Clinical trial NCT02305849
Conditions: Rheumatoid Arthritis
Keywords: ASP015K Rheumatoid Arthritis
Sponsor: Astellas Pharma Inc
Start date: 2014-07-25; Completion date: 2017-11-28
Enrollment: 519 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The objective of this study was to verify the efficacy of ASP015K versus placebo administrated in combination with methotrexate (MTX) over placebo in terms of efficacy in participants with rheumatoid arthritis (RA) who had an inadequate response to MTX

Detailed description:
This study was a multi-center, randomized, placebo-controlled, double-blind, parallel-group, confirmatory study to evaluate the efficacy and safety of ASP015K (100 and 150 mg/day) administered in combination with MTX in participants with RA who had an inadequate response to MTX.

Participants orally received ASP015K 100 mg, ASP015K 150 mg or placebo once daily (QD) in combination with MTX after breakfast for 52 weeks.

At Week 12, inadequate responders in the placebo group, as determined by a \< 20% improvement from baseline (i.e., treatment initiation day) in tender or painful joint count (TJC) and swollen joint count (SJC), were switched to either ASP015K 100 mg or ASP015K 150 mg, and the dosage was maintained until the end of treatment (EOT). In addition, participants who received placebo at Week 28 were switched to either ASP015K 100 mg or ASP015K 150 mg, and the dosage was maintained until the EOT.

The ASP015K dose that was started for placebo group participants at Week 12 or Week 28 was randomly chosen at baseline. The dose was switched under the blinded condition.

Participants who completed this study were eligible for participation in the open-label extension study (015K-CL-RAJ2). Participants made a follow-up visit after the week 52 visit if they did not enroll into the extension study on the day of the week 52 visit.

Arms: arm 1: Participants received 100 mg tablet of peficitinib orally once daily in combination with MTX for a period of 52 weeks. arm 2: Participants received 150 mg tablet of peficitinib orally once daily in combination with MTX for a period of 52 weeks. arm 3: Participants who received placebo matching to peficitinib 100 mg or 150 mg orally once daily in combination with MTX until week 12 or 28 were switched to receive 100 mg or 150 mg tablet of peficitinib orally once daily in combination with MTX from week 12 or 28 to week 52.
Interventions: intervention 1: Peficitinib intervention 2: Placebo intervention 3: Methotrexate
Intervention descriptions: intervention 1: oral tablet intervention 2: oral tablet intervention 3: Oral tablet/capsule

Protocol documents:
Prot_000.pdf: 
Phase III Study of ASP015K
−A Randomized, Double-Blind, Placebo-Controlled 
Confirmatory Study of Efficacy and Safety of ASP015K in 
Patients with Rheumatoid Arthritis (RA) Who Had an 
Inadequate Response to MTX−
ISN/Protocol 015K-CL-RAJ4
ClinicalTrials.gov Identifier: NCT02305849
Date of Protocol: Version 5.0, dated 03 March 2017
Sponsor: Astellas Pharma Inc. (API)
2-5-1 Nihonbashi-Honcho, Chuo-ku, Tokyo


Sponsor: Astellas Pharma Inc.
ISN/Protocol <015K-CL-RAJ4>
- CONFIDENTIAL -
3 March 2017
Astellas
Page 1 of 131
Protocol for Phase III Study of ASP015K
–A Randomized, Double-Blind, Placebo-Controlled Confirmatory Study of Efficacy and 
Safety of ASP015K in Patients with Rheumatoid Arthritis (RA) Who Had an Inadequate 
Response to MTX–
Sponsor: 
Astellas Pharma Inc. (API)
ISN/Protocol: 015K-CL-RAJ4
Created 3 March 2017 (Ver. 5.0)
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.


Sponsor: Astellas Pharma Inc.
ISN/Protocol <015K-CL-RAJ4>
- CONFIDENTIAL -
3 March 2017
Astellas
Page 2 of 131
Table of Contents
I.
SIGNATURE························································································ 8
II.
CONTACT DETAILS OF KEY SPONSOR’S PERSONNEL····························· 9
III.
LIST OF ABBREVIATIONS AND DEFINITION OF KEY TERMS ··················10
IV.
SYNOPSIS··························································································15
V.
FLOW CHART AND SCHEDULE OF ASSESSMENTS·································29
VI.
ACCEPTABLE RANGE OF SCHEDULE OF ASSESSMENTS ························33
1
INTRODUCTION·················································································38
1.1
Background ····················································································38
1.2
Non-clinical and Clinical Data ······························································39
1.2.1
Nonclinical Pharmacology and Safety Pharmacology ······························39
1.2.2
Pharmacokinetics and Pharmacodynamics···········································39
1.2.2.1
Nonclinical Pharmacokinetics····················································39
1.2.2.2
Clinical Pharmacokinetics and Pharmacodynamics ···························40
1.2.3
Toxicology ···············································································43
1.2.4
Efficacy···················································································43
1.3
Summary of Key Safety Information for Study Drugs ···································44
1.4
Risk-Benefit Assessment·····································································46
2
STUDY OBJECTIVE(S), DESIGN, AND VARIABLES ··································48
2.1
Study Objectives ··············································································48
2.2
Study Design and Dose Rationale···························································48
2.2.1
Study Design·············································································48
2.2.2
Dose Rationale···········································································49
2.3
Variables ·······················································································51
2.3.1
Primary Variables ·······································································51
2.3.2
Secondary Variables ····································································51
2.3.2.1
Secondary Efficacy Variables····················································51
2.3.2.2
Safety Variables····································································52
2.3.2.3
Pharmacokinetics Variables ······················································52
2.3.2.4
Pharmacodynamics Variables····················································52
2.3.2.5
Pharmacogenomics (Bio-Banking) ··············································53
2.3.3
Other Variables ··········································································53
3
STUDY POPULATION··········································································54


Sponsor: Astellas Pharma Inc.
ISN/Protocol <015K-CL-RAJ4>
- CONFIDENTIAL -
3 March 2017
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Page 3 of 131
3.1
Selection of Study Population ·······························································54
3.2
Inclusion Criteria··············································································54
3.3
Exclusion Criteria·············································································55
3.4
Discontinuation Criteria for Individual Subjects ··········································59
3.4.1
Suspension, Interruption, and Resumption of the Study Drug·····················60
3.4.1.1
Criteria for Suspension or Interruption of the Study Drug····················61
4
STUDY DRUGS ···················································································62
4.1
Description of Study Drugs ··································································62
4.1.1
Test Drug(s)··············································································62
4.1.2
Comparative Drug(s)····································································62
4.2
Packaging and Labeling······································································62
4.3
Study Drug Handling ·········································································63
4.4
Blinding ························································································63
4.4.1
Blinding Method·········································································63
4.4.2
Confirmation of the Indistinguishability of the Study Drugs ······················64
4.4.3
Retention of the Assignment Schedule and Procedures for Treatment Code 
Breaking ··················································································64
4.4.4
Breaking the Treatment Code for Emergency ·······································64
4.4.5
Breaking the Treatment Code by the Sponsor ·······································65
4.5
Assignment and Allocation ··································································65
5
TREATMENTS AND EVALUATION························································66
5.1
Dosing and Administration of Study Drugs and Other Medications····················66
5.1.1
Dose/Dose Regimen and Administration Period ····································66
5.1.2
Previous and Concomitant Medication (Drugs and Therapies)····················67
5.1.2.1
Previous Medication (Drugs and Therapies) ···································68
5.1.2.2
Concomitant Medication (Drugs and Therapies) ······························71
5.1.3
Treatment Compliance··································································74
5.1.4
Emergency Procedures and Management of Overdose ·····························74
5.1.5
Criteria for Continuation of Treatment ···············································74
5.1.6
Compliance Rules to be Observed by Subjects throughout the Study ············74
5.2
Demographics and Baseline Characteristics ···············································75
5.2.1
Demographics············································································75
5.2.2
Medical History··········································································75
5.2.3
Diagnosis of the Target Disease, Severity, and Duration of Disease··············76


Sponsor: Astellas Pharma Inc.
ISN/Protocol <015K-CL-RAJ4>
- CONFIDENTIAL -
3 March 2017
Astellas
Page 4 of 131
5.3
Efficacy, Pharmacodynamics, and Pharmacokinetics Assessments·····················76
5.3.1
Efficacy Assessments···································································76
5.3.1.1
Tender and Swollen Joint Counts················································76
5.3.1.2
Assessment of Pain and Overall Assessment of Disease Activity ···········77
5.3.1.3
Acute Phase Reactant (CPR and ESR)··········································77
5.3.1.4
EULAR Response Criteria ·······················································77
5.3.1.5
DAS28 ··············································································78
5.3.1.6
SDAI Score·········································································78
5.3.1.7
ACR Response Criteria Assessment ············································79
5.3.1.8
Patient Reported Outcomes/Assessments·······································79
5.3.1.9
Hand and Foot Radiography······················································79
5.3.2
Pharmacodynamic Assessments ·······················································80
5.3.2.1
Lymphocyte Subsets ······························································80
5.3.2.2
Biomarkers for Efficacy and Safety Assessments ·····························80
5.3.3
Pharmacokinetic Assessments ·························································80
5.4
Safety Assessment ············································································81
5.4.1
Vital Signs················································································81
5.4.2
Body Weight ·············································································81
5.4.3
Adverse Events ··········································································81
5.4.3.1
Adverse Events of Possible Hepatic Origin ····································82
5.4.4
Laboratory Assessments································································82
5.4.4.1
CPK Monitoring ···································································84
5.4.4.2
Hepatic Function Abnormal······················································85
5.4.5
Physical Examination···································································85
5.4.6
12-lead Electrocardiogram (ECG)·····················································85
5.4.7
Radiography··············································································85
5.4.8
Central ECG ·············································································86
5.5
Adverse Events and Other Safety Aspects ·················································86
5.5.1
Definition of Adverse Events (AEs) ··················································86
5.5.2
Definition of Serious Adverse Events (SAEs) ·······································87
5.5.3
Criteria for Causal Relationship to the Study Drug ·································87
5.5.4
Criteria for Defining the Severity of an Adverse Event ····························88
5.5.5
Reporting of Serious Adverse Events (SAEs) ·······································88
5.5.6
Follow-up of Adverse Events··························································89
5.5.7
Procedure in Case of Pregnancy·······················································89


Sponsor: Astellas Pharma Inc.
ISN/Protocol <015K-CL-RAJ4>
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5.5.8
Supply of New Information Affecting the Conduct of the Study··················90
5.5.9
Deviations from the Protocol and Other Actions Taken to Avoid 
Life-Threatening Risks to Subjects····················································90
5.6
Test Drug Concentration ·····································································91
5.7
Other Measurements, Assessments, or Methods ··········································92
5.7.1
Pharmacodynamic Measurements·····················································92
5.7.2
Purposes of Pharmacogenomics ·······················································92
5.7.3
Handling and Storage for Samples Used for Pharmacogenomics ·················92
5.7.4
Disposal of Pharmacogenomics Samples·············································93
5.7.5
Disclosure of Genetic Information ····················································93
5.8
Total Amount of Blood·······································································93
6
TERMINATION OF THE CLINICAL STUDY ············································95
7
STATISTICAL METHODOLOGY ···························································96
7.1
Sample Size····················································································96
7.2
Analysis Set····················································································97
7.2.1
Full Analysis Set (FAS) ································································97
7.2.2
Per Protocol Set (PPS)··································································97
7.2.2.1
PPS for Assessing ACR and DAS at Week 12 (PPS-ACR) ··················97
7.2.2.2
PPS for the Assessment of the Inhibition of Joint Destruction at Week 
28 (PPS-MTSS)····································································97
7.2.3
Safety Analysis Set (SAF)······························································98
7.2.4
Pharmacokinetic Analysis Set (PKAS) ···············································98
7.2.5
Pharmacodynamics Analysis Set (PDAS)············································98
7.3
Demographics and Other Baseline Characteristics········································98
7.4
Analysis of Efficacy ··········································································98
7.4.1
Analysis of Primary Variable ··························································98
7.4.1.1
Primary Analysis···································································98
7.4.1.2
Secondary Analysis································································99
7.4.1.3
Subgroup Analysis·································································99
7.4.2
Analysis of Secondary Variables ······················································99
7.5
Analysis of Safety··········································································· 100
7.5.1
Adverse Events ········································································ 100
7.5.2
Laboratory Assessments······························································ 100
7.5.3
Vital Signs·············································································· 100


Sponsor: Astellas Pharma Inc.
ISN/Protocol <015K-CL-RAJ4>
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Page 6 of 131
7.5.4
12-lead ECG ··········································································· 100
7.5.5
QT Assessment ········································································ 100
7.5.6
Body Weight ··········································································· 100
7.6
Analysis of Pharmacokinetics ····························································· 100
7.7
Other Analyses ·············································································· 101
7.7.1
Analysis of Pharmacodynamics ····················································· 101
7.7.2
Analysis of Pharmacogenomics ····················································· 101
7.8
Interim Analysis (and Early Discontinuation of the Clinical Study)·················· 101
7.9
Handling of Missing Data, Outliers, Visit Windows, and Other Information ······· 101
7.9.1
Handling of Schedule of Assessments of Efficacy Variables ···················· 101
7.9.2
Handling of Schedule of Assessments of Safety Variables ······················ 103
7.9.3
Handling of Schedule of Assessments of Pharmacodynamic Variables ········ 105
7.9.4
Handling of Schedule of Assessments of Pharmacokinetic Variables ·········· 105
8
OPERATIONAL AND ADMINISTRATIVE CONSIDERATIONS ·················· 106
8.1
Procedure for Clinical Study Quality Control ··········································· 106
8.1.1
Data Collection ········································································ 106
8.1.2
Specification of Source Documents················································· 106
8.1.3
Clinical Study Monitoring···························································· 107
8.1.4
Direct Access to Source Data/Documents·········································· 107
8.1.5
Data Management ····································································· 108
8.2
Ethics and Protection of Subject Confidentiality········································ 108
8.2.1
Institutional Review Board (IRB) ··················································· 108
8.2.2
Ethical Conduct of the Study························································· 108
8.2.3
Informed Consent of Subjects ······················································· 108
8.2.3.1
Subject Information and Consent·············································· 108
8.2.3.2
Subject Information and Consent for PGx Research ························ 109
8.2.3.3
Supply of New and Important Information Influencing the Subject’s 
Consent and Revision of the Written Information··························· 109
8.2.4
Subject Confidentiality ······························································· 110
8.3
Administrative Matters ····································································· 110
8.3.1
Arrangement for Use of Information and Publication of the Clinical Study ··· 110
8.3.2
Documents and Records Related to the Clinical Study ··························· 111
8.3.3
Protocol Amendment and/or Revision·············································· 113
8.3.4
Insurance of Subjects and Others···················································· 113
8.3.5
Signatory Investigator for Clinical Study Report·································· 114


Sponsor: Astellas Pharma Inc.
ISN/Protocol <015K-CL-RAJ4>
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Page 7 of 131
9
QUALITY ASSURANCE······································································ 115
10
STUDY ORGANIZATION···································································· 116
10.1
Independent Data and Safety Monitoring Board (DSMB) ····························· 116
10.2
Other Evaluation Committee(s) ··························································· 116
10.3
Other Study Organization ·································································· 116
10.4
Registration of Subjects ···································································· 117
11
REFERENCES ·················································································· 119
12
APPENDICES ··················································································· 122
APPENDIX <1>:
LIST OF PROHIBITED CONCOMITANT MEDICATION ········· 122
APPENDIX <2>:
LABORATORY TESTS ······················································ 123
APPENDIX <3>:
EVENTS ALWAYS CONSIDERED SERIOUS ························· 125
APPENDIX <4>:
LIVER SAFETY MONITORING AND ASSESSMENT··············· 126
APPENDIX <5>:
1987 ACR CRITERIA FOR THE CLASSIFICATION OF RA······· 129
APPENDIX <6>:
2010 ACR-EULAR CLASSIFICATION CRITERIA FOR RA ······· 130
APPENDIX <7>:
CRITERIA FOR THE CLASSIFICATION OF GLOBAL 
FUNCTIONAL STATUS IN RA (1991 REVISED CRITERIA) ······················· 131
APPENDIX <8>:
CLASSIFICATION OF DISEASE STAGE/PROGRESSION OF 
RA
····················································································· 131


Sponsor: Astellas Pharma Inc.
ISN/Protocol <015K-CL-RAJ4>
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Page 8 of 131
I.
SIGNATURE
AGREEMENT BETWEEN THE SPONSOR’S RESPONSIBLE PERSON AND THE 
INVESTIGATOR
This clinical study will be conducted in adherence to GCP, ICH Guidelines 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) inscribe in the bipartite agreement.


Sponsor: Astellas Pharma Inc.
ISN/Protocol <015K-CL-RAJ4>
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Page 9 of 131
II.
CONTACT DETAILS OF KEY SPONSOR’S PERSONNEL
Contact Information for the Sponsor
Corporate Name:
 
Location:
Phone No.:
Fax: 
Sponsor’s personnel:
[Contact numbers during non-business hours and for emergency]:
Contact Information for the Contract Research Organization (CRO)
Corporate name:
Location:
Phone No.:
Fax:
CRO’s personnel:
[Contact numbers during non-business hours and for emergency]:


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Page 10 of 131
III.
LIST OF ABBREVIATIONS AND DEFINITION OF 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 plasma 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
anti-CCP antibody 
anti-cyclic citrullinated peptide antibody
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
DIP
Distal interphalangeal joint
DILI
Drug-induced liver injury
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
FAS
Full analysis set
FDA
Food and Drug Administration
GCP
Good Clinical Practice
GFR
Glomerular filtration rate
GMP
Good Manufacturing 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
HBV
Hepatitis B virus
HCV
Hepatitis C virus


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Abbreviations
Description of abbreviations
HDL
High-density lipoprotein
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
IL
Interleukin
IND
Investigational new drug
INR
International normalized ratio
IP
Interphalangeal joint
IR
Inadequate response
IRB
Institutional review board
ISN
International study number
JAK
Janus kinase
LAtest
Latex agglutination test
LA-CRF
Liver abnormality - CRF
LC-MS
Liquid chromatography- mass spectrometry
LDL
Low-density lipoprotein
LOCF
Last observation carried forward
MCP
Metacarpophalangeal joint
MDRD
Modification of diet in renal disease
MedDRA
Medical Dictionary for Regulatory Activities
MMF
Mycophenolate mofetil
MMP-3
Matrix metalloproteinase 3
MPA
Mycophenolic acid
MPAG
Mycophenolic acid glucuronide
MTP
Metatarsophalangeal joint
mTSS
Modified Total Sharp Score
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
PDAS
Pharmacodynamic analysis set
PGA
Physician’s Global Assessment of Arthritis
PGx
Pharmacogenomics
PIP
Proximal interphalangeal joint
PK
Pharmacokinetic
PKAS
Pharmacokinetic analysis set
PPS
Per protocol set
QOL
Quality of life
RA
Rheumatoid arthritis
RF
Rheumatoid factor
SAE
Serious adverse event


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Abbreviations
Description of abbreviations
SAF
Safety analysis set
SDAI
Simplified Disease Activity Index
SF-36v2®
Short Form Health Survey – 36 questions, version 2
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
TBL
Total bilirubin
TEAE
Treatment emergent adverse event
TJC
Tender joint count
TNF
Tumor necrosis factor
t½
Apparent terminal elimination half-life
tmax
Time to attain Cmax
TYK
Tyrosine kinase
ULN
Upper limit of normal
VAS
Visual analog scale
VEGF
Vascular endothelial growth factor
WBC
White blood cell
WPAI
Work Productivity and Activity Impairment Questionnaire


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Definition of Key Study Terms
Terms
Definition of terms
Adverse event
An adverse event is defined as any untoward medical occurrence in a 
subject administered a study drug that does not necessarily have a causal 
relationship with this treatment.
Baseline
1) Values/findings observed prior to the initiation of study treatment, 
which are regarded as the starting point for comparison.
2) The time point at which those reference values/findings were observed.
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: 
discontinuation 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, which precedes or is 
contemporaneous with randomization.
Investigational period
The period of time where major interests of protocol objectives are 
observed. In general, the subject will receive a test drug or comparative 
drug (possibly without randomization) during this period, which extends 
until the last post-treatment assessment is completed.
Follow-up period
The follow-up period will be 4 weeks (on a per-protocol basis) starting 
after the early-termination visit for withdrawn subjects and after the Week
52 visit for subjects who completed the study but are not willing to enroll 
into the extension study. For subjects who completed the study and wish 
to enroll into the extension study, the follow-up period will last for a 
maximum of 4 weeks starting after the Week 52 visit and ending at the 
initiation of the extension study treatment.
Randomization
Action to allocate a subject to the treatment group or treatment cohort. 
Depending on the type of rules for handling for study drugs, 
‘Randomization’ is usually executed just before entering the 
‘investigational period.’
Screening
1) Process of searching for candidates for the study
2) Process of checking the eligibility of subjects, usually done during the 
“pre-investigational period”
Screening failure
Screened subject, but did not fulfill protocol inclusion and/or exclusion 
criteria and failed to receive randomized or open label study treatment, or 
decided not to participate anymore (withdrew consent) prior to completing 
pre-investigational period.


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Terms
Definition of terms
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.
Study period
The period of time from obtaining informed consent from the subject 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
A characteristic under study that varies: any attribute, phenomenon, or 
event that can have different qualitative or quantitative values.


