
>400-
<=500
>500
4.0
109
mg/d
L
Creatine 
Phosphoki
nase
CPK
n/a
Increase/
CPK increased
WNL
>ULN -
<=
2.5×UL
N
>2.5×U
LN -
<=
5×ULN
>5×UL
N - <=
10×UL
N
>10×
ULN
4.0
109
n/a
Creatinine
CRE
AT
n/a
Increase/
Creatinine 
increased
WNL
>ULN -
<=
1.5×UL
N
or
>ULN-
<=1.5×
Week 0 
value
>1.5×U
LN -
<=
3.0×UL
N
or
>1.5×U
LN -
<=3.0×
Week 0 
value
>3.0×U
LN -
<=6.0×
ULN
or
>3.0×
Week 0 
value
>6.0×
ULN
4.0
109
n/a


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Test 
Name
Direction of 
Change /
CTCAE Grade 2
NCI 
Ref.
Tes
t 
Co
de
  Units 
1
AE Term
0
1
2
3
4
Ver
sion
Pa
ge
Unit
s
Estimated 
glomerular 
filtration 
rate 
GFR
mL/m
in per 
1.73 
m^2
Decrease/
Chronic kidney 
disease
Not 
appli
cable
8
Not 
applicab
le8
30 - 59 
15 - 29 
<15 
4.0
147
mL/
min 
per 
1.73 
m^2
Gamma 
Glutamyl 
Transferase 
(GGT)
GGT
n/a
Increase/
GGT increased
WNL
>ULN -
<=2.5×U
LN
>2.5×U
LN -
<=5.0×
ULN
>5.0×U
LN -
<=20.0
×ULN
>20.0
×ULN
4.0
110
n/a
Glucose
GLU
C
mg/dL
Decrease/
Hypoglycemia
WNL
>=55 -
<LLN
>=40 -
<55
>=30-
<40
<30
4.0
117
mg/d
L
Hemoglobi
n
HGB
g/dL
Increase/
Hemoglobin 
increased
WNL
Increase 
in >0 - 2 
g/dL 
above 
ULN or 
above 
Week 0 
value if 
Week 0 
value is 
above 
ULN
Increas
e in >2 
- 4 g/dL 
above 
ULN or 
above 
Week 0 
value if 
Week 0 
value is 
above 
ULN
Increas
e in >4 
g/dL 
above 
ULN or 
above 
Week 0 
value if 
Week 0 
value is 
above 
ULN
4.0
111
g/dL
Hemoglobi
n
HGB
g/dL
Decrease/
Anemia
WNL
>=10 -
<LLN
>=8 -
<10.0
<8
4.0
3
g/dL
Leukocytes 
(WBC)
WB
C
103/μ
L
Decrease/
White blood 
cell decreased
WNL
>=3.0 -
<LLN
>=2.0 -
<3.0
>=1.0 -
<2.0
<1.0
4.0
113
103/μ
L
Lymphocyt
es, 
Absolute 
Units
LY
MP
HAB
103/μ
L
Decrease/
Lymphocyte 
count 
decreased
Not 
appli
cable
8
Not 
applicab
le8
>=0.5 -
<0.8 
>=0.2 -
<0.5 
<0.2
4.0
111
103/μ
L
Lymphocyt
es, 
Absolute 
Units
LY
MP
HAB
103/μ
L
Increase/ 
Lymphocyte 
count increased
Not 
appli
cable
8
>4 - 20
>20
4.0
111
103/μ
L
Magnesiu
m
MG
mg/dL
Increase/
Hypermagnese
-mia
WNL
>ULN -
<=3.0
>3.0 -
<=8.0
>8.0
4.0
115
mg/d
L
Magnesiu
m
MG
mg/dL
Decrease/
Hypomagnese
mia
WNL
>=1.2 -
<LLN
>=0.9 -
<1.2
>=0.7 -
<0.9
<0.7
4.0
117
mg/d
L 
Absolute 
Neutrophil 
Count 
ANC
103/μ
L
Decrease/
Neutrophil 
count 
decreased
Not 
appli
cable
8
Not 
applicab
le8
>=1.0 -
<1.5
>=0.5 -
<1.0 
<0.5
4.0
112
103/μ
L
Phosphate 
(Phosphoru
s)
PHO
S
mg/dL
Decrease/
Hypophosphat
emia
WNL
Not 
applicab
le8
>=2.0 -
<2.5
>=1.0 -
<2.0
<1.0
4.0
117
mg/d
L