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Page 15 of 131
IV.
SYNOPSIS
Title of Study
Phase III Study of ASP015K
–A randomized, double-blind, placebo-controlled confirmatory study of 
efficacy and safety of ASP015K in patients with rheumatoid arthritis (RA) 
who had an inadequate response to MTX–
(Protocol No.: 015K-CL-RAJ4)
Planned Study Period
From July 2014 to January 2018
Study Objectives
The objective of this study is to evaluate the efficacy of ASP015K (100 and 
150 mg/day) versus placebo administered in combination with methotrexate 
(MTX) in rheumatoid arthritis (RA) patients who had an inadequate response 
to MTX. The primary variables are the American College of Rheumatology 
(ACR) 20 response rate at Week 12 and suppression of joint destruction 
[change from baseline in Modified Total Sharp Score (mTSS)] at Week 28. 
This study will also investigate pharmacokinetic, pharmacodynamic, and 
safety profiles. Furthermore, this study will examine the long-term efficacy 
and safety (52 weeks).
Planned Total Number of 
Study Centers and 
Locations
Approximately 150 centers
Japan
Design and Methodology
This study is a multi-center, randomized, placebo-controlled, double-blind, 
parallel-group, confirmatory study to evaluate the efficacy and safety of 
ASP015K (100 and 150 mg) administered in combination with MTX in
patients with RA who had an inadequate response to MTX. After the 
screening period, subjects will be randomly assigned at a 1:1:1 ratio to 
receive ASP015K 100 mg, ASP015K 150 mg, or placebo once daily (QD) in 
combination with MTX. Subjects will orally receive the study drug after 
breakfast for 52 weeks. At Week 12, inadequate responders in the placebo 
group, as determined by a < 20% improvement from baseline (i.e., treatment 
initiation day) in tender or painful joint count (TJC) and swollen joint count 
(SJC), will be switched to either ASP015K 100 mg or ASP015K 150 mg,
and the dosage will be maintained until the end of treatment. In addition, 
subjects receiving placebo at Week 28 will be switched to either ASP015K 
100 mg or ASP015K 150 mg, and the dosage will be maintained until the 
end of treatment. The ASP015K dose that will be started for placebo group 
subjects at Week 12 or Week 28 (100 or 150 mg) will be randomly chosen at 
baseline. The dose will be switched under the blinded condition.
Subjects who complete this study will be eligible for participation in the 
open-label extension study (015K-CL-RAJ2). Subjects will make a 
follow-up visit after the Week 52 visit if they do not enroll into the extension 
study on the day of the Week 52 visit.
Number of Subjects to Be 
Enrolled/Randomized
A total of 510 treated patients, with 170 in each treatment group


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Inclusion/Exclusion 
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 is a man or woman aged ≥ 20 years at the time of informed 
consent.
3.
Subject has RA of < 10 years duration at baseline that was diagnosed 
according to the 1987 American College of Rheumatology (ACR)
criteria or the 2010 American College of Rheumatology/European 
League against Rheumatism (ACR/EULAR) criteria.
4.
Subject who did not receive the following drugs, or received the drugs 
with stable dosage for at least 28 days prior to the baseline (start of 
treatment) for RA treatment: 
Non-steroidal anti-inflammatory drugs (NSAIDs; excluding topical 
formulations with a local action), oral morphine or equivalent opioid 
analgesics (≤ 30 mg/day), acetaminophen, or oral corticosteroids (≤ 10 
mg/day in prednisolone equivalent).
5.
At screening subject has active RA as evidenced by both of the 
following:

≥ 6 tender/painful joints (using 68-joint assessment)

≥ 6 swollen joints (using 66-joint assessment)
6.
CRP (latex agglutination test) of ≥ 1.00 mg/dL at screening.
7.
Subject meets the ACR 1991 Revised Criteria for the Classification of 
Global Functional Status in RA Class I, II, or III at screening.
8.
Inadequate responders to MTX which was continuously administered 
for at least 90 days prior to screening and MTX ≥ 8 mg/week for at 
least 28 days prior to baseline. However, inadequate responder to MTX 
< 8 mg/week is eligible if intolerance precludes dose increase and 
defined as MTX-IR.
9.
Subject is able to continue stable dose of MTX (a maximum of 16 
mg/week) from at least 28 days prior to screening until the end of
treatment.
10.
Subjects has bone erosion at the joint (as evidenced by x-rays of hands 
and feet) assessed in mTSS and any of the following apply at screening. 
Bone erosion may be evidenced by x-rays within 90 days prior to 
baseline.

Positive anti-CCP antibody: ≥ 4.5 U/mL

Positive rheumatoid factor: > 15 IU/mL
11.
Subject must be willing and able to comply with the study 
requirements.


Sponsor: Astellas Pharma Inc.
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Inclusion/Exclusion 
Criteria
<Exclusion Criteria>
Subject will be excluded from participation if any of the following applies:
1.
Subject has received a biologic DMARD within the specified period:

Etanercept: within 28 days prior to baseline

Adalimumab, infliximab: within 56 days prior to baseline

Golimumab, certolizumab pegol: within 70 days prior to baseline

Abatacept, tocilizumab: within 84 days prior to baseline

Denosumab: within 150 days prior to baseline

Rituximab: within 180 days prior to baseline
2.
Inadequate responders to biologic DMARD as determined by 
investigator/sub-investigator.
3.
Subject has received a non-biologic DMARD listed below or other 
drugs used in the treatment of RA within 28 days prior to baseline. 
Leflunomide is prohibited within 180 days prior to baseline. 
Alternatively, leflunomide is prohibited within 28 days prior to baseline 
if washout with cholestyramine for at least 17 days is completed at least 
28 days prior to baseline. However, topical drugs other than those for 
the treatment of RA may be used concomitantly.

Salazosulfapyridine

Lobenzarit

Gold

Iguratimod

D-penicillamine

Bucillamine

Actarit

Leflunomide

Tacrolimus

Cyclosporine

Cyclophosphamide

Azathioprine

Minocycline

Mizoribine
4.
Subject has received tofacitinib and other JAK inhibitors (including 
other investigational drugs).
5.
Subject has received intra-articular, intravenous, intramuscular, or 
endorectal (excluding suppositories in patients with anal diseases) 
corticosteroid within 28 days prior to baseline.
6.
Subject has participated in any study of ASP015K and has received 
ASP015K and placebo.
7.
Subject received other investigational drug within 90 days or within 5 
half-lives, whichever is longer, prior to baseline.
8.
Subject has received plasma exchange therapy within 60 days prior to 
baseline.
9.
Subject has undergone joint drainage, has received local anesthesia and 
nerve block, or has received articular cartilage protectant at the assessed 
joint within 28 days prior to baseline.
10.
Subject has undergone surgery and has residual effects in the assessed 
joints at the discretion of investigator/sub-investigator, or is scheduled 
to undergo surgery that may affect the study evaluation of the assessed 
joints at the discretion of investigator/sub-investigator.


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Inclusion/Exclusion 
Criteria
11.
A diagnosis of inflammatory arthritis (psoriatic arthritis, ankylosing 
spondylitis, SLE, sarcoidosis, etc.) other than RA.
12.
Any of the following laboratory values during the screening test period:

Hemoglobin < 9.0 g/dL

Absolute neutrophil count < 1000/µL

Lymphocyte count < 800/µL

Platelet count < 75000/µL

ALT ≥ 2 ×ULN

AST ≥ 2 × ULN

Total bilirubin (TBL) ≥ 1.5 × ULN

Estimated GFR ≤ 40 mL/min as measured by the MDRD method

β-D-glucan ≥ 11 pg/mL

Positive HBs antigen, HBc antibody, HBs antibody, or HBV-DNA 
quantitation (However, subject with negative HBs antigen and 
HBV-DNA quantitation, and positive HBc antibody and/or HBs 
antibody is eligible if HBV-DNA is monitored by HBV-DNA 
quantitation at every scheduled visit after initiation of study drug 
administration.)

Positive HCV antibody
13.
Subject has a history of or concurrent active tuberculosis (TB). 
Eligibility criteria for TB are tabulated below:
History of 
active TB
Chest x-ray
(for TB)
TB
infectionb)
Exposure to patients
with infective TB
(interview)
Eligibility
Present
-
-
-
Not eligible
Absent
Abnormal 
(active)
-
-
Not eligible
Abnormal (old)a)
-
Eligible
Eligible if  
prophylaxis 
is givenc)
Normal
Positive
Eligible
Eligible if  
prophylaxis 
is givenc)
Negative
Exposed
Eligible if  
prophylaxis 
is givenc)
Not exposed
Eligible
a) Old TB is evidenced if chest x-ray reveals pleural thickening, band-like shadow, and 
calcification ≥5 mm. Chest x-ray within 90 days prior to baseline may substitute the screening 
test.
b) T-spot or Quantiferon Gold test is of first priority. When the result is equivocal or invalid, 
retest including other test methods may be allowed. If a retest is not performed, criteria for 
positive results will be followed. When T-spot or Quantiferon Gold test is not feasible, 
tuberculin test will be performed. Tuberculin is defined as positive with a red spot covering an 
area of 20 mm or more or induration. Tests conducted within 90 days prior to baseline may be 
used for diagnosis.
c) Subject must receive or have received prophylaxis with isoniazid or rifampicin. Prophylaxis 
will be administered for 6 to 9 months, starting from at least 21 days prior to baseline.


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Inclusion/Exclusion 
Criteria
14.
Subject meets any of the following in terms of infections except for TB:

History of or concurrent severe herpes zoster (associated with Hunt 
syndrome or having ulcerative lesions) or disseminated herpes 
zoster

History of multiple recurrences (at least twice) of localized herpes 
zoster

Serious infection requiring hospitalization within 90 days prior to 
baseline

Subject received intravenous antibiotics within 90 days prior to 
baseline. (However, prophylactic antibiotics are allowed.)

Subject with high risk of infection (e.g., subject with urinary 
catheter) at the discretion of investigator/sub-investigator
15.
Subject has a history of or concurrent interstitial pneumonia and 
investigator/sub-investigator judges that it is inappropriate for the 
subject to participate in this study.
16.
Subject has a history of or concurrent malignant tumor (except for 
successfully treated basal cell carcinoma).
17.
Subject has received live or live attenuated virus vaccination within 56 
days prior to baseline. (Inactivated vaccines including influenza and 
pneumococcal vaccines are allowed.)
18.
Subject has any ongoing severe, progressive, or uncontrolled renal, 
hepatic, hematological, gastrointestinal, metabolic, endocrine, 
pulmonary, cardiac, neurological, infectious, or autoimmune disease 
except for RA (excluding Sjogren’s syndrome and chronic thyroiditis), 
or any ongoing illness which would make the subject unsuitable for the 
study as determined by the investigator/sub-investigator.
19.
Subject has a history of clinically significant allergy. (Clinically 
significant allergy includes allergies such as systemic urticaria induced 
by specific antigens and drugs, anaphylaxis, and allergy associated with 
shock necessitating hospitalized treatment.)
20.
Subject has received medications that are CYP3A substrates with 
narrow therapeutic range within 14 days prior to baseline. These 
medications include: dihydroergotamine, ergotamine, fentanyl, 
pimozide, quinidine, temsirolimus, and disopyramide.
21.
Subject has concurrent cardiac failure, defined as NYHA classification 
Class III or higher, or a history of it.
22.
Subject has concurrent prolonged QT syndrome or a history of it. 
Subject has prolonged QT interval (defined as QTc ≥500 msec. Subject 
has QTc ≥500 msec at retest will be excluded) at screening.
23.
Subject has a history of positive HIV infection.
24.
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 serum 
pregnancy test given at the time of screening.
25.
Subject is a man who cannot practice at least 2 types of contraception 
from the time of informed consent to 90 days after the end of treatment, 
or subject is a woman with childbearing potential who cannot practice 
at least 2 types of contraception from the time of informed consent to 
60 days after the end of treatment.


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Inclusion/Exclusion 
Criteria
26.
Male subject who do not agree not to donate sperm starting at informed 
consent and through the treatment period and for at least 90 days after 
final study drug administration. Female subject who do not agree not to 
donate ova starting at informed consent through the treatment period 
and for 60 days after final study drug administration.
27.
The subject has been judged unsuitable to participate in the study for 
other reasons by the investigator/sub-investigator.
28.
Subject has a history or complication of lymphatic diseases such as 
lymphoproliferative disorder, lymphoma, and leukemia.
29. Subject has congenital short QT syndrome or a history of it. Subject has 
shortened QT interval (defined as QTc < 330 msec. Subject has QTc < 
330 msec at retest will be excluded) at screening.


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Discontinuation Criteria
The investigator/sub-investigator should discontinue the study if any of the 
following occur:
1.
The subject withdraws consent.
2.
The investigator/sub-investigator judges that the study drug is not 
sufficiently effective and the treatment method needs to be changed.
3.
Symptomatic CPK elevation (> 1.5 × ULN accompanied with severe 
and unusual episodes of myalgia, muscular weakness, or muscle 
twitching).
4.
Any case of myopathy involving severe and unusual episodes of 
myalgia, muscular weakness, or muscle twitching that persists for no 
less than, or aggravates rapidly within, 2 weeks, regardless of the CPK 
level.
5.
A previously HBV-infected patient with positive HBc antibody, 
positive HBs antibody, or both has been shown positive for HBV-DNA 
during the study.
Attention should be paid that abrupt discontinuation of immunotherapy 
may cause fulminant or severe liver failure. Therefore, if the subject 
manifests HBV reactivation, the investigator/sub-investigator will 
administer nucleoside analogs without delay according to the “Proposal 
for Management of Rheumatic Disease Patients with Hepatitis B Virus 
Infection Receiving Immunosuppressive Therapy” (Japan College of 
Rheumatology). The investigator/sub-investigator will carefully decide 
whether to continue or discontinue the study drug and concomitant 
DMARDs in consultation with the hepatology specialist.
6.
Malignant tumor
7.
The subject develops a serious infection or other adverse events (AEs), 
and continued administration of the study drug is not deemed 
appropriate in the subject’s best interest by the 
investigator/sub-investigator.
8.
The subject has been treated with a prohibited concomitant drug or 
therapy (including another investigational product) that may impact 
efficacy evaluation. The subject has been, or needs to be, treated with a 
rescue medication for a period extending beyond its allowable time. 
Otherwise, the subject has been, or needs to be, treated with a live or 
live attenuated vaccine.
9.
The subject has been judged by the investigator/sub-investigator to be 
non-compliant to the medication requirements for the study drug or 
MTX.
10.
The subject is deemed incapable of continuing the follow-up based on 
the opinion of 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 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.
The subject needs the study drug to be interrupted beyond its allowable 
time limit.
13.
Investigator/sub-investigator decides it is in the subject’s best interest.
14.
The sponsor has requested that the study be discontinued because of a 
safety problem in a particular subject, or the sponsor has decided to 
discontinue the study altogether.
15.
The subject shows QTc interval < 300 msec at Central ECG, or the 
subject shows QTc interval < 300 msec at the study site’s ECG and also 
shows QTc interval < 300 msec at retest of study site’s ECG.


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Suspension, Interruption, 
and Resumption of the 
Study Drug
If the subject meets during the treatment period any of the criteria provided 
in “Criteria for Suspension or Interruption of the Study Drug,” the 
investigator/sub-investigator will immediately suspend or interrupt the 
treatment. The investigator/sub-investigator can resume the study treatment 
only if re-examinations and other assessments performed after the suspension 
or interruption confirm that none of the conditions listed below are 
applicable to the subject and the investigator/sub-investigator considers it 
desirable for the interest of the subject on the basis of risk–benefit analysis.
The maximum allowable time for “suspension” is 7 days. If the study 
treatment is halted beyond the suspension period, i.e., longer than 7 days, the 
period of no treatment is categorized as an “interruption.”
Upper limits have been set to the number of interruptions 1 subject can have 
and to the duration of 1 interruption. One interruption period may last for 28 
days. One subject is allowed to have a maximum of 2 interruptions, which 
must be separated by 16 or more weeks.
The investigator will consult the sponsor regarding the handling of a subject 
who repeatedly requires treatment suspension.
The subject must be withdrawn from the study, if he or she requires either a 
third interruption or a second interruption within 16 weeks from the first one.
Criteria for Suspension or Interruption of the Study Drug
The investigator/sub-investigator will suspend or interrupt the study drug if 
any of the following becomes applicable during the treatment period:
1.
Clinical laboratory tests yielded any of the following results:

Hemoglobin < 8.0 g/dL

Absolute neutrophil count < 500/µL

Absolute lymphocyte count < 500/µL

Platelet count < 50000/µL

Creatinine (serum) levels measured at 2 consecutive hospital visits: 
above 150% of the baseline level

CPK > 10 × ULN
2.
β-D-glucan test result of 11 pg/mL or higher.
3.
The subject requires a medication whose concomitant administration is 
prohibited in the protocol because of possible drug–drug interaction.
4.
The subject is suspected to be pregnant.
5.
The investigator/sub-investigator judged it appropriate in the interest of 
the subject to suspend or interrupt the study drug.
6.
The sponsor made a request to suspend or interrupt the study drug out 
of safety concerns for the subject.
Participation in
Open-Label Extension 
Study
Subjects who complete this study will be eligible for participation in the 
open-label extension study (Protocol No.: 015K-CL-RAJ2).
Test Drugs:
Mode of Administration:
Dose:
Duration of Treatment:
Test drugs: ASP015K 100 mg and 150 mg tablets
Dose: 100 mg/day, 150 mg/day
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 baseline visit after all the necessary 
assessments and tests have been completed.
Duration of treatment:
52 weeks


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Page 23 of 131
Comparative Drugs:
Mode of Administration:
Dose:
Duration of Treatment:
ASP015K placebo tablets
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 baseline visit after all the necessary 
assessments and tests have been completed.
Duration of treatment:
52 weeks (placebo will be administered for a 
maximum of 28 weeks. Subjects in the placebo 
group will be switched to either ASP015K 100 mg 
or ASP015K 150 mg at Week 12 or Week 28.)
Concomitant Medication
1) Necessary concomitant medications
MTX

MTX will be initiated 90 or more days prior to screening. The same 
dosage and administration schedule (≤16 mg/week) must be followed 
at least 28 days prior to screening and during the screening and 
treatment periods. 

If MTX is temporarily interrupted or its dose is reduced within 28 days 
prior to the baseline visit in a subject eligible at screening for the study 
based on inclusion and exclusion criteria, the screening period will be 
extended to allow for the same dosage and administration schedule to 
be observed for 28 days prior to the baseline visit.

In the case of AEs, administration may be temporarily interrupted, or 
the dose may be temporarily reduced. The period of interruption is up to 
28 days. When resuming administration, the dose may be increased 
with the baseline dose as the upper limit. Administration may only be
interrupted once.

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 ALT/AST becomes ≥ 3 × ULN, MTX must be interrupted, or the 
dose must be reduced, and daily administration of folic acid should be 
considered.
2) Prohibited concomitant medications and therapies

Biologic DMARDs
The following biologic DMARDs will be prohibited during the period 
shown below and during the treatment period:

Etanercept: within 28 days prior to baseline

Adalimumab, infliximab: within 56 days prior to baseline

Golimumab, certolizumab pegol: within 70 days prior to baseline

Abatacept, tocilizumab: within 84 days prior to baseline

Denosumab: within 150 days prior to baseline

Rituximab: within 180 days prior to baseline

Non-biologic DMARD
Non-biologic DMARDs, excluding MTX, will be prohibited within 28 
days prior to baseline and during the treatment period. In addition, the 
use of leflunomide is prohibited within 180 days prior to baseline. 
However, if washout with cholestyramine for at least 17 days is 
completed before 28 days prior to baseline, the use of leflunomide will 
be prohibited within 28 days prior to baseline. 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, minocycline, and other 
drugs indicated for the treatment of RA will be prohibited within 28 
days prior to baseline and during the treatment period.


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Concomitant Medication

Corticosteroids
Oral corticosteroids at doses exceeding 10 mg per day in the 
prednisolone equivalent will be prohibited within 28 days prior to
baseline and during the treatment period. 
The intra-articular, intravenous, intramuscular, and endorectal 
corticosteroid administration will also be prohibited within 28 days
prior to baseline and during the treatment period. However, 
suppositories for anal diseases may be used concomitantly.

Oral morphine
Oral morphine at doses exceeding 30 mg per day (or equivalent doses 
of other opioid analgesics) will be prohibited within 28 days prior to
baseline and during the treatment period. 

Other study drugs
Other study drugs will be prohibited within 90 days or 5 half-lives, 
whichever is longer, prior to baseline. In addition, the use of other study 
drugs will be prohibited during the study period.

CYP3A substrates
The following CYP3A substrate drugs with a narrow therapeutic range 
will be prohibited within 14 days prior to baseline and during the 
treatment and follow-up periods: dihydroergotamine, ergotamine, 
fentanyl, pimozide, quinidine, temsirolimus, disopyramide, etc.

Vaccines
Live and live attenuated vaccines will be prohibited within 56 days 
prior to baseline and during the treatment and follow-up periods. 
Inactivated vaccines may be administered (influenza, pneumococcal 
vaccines, etc.)

Plasma exchange therapy
Plasma exchange therapy will be prohibited within 60 days prior to
baseline and during the treatment period.

Surgical treatment methods
Surgery involving the target joint will be prohibited from the time of 
informed consent to the end of the treatment period.

Effusion drainage, local anesthesia, and nerve block of the target joint
Effusion drainage, local anesthesia, and nerve block of the target joint 
will be prohibited within 28 days prior to baseline and during the
treatment period.

Articular cartilage protective agents
The use of articular cartilage protective agents in the target joint will be 
prohibited within 28 days prior to baseline and during the treatment 
period.
3) Restricted concomitant medications
Regarding the drugs listed below, changes to the dosage, administration 
schedule, or route of administration will not be allowed within 28 days prior 
to baseline and during the treatment period, unless the specific conditions for 
the change are met.

The drugs listed below will be prohibited within 28 days prior to
baseline and during the treatment period if they are discontinued before
the initiation of study treatment [except in cases where NSAIDs and 
non-NSAID analgesics (e.g., acetaminophen, opioid analgesics, 
all-in-one flu and cold medications) are used as rescue medication].


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Concomitant Medication

In the case of AEs, administration may be temporarily interrupted, or 
the dose may be temporarily reduced. The period of interruption is up to 
28 days. When resuming administration, the baseline dose is the upper 
limit.

From the visit at Week 28, the drugs below may be discontinued, new 
drugs may be used, and the dosage, administration schedule, or route of 
administration of the concomitant drugs may be changed. However, 
with the exception of oral corticosteroids, after changing the conditions, 
administration must be continued under the same conditions for 12 
weeks or longer.

NSAIDs (excluding topical drugs with a local action)

Oral morphine (not more than 30 mg per day, or equivalent doses 
of other opioid analgesics)

Acetaminophen

Oral corticosteroids (however, at 10 mg per day or less in the 
prednisolone equivalent and from the visit at Week 28, the dose 
may be reduced or increased within the range not exceeding the 
baseline dose.)
4) Rescue medications
The drugs listed below may be administered only if they are necessary for 
treating an untoward medical occurrence, AEs, comorbid conditions, or acute 
aggravation of the primary disease within 28 days prior to baseline and 
during the treatment period. However, these medications may not be taken 
within 24 hours before joint assessment at each visit.

NSAIDs: For 3 days or less

Analgesics other than NSAIDs (acetaminophen, opioid analgesics, 
all-in-one flu and cold medications, etc.): For 7 consecutive days or 
less


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Major Outcome Variables
Efficacy
<Primary Variables>

ACR20 response rate at Week 12

Change from baseline in mTSS at Week 28 (suppression of joint 
destruction)
<Secondary Variables>

ACR20 response rate

ACR50 response rate

ACR70 response rate

Change from baseline in mTSS

Change in joint space narrowing score

Change in erosion score

Percentage of subjects showing no progression of joint damage 
(ΔmTSS ≤ 0.5)

Change from baseline in DAS28-CRP and DAS28-ESR scores

Change from baseline in TJC (68 joints)

Change from baseline in SJC (66 joints)

Percentage of subjects achieving DAS28-CRP and DAS28-ESR scores 
for remission

Percentage of subjects achieving low disease activity by DAS28-CRP 
and DAS28-ESR

Change from baseline in CRP and ESR

Percentage of subjects with good EULAR response

Percentage of subjects with good or moderate EULAR response

Percentage of subjects achieving ACR/EULAR remission
If all of the following 4 parameters are fulfilled, it is defined as 
remission:

TJC ≤ 1

SJC ≤ 1

CRP ≤ 1 mg/dL

SGA ≤ 1 cm (on a VAS of 0-100 mm)

Change from baseline in the percentage of subjects achieving 
ACR/EULAR remission

Percentage of subjects achieving SDAI remission (SDAI score ≤ 3.3)

Change from baseline in SDAI score

Change from baseline in Physician’s Global Assessment of Arthritis 
(PGA) (VAS)

Change from baseline in Subject’s Global Assessment of Arthritis 
(SGA) (VAS)

Change from baseline in subject’s assessment of pain (VAS)

Incidence of subject withdrawal due to lack of efficacy

Change from baseline in HAQ-DI score

Change from baseline in SF-36v2® score

Change from baseline in WPAI score
Variables (Safety)

AEs

Vital signs (body temperature, pulse rate and blood pressure in sitting 
position)

Body weight

12-lead electrocardiogram (ECG)

Central electrocardiogram

Chest radiography

Laboratory assessments
Variables 
(Pharmacokinetics)
Plasma ASP015K concentration on each day of the study visit


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Variables 
(Pharmacodynamics)

Change from baseline in VEGF level

Change from baseline in MMP-3 level

Change from baseline in lymphocyte subset assays (CD3, CD4, CD8, 
CD16, CD19, CD56, CD56/16)
Additional analysis may be performed for biomarkers for efficacy and safety 
assessments based on study results using blood samples that have been 
collected during the study and biobanked (i.e., residual sample stored for 
retrospective analysis). These could include biomarkers of inflammation, 
bone or cartilage metabolism, or inhibitory activity of JAK, but other 
biomarkers may also be subject to analysis.
Pharmacogenomics 
(Bio-Banking)
To prepare for future research to analyze the relationship between genes and 
the efficacy, safety, or pharmacokinetics of the study drug, blood sample will 
be collected and stored with the consent of the subject.
Statistical Methods
[Sample Size Calculation]
The sample size calculation was based on ASP015K Japanese Phase IIb 
study (015K-CL-RAJ1) result and other Japanese studies for patients with 
RA [XELJANZ®, tablet, 5 mg CTD (2013)] [CIMZIA, sc, 200 mg, Syringe,
CTD (2012)]. In the 015K-CL-RAJ1 study, the primary efficacy endpoint, 
which was Percentage of Subjects achieving ACR 20 response at Week 
12/ET, was 54.5% in the 100 mg, and 65.5% in the 150 mg. Therefore, in the 
015K-CL-RAJ4 study, it can be assumed to achieve same magnitude of 
ACR20 response at Week 12/ET for both 100 mg and 150 mg. For ACR20 
response at Week 12/ET in the placebo group, it was assumed 25% based on 
other Japanese drugs for RA.
On the other hand, for the modified Total Sharp Score (mTSS) change from 
baseline at Week 28/ET, it was assumed that mTSS change from baseline at 
Week 28/ET would be at least 0.5 in the 150 mg. For mTSS change from 
baseline at Week 28/ET in the placebo, it was assumed 2.0. Standard 
deviation for difference between groups in mTSS change from baseline at 
Week 28/ET was assumed 4.0.
Under these assumptions, Fisher’s exact test for ACR20 response at Week 
12/ET and t-test for mTSS change from baseline at Week 28/ET were used 
for sample size calculation in consideration for the multiplicity adjustment 
by closed testing procedure which is described in the Primary Efficacy 
Variable Analysis. As a result, 151 patients per group were needed to reach 
90% power to detect the treatment difference which was assumed in the Step
3 at a two-sided 0.05 significance level. By considering about 10% drop-out, 
this study will enroll 170 patients in each treatment group.
[Primary Efficacy Variable Analysis]
For ACR20 response at Week 12/ET, pairwise comparisons to placebo will 
be performed at each ASP015K dose level using Fisher's exact test in the 
primary analysis. For mTSS change from baseline at Week 28/ET, pairwise 
comparisons to placebo will be performed at each ASP015K dose level using 
rank analysis of covariance (ANCOVA) with treatment group (Placebo, 
ASP015K 100 mg, ASP015K 150 mg) as factor and baseline rank mTSS as 
covariate in the primary analysis.
Closed testing procedure shown below will be used for multiplicity 
adjustment in the primary analysis.


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Step 1. ACR20 response at Week 12/ET: ASP015K 150 mg vs. Placebo
Step 2. ACR20 response at Week 12/ET: ASP015K 100 mg vs. Placebo
Step 3. mTSS change from baseline at Week 28/ET: ASP015K 150 mg vs. 
Placebo
Step 4. mTSS change from baseline at Week 28/ET: ASP015K 100 mg vs. 
Placebo
The null hypothesis at Step 1 will be tested at a significance level of 0.05. If 
it is statistically significant, the next step will be initiated. Otherwise, it is 
completion of the hypothesis test. These hypothesis tests continue up to Step
4 unless it is rejected.
For the missing imputation of ACR20 at Week 12/ET, Last Observation 
Carried Forward (LOCF) methodology will be used.
For the missing imputation of mTSS at Week 28/ET, Linear Extrapolation 
(LEP) methodology will be applied using baseline value and post Week 12 
value.
[Secondary Efficacy Variable Analysis]
For secondary efficacy endpoints, binary variables such as Percentage of 
subjects achieving ACR50 response at Week 12/ET, Percentage of subjects 
achieving ACR70 response at Week 12/ET will be analyzed using Fisher’s 
exact test, and continuous variables, such as Change from baseline/Day 1 to 
Week 12/ET in DAS28-CRP and DAS28-ESR scores, will be analyzed using 
ANCOVA with treatment group as factor and baseline as covariate. Each 
ASP015K group will be compared with placebo group and multiplicity for 
the secondary efficacy variables will not be adjusted.
[Safety and Other Variables Analyses]
Summary statistics will be calculated for trough levels and biomarker 
concentrations by dose and time point.
AEs will be coded using the Medical Dictionary for Regulatory Activities 
(MedDRA). The incidence of AEs, serious AEs (SAEs), AEs leading to 
discontinuation, and AEs related to study drug will be summarized. All AEs 
will be listed. Descriptive statistics for laboratory values, vital signs, ECG 
results, QT variables (including QTc), body weight, and their changes from 
baseline if quantitative, will be provided by treatment group and time.


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V.
FLOW CHART AND SCHEDULE OF ASSESSMENTS
Flow Chart
Obtain 
informed 
consent
Screening period 
(The screening test 
period must be 
within 28 days 
prior to the 
baseline visit.)
Confirmation of 
inclusion/exclusion 
criteria
Preliminary 
registration
Baseline
Confirmation of 
inclusion/exclusion 
criteria
Enrollment & 
randomization
Treatment period:
maximum of 52 
weeks, ranging 
from the start of 
the study treatment 
to the completion 
of 
tests/assessments 
schedule at the end 
of treatment (Week 
52 or early 
termination)
See figure below.
Entry into the 
extension study
Subjects not 
enrolling into the 
extension study will 
undergo follow-up 
observation 4 weeks 
after the end of the 
study treatment.





Initiation of screening
Placebo group
Screening period
Screening test period 
(28 days)
ASP015K 100 mg
group
ASP015K 150 mg 
group
MTX-IR 
evaluation
Subjects with IR will be switched to 100 or 150 mg under the 
blinded condition (Evaluation of MTX response: all subjects).
Dose change under the blinded condition.
Placebo
Placebo
ASP015K 100 mg/day
Placebo
ASP015K 150 mg/day
ASP015K 100 mg/day
ASP015K 150 mg/day
ASP015K 
100 mg/day
ASP015K 
150 mg/day
Subjects completing the study can enroll into the open-label extension study.
0 W
Baseline
Random allocation (including 
the doses to be assigned to 
subjects in the placebo group 
at Weeks 12 and 28)
12 W
Primary efficacy variable: 
ACR20
28 W
Primary efficacy variable: 
mTSS
52 W


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Table 1 Schedule of Assessments
Visit
Initiation 
of 
Screening1)
Screening
Test 
Period
0
W
4
W
8
W
12
W
16
W
20
W
24
W
28
W
32
W
36
W
40
W
44
W
48
W
52
W
Early 
Termination
Follow-up2)
Unscheduled 
Visit
Visit day
−1 at latest
−28 to −1
1
29
57
85
113
141
169
197
225
253
281
309
337
365
Within 2 
days of 
withdrawal
28 days after 
Week 52 or 
early 
termination 
visit
-
Allowable range from 
specified date
±7
±7
±7
±7
±7
±7
±7
±7
±7
±7
±7
±7
±7
+2
±7
-
Informed consent
○
Inclusion/exclusion 
criteria
○
○
○
Subject registration
○
○
○
○
○
○
○
Inadequate response to 
MTX
○
○
Demographics
○
○
○
Medical history
○
○
○
Height
○
TB
○
Anti-CCP antibody, RF
○
Safety
Physical examination
○
○
○
○
○
○
○
○
○
○
○
○
○
○
○
○
○
▲
Body weight
○
○
○
○
○
○
○
▲
Vital signs
○
○
○
○
○
○
○
○
○
○
○
○
○
○
○
○
○
▲
Hepatitis examination
○
▲
Hematology3)
○
○
○
○
○
○
○
○
○
○
○
○
○
○
○
○
○
▲
Serum biochemistry3)
○
○
○
○
○
○
○
○
○
○
○
○
○
○
○
○
○
▲
Urinalysis3)
○
○
○
○
○
○
○
○
○
○
○
○
○
○
○
○
○
▲
Fasting lipid profile test
○
○
○
○
○
○
○
○
▲
Chest radiography
○
○
○
▲
▲
12-lead ECG
○
○
○
○
▲
Central ECG6)
○
○


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Visit
Initiation 
of 
Screening1)
Screening
Test 
Period
0
W
4
W
8
W
12
W
16
W
20
W
24
W
28
W
32
W
36
W
40
W
44
W
48
W
52
W
Early 
Termination
Follow-up2)
Unscheduled 
Visit
Visit day
−1 at latest
−28 to −1
1
29
57
85
113
141
169
197
225
253
281
309
337
365
Within 2 
days of 
withdrawal
28 days after 
Week 52 or 
early 
termination 
visit
-
Allowable range from 
specified date
±7
±7
±7
±7
±7
±7
±7
±7
±7
±7
±7
±7
±7
+2
±7
-
Pregnancy test5)
○
○
○
○
○
○
○
○
○
○
○
○
○
○
○
○
○
▲
Adverse event
○
○
○
○
○
○
○
○
○
○
○
○
○
○
○
○
▲
Efficacy
Hand and foot 
radiography
○
○
○4)
○
○
○
CRP and ESR
○
(CRP
only)
○
○
○
○
○
○
○
○
○
○
○
○
○
○
○
○
▲
TJC/SJC (68/66 joints)
○
○
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○
○
○
○
○
○
○
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○
○
▲
PGA (VAS), SGA 
(VAS), and subject's 
assessment of pain
(VAS)
○
○
○
○
○
○
○
○
○
○
○
○
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▲
SF-36 v2®
○
○
○
○
○
○
○
○
▲
WPAI
○
○
○
○
○
○
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○
▲
HAQ-DI
○
○
○
○
○
○
○
○
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○
○
○
▲
PK/PD
▲
Blood sampling for 
trough concentration 
○
○
○
○
○
○
○
○
○
Blood sampling for 
post-dose drug 
concentration
○
Blood sampling for PD
(biomarkers)
○
○
○
○
○
○
○
○
▲
Blood sampling for PD
(lymphocyte subset)
○
○
○
○
○
○
○
○
▲
Informed consent for 
PGx research (relevant 
sites only)
○


Sponsor: Astellas Pharma Inc.
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Page 32 of 131
Visit
Initiation 
of 
Screening1)
Screening
Test 
Period
0
W
4
W
8
W
12
W
16
W
20
W
24
W
28
W
32
W
36
W
40
W
44
W
48
W
52
W
Early 
Termination
Follow-up2)
Unscheduled 
Visit
Visit day
−1 at latest
−28 to −1
1
29
57
85
113
141
169
197
225
253
281
309
337
365
Within 2 
days of 
withdrawal
28 days after 
Week 52 or 
early 
termination 
visit
-
Allowable range from 
specified date
±7
±7
±7
±7
±7
±7
±7
±7
±7
±7
±7
±7
±7
+2
±7
-
Blood sampling for 
PGx (relevant sites 
only)
○
Study drug
Confirmation of 
remaining unused drug
○
○
○
○
○
○
○
○
○
○
○
○
○
○
Prescription
○
○
○
○
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○
○
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○
○
○
○
The symbol “○” designates mandatory items, whereas the symbol “▲” denotes the optional items to be investigated on the basis of the clinical judgment of the 
investigator/sub-investigator.
For details, see the respective sections of the protocol.
1) Subjects who have signed the informed consent will undergo evaluation of MTX response at the screening visit.
2) Follow-up will not be performed for subjects starting the extension study immediately after the Week 52 visit. 
3) For details of the test parameters, refer to Section 5.4.4.
4) At Week 12, subjects with < 20% improvement from baseline in TJC and SJC will be required to undergo radiographic examination of their hands and feet.
5) For pregnancy tests, serum samples will be used at the screening visit, and urine samples will be used at and after the baseline visit.
6) Central ECG should be performed on the same day as blood sampling for post-dose drug concentration at Week 4 or Week 8 before and after study drug 
administration.


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VI.
ACCEPTABLE RANGE OF SCHEDULE OF ASSESSMENTS
The paragraphs that follow describe the allowable time windows on scheduled test and 
observation dates.
Reasonable efforts must be made to perform the tests and observations specified for early 
termination and follow-up, even if they cannot be conducted within the allowable time frame.
[Acceptable Time Ranges for Efficacy Tests]
Hand and foot radiography
Screening
From 1 to 90 days prior to the baseline visit.
Radiographs taken before the informed consent 
will be acceptable as long as they satisfy the 
abovementioned time frame.
Baseline
On the day of the baseline visit.
If re-examination is requested by the third-party 
evaluator, new radiographs must be taken within 
30 days of the baseline visit. Only the radiographs 
taken on the day of the baseline visit will be 
acceptable if no re-examination is required.
Weeks 12, 28, and 52
At Week 12, hand and foot 
radiographs will be required 
for subjects with < 20% 
improvement from baseline in 
TJC and SJC.
Within ± 7 days of the protocol-specified date.
If re-examination is requested by the third-party 
evaluator, new radiographs must be taken within 
30 days of the previous measurement date.
Radiographs taken within ± 7 days of the specified 
date will be acceptable if no re-examination is 
required.
Early termination
Within 2 days of the early termination visit.
If re-examination is requested by the third-party 
evaluator, new radiographs must be taken within 
approximately 30 days of the previous 
measurement date.
Radiographs taken within 2 days of withdrawal
will be acceptable if no re-examination is required.


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TJC/SJC (68/66 joints) and CRP
Screening
From 1 to 28 days prior to the baseline visit.
Baseline
Before the initiation of treatment with the study 
drug on the baseline visit day.
Study visits from Week 4 to 
Week 48
Within ± 7 days of the protocol-specified date 
AND before the initiation of treatment with the 
study drug on the baseline visit day.
Week 52
Within ± 7 days of the protocol-specified date.
Early termination
Within 2 days of withdrawal.
Follow-up
Within ± 7 days of the date 28 days after the Week 
52 OR early termination visit.
PGA (VAS), SGA (VAS), Subject’s Assessment of Pain (VAS), HAQ-DI, and ESR
Baseline
Before the initiation of treatment with the study 
drug on the baseline visit day.
Study visits from Week 4 to 
Week 48
Within ± 7 days of the protocol-specified date 
AND before the initiation of treatment with the 
study drug on the baseline visit day.
Week 52
Within ± 7 days of the protocol-specified date.
Early termination
Within 2 days of withdrawal.
Follow-up
Within ± 7 days of the date 28 days after the Week 
52 OR early termination visit.
SF-36 v2®, WPAI
Baseline
Before the initiation of treatment with the study 
drug on the baseline visit day.
Weeks 4, 8, 12, and 28
Within ± 7 days of the protocol-specified date 
AND before the initiation of treatment with the 
study drug on the baseline visit day.
Week 52
Within ± 7 days of the protocol-specified date.
Early termination
Within 2 days of withdrawal.
Follow-up
Within ± 7 days of the date 28 days after the Week 
52 OR early termination visit.


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[Acceptable Time Ranges for Safety Tests]
Physical Examination, Vital Signs, Laboratory Tests [Hematology, Serum Biochemistry, 
Urinalysis, Pregnancy Test (serum/urine)]
Screening
From 1 to 28 days prior to the baseline visit.
Baseline
Before the initiation of treatment with the study 
drug on the baseline visit day.
Study visits from Week 4 to 
Week 48
Within ± 7 days of the protocol-specified date 
AND before the initiation of treatment with the 
study drug on the baseline visit day.
Week 52
Within ± 7 days of the protocol-specified date.
Early termination
Within 2 days of withdrawal.
Follow-up
Within ± 7 days of the date 28 days after the Week 
52 OR early termination visit.
Body Weight
Screening
From 1 to 28 days prior to the baseline visit.
Weeks 12, 28, and 40
Within ± 7 days of the protocol-specified date 
AND before the initiation of treatment with the 
study drug on the baseline visit day.
Week 52
Within ± 7 days of the protocol-specified date.
Early termination
Within 2 days of withdrawal.
Follow-up
Within ± 7 days of the date 28 days after the Week 
52 OR early termination visit.
Fasting Lipid Profile Test
Baseline
Before the initiation of treatment with the study 
drug on the baseline visit day AND 8 or more 
hours after the last meal.
Weeks 12, 20, 28, and 40
Within ± 7 days of the protocol-specified date 
AND before the initiation of treatment with the 
study drug on the baseline visit day AND 8 or 
more hours after the last meal.
Week 52
Within ± 7 days of the protocol-specified date 
AND 8 or more hours after the last meal.
Early termination
Within 2 days after withdrawal AND 8 or more 
hours after the last meal (the nutritional condition 
is recommended but not compulsory).
Follow-up
Within ± 7 days of the date 28 days after the Week 
52 OR early termination visit.


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Chest Radiography
Screening
From 1 to 28 days prior to the baseline visit.
Radiographs taken before the informed consent 
will be acceptable as long as they were taken 
within 90 days before the baseline visit.
Weeks 28 and 52
Within ± 7 days of the protocol-specified date.
Early termination
Within 2 days of withdrawal.
Not mandatory; may be required at the discretion 
of the investigator/sub-investigator.
12-lead ECG
Screening
From 1 to 28 days prior to the baseline visit.
Week 28
Within ± 7 days of the protocol-specified date 
AND before the initiation of treatment with the 
study drug on the baseline visit day.
Week 52
Within ± 7 days of the protocol-specified date.
Early termination
Within 2 days of withdrawal.
Central ECG
Baseline
Before the initiation of treatment with the study 
drug on the baseline visit day.
Week 4 or Week 8
(before study drug 
administration)
Within ± 7 days of the protocol-specified date 
AND before the initiation of treatment with the 
study drug on the baseline visit day.
Week 4 or Week 8
(after study drug 
administration)
Within ± 7 days of the protocol-specified date
AND 2-hour post-dose on the visit day 
(Recommended time point. Sampling from 1 hour 
to 4 hours post-dose will be acceptable.)