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Test 
Name
Direction of 
Change /
CTCAE Grade 2
NCI 
Ref.
Tes
t 
Co
de
  Units 
1
AE Term
0
1
2
3
4
Ver
sion
Pa
ge
Unit
s
Platelets
PLT
103/μ
L
Decrease/
Platelet count 
decreased
WNL
>=75.0 -
<LLN
>=50.0 
- <75.0
>=25.0 
- <50.0
<25.0
4.0
112
103/μ
L 
Potassium
K
mEQ/
L
Increase/
Hyperkalemia
WNL
>ULN -
<=5.5
>5.5 -
<=6.0
>6.0 -
<=7.0
>7.0
4.0
115
mEQ/
L 7
Potassium 4
K
mEQ/
L
Decrease/ 
Hypokalemia
WNL
>=3.0 -
<LLN 
>=2.5 -
<3.0
<2.5
4.0
117
mEQ/
L 7
Urine 
Protein5
UPR
OT
Increase/
Proteinuria
WNL
+
++
+++ or 
++++
4.0
149
n/a
Sodium
NA
mEQ/
L
Increase/
Hypernatremia
WNL
>ULN -
<=150
>150 -
<=155
>155 -
<=160
>160
4.0
116
mEQ/
L 7
Sodium
NA
mEQ/
L
Decrease/
Hyponatremia
WNL
>=130 -
<LLN
>=120 -
<130
<120
4.0
117
mEQ/
L 7
Total 
Bilirubin
TBI
LI
n/a
Increase/
Blood bilirubin 
increased
WNL
>ULN -
<=1.5×U
LN
>1.5×U
LN -
<=3.0×
ULN
>3.0×U
LN -
<=10.0
×ULN
>10.0
×ULN
4.0
107
n/a
Triglycerid
es
TRI
G
mg/dL
Increase/
Hypertriglyceri
demia
WNL
> ULN 9
- <=300
>300 -
<=500
>500 -
<=1000
>1000
4.0
116
mg/d
L
Uric Acid 6
UAC
ID
mg/dL
Increase/
Hyperuricemia
WNL
>ULN -
10 
>10 
4.0
116
mg/d
L
1   "n/a" is specified if the criteria are based strictly on a comparison of the value to its reference range.
2    WNL = Within Normal Limits; LLN = Lower Limit of Normal; ULN = Upper Limit of Normal.
3     Calcium Corrected will be derived using the following formula: Calcium Corrected = 0.8 × (4.0 – Albumin) 
+ Calcium, where 4.0 represents the average albumin level in g/dL,  Albumin is measured in unit of g/dL, and 
Calcium is measured in unit of mg/dL.
4    Hypokalemia Grade 2 is the same as Grade1 but has additional clinical criteria that cannot be assessed.  
Therefore, it was decided to grade all criteria falling within >=3.0 - <LLN as grade 2.
5    For Urine Protein, the maximum category is "++++", while NCI CTCAE version4.0 doesn't define "+++", 
"++++". So, these are defined as grade 3 per internal discussion.
6     Hyperuricemia Grade 3 is the same as Grade1 but has additional clinical criteria that cannot be assessed.  
Therefore, it was decided to grade all criteria falling within >ULN – 10 mg/dL as grade 3.
7 For hyperkalemia, hypokalemia, hypernatremia and hyponatremia, the unit in the NCI reference is mmol/L, 
which has been converted to mEQ/L by multiplying 1.
8 For ANC, LYMPHAB, GFR, there are no reference range in central laboratory, so, NCI CTCAE grading scale 
is only defined for not-related reference range category. For PHOS, LLN=2.5mg/dL, while NCI Grade 1 is 
defined ">=2.5 - <LLN", so Grade 1 can't be defined.
9 For TRIG, the upper limit of normal range is 149 mg/dL. Therefore, WNL for Grade 0 is up to 149 mg/dL. But 
the lower limit of Grade 1 is originally more than 150 mg/dL. So, the definition for the lower limit of grade 1 is 


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Test 
Name
Direction of 
Change /
CTCAE Grade 2
NCI 
Ref.
Tes
t 
Co
de
  Units 
1
AE Term
0
1
2
3
4
Ver
sion
Pa
ge
Unit
s
changed from 150 mg/dL to ULN.
●
Hyperuricemia (see pg. 116 of NCI document) cannot be assessed accurately without knowing whether or 
not the subject was experiencing physiologic consequences, so it is not included in the table.
●
Hemoglobinuria (see pg. 148 of NCI document) cannot be assessed accurately without knowing clinical or 
diagnostic observations, so it is not included in the table.
●
Troponin T (see pg. 109 of  NCI document) cannot be assessed accurately without knowing manufacturer 
ranges, so it is not included in the table.


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10.10 Appendix 10: Key Contributors and Approvers
List of Key Contributors and Approvers
Key Contributors
The following contributed to or reviewed this Statistical Analysis Plan as relevant to their 
indicated discipline or role.
Primary author (s)
 
 
 
 
 
 
 
 
 
Contributors and Reviewers
, Medical Expert 
, 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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Author and Approver Signatories 
(E-signatures are attached at end of document) 
This Statistical Analysis Plan was prepared by:
, 
This Statistical Analysis Plan was prepared by:
, 
This Statistical Analysis Plan was approved by:
, 
This Statistical Analysis Plan was approved by:
,