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[Acceptable Time Ranges for PD Tests: Biomarker and Lymphocyte Subset 
Measurements]
Baseline
Before the initiation of treatment with the study 
drug on the baseline visit day.
Weeks 4, 8, 12, and 28
Within ± 7 days of the protocol-specified date 
AND before the initiation of treatment with the 
study drug on the baseline visit day.
Week 52
Within ± 7 days of the protocol-specified date.
Early termination
Within 2 days of withdrawal.
Follow-up
Within ± 7 days of the date 28 days after the Week 
52 OR early termination visit.
[Acceptable Time Ranges for Blood Sampling for Plasma Drug Concentration]
Trough Concentration
Baseline
Before the initiation of treatment with the study 
drug on the baseline visit day.
Weeks 4, 8, 12, 20, 28, 40, and 
52
Within ± 7 days of the protocol-specified date
AND within 19 to 29 hours between the time of 
treatment with the study drug before blood 
collection and the time of blood collection.
Early termination
Within 2 days after withdrawal.
Post-Dose Drug Concentration
Week 4 or 8
The recommended time point is 2 hours post-dose. 
Sampling from 1 hour to 4 hours post-dose will be 
acceptable.


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Page 38 of 131
1
INTRODUCTION
1.1
Background
Rheumatoid arthritis (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 
decreased 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 
disease-modifying antirheumatic drugs (DMARDs) have been combined [Nakajima, 2009]. 
After the approval of methotrexate (MTX) and biologics, RA treatment improved greatly, 
shifting its goal from pain control to induction and maintenance of remission. In more recent 
years, the ultimate goal of RA therapy evolved to include clinical, structural, and functional 
remission. Now, researchers are attempting to achieve drug-free remission.
In Japan, MTX has been established as the standard first-line therapy for RA. The 
combination of tumor necrosis factor (TNF) inhibitors and other biological agents with MTX 
has paved the way for the treat-to-target (T2T) approach aimed at clinical and structural 
remission.
However, it has been that such combination therapies induced clinical remission in 
approximately 30% to 50% of treated patients [Y. Tanaka, 2009; K. Yamaoka, 2008], failing 
to control disease in most cases. In addition, MTX, a non-specific inhibitor of cellular 
proliferation, frequently causes adverse drug reactions in proliferative tissues such as the 
gastrointestinal epithelium and bone marrow, and these reactions lead to premature 
discontinuation in a certain proportion of patients. TNF inhibitors (e.g., etanercept, 
infliximab, adalimumab), selective T-cell co-stimulation modulators (e.g., abatacept), and 
other biologics are very expensive and require intravenous or subcutaneous administration; 
the issues of cost, cumbersome dosing procedure, and other factors are a hindrance to their 
application. Under these circumstances, low-molecular-weight DMARDs acting on a novel 
molecular target have captured increasing interest from drug companies.
ASP015K is an oral Janus kinase (JAK) inhibitor discovered by Astellas Pharma. In vitro 
kinase assays demonstrated that this agent effectively inhibited JAK1, JAK2, JAK3, and 
tyrosine kinase 2 (TYK2). In particular, JAK3 was suppressed in a relatively selective 
manner. The binding of the ligand to the cytokine receptor triggers JAK activation, and 
activated JAK molecules in turn phosphorylate the receptor. The phosphorylation of the 
cytokine receptor creates a site for interaction with the signal transducer and activator of 
transcription (STAT). Upon JAK-induced phosphorylation, STAT forms a dimer complex
and enters into the nucleus, where the STAT dimer binds with DNA to regulate gene 


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Page 39 of 131
transcription. Because JAK3 expression is restricted to primarily hematopoietic cells, JAK3 
inhibition is a desirable therapeutic target for immunosuppression in human organ 
transplantation and immunomodulation in autoimmune disorders [Papageorgiou and
Wikman, 2004], without significantly affecting other organ systems [Kremer et al, 2009].
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) 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 
015K-CL-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. In a study using a rat model of adjuvant-induced arthritis, 
prophylactic use of ASP015K significantly suppressed the swelling of the injected limb and 
prevented the worsening of the bone destruction score assessed by radiography. 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 ether-a-go-go related 
gene (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 
[electrocardiogram (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, 


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Page 40 of 131
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 
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 orally administered a single 14C-ASP015K dose, 25.2% and 46.7% of the administered 
radioactivity was eliminated into urine and bile at 72 hours, respectively, suggesting an 
excellent oral absorption profile of ASP015K. In monkeys orally administered a single 
14C-ASP015K dose, 22.3% and 26.4% of the administered radioactivity was eliminated into 
urine and bile at 72 hours, 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 


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Page 41 of 131
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 
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.


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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.
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 


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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 (MMP-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/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/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/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 
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. 
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 


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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 
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).
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 subject and mild in 6 subjects); mild, tension headache 
(3 subjects); flatulence (3 subjects; moderate in 1 subject and mild in 2 subjects); and mild, 
asymptomatic bradycardia (2 subjects).


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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).
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 WBC 
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 (possibly 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, 


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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, ASP015K 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, ASP015K 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 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 
increased CPK 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, triglycerides, and 
total cholesterol were observed, there was no change from baseline in LDL.
For more information regarding the efficacy and safety of ASP015K, refer to the current 
version of the Investigator’s Brochure.
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), CPK 
elevations 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, 


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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 hour 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.
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, have 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.
One can also expect that long-term use of ASP015K will improve QOL of RA patients by 
successfully controlling the RA disease activity over an extended period.


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2
STUDY OBJECTIVE(S), DESIGN, AND VARIABLES
2.1
Study Objectives
The main objective of this study is to evaluate the efficacy of ASP015K (100 and 150 
mg/day) versus placebo administered in combination with MTX in RA patients who had an 
inadequate response to MTX. The primary efficacy variables are the ACR20 response rate at 
Week 12 and suppression of joint destruction (change from baseline in mTSS) at Week 28.
This study will also investigate pharmacokinetic, pharmacodynamic, and safety profiles.
Furthermore, this study will examine the long-term efficacy and safety (52 weeks).
2.2
Study Design and Dose Rationale
2.2.1
Study Design
This study is a multi-center, randomized, placebo-controlled, double-blind, parallel-group,
confirmatory study to evaluate the efficacy and safety of ASP015K (100 and 150 mg/day) 
administered in combination with MTX in patients with RA who had an inadequate response 
to MTX. The geographical scope of this study will be confined to Japan. MTX response is 
evaluated at the initiation of screening and then after the screening period, subjects will be 
randomly assigned at a 1:1:1 ratio to receive ASP015K 100 mg, ASP015K 150 mg, or 
placebo QD in combination with MTX. Subjects will orally receive the study drug after 
breakfast for 52 weeks. The target number of subjects is 170 patients per group.
Re-screening is allowed only in situations in which a subject underwent the screening 
procedures (i.e., scans and laboratory work) and owing to logistical circumstances, the 
allocated time window for these tests has expired. Re-screening is not permitted in cases in 
which the initial test results do not support eligibility based on inclusion and exclusion 
criteria. The subject must be classified as a screening failure at that time point. 
Any subject found not to meet the inclusion criterion (CRP) is permitted to undergo retest 
only once during the screening period. This however only applies to cases in which the CRP 
value measured at screening exceeds 0.50 mg/dL and the most resent CRP value measured at 
least 28 days before the screening procedures is 1.0 mg/dL or greater.
Based on the consideration of the ethical issues related to long-term placebo use, inadequate
responders in the placebo group, as determined by < 20% improvement from baseline in 
tender or painful joint count (TJC) and swollen joint count (SJC), will be switched at Week 
12 to either ASP015K 100 mg or ASP015K 150 mg, and the dosage will be maintained until 
the end of treatment. In addition, subjects receiving placebo at Week 28 will be switched to 
either ASP015K 100 mg or ASP015K 150 mg, and the dosage will be maintained until the 
end of treatment. The ASP015K dose that will be started for placebo group subjects at Week 
12 or Week 28 (100 or 150 mg) will be randomly chosen at baseline. The dose will be 
switched under the blinded condition.


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Subjects who complete this study will be eligible for participation in the open-label extension 
study (015K-CL-RAJ2). Subjects will make a follow-up visit after the Week 52 visit if they 
do not enroll into the extension study on the day of the Week 52 visit.
Safety data obtained from this study will be reviewed by the Independent Data and Safety 
Monitoring Board (DSMB), which will make recommendations on study continuation, 
termination, or protocol revision from the safety perspective.
[Study Design Rationale]
According to “Guidelines on methodology for clinical assessment of antirheumatic drugs” 
(PFSB/ELD Notification No. 0217001, dated 17 February 2006), the appropriate treatment 
period for clinical studies including a group taking a placebo alone is generally held to be 12 
weeks or less, and the Guidelines state that the study should be planned so that a sufficient 
investigation can be performed within this time frame. Taking note that 015K-CL-RAJ1 and 
clinical trials of similar drugs documented treatment responses sufficient for efficacy 
evaluation within 12 weeks of treatment, this study was designed to assess the ACR20 
response rate, a primary efficacy variable, at 12 weeks of treatment.
For the other primary efficacy variable, change from baseline in mTSS (suppression of joint 
destruction), published guidelines recommended at least 6 months of treatment for mTSS and 
other radiographic assessments. In the case of similar drugs, approximately 6 months were 
required to monitor treatment responses for efficacy evaluation. Consequently, this study was 
designed to evaluate mTSS at 28 weeks of treatment, and this design required that subjects 
assigned to receive placebo would remain on placebo during the period, where possible.
Taking into consideration the ethical issues related to long-term placebo use, this study was 
designed to enable switching to the active drug for subjects showing inadequate response 
(< 20% improvement from baseline in TJC and SJC) at Week 12. In addition, this study was 
designed such that all placebo group subjects would receive the active drug no later than 
Week 28. Because subjects of this clinical trial will receive MTX in combination with the 
investigational product, 28-week treatment with placebo will be ethically acceptable as long 
as inadequate responders of the placebo group switch to the active drug at Week 12. 
Moreover, taking note of the “Guidelines on methodology for clinical assessment of 
antirheumatic drugs” (PFSB/ELD Notification No. 0217001, dated 17 February 2006), the 
duration of treatment was set at 52 weeks to evaluate the 1-year efficacy and safety as 
secondary endpoints.
2.2.2
Dose Rationale
[Dose Rationale]
Study 015K-CL-RAJ1 evaluated the efficacy, safety, and dose response of ASP015K as
single-agent therapy in RA patients. This study employed 25, 50, 100, and 150 mg doses.
The primary efficacy variable of this study, the ACR20 response rate at Week 12 (or early 
termination), showed statistically significant improvements for 50 mg and higher doses 
relative to placebo, and dose-dependent improvements were noted up to 150 mg. Compared 


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with placebo, statistically significant dose-dependent decreases in the DAS28-CRP score 
were observed for 50 mg, 100 mg, and 150 mg groups at Week 12 (or early termination).
When the effect size between ASP015K versus placebo for the ACR20 response rate was 
compared with the effect sizes reported from clinical trials of a similar design (12- to 
14-week, double-blind, single-agent studies) conducted in Japan for other drugs, ASP015K 
100 mg or higher doses were likely to provide levels of efficacy comparable with those of 
other agents.
AEs reported from 1 or more groups of Study 015K-CL-RAJ1 at ≥5% incidence rates were 
nasopharyngitis, rheumatoid arthritis aggravated, diarrhoea, constipation, blood creatine 
phosphokinase increased, stomatitis, dyspepsia, lipids increased, and blood triglycerides 
increased. Compared with placebo, the incidence rates of AEs were not significantly elevated 
for the ASP015K groups. The reported AEs were mostly Grade 1 or Grade 2 by severity 
(NCI-CTCAE), involving a high proportion of events known as the class effect of JAK 
inhibitors. The ASP015K 150 mg group had the highest incidence rate of study-related AEs.
This group had a particularly high incidence rate of blood creatine phosphokinase increased, 
reported in 7 subjects. AEs of increased CPK levels were mostly transient; in all the cases, 
the subjects recovered completely, including 1 subject who prematurely discontinued the 
study owing to logistic issues. No collateral symptoms suggestive of rhabdomyolysis or 
myopathy were detected. Although careful monitoring of CPK levels will be necessary for 
individual subjects of this Phase III study, currently available data suggest that 
ASP015K-induced changes in CPK are reversible and that subject safety associated with 
CPK changes can be properly monitored. The mean changes in CPK levels reported for the 
ASP015K and placebo groups were comparable with those reported from tofacitinib clinical 
trials.
Ten SAEs were reported from 7 subjects; there was no characteristic pattern of occurrence, 
and no dose–response relationship was noted. 
Thus, the results of Study 015K-CL-RAJ1 raised no safety concerns with the use of 100 and 
150 mg/day doses in this Phase III study.
With regard to efficacy, ACR20 response rate and DAS28 score, the primary variables of the 
Phase II study, showed dose-dependent improvements up to 150 mg, and the observed effects 
were statistically significant in comparison with placebo for 50 mg and higher doses. 
Comparison of published data [Enbrel® Pharmaceutical Interview Form, Simponi® 
Pharmaceutical Interview Form, Xeljanz® Pharmaceutical Interview Form, Humira® 
Pharmaceutical Interview Form] showed that 100 mg and higher doses of ASP015K could 
provide efficacy comparable with that of the approved doses of similar drugs, supporting the 
validity of using 100 mg and higher doses in this Phase III study. From the safety 
perspective, the results of Study 015K-CL-RAJ1 confirmed the tolerability of ASP015K 
doses up to 150 mg.
Based on the abovementioned discussion, 100 and 150 mg/day doses were selected for this 
Phase III clinical trial.


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[Rationale for the Mode of Administration]
Nonclinical study results showed that AUC was the most important pharmacokinetic 
parameter for characterizing the therapeutic effect of ASP015K. While admitting that 
015K-CL-PS01 focused on a clinical condition different from that of this Phase III study, this 
clinical trial conducted in patients with psoriasis demonstrated no significant differences 
between 50 mg QD and 25 mg BID doses of ASP015K.
In Study 015K-CL-RAJ1, ASP015K was administered once daily after breakfast. This 
method of administration was based on the idea that the desired efficacy could be achieved 
regardless of the differences in the mode of administration, as long as the target AUC is 
attained. In addition, this method of administration was favorable from the view point of 
subject convenience, medication adherence, and other aspects of study implementation. 
Study 015K-CL-RAJ1 showed excellent medication adherence and demonstrated the efficacy 
of ASP015K in terms of the ACR20 response rate and other outcome measures. Therefore, 
administration once daily after breakfast was also adopted in this clinical trial.
2.3
Variables
2.3.1
Primary Variables
●
ACR20 response rate at Week 12
●
Change from baseline in mTSS at Week 28 (suppression of joint destruction)
[Rationale]
Taking note of the “Guidelines on methodology for clinical assessment of antirheumatic 
drugs,” the ACR20 response rate, an indicator of RA disease activity and response to 
treatment, was chosen as a primary variable. The evaluation time point was set at Week 12 of 
treatment on the basis of the guidelines.
The assessment of mTSS using radiographs of the hand and foot, a measure of joint 
destruction suppression, was also included as a primary endpoint on the basis of the 
guidelines. This variable has been commonly used for clinical evaluation of similar drugs.
The evaluation time point was set at 28 weeks of treatment or half a year after the start of 
therapy. This was chosen taking note of the longest possible duration of placebo treatment, 
study designs for similar drugs, and published guidelines.
2.3.2
Secondary Variables
2.3.2.1
Secondary Efficacy Variables
●
ACR20 response rate
●
ACR50 response rate
●
ACR70 response rate
●
Change from baseline in mTSS
●
Change in joint space narrowing score
●
Change in erosion score


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●
Percentage of subjects showing no progression of joint damage (ΔmTSS ≤ 0.5)
●
Change from baseline in DAS28-CRP and DAS28-ESR scores
●
Change from baseline in TJC (68 joints)
●
Change from baseline in SJC (66 joints)
●
Percentage of subjects achieving DAS28-CRP and DAS28-ESR scores for remission
●
Percentage of subjects achieving low disease activity by DAS28-CRP and DAS28-ESR
●
Change from baseline in CRP and ESR
●
Percentage of subjects with good EULAR response
●
Percentage of subjects with good or moderate EULAR response
●
Percentage of subjects achieving ACR/EULAR remission
If all of the following 4 parameters are fulfilled, it is defined as remission:

TJC ≤ 1

SJC ≤ 1

CRP ≤ 1 mg/dL

SGA ≤ 1 cm (on a VAS of 0-100 mm)
●
Percentage of subjects achieving SDAI remission (SDAI score ≤ 3.3) 
●
Change from baseline in SDAI score
●
Change from baseline in Physician’s Global Assessment of Arthritis (PGA) (VAS)
●
Change from baseline in Subject’s Global Assessment of Arthritis (SGA) (VAS)
●
Change from baseline in subject’s assessment of pain (VAS)
●
Incidence of subject withdrawal due to lack of efficacy
●
Change from baseline in HAQ-DI score
●
Change from baseline in SF-36v2® score
●
Change from baseline in WPAI score
2.3.2.2
Safety Variables
●
AEs
●
Vital signs (body temperature, pulse rate and blood pressure in sitting position)
●
Body weight
●
12-lead ECG
●
Central electrocardiogram
●
Chest radiography
●
Laboratory assessments
2.3.2.3
Pharmacokinetics Variables
Plasma ASP015K concentration
2.3.2.4
Pharmacodynamics Variables
●
Change from baseline in MMP-3 level
●
Change from baseline in vascular endothelial growth factor (VEGF) level
●
Change from baseline in lymphocyte subset assays (CD3, CD4, CD8, CD16, CD19, 
CD56, CD56/16)


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2.3.2.5
Pharmacogenomics (Bio-Banking)
To prepare for future research to analyze the relationship between genes and the efficacy, 
safety, or pharmacokinetics of the study drug, blood sample will be collected and stored with 
the consent of the subject.
2.3.3
Other Variables
Not applicable.


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3
STUDY POPULATION
3.1
Selection of Study Population
The target population for this study is patients with RA who had an inadequate response to
MTX.
3.2
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 is a man or woman aged ≥ 20 years at the time of informed consent.
3.
Subject has RA of < 10 years duration at baseline that was diagnosed according to the
1987 American College of Rheumatology (ACR) criteria or the 2010 American College 
of Rheumatology/European League against Rheumatism (ACR/EULAR) criteria.
4.
Subject who did not receive the following drugs, or received the drugs with stable 
dosage for at least 28 days prior to the baseline (start of treatment) for RA treatment:
Non-steroidal anti-inflammatory drugs (NSAIDs; excluding topical formulations with a 
local action), oral morphine or equivalent opioid analgesics (≤ 30 mg/day),
acetaminophen, or oral corticosteroids (≤ 10 mg/day in prednisolone equivalent).
5.
At screening subject has active RA as evidenced by both of the following:

≥ 6 tender/painful joints (using 68-joint assessment)

≥ 6 swollen joints (using 66-joint assessment)
6.
CRP (latex agglutination test) of ≥ 1.00 mg/dL at screening.
7.
Subject meets the ACR 1991 Revised Criteria for the Classification of Global Functional 
Status in RA Class I, II, or III at screening.
8.
Inadequate responders to MTX which was continuously administered for at least 90 days 
prior to screening and MTX ≥ 8 mg/week for at least 28 days prior to baseline. However, 
inadequate responder to MTX < 8 mg/week is eligible if intolerance precludes dose 
increase and defined as MTX-IR.
9.
Subject is able to continue stable dose of MTX (a maximum of 16 mg/week) from at 
least 28 days prior to screening until the end of treatment.
10. Subjects has bone erosion at the joint (as evidenced by x-rays of hands and feet) assessed 
in mTSS and any of the following apply at screening. Bone erosion may be evidenced by 
x-rays within 90 days prior to baseline.

Positive anti-CCP antibody: ≥ 4.5 U/mL

Positive rheumatoid factor: > 15 IU/mL
11. 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.


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2: Established to ensure ethical and safe conduct of the study.
3: Established to select RA patients relevant for this study. Taking note of the recent changes 
in RA diagnostic criteria and current practices in clinical settings, patients conforming to 
either the 1987 ACR or the 2010 ACR/EULAR criteria have been defined eligible for 
inclusion.
4: Established because these drugs are used to improve QOL of RA patients and may 
possibly impact the efficacy evaluation of ASP015K.
5 and 6: Established to define the range of RA disease activity pertinent to this study.
7: Established to identify patients appropriate for evaluation using the classification criteria 
for functional status.
8: Established to select patients who had an inadequate response to, and require concomitant 
administration of, MTX. 
9: Established to choose patients who can maintain the same dosage and administration
schedule from before baseline and throughout the treatment period.
10: Established to include patients who have poor prognostic factors for joint destruction for 
the evaluation of joint damage prevention.
11: Established to ensure the integrity of the study evaluation.
3.3
Exclusion Criteria
Subject will be excluded from participation if any of the following applies:
1.
Subject has received a biologic DMARD within the specified period:

Etanercept: within 28 days prior to baseline

Adalimumab, infliximab: within 56 days prior to baseline

Golimumab, certolizumab pegol: within 70 days prior to baseline

Abatacept, tocilizumab: within 84 days prior to baseline

Denosumab: within 150 days prior to baseline

Rituximab: within 180 days prior to baseline
2.
Inadequate responders to biologic DMARD as determined by 
investigator/sub-investigator.
3.
Subject has received a non-biologic DMARD listed below or other drugs used in the 
treatment of RA within 28 days prior to baseline. Leflunomide is prohibited within 180 
days prior to baseline. Alternatively, leflunomide is prohibited within 28 days prior to 
baseline if washout with cholestyramine for at least 17 days is completed at least 28 days 
prior to baseline. However, topical drugs other than those for the treatment of RA may 
be used concomitantly.

Salazosulfapyridine

Lobenzarit

Gold


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
Iguratimod

D-penicillamine

Bucillamine

Actarit

Leflunomide

Tacrolimus

Cyclosporine

Cyclophosphamide

Azathioprine

Minocycline

Mizoribine
4.
Subject has received tofacitinib and other JAK inhibitors (including other investigational 
drugs).
5.
Subject has received intra-articular, intravenous, intramuscular, or endorectal (excluding 
suppositories in patients with anal diseases) corticosteroid within 28 days prior to 
baseline.
6.
Subject has participated in any study of ASP015K and has received ASP015K and 
placebo.
7.
Subject received other investigational drug within 90 days or within 5 half-lives, 
whichever is longer, prior to baseline.
8.
Subject has received plasma exchange therapy within 60 days prior to baseline.
9.
Subject has undergone joint drainage, has received local anesthesia and nerve block, or 
has received articular cartilage protectant at the assessed joint within 28 days prior to 
baseline.
10. Subject has undergone surgery and has residual effects in the assessed joints at the 
discretion of investigator/sub-investigator, or is scheduled to undergo surgery that may 
affect the study evaluation of the assessed joints at the discretion of 
investigator/sub-investigator.
11. A diagnosis of inflammatory arthritis (psoriatic arthritis, ankylosing spondylitis, SLE, 
sarcoidosis, etc.) other than RA.
12. Any of the following laboratory values during the screening test period:

Hemoglobin < 9.0 g/dL

Absolute neutrophil count < 1000/µL

Lymphocyte count < 800/µL

Platelet count < 75000/µL

ALT ≥2 × ULN

AST ≥2 × ULN

Total bilirubin (TBL) ≥1.5 × ULN

Estimated GFR ≤ 40 mL/min as measured by the MDRD method

β-D-glucan ≥ 11 pg/mL

Positive HBs antigen, HBc antibody, HBs antibody or HBV-DNA quantitation 
(However, subject with negative HBs antigen and HBV-DNA quantitation, and 
positive HBc antibody and/or HBs antibody is eligible if HBV-DNA is monitored 


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by HBV-DNA quantitation at every scheduled visit after initiation of study drug 
administration.)

Positive HCV antibody
13. Subject has a history of or concurrent active tuberculosis (TB). Eligibility criteria for TB 
are tabulated below:
History of active 
TB
Chest x-ray
(for TB)
TB infectionb)
Exposure to patients with 
infective TB (interview)
Eligibility
Present
-
-
-
Not eligible
Absent
Abnormal (active)
-
-
Not eligible
Abnormal (old)a)
-
Eligible
Eligible if  
prophylaxis is givenc)
Normal
Positive
Eligible
Eligible if  
prophylaxis is givenc)
Negative
Exposed
Eligible if  
prophylaxis is givenc)
Not exposed
Eligible
a) Old TB is evidenced if chest x-ray reveals pleural thickening, band-like shadow, and calcification ≥ 5 mm. 
Chest x-ray within 90 days prior to baseline may substitute the screening test.
b) T-spot or Quantiferon Gold test is of first priority. When the result is equivocal or invalid, retest including 
other test methods may be allowed. If a retest is not performed, criteria for positive results will be followed. 
When T-spot or Quantiferon Gold test is not feasible, tuberculin test will be performed. Tuberculin is defined as 
positive with a red spot covering an area of 20 mm or more or induration. Tests conducted within 90 days prior 
to baseline may be used for diagnosis.
c) Subject must receive or have received prophylaxis with isoniazid or rifampicin. Prophylaxis will be 
administered for 6 to 9 months, starting from at least 21 days prior to baseline.
14. Subject meets any of the following in terms of infections except for TB:

History of or concurrent severe herpes zoster (associated with Hunt syndrome or 
having ulcerative lesions) or disseminated herpes zoster

History of multiple recurrences (at least twice) of localized herpes zoster

Serious infection requiring hospitalization within 90 days prior to baseline

Subject received intravenous antibiotics within 90 days prior to baseline. (However, 
prophylactic antibiotics are allowed.)

Subject with high risk of infection (e.g., subject with urinary catheter) at the 
discretion of investigator/sub-investigator
15. Subject has a history of or concurrent interstitial pneumonia and 
investigator/sub-investigator judges that it is inappropriate for the subject to participate 
in this study.
16. Subject has a history of or concurrent malignant tumor (except for successfully treated 
basal cell carcinoma).
17. Subject has received live or live attenuated virus vaccination within 56 days prior to 
baseline. (Inactivated vaccines including influenza and pneumococcal vaccines are 
allowed.)
18. Subject has any ongoing severe, progressive, or uncontrolled renal, hepatic, 
hematological, gastrointestinal, metabolic, endocrine, pulmonary, cardiac, neurological, 
infectious, or autoimmune disease except for RA (excluding Sjogren’s syndrome and 


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chronic thyroiditis), or any ongoing illness which would make the subject unsuitable for 
the study as determined by the investigator/sub-investigator.
19. Subject has a history of clinically significant allergy. (Clinically significant allergy 
includes allergies such as systemic urticaria induced by specific antigens and drugs, 
anaphylaxis, and allergy associated with shock necessitating hospitalized treatment.)
20. Subject has received medications that are CYP3A substrates with narrow therapeutic 
range within 14 days prior to baseline. These medications include: dihydroergotamine, 
ergotamine, fentanyl, pimozide, quinidine, temsirolimus, and disopyramide.
21. Subject has concurrent cardiac failure, defined as NYHA classification Class III or 
higher, or a history of it.
22. Subject has concurrent prolonged QT syndrome or a history of it. Subject has prolonged 
QT interval (defined as QTc ≥ 500 msec. Subject has QTc ≥ 500 msec at retest will be 
excluded) at screening.
23. Subject has a history of positive HIV infection.
24. 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 
serum pregnancy test given at the time of screening.
25. Subject is a man who cannot practice at least 2 types of contraception from the time of 
informed consent to 90 days after the end of treatment, or subject is a woman with 
childbearing potential who cannot practice at least 2 types of contraception from the time 
of informed consent to 60 days after the end of treatment.
26. Male subject who do not agree not to donate sperm starting at informed consent and 
through the treatment period and for at least 90 days after final study drug 
administration. Female subject who do not agree not to donate ova starting at informed 
consent through the treatment period and for 60 days after final study drug 
administration.
27. The subject has been judged unsuitable to participate in the study for other reasons by 
the investigator/sub-investigator.
28. Subject has a history or complication of lymphatic diseases such as lymphoproliferative 
disorder, lymphoma, and leukemia.
29. Subject has congenital short QT syndrome or a history of it. Subject has shortened QT 
interval (defined as QTc < 330 msec. Subject has QTc < 330 msec at retest will be 
excluded) at screening.
[Rationale for exclusion criteria]
1, 2, 4, 5, 6, 7: Established to eliminate confounding factors affecting evaluation.
3, 8, 9, 10, 11: Established to eliminate confounding factors affecting efficacy evaluation.
12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 28, 29: Established out of safety 
concerns.


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29: The QTc criterion is quoted from Expert Consensus [Silvia G. Priori, 2014] of 
HRS/EHRA/APHRS.
27: Established in anticipation for a case where the investigator/sub-investigator judges a 
patient to be inappropriate for participation in the study.
3.4
Discontinuation Criteria for Individual Subjects
A discontinuation is a subject who enrolled in the study and for whom study treatment is 
permanently prematurely discontinued for any reason.
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 the 
subject’s clinical condition warrants it.
The Appendix 4 entitled “Liver Safety Monitoring and Assessment” describes liver function 
tests raised that provide grounds for discontinuation. Refer to Appendix 4 concerning the 
measures to take for increases in liver function test parameters.
The investigator/sub-investigator should discontinue the study if any of the following occurs:
1.
The subject withdraws consent.
2.
The investigator/sub-investigator judges that the study drug is not sufficiently effective 
and the treatment method needs to be changed.
3.
Symptomatic CPK elevation (> 1.5 × ULN accompanied with severe and unusual 
episodes of myalgia, muscular weakness, or muscle twitching).
4.
Any case of myopathy involving severe and unusual episodes of myalgia, muscular 
weakness, or muscle twitching that persists for no less than, or aggravates rapidly within, 
2 weeks, regardless of the CPK level. 
5.
A previously HBV-infected patient with positive HBc antibody, positive HBs antibody, 
or both has been shown positive for HBV-DNA during the study.
Attention should be paid that abrupt discontinuation of immunotherapy may cause 
fulminant or severe liver failure. Therefore, if the subject manifests HBV reactivation, 
the investigator/sub-investigator will administer nucleoside analogs without delay 
according to the “Proposal for Management of Rheumatic Disease Patients with 
Hepatitis B Virus Infection Receiving Immunosuppressive Therapy” (Japan College of 
Rheumatology). The investigator/sub-investigator will carefully decide whether to 
continue or discontinue the study drug and concomitant DMARDs in consultation with 
the hepatology specialist.
6.
Malignant tumor
7.
The subject develops a serious infection or other AEs, and continued administration of 
the study drug is not deemed appropriate in the subject’s best interest by the 
investigator/sub-investigator.


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8.
The subject has been treated with a prohibited concomitant drug or therapy (including 
another investigational product) that may impact efficacy evaluation. The subject has 
been, or needs to be, treated with a rescue medication for a period extending beyond its 
allowable time. Otherwise, the subject has been, or needs to be, treated with a live or live
attenuated vaccine.
9.
The subject has been judged by the investigator/sub-investigator to be non-compliant to 
the medication requirements for the study drug or MTX.
10. The subject is deemed incapable of continuing the follow-up based on the opinion of 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. The subject needs the study drug to be interrupted beyond its allowable time limit.
13. Investigator/sub-investigator decides it is in the subject’s best interest.
14. The sponsor has requested that the study be discontinued because of a safety problem in 
a particular subject, or the sponsor has decided to discontinue the study altogether.
15. The subject shows QTc interval < 300 msec at Central ECG, or the subject shows QTc
interval < 300 msec at the study site’s ECG and also shows QTc interval < 300 msec at 
retest.
Subjects who discontinue early from the study should be given the necessary tests and 
assessments specified for early termination within 2 days of withdrawal. They should also 
undergo follow-up tests and assessments. Subjects with early termination will be treated as 
discontinuations, and the investigator/sub-investigator must make clear the reason for 
discontinuation and the day of early termination (the date on which the 
investigator/sub-investigator has decided to discontinue the subject) as well as retain all 
clinical study data on the discontinuations and submit them to the sponsor in eCRF, etc.
3.4.1
Suspension, Interruption, and Resumption of the Study Drug
If the subject meets during the treatment period any of the criteria provided in Section 3.4.1.1 
Criteria for Suspension or Interruption of the Study Drug, the investigator/sub-investigator 
will immediately suspend or interrupt the treatment. The investigator/sub-investigator can 
resume the study treatment only if re-examinations and other assessments performed after the 
suspension or interruption confirm that none of the conditions listed below are applicable to 
the subject and the investigator/sub-investigator considers it desirable for the interest of the 
subject on the basis of risk–benefit analysis.
The maximum allowable time for “suspension” is 7 days. If the study treatment is halted 
beyond the suspension period, i.e., longer than 7 days, the period of no treatment is 
categorized as an “interruption.” 


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Upper limits have been set to the number of interruptions 1 subject can have and to the 
duration of 1 interruption. One interruption period may last for 28 days. One subject is 
allowed to have a maximum of 2 interruptions, which must be separated by 16 or more 
weeks. 
The investigator will consult the sponsor regarding the handling of a subject who repeatedly 
requires treatment suspension.
The subject must be withdrawn from the study, if he or she requires either a third interruption
or a second interruption within 16 weeks from the first one.
3.4.1.1
Criteria for Suspension or Interruption of the Study Drug
The investigator/sub-investigator will immediately suspend or interrupt the study drug if any 
of the following becomes applicable during the treatment period:
1.
Clinical laboratory tests yielded any of the following results:

Hemoglobin < 8.0 g/dL

Absolute neutrophil count < 500/µL

Absolute lymphocyte count < 500/µL

Platelet count < 50000/µL

Creatinine (serum) levels measured at 2 consecutive hospital visits: above 150% of 
the baseline level

CPK > 10 × ULN
2.
β-D-glucan test result of 11 pg/mL or higher.
3.
The subject requires a medication whose concomitant administration is prohibited in the 
protocol because of possible drug–drug interaction.
4.
The subject is suspected to be pregnant.
5.
The investigator/sub-investigator judged it appropriate in the interest of the subject to 
suspend or interrupt the study drug.
6.
The sponsor made a request to suspend or interrupt the study drug out of safety concerns 
for the subject.


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4
STUDY DRUGS
4.1
Description of Study Drugs
The test drugs for this study are ASP015K tablets of 100 mg and 150 mg, and the 
comparative drugs are placebo tablets for ASP015K of 100 mg and 150 mg.
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 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)
Code name
ASP015K
Content and dosage form
ASP015K tablet 100 mg placebo: An elliptical, pale-red, film-coated 
tablet indistinguishable from the ASP015K tablet 100 mg
ASP015K tablet 150 mg placebo: An elliptical, yellow, film-coated 
tablet indistinguishable from the ASP015K tablet 150 mg
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
4.2
Packaging and Labeling
All medications used in this study will be manufactured, packaged, and labeled under the 
responsibility of the Quality Assurance Manager in accordance with sponsor’s Standard 
Operating Procedures (SOP), GMP guidelines, GCP and applicable local laws/regulations.
(Refer to the study drug handling manual for details)
(Packaging form)
The study drugs will be packaged in a small box containing 28 day’s worth of medication 
and 7 day’s worth of spare medication. One PTP sheet (aluminium/aluminium) holds a total 
of 14 tablets: 7 tablets of ASP015K at 100 mg or placebo for ASP015K at 100 mg and 7 
tablets of ASP015K at 150 mg or placebo for ASP015K at 150 mg. Five PTP sheets 
(including 1 spare sheet) will be packaged in the small box.


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(Small box)
Lot No.●●
70 tablets (14 tablets × 5 sheets)
Phase III Study of ASP015K (DBT)
(015K-CL-RAJ4)
Caution: 1.
Please retain any remaining medication and this box without discarding them until 
they are collected by the sponsor.
2.
Please make certain that the medication allocated for each patient is used for the 
same patient and is not used for any other patient.
Storage method: Store at room temperature 
Expiration date: Specified in SOP for handling of the study drugs
Astellas Pharma Inc. (API)
2-5-1 Nihonbashi-Honcho, Chuo-ku, Tokyo
Lot No. is noted in SOP for handling of study drugs.
4.3
Study Drug Handling
The head of the study center or the study drug storage manager should take accountability of 
the study drugs as following issues.
●
The study drug storage manager should store and take accountability of the study drugs 
in conforming to the procedures for handling the study drugs written 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 by the protocol, and 
reconcile all the study drugs supplied from the sponsor.
4.4
Blinding
4.4.1
Blinding Method
Treatment allocation to the ASP015K 100 mg, ASP015K 150 mg, or placebo groups is 
double-blinded. The ASP015K tablet 100 mg, ASP015K tablet 100 mg placebo, or ASP015K 
tablet 150 mg, ASP015K tablet 150 mg placebo are indistinguishable from each other in 
appearance, and the packaging for each treatment group (100 mg, 150 mg, and placebo) is 
also indistinguishable from that for other groups in appearance. The treatment code will only 
be known to the person responsible for assigning study drugs, person appointed at the 
For clinical trial


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institution performing measurements of plasma drug concentrations, persons in the Safety 
Control Division when necessary for Suspected Unexpected Serious Adverse Reaction 
(SUSAR) handling, and independent Data and Safety Monitoring Board (DSMB).
4.4.2
Confirmation of the Indistinguishability of the Study Drugs
The appearance and the form of both the drug and packaging of the ASP015K tablet 100 mg 
and ASP015K tablet 150 mg are identical to those of their matching placebo. The person 
responsible for assigning study drugs will confirm the indistinguishability of the study drugs 
and their packaging in appearance before the assignment of the study drugs and during the 
period from collection of the study drugs to the breaking of the treatment code.
4.4.3
Retention of the Assignment Schedule and Procedures for Treatment Code 
Breaking
The person responsible for assigning study drugs will create a randomization list (original 
document) plus 3 copies (reproductions) in advance of the assignment of the study drug and 
seal each separately. The person responsible for assigning study drugs will retain the original 
randomization list. One copy of the randomization list (reproduction) will be retained by the 
sponsor in a sealed state even after the breaking of the treatment code, one copy will be 
prepared for use by DSMB, and the third copy will be provided to the institution performing 
measurements of plasma drug concentrations by the person responsible for assigning study 
drugs to be used as a sample measurement instruction sheet bearing treatment code 
information.
The person responsible for assigning study drugs will also create a treatment code for 
emergency and provide it to the person responsible for managing the treatment code for 
emergency. The person responsible for managing the treatment code for emergency will 
manage individual treatment code for emergency with code breaking permission in the 
web-based system. The web treatment code system can only be accessed by the person 
responsible for managing treatment code for emergency, the sponsor’s responsible personnel 
(or sponsor), and the person in charge of the Safety Control Division when necessary for 
SUSAR handling. The “SOPs for the Phase III Study of ASP015K DSMB” should be 
followed for treatment code retention, breaking, and code information conservation at the 
time of safety data review and safety evaluation.
4.4.4
Breaking the Treatment Code for Emergency
In the event of a medical emergency requiring knowledge of the treatment assigned to the 
subject, the investigator/sub-investigator can ask the sponsor to break the treatment code for 
emergency for the subject in question. The sponsor will make the decision as to whether or 
not to break the treatment code for emergency. The “SOPs for breaking the treatment code 
for emergency in Phase III study of ASP015K (015K-CL-RAJ4)” should be followed when 
the treatment code is broken. The investigator/sub-investigator, sponsor, and the person 
responsible for managing the treatment code for emergency should maintain contact so that 
the treatment code can be broken immediately in an emergency. When a sub-investigator 
requests that the treatment code be broken in an emergency, the consent of the investigator 


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should in principle be obtained in advance. However, in cases where it is difficult to obtain 
the understanding of the investigator in advance, the sub-investigator should immediately 
report the request to break the treatment code for an emergency to investigator after the fact. 
After the treatment code has been broken by the investigator or other responsible personnel, 
the study center must report the breaking of the treatment code and the reason for doing so to 
the contacts listed in the “Section II CONTACT DETAILS OF KEY SPONSOR’S 
PERSONNEL.”
4.4.5
Breaking the Treatment Code by the Sponsor
The sponsor may break the treatment code for subjects who experience SUSAR if regulatory 
reporting is considered necessary. An individual emergency code will be provided to the 
limited staff who are empowered to break the code for all SUSAR cases for reporting 
purposes.
4.5
Assignment and Allocation
The person responsible for assigning study drugs will randomly assign the study drugs and 
retain the treatment code under secrecy until the breaking of the treatment code. 
The Case Registration Center will assign subjects who have been found to be eligible for 
enrollment in accordance with the case registration procedures to 1 of the following groups: 
ASP015K 100 mg, ASP015K 150 mg, or placebo groups at baseline in 1:1:1 ratio. At Week
12, subjects in the placebo group whose tender and swollen joint counts have not improved 
by 20% from baseline will be assessed as having an inadequate response, and they will be 
switched to receiving either ASP015K at a dose of 100 mg or ASP015K at a dose of 150 mg. 
Subjects who are continuing to receive placebo at Week 28 will be switched to receiving
either ASP015K at a dose of 100 mg or ASP015K at a dose of 150 mg.
The dose of ASP015K (100 mg or 150 mg) to be administered to the placebo group from 
Week 12 or Week 28 is decided randomly at baseline, and study drugs must always be 
switched under double-blind conditions.
All drug numbers are assigned randomly by the Case Registration Center under blind 
conditions.


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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)
Dose and administration period
The following 3 treatment groups will be set up: ASP015K 100 mg group, ASP015K 150 mg 
group, and placebo group. The dose for each treatment group is shown in the table below.
The administration period will be 52 weeks. Two tablets of the drug described in the table 
below will be administered QD. Subjects in the placebo group who are showing an 
inadequate response at Week 12 will be switched to receiving either ASP015K at a dose of 
100 mg or ASP015K at a dose of 150 mg under blind conditions. Subjects who are 
continuing to receive placebo at Week 28 will be switched to receiving either ASP015K at a 
dose of 100 mg or ASP015K at a dose of 150 mg. The dose of ASP015K to be administered 
to the placebo group after the switching at Week 12 or Week 28 will be determined in 
advance at baseline and will be continued until Week 52.
●
Confirmation of inadequate response at Week 12
The investigator/sub-investigator will confirm the numbers of tender joints (of 68) and 
swollen joints (of 66) at Week 12 and confirm the rate of improvement from baseline. 
Subjects in the placebo group whose rate of improvement in tender and swollen joint 
counts is less than 20% will receive a different dose from Week 12. The rate of 
improvement will be confirmed for all subjects to maintain the blindness of the placebo 
group during the dose change at Week 12.


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Table Treatment Periods and Doses by Treatment Period (Administered Drug) in Study 
015K-CL-RAJ4
Baseline–Week 12
Week 12–Week 281)
Week 28–Week 522)
Placebo group
ASP015K placebo
(ASP015K tablet 100 mg 
placebo and 
ASP015K tablet 150 mg 
placebo
ASP015K placebo
(ASP015K tablet 100 mg 
placebo and 
ASP015K tablet 150 mg 
placebo)
100 mg/day as ASP015K
(ASP015K tablet 100 mg 
and 
ASP015K tablet 150 mg 
placebo)
150 mg/day as ASP015K
(ASP015K tablet 100 mg 
placebo 
and ASP015K tablet 150 mg)
100 mg/day as ASP015K
(ASP015K tablet 100 mg and 
ASP015K tablet 150 mg placebo)
150 mg/day as ASP015K
(ASP015K tablet 100 mg placebo and 
ASP015K tablet 150 mg)
ASP015K 100 mg
group
100 mg/day as ASP015K
(ASP015K tablet 100 mg and ASP015K tablet 150 mg placebo)
ASP015K 150 mg
group
150 mg/day as ASP015K
(ASP015K tablet 100 mg placebo and ASP015K tablet 150 mg)
1) Subjects in the placebo group whose rate of improvement in tender and swollen joint counts is less than 20% 
at Week 12 will be assigned to receiving either ASP015K 100 mg or ASP015K 150 mg. Subjects will continue 
receiving the assigned dose thereafter.
2) Subjects in the placebo group who continued receiving placebo until the visit at Week 28 will be assigned to 
receiving either ASP015K 100 mg or ASP015K 150 mg. Subjects will continue receiving the assigned dose 
thereafter.
(2)
Mode of administration
The assigned study drug will be orally administered to subjects under double-blind 
conditions QD after breakfast. The baseline dose should be given at each study center on the 
day of the baseline visit after all assessments and tests are completed.
Doses on the day of scheduled visits during the treatment period should be given on the day 
of the visit after all assessments and tests are completed, except for blood sampling for the 
assessment of post-dose concentrations.
5.1.2
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.
(1)
Previous medications
Pharmaceutical name, daily dose, route of administration, period of administration, and 
reason for administration of drugs used within the past 90 days, counting back from before 
administration on the day of the baseline visit

DMARD, prohibited concomitant medications, restricted concomitant medications 
(taken within 28 days prior to baseline), rescue medications (taken within 28 days prior 
to baseline)


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Medications for the treatment of RA (biologic DMARD, non-biologic DMARD) should be 
entered separately in the eCRF as the treatment history of the target disease described in 
Section 5.2.3 Diagnosis of the Target Disease, Severity, and Duration of Disease.
(2)
Previous therapies
None
(3)
Concomitant medications
The survey period will be from the initiation of study treatment on the day of the baseline 
visit.
Information on pharmaceutical name, daily dose, route of administration, period of 
administration, and reason for administration of DMARD, prohibited concomitant 
medication, restricted concomitant medication, and rescue medication will be collected.
In addition, pharmaceutical name, route of administration, period of administration, and 
reason for administration of medications other than DMARD, prohibited concomitant 
medication, restricted concomitant medication, rescue medication, and the following will be 
obtained.

Solution for dissolving or diluting (water for injection, saline), disinfectant, rinsing fluid, 
surface anesthetic for tests and procedures (such as Xylocaine jelly), contrast media for 
tests (such as barium, noniodinated contrast media), anticoagulants for use by the IV 
placement route, foaming agents and laxatives for use during tests, and topical drugs for 
local effect and for purposes other than RA.
*However, if such medications are used for the purpose of treating an adverse event, 
they should be entered in the eCRF.
Medications for the treatment of RA (biologic DMARD, non-biologic DMARD) should be 
entered separately in the eCRF as the treatment history of the target disease described in 
Section 5.2.3 Diagnosis of the Target Disease, Severity, and Duration of Disease.
(4)
Concomitant therapies
The survey period will be from the initiation of study treatment on the day of the baseline 
visit.
The name, purpose, and duration of therapies performed for RA, and adverse events will be 
obtained. Procedures (such as gauze replacement) and therapies (such as rehabilitation) 
performed for surgery will not be considered as concomitant therapies.
5.1.2.1
Previous Medication (Drugs and Therapies)
A period during which a drug cannot be used or a therapy is prohibited will be established as 
follows before the initiation of administration of the study drug for any previous medication 
(drugs and therapies) that could affect the evaluation of ASP015K:


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1)
Necessary concomitant medications

MTX
The use of MTX will be continued from 90 or more days before the initiation of screening 
and under the same dosage and administration schedule (≤ 16 mg/week) from 28 or more 
days before the initiation of screening until the day of the baseline visit. If MTX is 
temporarily interrupted or its dose is reduced within 28 days prior to the baseline visit in a 
subject eligible at screening for the study based on inclusion and exclusion criteria, the 
screening period will be extended to allow for the same dosage and administration schedule 
to be observed for 28 days prior to the baseline visit.

Folic acid
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 ALT/AST becomes ≥ 3 × ULN, MTX must be interrupted, or the dose must be reduced, 
and daily administration of folic acid should be considered.
2)
Prohibited concomitant medications and therapies:
●
Biologic DMARD
The following biologic DMARDs will be prohibited during the period shown below:

Etanercept: within 28 days prior to baseline

Adalimumab, infliximab: within 56 days prior to baseline

Golimumab, certolizumab pegol: within 70 days prior to baseline

Abatacept, tocilizumab: within 84 days prior to baseline

Denosumab: within 150 days prior to baseline

Rituximab: within 180 days prior to baseline
●
Non-biologic DMARD
Non-biologic DMARDs, excluding MTX, will be prohibited within 28 days prior to baseline. 
In addition, the use of leflunomide will be prohibited within 180 days prior to baseline. 
However, if washout with cholestyramine for at least 17 days is completed before 28 days 
prior to baseline, the use of leflunomide is prohibited within 28 days prior to baseline.
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, minocycline, and other drugs indicated for 
the treatment of RA will be prohibited within 28 days prior to baseline.


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●
Corticosteroids
Oral corticosteroids at doses exceeding 10 mg per day in the prednisolone equivalent will be 
prohibited within 28 days prior to baseline.
The intra-articular, intravenous, intramuscular, and endorectal corticosteroid administration 
will also be prohibited within 28 days prior to baseline. However, suppositories for anal 
diseases may be used concomitantly.
●
Oral morphine
Oral morphine at doses exceeding 30 mg per day (or equivalent doses of other opioid 
analgesics) will be prohibited within 28 days prior to baseline.
●
Other study drugs
Other study drugs will be prohibited within 90 days or 5 half-lives, whichever is longer, prior 
to baseline.
●
CYP3A substrates
The following CYP3A substrates with a narrow therapeutic range will be prohibited within 
14 days prior to baseline: dihydroergotamine, ergotamine, fentanyl, pimozide, quinidine, 
temsirolimus, disopyramide, etc.
●
Vaccines
Live or live attenuated virus vaccinations will be prohibited within 56 days prior to baseline. 
Inactivated vaccines may be administered (influenza, pneumococcal vaccines, etc.).
●
Plasma exchange therapy
Plasma exchange therapy will be prohibited within 60 days prior to baseline.
●
Surgical treatment methods
After obtaining informed consent, surgery involving the target joint will be prohibited.
●
Effusion drainage, local anesthesia, and nerve block of the target joint
Effusion drainage, local anesthesia, and nerve block of the target joint will be prohibited 
within 28 days prior to baseline.
●
Articular cartilage protective agents
The use of articular cartilage protective agents in the target joint will be prohibited within 28 
days prior to baseline.
3)
Restricted concomitant medications
●
If administration of concomitant medication is to be continued during the treatment 
period, changes to the dosage, administration schedule, or route of administration of the 
drugs below will not be allowed within 28 days prior to baseline.
●
If administration of concomitant medication is discontinued before the initiation of study 
treatment, administration of the drugs below is prohibited within 28 days prior to


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baseline [except in cases where NSAIDs and analgesics other than NSAIDs 
(acetaminophen, opioid analgesics, all-in-one cold and flu medications, etc.) are used as 
rescue medication].
●
In the case of a medically unfavourable event during the screening period, administration 
may be temporarily interrupted, or the dose may be temporarily reduced. The period of 
interruption is up to 28 days. When resuming administration, the dose prior to 
interruption/reduction is the upper limit.

NSAIDs (excluding topical drugs with a local action)

Oral morphine
(Not more than 30 mg per day, or equivalent doses of other opioid analgesics)

Acetaminophen

Oral corticosteroids
(However, at 10 mg per day or less in the prednisolone equivalent and from the visit 
at Week 28, the dose may be reduced or increased within the range not exceeding 
the baseline dose.)
4)
Rescue medications
The drugs listed below may be used within 28 days prior to baseline only if they are 
necessary for treating a medically unfavourable event or acute worsening of the primary 
disease. However, these medications may not be taken within 24 hours before joint 
assessment at baseline.

NSAIDs: For 3 days or less

Analgesics other than NSAIDs (acetaminophen, opioid analgesics, all-in-one cold 
and flu medications, etc.): For 7 consecutive days or less.
5.1.2.2
Concomitant Medication (Drugs and Therapies)
1)
Necessary concomitant medications

MTX
MTX will be used from 28 or more days before the initiation of screening under the same 
dosage and administration schedule (≤ 16 mg/week) and continued during the treatment 
period under the same dosage.
In the case of AEs, administration may be temporarily interrupted, or the dose may be 
temporarily reduced. The period of interruption is up to 28 days. When resuming 
administration, the dose may be increased with the baseline dose as the upper limit. 
Administration may only be interrupted once.
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 ALT/AST becomes ≥ 3 × ULN, MTX must be interrupted, or the dose must be reduced, 
and daily administration of folic acid should be considered.


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2)
Prohibited concomitant medications and therapies:
●
Biologic DMARDs
The following biologic DMARDs will be prohibited during the treatment period:
Adalimumab, infliximab, golimumab, certolizumab pegol, abatacept, tocilizumab, 
rituximab, etanercept, and denosumab
●
Non-biologic DMARDs
Non-biologic DMARDs, excluding MTX, will be prohibited during the treatment period.
However, topial 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, and other drugs indicated for 
the treatment of RA will be prohibited during the treatment period.
●
Corticosteroids
Oral corticosteroids at doses exceeding 10 mg per day in the prednisolone equivalent will be 
prohibited during the treatment period.
The intra-articular, intravenous, intramuscular, and endorectal corticosteroid administration 
will also be prohibited during the treatment period. However, suppositories for anal disease 
may be used concomitantly.
●
Oral morphine
Oral morphine at doses exceeding 30 mg per day (or equivalent doses of other opioid 
analgesics) will be prohibited during the treatment period.
●
Other study drugs
Other study drugs will be prohibited during the treatment period and follow-up period.
●
CYP3A substrates
The following CYP3A substrates with a narrow therapeutic range will be prohibited during 
the treatment period and follow-up period: dihydroergotamine, ergotamine, fentanyl, 
pimozide, quinidine, temsirolimus, disopyramide, etc.
●
Vaccines
Live or live attenuated virus vaccinations will be prohibited during the treatment period and 
the follow-up period. Inactivated vaccines may be administered (influenza, pneumococcal 
vaccines, etc.)
●
Plasma exchange therapy
Plasma exchange therapy will be prohibited during the treatment period.
●
Surgical treatment methods
Surgery involving the target joint will be prohibited during the treatment period.


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●
Effusion drainage, local anesthesia, and nerve block of the target joint
Effusion drainage, local anesthesia, and nerve block of the target joint will be prohibited 
during the treatment period.
●
Articular cartilage protective agents
The use of articular cartilage protective agents in the target joint will be prohibited during the 
treatment period.
3)
Restricted concomitant medications
If the drugs below are to be continued during the treatment period, changes to the dosage, 
administration schedule, or route of administration of the drugs below will not be allowed
from 28 days prior to baseline to the end of treatment, unless the specific conditions for the 
change are met.
●
If the drugs below are discontinued before the initiation of study treatment, 
administration of the drugs below is prohibited from 28 days prior to baseline to the end 
of treatment [except in cases where NSAIDs and analgesics other than NSAIDs 
(acetaminophen, opioid analgesics, all-in-one cold and flu medications, etc.) are used as 
rescue medication].
●
In the case of AEs, administration may be temporarily interrupted, or the dose may be 
temporarily reduced. The period of interruption is up to 28 days. When resuming 
administration, the baseline dose is the upper limit.
●
From the visit at Week 28, the drugs below may be discontinued, new drugs may be 
used, and the dosage, administration schedule, or route of administration of the 
concomitant drugs may be changed. However, with the exception of oral corticosteroids, 
after changing the conditions, administration must be continued under the same 
conditions for 12 weeks or longer.

NSAIDs (excluding topical drugs with a local action)

Oral morphine
(Not more than 30 mg per day, or equivalent doses of other opioid analgesics)

Acetaminophen

Oral corticosteroids
(However, at 10 mg per day or less in the prednisolone equivalent and from the visit 
at Week 28, the dose may be reduced or increased within the range not exceeding 
the baseline dose.)
4)
Rescue medications
During the treatment period, the drugs listed below may be used if they are necessary for 
treating AEs, comorbid conditions, or acute aggravation of the primary disease. However, 
these medications may not be taken within 24 hours before joint assessment at each visit.

NSAIDs: For 3 days or less

Analgesics other than NSAIDs (acetaminophen, opioid analgesics, all-in-one flu and 
cold medications, etc.): For 7 consecutive days or less


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5.1.3
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.
●
Do not take multiple doses all at once if doses of the study drug have been missed.
●
Bring any remaining study drug with you to the next scheduled examination.
●
Immediately contact the investigator, sub-investigator, or collaborator if there is a 
shortage of the study drug before the next visit due to the loss of study drugs, etc.
The investigator/sub-investigator will confirm each subject’s compliance status during the 
treatment period with the study drug on the basis of information given by the subject and the 
number of tablets of the study drug collected from the subject, and the 
investigator/sub-investigator will record the number of tablets prescribed and the number of 
unused tablets in the eCRF. 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, each subject should be asked regarding the most recent day on which the study 
drug was taken and the time at which it was taken, at each scheduled visit at Weeks 4, 8, 12, 
20, 28, 40, and 52, and at discontinuation, and information should be recorded in the eCRF.
5.1.4
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 
under full monitoring to ensure the safety of the subject.
Experience with administration of ASP015K to humans remains limited, and overdose of 
ASP015K has not been reported. However, based on data on AEs from previous studies, the 
first sign of overdose of ASP015K may be nausea, diarrhoea, other GI symptoms, CPK 
increased, lymphocytes decreased, or neutropenia.
5.1.5
Criteria for Continuation of Treatment
Subjects in the ASP015K 100 mg, ASP015K 150 mg, or placebo groups who completed the 
assessment at study visit at Week 52 may participate in an extension study (015K-CL-RAJ2) 
if they wish to do so. Each subject must provide informed consent for the extension study 
before completing the assessment at study visit at Week 52.
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.

In principle, subjects should visit the study center for the study visit on the specified 
date. The visits may be adjusted within an allowable range, but the visit dates must be 
adjusted so that the intervals between the specified visits are 5 weeks at most.


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
The subject should come to the study center on the day of each study visit without taking 
the 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 a subject must make an 
unscheduled visit due to adverse events, etc., on the day of taking the study drug, the 
unscheduled visit will be prioritized regardless of whether the study drug was taken and 
the timing of meals.

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/sub-investigator in advance, the subject should 
contact one of them, or the collaborator, as soon as possible.

Any subject who wishes to take prescription medication or over-the-counter drugs 
unconfirmed by the investigator/sub-investigator should confirm with the investigator, 
sub-investigator, or collaborator in advance whether to take the drug. If it is not possible 
to contact the investigator/sub-investigator in advance, the subject should contact one of 
them, or the collaborator, as soon as possible.

Subjects must practice contraception through 2 or more appropriate contraceptive 
methods throughout the study period, and for 90 days after the end of treatment in the 
case of male subjects and for 60 days after the end of treatment in the case of female 
subjects of childbearing potential.

Female subjects must not breastfeed throughout the study period and for 60 days after 
the end of treatment.

If another visit is instructed by the investigator/sub-investigator due, for example, to a 
laboratory finding subject to CPK monitoring and liver function monitoring, the subject 
must promptly visit the study center.
5.2
Demographics and Baseline Characteristics
5.2.1
Demographics
The date of obtaining informed consent, date of birth, and sex will be recorded in the eCRF. 
In addition, height, history of smoking, and alcohol consumption habits will be confirmed 
during the screening test period and recorded in the eCRF.
5.2.2
Medical History
Diseases cured before the initiation of study treatment will be regarded as previous diseases, 
and diseases that remain uncured at the initiation of study treatment will be regarded as 
concurrent diseases. All concurrent diseases will be investigated, and the name of the 
diagnosis will be recorded in the medical record or other source documents, as well as in the 
eCRF. Serious infectious diseases (in the past 365 days from baseline) and herpes zoster are 


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subjects to investigation, and the history, name of diagnosis, date of onset, and date of 
recovery will be entered in the eCRF.
5.2.3
Diagnosis of the Target Disease, Severity, and Duration of Disease
Information on following items will be obtained and entered in the eCRF:
●
Name of diagnosis, onset date of RA, and criteria for the classification of RA used for 
the diagnosis (Appendix 5, Appendix 6)
●
ACR 1991 revised criteria for the classification of global functional status in RA 
(Appendix 7) at screening
●
Classification of disease stage/progression of RA (Appendix 8) at screening
●
History of surgery for RA (name of surgery, joint operated, possibility of joint 
assessment)
●
Names of RA treatment drugs used in the past (DMARD), treatment response, and 
tolerability
●
Timing for the initiation of MTX for the treatment of RA, dose of MTX from 90 days 
before the initiation of screening, treatment response at the initiation of screening, 
tolerability at the initiation of screening, and reason for the assessed tolerability (reason 
why the dose of MTX cannot be increased)
●
Measurements of anti-CCP antibody and RF at the time of the screening test (obtained as 
laboratory results)
●
Date of performing hand and foot radiography during the screening period (radiography 
results from within 90 days prior to baseline may be used), and presence or absence of 
bone erosion
5.3
Efficacy, Pharmacodynamics, and Pharmacokinetics Assessments
5.3.1
Efficacy Assessments
5.3.1.1
Tender and Swollen Joint Counts
The following assessments will be performed on the scheduled assessment days from the 
screening visit onward:
(1)
Tender joint count
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. The 28 joints 
subject to assessment will also be examined for tender joints and the location will be 
confirmed. The number of respective confirmed joints and the date of assessment will 
be entered in the eCRF.
(2)
Swollen joint count
The investigator/sub-investigator will examine the subject for swollen joints, assessing 
the 66 joints listed below, with the exception of the hip joints, and confirm the location 
of the swollen joints. The 28 joints subject to assessment will also be examined for 


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swollen joints and the location will be confirmed. The number of respective confirmed 
joints and the date of assessment will be entered in the eCRF.
Table Joints Subject to Assessment
Temporomandibular joints (2), sternoclavicular joints (2), acromioclavicular joints (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
5.3.1.2
Assessment of Pain and Overall Assessment of Disease Activity
The following assessments will be performed on the scheduled assessment days from the 
baseline onward:
(1)
Subject’s assessment of pain: The subject assesses his/her own pain severity on a VAS 
of 0–100 mm on the questionnaire form. The measured value and the date of 
assessment will be entered in the eCRF.
(2)
SGA: The subject assesses his/her own disease activity on a VAS of 0–100 mm on the 
questionnaire form. The measured value and the date of assessment will be entered in 
the eCRF.
(3)
PGA: The investigator/sub-investigator assesses the subject’s disease activity on a VAS 
of 0–100 mm on the physician assessment table. The measured value and the date of 
assessment will be entered in the eCRF.
5.3.1.3
Acute Phase Reactant (CPR and ESR)
Only CRP is measured during the screening test period. Blood sampling is performed on the 
scheduled assessment days from baseline to measure CRP and ESR. 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, SDAI, and ACR response criteria assessment.
One-hour value of ESR will be measured. The measured ESR and the date of measurement 
will be entered in the eCRF.
5.3.1.4
EULAR Response Criteria
Based on DAS28 scores and changes in DAS28 scores before and after treatment with the 
study drug, EULAR Response Criteria categorize response to treatment as “No response,” 
“Moderate response,” or “Good response” according to the definition given in the table 
below [van Gestel et al, 1996; van Gestel et al, 1998].


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Table Definition of EULAR Response Criteria Assessment
DAS28 after treatment
DAS28 response (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 the screening visit and at each subsequent 
assessment days specified in the 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 of > 5.1

Moderate disease activity: DAS28 score of > 3.2 and ≤5.1

Low disease activity: DAS28 score of ≤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 baseline and Week 12 will be calculated using data from the following 
assessments, together with 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 HAQ-DI, and acute 
phase reactant (CRP or ESR).
The ACR20 response requires that all criteria from (1) to (3) below be met. The ACR50 
response indicates a 50% improvement in all criteria from (1) to (3) below, and the ACR70 
response similarly indicates a 70% improvement. In this study, [5] is assessed with CRP.
(1)
TJC: ≥ 20% reduction compared with baseline
(2)
SJC: ≥ 20% reduction compared with baseline
(3)
≥ 20% improvement in 3 or more of the following 5 parameters compared with 
baseline
[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 assessments at baseline and on days specified in the 
Schedule of Assessments. The outcome of the assessments will be recorded in the eCRF. In 
principle, the copy of assessment forms will be provided to the sponsor.
●
HAQ-DI [Fries et al, 1982; Ramey et al, 1992]
●
SF-36v2® [Ware, 2004]
●
WPAI [Takeuchi T, 2011; Reilly MC, 1993]
5.3.1.9
Hand and Foot Radiography
Radiography of hands and feet (posterioranterior radiograph of both hands and dorsoplantar 
radiograph of both feet) will be taken at baseline, Week 12 (only for subjects whose 
improvement in TJC and SJC from baseline is less than 20%), Week 28, Week 52, and at 
early termination.
The subject information on hand and foot radiography images (film or digital data) taken 
from baseline will be masked, and the images will be sent to the institution performing the 
assessment of hand and foot radiography images. If retake of the images is requested by a 
third party institution due to faults of the location or quality of the sent images, the images 
must be retaken immediately and sent within 30 days of the request for retake. The date of 
taking radiography will be entered in the eCRF.


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The manual provided by sponsor will be followed for the method of taking radiography and 
sending the images.
The third party institution will assess the severity of joint destruction in hands and feet (bone 
erosion and joint fissure narrowing) through the mTSS method by scoring the severity of 
bone erosion and joint fissure narrowing of the target joints and calculate the total score. The 
target joints and the scoring method are described in the SOP prepared by the third party 
institution.
The results of the assessment will be sent to the sponsor by the third party institution.
The attending physician will confirm the hand and foot radiography at screening for the 
presence/absence of bone erosion, and this physician will enter the date of taking the images, 
date of assessment, and the presence/absence of erosion in the eCRF. However, the 
presence/absence of bone erosion may be confirmed from hand and foot radiography taken 
within 90 days prior to baseline.
5.3.2
Pharmacodynamic Assessments
Blood samples will be collected at baseline and on days specified in the Schedule of 
Assessments. At the study visit points where blood sample collection for PK assessment is 
performed, sample collection for PD assessment will be performed before study drug 
administration and at the same time as that for the sampling for PK assessment. These 
measurements will be performed at the central laboratory (
), and 
the results will be reported to the sponsor and the study center after the breaking of the 
treatment code.
5.3.2.1
Lymphocyte Subsets
Lymphocyte subset quantification of CD3, CD4, CD8, CD16, CD19, CD56, and CD56/16 
will be performed, and the changes from baseline will be calculated. The date of blood 
sampling will be entered in the eCRF.
5.3.2.2
Biomarkers for Efficacy and Safety Assessments
To assess the effects of ASP015K on biomarkers, VEGF and MMP-3 will be measured, and 
the changes from baseline will be calculated. The date of blood sampling will be entered in 
the eCRF.
Additional analysis may be performed for biomarkers for efficacy and safety assessments 
based on study results using blood samples that have been collected during the study and 
biobanked (i.e., residual sample stored for retrospective analysis). These could include 
biomarkers of inflammation, bone or cartilage metabolism, or inhibitory activity of JAK, but 
other biomarkers may also be subject to analysis.
5.3.3
Pharmacokinetic Assessments
The concentration of ASP015K will be measured. If necessary, the concentrations of 
ASP015K metabolites will be measured. Blood samples will be collected at baseline and on 
the days specified in the Schedule of Assessments. Moreover, the date and time on which the 


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last dose of study drug will be taken just prior to blood sampling will be recorded in the 
eCRF, together with the date and time of blood sampling.
The sampling for the assessment of post-dose concentrations will be performed as a substudy 
at study centers approved for the sampling. The sampling for the assessment of post-dose 
concentrations will be performed at either Week 4 or Week 8, 2 hours after the administration 
of the study drug (the acceptable time range is from 1 hour to 4 hours post-dose). In addition, 
the sampling for post-dose concentrations will be performed on the same day as Central ECG
at Week 4 or Week 8, promptly after the Central ECG.
5.4
Safety Assessment
The following tests and observations will be made for the purpose of safety assessments at 
baseline and on the days specified in the Schedule of Assessments. The requirements for 
reporting and analysis of information on drug-induced liver injury (DILI) are in Appendix 4
“Liver Safety Monitoring and Assessment.” If marked liver function abnormal in Appendix 4 
is observed, the investigator or the responsible personnel should contact the sponsor or CRO 
by telephone or fax (within 24 hours of awareness).
5.4.1
Vital Signs
Blood pressure (in the sitting position), pulse rate, and body temperature at rest will be 
measured at screening and on the days specified in the Schedule of Assessments. The date of 
measuring and measurements taken (blood pressure and the measuring position, systolic 
blood pressure, diastolic blood pressure, pulse rate, and body temperature) will be entered in 
the eCRF.
5.4.2
Body Weight
Body weight will be measured at screening and on the days specified in the Schedule of 
Assessments. The date of measuring and measurements taken will be entered in the eCRF.
5.4.3
Adverse Events
The survey period for AEs will be from the initiation of study treatment to before the 
initiation of administration in the extension study or until the end of follow-up.
Events that occurred after study drug administration until before the initiation of 
administration in the extension study or until the end of follow-up will be recorded as AEs. 
Concurrent diseases that worsened during the study will also be recorded as AEs. AEs that 
occurred after the subject has completed the study plan or has been discharged from the 
hospital or the study center will not be recorded.
AEs that have not resolved before the initiation of administration in the extension study or at 
the end of follow-up must 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 
the event resolves during the study period, the date of resolution is to be entered in the eCRF.


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See Appendix 4 “Liver Safety Monitoring and Assessment” for the assessment of AEs 
caused by DILI.
Herpes zoster should be entered as an AE information in the eCRF, and also, a separate 
Herpes Zoster (shingles) Worksheet should be prepared, and a copy should be submitted to 
the sponsor. If the sponsor considers necessary and requests for submission of forms for the 
purpose of providing additional information on other AEs, a form must be prepared to report 
to the sponsor.
5.4.3.1
Adverse Events of Possible Hepatic Origin
Subjects with liver-derived AEs associated with hepatic function abnormal should be 
monitored carefully.
5.4.4
Laboratory Assessments
The below hematology, biochemistry, fasting lipid profile, and urinalysis will be performed 
at screening and on each of the days specified in the Schedule of Assessments. These 
measurements will be performed at the central laboratory (
). For 
the period of performing additional laboratory tests for DILI, see Appendix 4 “Liver Safety 
Monitoring and Assessment.”
Additional sampling and tests may be performed if it is considered necessary by the 
investigator/sub-investigator or if retesting is considered necessary by the 
investigator/sub-investigator because the results could not be obtained due to defects in the 
sample. Additional tests and analysis may be performed based on the study results using 
blood samples for laboratory assessments that have been collected during the study and have 
been biobanked (i.e., residual samples stored for retrospective analyses).
1)
Hematology, biochemistry (including fasting lipid profile tests), urinalysis
The following hematology, biochemistry, fasting lipid profile tests, and urinalysis will be 
performed:
●
Hematology
Hemoglobin, hematocrit, erythrocytes (RBC), leukocytes (WBC), differential WBC 
(neutrophils, lymphocytes, monocytes, eosinophils, basophils), platelet count
Each blood cell count will be calculated from the differential WBC.
●
Biochemistry
Na, K, Ca, Cl, Mg, HCO3, BUN, phosphorus, glucose, creatinine, ALP, AST (GOT), 
ALT (GPT), γ-GTP, total bilirubin, total protein, albumin, uric acid, CPK, LDH, serum 
amylase, eGFR, β-D-glucan
●
Fasting lipid profile
Total cholesterol, LDL, HDL, triglycerides
The date of sample collection will be entered in the eCRF.


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
Blood specimens for scheduled fasting lipid profile tests should be drawn after the 
subject has fasted for at least 8 hours, unless it is at termination or at an unscheduled 
visit when the subject could not fast.
●
Urinalysis
pH, specific gravity, protein (qualitative), glucose (qualitative), keton bodies 
(qualitative), bilirubin (qualitative), occult blood, sediment
2)
Pregnancy test (for females only)
Pregnancy testing will be performed from screening according to the Schedule of 
Assessments. Serum pregnancy testing is required only at screening, and urine 
pregnancy testing will be performed after baseline. The serum pregnancy testing will be 
performed by the central laboratory and the urine pregnancy testing will be performed by 
the study centers using the kits provided by the central laboratory. If, in the serum 
pregnancy test, hCG level exceeds ULN, but the possibility of pregnancy can be 
completely ruled out by another test, the subject is eligible for enrollment. Pregnancy 
testing is not subject to the safety assessment.

If a urine pregnancy test is positive at any time, a negative serum pregnancy is 
required for the subject to continue participation in the study. If the possibility of 
pregnancy can be completely ruled out by another test, the subject may continue to 
participate 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.
3)
Tuberculosis test
The tuberculosis test will be performed at screening to confirm the eligibility of the 
subject in accordance with Exclusion Criterion 13. T-SPOT or QuantiFERON Gold test 
is the preferential test for tuberculosis infection. If T-SPOT or QuantiFERON Gold test 
cannot be performed, tuberculin skin test may be performed instead. Tuberculin test and 
QuantiFERON Gold test cannot be performed at the central laboratory.
Tuberculosis test is not required at screening provided that there is documentation of a 
negative tuberculosis test within 90 days prior to baseline.
4)
Hepatitis test
Tests for HBs antigens, HBs antibodies, the HBV-DNA assay, HBc antibodies, and 
HCV antibodies will be performed at the screening visit to confirm the eligibility of the 
subject. If a subject is positive for either or both HBc antibodies and HBs antibodies, the 
subject will be monitored during the treatment period by performing an HBV-DNA 
assay at scheduled visits and early termination. Safety analysis will not be performed for 
the results of HBV-DNA assays from baseline.


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5)
CPK monitoring
If an increase in CPK is observed, in accordance with Section 5.4.4.1 CPK Monitoring, 
when CPK is retested, CPK, CK-MB, troponin T, and aldolase should also be tested. 
Urinalysis (blood and microscopy) will be performed as part of the targeted physical 
examination.
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 laboratory testing reveals CPK > 3 × ULN, and the subject is asymptomatic, retest 
CPK preferably within 1 week of previous blood sampling to confirm it. Subsequently, 
retest CPK weekly (from the date of the initial CPK elevation) until CPK is ≤3 × ULN 
or is stable according to the judgment of the investigator/sub-investigator. If the retest 
cannot be performed within 1 week of blood sampling, which marks the starting point of 
CPK monitoring, suspension or interruption of the study drug should be considered until 
the retest results are obtained.
●
In subjects whose baseline CPK is already > 3 × ULN, if laboratory testing reveals CPK 
> 2 × baseline, and the subject is asymptomatic, retest CPK preferably within 1 week of 
previous blood sampling to confirm it. Subsequently, retest CPK weekly (from the date 
of CPK elevation to > 2 × baseline) until CPK is ≤2 × baseline, or is stable in the 
judgment of the investigator/sub-investigator. If the retest cannot be performed within 1 
week of blood sampling, which marks the starting point of CPK monitoring, suspension 
or interruption of the study drug should be considered until the retest results are 
obtained.
●
If CPK is > 10 × ULN at any time, treatment will be immediately suspended or 
interrupted (see Section 3.4 Discontinuation Criteria for Individual Subjects), and retest 
CPK.
●
If there is a symptomatic CPK elevation (CPK elevation > 1.5 × ULN accompanied by 
severe and unusual episodes of myalgia, muscular weakness, or muscle twitching), as 
reported by the investigator/sub-investigator, treatment will be immediately discontinued 
(see Section 3.4 Discontinuation Criteria for Individual Subjects). 
In the retest for CPK monitoring, the following tests will be performed in addition to CPK 
measurements. The content of the subject questionnaire will be entered in the eCRF.

Laboratory tests
(Measurement parameters: CK-MB, troponin T, aldolase)

A targeted physical examination* and subject questionnaire to assess muscle strength 
and pain
*: As part of the targeted physical examination, urinalysis (blood and microscopy) will 
be performed.


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5.4.4.2
Hepatic Function Abnormal
If laboratory testing for a subject enrolled in the study and receiving the study drug reveals an 
increase in serum aminotransferase (ALT, AST) > 3 ULN or TBL > 2 ULN, at least 4 
parameters (ALT, AST, ALP, and TBL) of the usual hepatic function test parameters should 
be retested. The retest should be performed between 48 hours and 72 hours after notification 
of the test results.
For additional information on monitoring and the assessment of the hepatic function test, see 
Appendix 4 “Liver Safety Monitoring and Assessment.”
If laboratory testing for a subject enrolled in the study receiving the study drug reveals an 
increase in serum aminotransferase (ALT, AST) > 3 × ULN and TBL > 2 × ULN, the 
investigator will determine whether it is an SAE. Even if the abnormality is not considered an 
SAE by the investigator/sub-investigator, it will be reported to the sponsor or CRO in writing 
as in the case of SAEs.
5.4.5
Physical Examination
A physical examination will be performed at scheduled visits and early termination to 
confirm physical findings.
Physical findings and RA symptoms will be confirmed at unscheduled visits whenever 
possible.
5.4.6
12-lead Electrocardiogram (ECG)
A 12-lead ECG will be obtained at screening and on the assessment dates specified in the 
Schedule of Assessments. The investigator/sub-investigator will confirm the ECG chart, 
assess the results as “normal,” “abnormal but not to a clinically important degree,” or 
“clinically important abnormality,” and record the results of the assessment in the CRF. If the 
finding is “abnormal but not to a clinically important degree” or “clinically important 
abnormality,” the finding will be recorded in the CRF.
The screening 12-lead ECG must be performed within 4 weeks prior to the first dose of study 
drug. In addition, the clinical interpretation of the results of this examination must be 
completed prior to the first dose of study drug.
5.4.7
Radiography
Chest radiography will be performed at screening and on the assessment dates specified in 
the Schedule of Assessments. Chest radiography examination will be performed at early 
termination if it is determined necessary by the investigator/sub-investigator. However, chest 
radiography at screening is not required provided that there is documentation of a normal 
chest radiograph within 90 days of baseline. The investigator/sub-investigator will confirm 
the chest radiographic images, assess the results as “normal,” “abnormal but not to a 
clinically important degree,” or “clinically important abnormality,” and the 
investigator/sub-investigator record the results of the assessment in the eCRF.


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If the results of chest radiography at screening reveal findings of tuberculosis, the subject’s 
eligibility will be decided in accordance with Exclusion Criterion 13.
5.4.8
Central ECG
Central ECG is conducted as sub-study at the sites which approved blood sampling for 
post-dose drug concentration. Subjects in the reference group will be excluded from Central 
ECG. Central ECG is performed at baseline before study drug administration, as well as 
before study drug administration and 2 hours after study drug administration at Week 4 or 
Week 8 on the same day as blood sampling for post-dose drug concentration at Week 4 or 
Week 8. 12-lead ECG is performed as Central ECG. The measurement date and time of 
central ECG is recorded in the eCRF.
The measuring and transmittal method of Central ECG in the handling manual provided by 
sponsor is followed. The QT interval, QTcF, and QTcB will be calculated by the third party 
using the Central ECG data transmitted and the method of ECG analysis is described in the 
handling manual prepared by the third party.
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 
or has undergone study procedures and which does not necessarily have a causal relationship 
with this treatment. An AE can therefore be any unintended sign (including an abnormal 
laboratory finding), symptom, or disease temporally associated with the use of a medicinal 
(investigational) product, whether or not related to the medicinal (investigational) product.
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 the study drug
●
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. The rationale for the assessment of the causal relationship does not need 
to be recorded for all AEs but only at the request of the sponsor. The severity of each event 
should be recorded on a scale of Grade 1 to Grade 5 in the eCRF, and the causal relationship 
to the study drug should be recorded as “Probable,” “Possible,” or “Not related” (see Section 


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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 documents and in the eCRF. The outcome 
should be recorded in the medical record or other source documents and in the eCRF as 
“resolved,” “alleviated,” “unresolved,” “resolved but with late effects,” “death,” or 
“unknown.”
5.5.2
Definition of Serious Adverse Events (SAEs)
An adverse event is considered “serious” if, in the view of either the investigator or Sponsor, 
it results in any of the following outcomes:
●
Results in death
●
Is life threatening (an adverse event 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 adverse event that, had it occurred in a more severe form, 
might have caused death)
●
Results in persistent or significant disability/incapacity or substantial disruption of the 
ability to conduct normal life functions
●
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 to be considered 
as 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 one 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 intensive treatment in 
an emergency room or at home for allergic bronchospasm; 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 the medical events 
described in Appendix 3 “Events Always considered to be Serious” and Appendix 4 “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 drug could not be ruled out.”


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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 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
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 a serious adverse event (SAE), the investigator must contact the 
Sponsor/delegated CRO by telephone or fax immediately (within 24 hours of awareness).
The investigator should complete and submit an SAE Worksheet containing all information 
that is required by the Regulatory Authorities to the Sponsor/delegated CRO by fax 
immediately (within 24 hours of awareness). If the faxing of an SAE Worksheet is not 
possible or is not possible within 24 hours, the local drug safety contact should be informed 
by phone.
For contact details, see Section II CONTACT DETAILS OF KEY SPONSOR’S 
PERSONNEL. 
Please fax the SAE Worksheet to:


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Contact Information of the Sponsor
TEL: 
, FAX: 
Contact Information of CRO
TEL: 
, FAX: 
5.5.6
Follow-up of 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 adverse event progresses to an "SAE", or if a subject experiences 
a new SAE, the investigator must immediately report the information to the Sponsor.
Even if the subject does not return to normal or to his/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 on the case report form for the 
follow-up, and
3.
The Sponsor judges that the reason is acceptable with regard to the safety of the subject 
concerned.
For details of follow-up of DILI (medical history, concomitant medications, history of 
alcohol intake and narcotic use), see Appendix 4 “Liver Safety Monitoring and Assessment.”
5.5.7
Procedure in Case of Pregnancy
If a woman is proven to be pregnant during the treatment period or within 28 days from the 
end of treatment or at early termination, the investigator should report this information to the 
sponsor/CRO in the same manner as that for an SAE. The expected date of delivery, last 
menstruation, 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 


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miscarried fetus)] and when information on newborn falls under the criteria for SAEs 
(including death, congenital anomaly, and other anomalies), 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 the miscarried fetus is evaluated by visual examination unless test results 
which 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, and the 
investigator must report the pregnancy to the sponsor/CRO.
5.5.8
Supply of New Information Affecting the Conduct of the Study
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, the Sponsor 
should inform all the investigators involved in the clinical study, the head of the study 
site, and the regulatory authorities of such information. The head of the study site who 
receives such information 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 8.2.3.3 Supply of New and Important 
Information Influencing the Subject’s Consent and Revision of the Written Information.
2.
In addition to the above item 1, when the head of the study site receives the revisions of 
the Investigator’s Brochure, protocol, or written information, information on the matters
covering the quality of the study drug, efficacy and safety, information necessary for 
conducting the clinical study properly, or documents to be examined by the IRB should 
be sent to the IRB.
5.5.9
Deviations from the Protocol and Other Actions Taken to Avoid 
Life-Threatening Risks to Subjects
The investigator must not deviate from or amend the protocol, excluding an emergency case 
for avoiding risks to the subjects. When the investigator does not follow the protocol in order 
to avoid urgent risks for subjects, the investigator should take the following actions. 


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1.
Describe the contents of the deviation or amendment and the reasons 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 site. 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. Obtain approval for a draft of the amended protocol from the IRB 
and the head of the study site as well as written approval from the Sponsor.
5.6
Test Drug Concentration
The plasma concentrations of ASP015K will be measured in the samples collected at the time 
points in Table 1 Schedule of Assessments. The concentrations of ASP015K metabolites H1, 
H2, and H4 will be measured if necessary.
In the placebo group, the concentrations of samples collected during the period of the 
administration of placebo will not be measured, but the concentration of samples collected 
after switching to ASP015K 100 mg or ASP015K 150 mg will be measured. The 
concentration of the sample collected on the day of the visit for switching will be measured 
as baseline. 
The subject registration center will provide information on study drug assignment to the 
institution performing measurements of drug concentrations.
Whether to measure the concentrations of samples from the placebo group depends on 
switching to ASP015K 100 mg or ASP015K 150 mg; thus, the subject registration center will 
provide the institution performing measurements of drug concentrations with information on 
whether subjects switched to ASP015K 100 mg or ASP015K 150 mg at Week 12. After 
obtaining information on switching, the institution performing measurements of drug 
concentrations will measure the drug concentrations of samples of subjects in the placebo 
group who switched to ASP015K 100 mg or ASP015K 150 mg.
Concentration measurements will be performed by 
 using a 
validated, established LC-MS/MS method [Test No.: 
 (ASP015K, H2), 
 (H4), 
 (H1)]. The lower limit of quantification is 0.25 ng/mL. Blood 
samples for drug concentration (2 mL/sample) will be collected into a 2 mL vacutainer tube 
containing ethylenediamine-tetra-acetic acid (K3EDTA-3K). See the written explanation of 
testing procedure enclosed in the clinical laboratory testing kit for descriptions of the 
procedure for sampling blood and storing and shipping the blood samples. The central 
laboratory (
) will not report the results of determinations to the 
investigator, sub-investigator, sponsor, or other third parties until the breaking of the 
treatment code.


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5.7
Other Measurements, Assessments, or Methods
5.7.1
Pharmacodynamic Measurements
In this study, the following will be measured as part of the pharmacodynamic evaluation: 
biomarkers of bone or cartilage metabolism and lymphocyte subsets (see Section 5.3.2.2 
Biomarkers for Efficacy and Safety Assessments).
Blood samples for biomarkers of bone or cartilage metabolism will be collected in a 2 mL
sampling tube containing EDTA-2Na, and samples for lymphocyte subsets will be collected 
in a 2 mL vacutainer tube containing EDTA-2K. See the written explanation of testing 
procedure enclosed in the clinical laboratory testing kit for descriptions of the procedure for 
sampling blood and storing and shipping the blood samples.
The central laboratory (
) will not report the results to the 
investigator, sub-investigator, sponsor, or other third parties until the breaking of the 
treatment code.
5.7.2
Purposes of Pharmacogenomics
●
Pharmacogenomics will only be performed at study centers that have approved to the 
content of the research, and only those study centers will follow the procedures described 
in Sections 5.7, 8.2, and 8.3.
●
To prepare for future research that will analyze the relationship between genes and the 
efficacy, safety, or pharmacokinetics of the test drug, blood samples will be collected 
and stored.
●
To prepare for future research that will analyze the relationship between genome and the 
efficacy or safety of the test drug, biological samples will be stored over long-term. 
Details will be described in the “Bio-Banking Procedures” prepared separately.
●
To prepare for future exploratory research on biomarkers that can predict the 
pharmacologic response [efficacy and toxicity (adverse drug reactions)] through the 
analysis of genetic information from this study or from integration of other studies using 
this test drug, biological samples will be collected and stored.
●
If a serious adverse drug reaction is observed, samples for genomic/genetic analysis will 
be collected to explore the markers related to the adverse drug reaction.
5.7.3
Handling and Storage for Samples Used for Pharmacogenomics
To prepare for future research that will analyze the relationship between genes and the 
efficacy, safety, or pharmacokinetics of the study drug, blood samples will be collected and 
stored after obtaining consent from the subject to participate in PGx research and after 
randomization of blood samples and, whenever possible, before the first dose of the study 
drug. If it is not possible to take the sample before the first dose, it should be taken by the end 
of the study. The subject’s consent to participate in the PGx research must be obtained after 
the subject has given consent to participate in the main study and by the time the blood 
sample for bio-banking is taken.


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At study centers approved to conduct PGx research, blood samples will be taken from those 
subjects participating in the main study who have given written consent for the collection and 
storage of blood samples for use in PGx research. On one occasion during the study period, 
the investigator, sub-investigator, or collaborator will collect 5 mL of peripheral blood from a 
forearm vein(s) in a storage tube and store it at the study center at 4ºC until the time of 
specimen collection. The date on which informed consent was obtained and the sampling 
date should be recorded for each subject and entered into the eCRF. The sample collection 
and shipping agency should then temporarily store the blood sample for PGx research (at 
−20ºC or −80ºC) and send it to the prolonged storage laboratory for samples used in PGx 
research. The prolonged storage laboratory for samples used in PGx research will collect the 
blood samples and store them at −80ºC until it is time to analyze them. All collected PGx 
samples will be maintained for a period of up to 15 years after database hard lock.
●
Sample anonymization: Because the specific content of the analyses to be performed in 
the PGx research has not yet been determined, the specimens will be double coded and 
anonymized. After the first code (subject identification code) has been assigned by the 
study center, the second code will be assigned by the prolonged storage laboratory for 
samples used in PGx research.
5.7.4
Disposal of Pharmacogenomics Samples
At the conclusion of the retention period, or if the prolonged storage laboratory for samples 
used in PGx research has been notified by the investigator to the effect that the subject has 
withdrawn consent for PGx research or that the sponsor has decided to dispose of the stored 
samples, the prolonged storage laboratory for samples used in PGx research should promptly 
remove the labels from the tubes holding the subject’s samples and dispose of the samples as 
appropriate. If genome/gene analysis has been performed before the end of the storage period 
or before consent is withdrawn, the data obtained through that analysis will not be destroyed.
5.7.5
Disclosure of Genetic Information
Even if PGx research is conducted in the future, the research will be exploratory, and since 
any results obtained from the gene analyses (results of gene assays, relationship between 
genes and drug response) are expected to be lacking in accuracy and definitiveness, the 
results of the gene analysis will not be disclosed.
5.8
Total Amount of Blood
The approximate total volume of blood required for tests performed at the central laboratory 
(
) during the study period is as follows:
Additionally, there will be 15 samplings for ESR at the study center, and the amount will 
differ between the centers (1 mL to 2 mL). The amount of blood required for T-SPOT 
(tuberculosis test) to be performed at the central laboratory is 10 mL.


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Subjects who are positive for hepatitis and continuing the study will require a HBV-DNA 
assay at each scheduled visit after initiation of study drug administration, and the amount of 
blood required is 5 mL per assay.
Moreover, if blood samples are required at unscheduled visits or follow-up, the amount will 
increase. If CK-MB, troponin T, and aldolase are measured as part of CPK monitoring, the 
amount of blood required is 4 mL per assessment.
Assessment
Screening
Baseline
Week
4
Week
8
Week
12
Weeks 
16, 20, 
24, 28,
32, 36,
40, 44,
48
Week 52 or 
at early 
termination
Follow
-up
Volume
of
sample 
(mL)
Hematology, 
biochemistry 
(including CRP, 
fasting lipid 
profile test)
16
16
16
16
16
144
(16 × 9)
16
16
256
Hepatitis test, 
anti-CCP 
antibody, RF
9
0
0
0
0
0
0
0
9
Hepatitis DNA 
testing*
5
0
0
0
0
0
0
0
5
Trough 
concentration
0
2
2
2
2
6 (2 × 
3)
(Weeks 
20, 28, 
40 only)
2
0
16
PD sampling
0
4
4
4
4
4 
(Week 
28 only)
4
4
28
PGx
0
5
0
0
0
0
0
0
5
Post-dose 
concentration (if 
performed)
2
2
Total
30
27
24**
22
22
154
22
20
321
*:
HBs antibody, if a subject is HBc antibody-positive and requires hepatitis DNA testing from baseline, 5 mL of the blood 
sample are required at each scheduled visit.
**: For convenience, the sampling for the assessment of post-dose concentration is summarized at Week 4.


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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 and 
the head of the study center.
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 and the head of the 
study center immediately to inform them of the discontinuation and the reason for it.


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7
STATISTICAL METHODOLOGY
A detailed elaboration of the statistical analysis will be included in a separate statistical 
analysis plan and PK analysis plan based on the opinions and advice from a medical expert 
and/or statistical advisor. After review, it will be finalized prior to unblinding.
7.1
Sample Size
A total of 510 treated patients, with 170 in each treatment group
[Rationale for the sample size]
The sample size calculation was based on ASP015K Japanese Phase IIb study 
(015K-CL-RAJ1) result and other Japanese studies for patients with RA [XELJANZ®, tablet, 
5 mg, CTD (2013)] [CIMZIA, sc, 200 mg, Syringe, CTD (2012)]. In the 015K-CL-RAJ1 
study, the primary efficacy endpoint, which was Percentage of Subjects achieving ACR20 
response at Week 12/ET, was 54.5% in the 100 mg, and 65.5% in the 150 mg. Therefore, in 
the 015K-CL-RAJ4 study, it can be assumed to achieve same magnitude of ACR20 response 
at Week 12/ET for both 100 mg and 150 mg. For ACR20 response at Week 12/ET in the 
placebo group, it was assumed 25% based on other Japanese drugs for RA.
Meanwhile, the change in mTSS at Week 28 was estimated to be 0.5 in ASP015K 150 mg 
group, considering the results of the Japanese subgroup analysis of the Oral Scan Study of 
Tofacitinib, a drug of same class and indication (5 mg group: −0.0, 10 mg group: 0.5), Study 
CDP870-041 of Cimzia (100 mg group: 1.05, 200 mg group: 0.21, 400 mg group: 0.65), and 
Study RA0006 (200 mg group: 0.44). Similarly, the change in mTSS at Week 28 was 
estimated to be 2.0 in the placebo group, considering the results of the Japanese subgroup 
analysis of the Oral Scan Study (placebo group: 1.4), Study CDP870-041 (placebo group: 
2.78), and Study RA0006 (placebo group: 2.49). The standard deviation of the change was 
also estimated and set to 4.0 based on the results reported from the same studies [Japanese 
subgroup analysis of the Oral Scan Study (placebo group: 3.15, 5 mg group: 1.09, 10 mg 
group: 1.54), Study CDP870-041 (placebo group: 5.15, 100 mg group: 2.85, 200 mg group: 
2.01, 400 mg group: 2.95), and Study RA0006 (placebo group: 5.52, 200 mg group: 1.83)].
On this assumption, the necessary sample size was calculated to enable to analyze ACR20 
using the Fisher’s exact test and the change in mTSS at Week 28 using the t-test. When a 
closed testing procedure (in Section 7.4.1.1 Primary Analysis) considering multiplicity is 
used in the primary analysis, the sample size needed to verify the hypotheses Step 1 through 
Step 3 at a 2-sided 5% significance level with 90% power is 151 subjects per group. By 
considering about 10% drop-out, this study will enroll 170 patients in each treatment group.
Moreover, from the long term safety point of view, this sample size is also needed to keep 
300 subjects for 6 month period, 100 subjects for 1 year period in both ASP015K 100 mg and 
150 mg among RAJ2/RAJ3/RAJ4 studies.


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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 at the Case Review Meeting 
based on the opinions and advice from a medical expert and/or statistical advisor.
7.2.1
Full Analysis Set (FAS)
The FAS will consist of all subjects who are randomized and receive at least one dose of the 
study drug. This will be the primary data set for efficacy analyses.
7.2.2
Per Protocol Set (PPS)
7.2.2.1
PPS for Assessing ACR and DAS at Week 12 (PPS-ACR)
The PPS-ACR includes all subjects of the FAS who meet the following criteria. PPS-ACR is 
defined based on the data up to Week 12.

Have no violation of inclusion criteria;

Do not meet any exclusion criteria possibly interfering with the efficacy evaluation;

Period of study treatment between the initiation of administration and Week 12 is 8 
weeks (56 days) or longer (those who have discontinued study treatment due to the 
lack of efficacy will be included in PPS);

Have treatment compliance of 75% or higher during the 12 weeks of study 
administration (Week 12 or at early termination before Week 12);

Have evaluable ACR20 at the end of Week 12 (Week 12 or at early termination 
before Week 12);

Have no major protocol violations after registration.
Subjects who are considered to have no impact on the efficacy evaluation at the Case Review 
Meeting will also be included in the PPS-ACR, if they are not satisfying these criteria.
7.2.2.2
PPS for the Assessment of the Inhibition of Joint Destruction at Week 28 
(PPS-MTSS)
The PPS-MTSS includes all subjects of the FAS who meet the following criteria. PPS-MTSS 
is defined based on the data up to Week 28.

Have no violation of inclusion criteria;

Do not meet any exclusion criteria possibly interfering with the efficacy evaluation;

Period of study treatment between the initiation of administration and Week 28 is 8 
weeks (56 days) or longer (those who have discontinued study treatment due to the 
lack of efficacy will be included in PPS);

Have treatment compliance of 75% or higher during the 28 weeks of study 
administration (Week 28 or at early termination before Week 28)

Have evaluable change in mTSS from baseline at the end of Week 28 (Week 28 or 
at early termination before Week 28)

Have at least 1 mTSS data at baseline and from Week 12

Have no major protocol violations after registration


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Subjects who are considered to have no impact on the efficacy evaluation at the Case Review 
Meeting will also be included in the PPS-MTSS, if they are not satisfying these criteria.
7.2.3
Safety Analysis Set (SAF)
The SAF is defined as all subjects who received at least one dose of the study drug.
7.2.4
Pharmacokinetic Analysis Set (PKAS)
The PKAS will consist of all subjects who receive at least one dose of the study drug and 
who provide samples for drug concentrations for at least one time point.
7.2.5
Pharmacodynamics Analysis Set (PDAS)
All subjects who receive at least one dose of the study drug and who provide samples for the 
determination of pharmacodynamic parameters at least one time point will be included in the 
PDAS.
7.3
Demographics and Other Baseline Characteristics
Demographics and other baseline characteristics will be summarized by treatment group 
(ASP015K 100 mg group, ASP015K 150 mg group, placebo group) for SAF. Descriptive 
statistics will include sample size, mean, standard deviation, minimum, median and 
maximum for continuous variables, and frequency and percentage for categorical variables. 
To detect a possible treatment imbalance among treatment groups, chi-squared test will be 
used to analyze categorical variables and one-way analysis of variance (ANOVA) will be 
used to analyze continuous variables. The significance level is set at 0.05.
7.4
Analysis of Efficacy
Efficacy analysis will be conducted on FAS and PPS. The interpretation of results from 
statistical tests will be based on the FAS. In the primary analysis of the primary variable, the 
purpose of using PPS is to assess the robustness of the results from the statistical tests based 
on FAS. Unless otherwise noted, analysis will performed in the treatment groups at allocation 
(ASP015K 100 mg group, ASP015K 150 mg group, placebo group) and, if necessary, in the 
treatment groups taking into consideration a switch from placebo to active treatment 
(ASP015K 100 mg group, ASP015K 150 mg group, placebo–ASP015K 100 mg group at 
Week 12, placebo–ASP015K 150 mg group at Week 12, placebo–ASP015K 100 mg group at 
Week 28, placebo–ASP015K 150 mg group at Week 28).
7.4.1
Analysis of Primary Variable
7.4.1.1
Primary Analysis
Primary analysis will be conducted on FAS. However, the assessment of joint destruction 
will be performed in subjects with at least 1 data at baseline and from Week 12.


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For ACR20 response at Week 12/ET, pairwise comparisons to placebo will be performed at 
each ASP015K dose level using Fisher's exact test in the primary analysis. For mTSS change 
from baseline at Week 28/ET, pairwise comparisons to placebo will be performed at each 
ASP015K dose level using rank analysis of covariance (ANCOVA) with treatment group 
(Placebo, ASP015K 100 mg, ASP015K 150 mg) as factor and baseline rank mTSS as 
covariate in the primary analysis.
Closed testing procedure shown below will be used for multiplicity adjustment in the primary 
analysis.
Step 1. ACR20 response at Week 12/ET: ASP015K 150 mg vs. Placebo
Step 2. ACR20 response at Week 12/ET: ASP015K 100 mg vs. Placebo
Step 3. mTSS change from baseline at Week 28/ET: ASP015K 150 mg vs. Placebo
Step 4. mTSS change from baseline at Week 28/ET: ASP015K 100 mg vs. Placebo
The null hypothesis at Step 1 will be tested at a significance level of 0.05. If it is statistically 
significant, the next step will be initiated. Otherwise, it is completion of the hypothesis test. 
These hypothesis tests continue up to Step 4 unless it is rejected.
For the missing imputation of ACR20 at Week 12/ET, Last Observation Carried Forward 
(LOCF) methodology will be used.
For subjects who discontinued at or before Week 28 or switched to receive ASP015K instead 
of placebo at Week 12 due to the lack of efficacy, mTSS at Week 28 will be extrapolated 
using linear extrapolation method based on the mTSS at baseline and early termination or 
Week 12 (before switching).
7.4.1.2
Secondary Analysis
The same analysis of the primary variable as described in Section 7.4.1.1 will be conducted 
using the PPS. A sensitivity analysis will be conducted to impute the missing data.
7.4.1.3
Subgroup Analysis
Subgroup analyses for sex, age, and other categories may be explored.
7.4.2
Analysis of Secondary Variables
For secondary efficacy endpoints, binary variables such as Percentage of subjects achieving 
ACR50 response at Week 12/ET, Percentage of subjects achieving ACR70 response at Week 
12/ET will be analyzed using Fisher’s exact test, and continuous variables, such as Change 
from baseline/Day 1 to Week 12/ET in DAS28-CRP and DAS28-ESR scores, will be 
analyzed using ANCOVA with treatment group as factor and baseline as covariate. Each 
ASP015K group will be compared with placebo group and multiplicity for the secondary 
efficacy variables will not be adjusted.


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7.5
Analysis of Safety
The following analyses will be performed in SAF. Unless otherwise noted, analyses will be 
performed in the treatment groups at allocation (ASP015K 100 mg group, ASP015K 150 mg 
group, placebo group) and, when necessary, in the treatment groups after placebo was 
switched to active treatment (ASP015K 100 mg group, ASP015K 150 mg group, placebo–
ASP015 100 mg group at Week 12, placebo–ASP015K 150 mg group at Week 12, placebo–
ASP015K 100 mg group at Week 28, and placebo–ASP015K 150 mg group at Week 28).
7.5.1
Adverse Events
AEs will be coded using the Medical Dictionary for Regulatory Activities (MedDRA). The 
incidence of AEs, SAEs, AEs leading to discontinuation, and AEs whose relationship to the 
study drugs could not be ruled out will be summarized by system organ class and preferred 
term, as well as the treatment group. The incidence of AEs by severity will also be 
summarized.
7.5.2
Laboratory Assessments
Descriptive statistics will be used to summarize clinical laboratory measurements and the 
change from baseline if quantitative, by time point. The frequency of each discrete value will 
be summarized by time point.
7.5.3
Vital Signs
Descriptive statistics will be used to summarize vital sign measurements and the 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
QT Assessment
●
Descriptive statistics will be used to summarize QT assessment (including QTc 
assessment) measurements and the change from baseline.
●
The frequency of each category of QT assessment (including QTc assessment) will be 
summarized by time point.
In addition, the relationship between quantity of QT change and concentration of ASP015K 
may be explored.
7.5.6
Body Weight
Descriptive statistics will be used to summarize measurements by time point.
7.6 Analysis of Pharmacokinetics
A detailed elaboration of the PK analysis will be included in a separate PK analysis plan. The 
trough plasma concentrations of ASP015K will be summarized by treatment group and visit. 
Exploratory population PK analysis may be performed by pooling the results obtained so far.


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7.7 Other Analyses
7.7.1
Analysis of Pharmacodynamics
Analysis will be performed in PDAS. Descriptive statistics will be used to summarize PD 
measurements and the change from baseline by time point.
7.7.2
Analysis of Pharmacogenomics
At present, the content of analysis as part of pharmacogenomic research has not been 
determined yet. The relationship between the results from genetic analyses and study data 
(clinical information such as pharmacological activity, toxicity and PK) may be explored in 
the future. The sponsor can initiate such research once a specific methodology is established. 
Prior to research, the sponsor will prepare a research plan (including procedures and timing 
of document disposal) and have appropriateness of conduct of the research reviewed and 
approved by the sponsor's ethics review committee from ethical and scientific viewpoints.
7.8 Interim Analysis (and Early Discontinuation of the Clinical Study)
Not applicable. Review of safety data and safety evaluation will be completed by an 
independent DSMB [see Section 10.1 Independent Data and Safety Monitoring Board 
(DSMB)] during the study in accordance with separate SOP.
7.9 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 and/or statistical advisor prior to treatment code breaking 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 date 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. Subjects who have no evaluable post-dose data on ACR20, ACR50, and 
ACR70 response rates will be counted as non-responders and included in the analysis at the 
end of Week 12 (Week 12 or at early termination before Week 12).
7.9.1
Handling of Schedule of Assessments of Efficacy Variables
For data after the end of study treatment, data obtained within + 2 days after the last dose is 
taken will be included in analysis.


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(1)
TJC (68 joints)/SJC (66 joints), laboratory test (CRP)
Time points defined in analysis
Reference date*
Acceptable time range
Screening**
Day −28 to Day −1
Day −28 to Day −1
Baseline
Day 1
Day 1
Week 4 to Week 48***
Day 7×x + 1
Day (7×x − 6) to Day (7×x + 8) and
before drug administration on the visit day
Week 52
Day 365
Day 358 to Day 372
End of Week 12 (Week 12 or at 
early termination before Week 12)
Day 85
Day 2 to Day 92
End of Week 28 (Week 28 or at 
early termination before Week 28)
Day 197
Day 2 to Day 204
End of treatment (Week 52 or at 
early termination)
Day 365
Day 2 to Day 372
*: Day 1 represents the first day of study treatment. The day before is expressed as Day −1.
**: PGA, SGA, subject’s assessment of pain, CRP, and ESR are not applicable.
***: Represents the reference date and acceptable time range for Week x.
(2)
Hand and foot radiography
Time points defined in analysis
Reference date*
Acceptable time range
Baseline
Day 1
Day 1 to Day 30
Week 28
Day 197
Day 160 to Day 234
Week 52
Day 365
Day 328 to Day 402
End of Week 28 (Week 28 or at 
early termination before Week 28)
Day 197
Day 48 to Day 234
End of treatment (Week 52 or at 
early termination)
Day 365
Day 48 to Day 402
*: Day 1 represents the first day of study treatment. The day before is expressed as Day −1.
(3)
PGA and SGA (VAS), subject’s assessment of pain (VAS), HAQ-DI, laboratory test 
(ESR)
Time points defined in analysis
Reference date*
Acceptable time range
Baseline
Day 1
Day 1
Week 4 to Week 48**
Day 7×x + 1
Day (7×x − 6) to Day (7×x + 8) and
before drug administration on the visit day
Week 52
Day 365
Day 358 to Day 372
End of Week 12 (Week 12 or at 
early termination before Week 12)
Day 85
Day 2 to Day 92
End of Week 28 (Week 28 or at 
early termination before Week 28)
Day 197
Day 2 to Day 204
End of treatment (Week 52 or at 
early termination) 
Day 365
Day 2 to Day 372
*: Day 1 represents the first day of study treatment. The day before is expressed as Day −1.
**: Represents the reference date and acceptable time range for Week x.


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(4)
SF-36 v2®, WPAI
Time points defined in analysis
Reference date*
Acceptable time range
Baseline
Day 1
Day 1
Week 4 to Week 28**
Day 7×x + 1
Day (7×x − 6) to Day (7×x + 8) and
before drug administration on the visit day
Week 52
Day 365
Day 358 to Day 372
End of Week 12 (Week 12 or at 
early termination before Week 12)
Day 85
Day 2 to Day 92
End of Week 28 (Week 28 or at 
early termination before Week 28)
Day 197
Day 2 to Day 204
End of treatment (Week 52 or at 
early termination)
Day 365
Day 2 to Day 372
*: Day 1 represents the first day of study treatment. The day before is expressed as Day −1.
**: Represents the reference date and acceptable time range for Week x.
7.9.2
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 is taken will be included in analysis.
(1)
Physical examination, vital signs, laboratory test (hematology, biochemistry, urinalysis)
Time points defined in analysis
Reference date*
Acceptable time range
Screening
Day −28 to Day −1
Day −28 to Day −1
Baseline
Day 1
Day 1
Week 4 to Week 48**
Day 7×x + 1
Day (7×x − 6) to Day (7×x + 8) and
before drug administration on the visit day
Week 52
Day 365
Day 358 to Day 372
End of Week 12 (Week 12 or at 
early termination before Week 12)
Day 85
Day 2 to Day 92
End of Week 28 (Week 28 or at 
early termination before Week 28)
Day 197
Day 2 to Day 204
End of treatment (Week 52 or at 
early termination)
Day 365
Day 2 to Day 372
*: Day 1 represents the first day of study treatment. The day before is expressed as Day −1.
**: Represents the reference date and acceptable time range for Week x.
(2)
Laboratory test (fasting lipid profile test)
Time points defined in analysis
Reference date*
Acceptable time range
Baseline
Day 1
Before drug administration on Day 1 and 
8 hours after the last meal
Week 12
Day 85
Day 78 to Day 92
Week 28
Day 197
Day 190 to Day 204
Week 40
Day 281
Day 274 to Day 288
Week 52
Day 365
Day 358 to Day 372
End of Week 12 (Week 12 or at 
early termination before Week 12)
Day 85
Day 2 to Day 92
End of Week 28 (Week 28 or at 
early termination before Week 28)
Day 197
Day 2 to Day 204
End of treatment (Week 52 or at 
early termination)
Day 365
Day 2 to Day 372
*: Day 1 represents the first day of study treatment.
**: Represents the reference date and acceptable time range for Week x.


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(3)
12-lead ECG
Time points defined in analysis
Reference date*
Acceptable time range
Screening
Day −28 to Day −1
Day −28 to Day −1
Week 28
Day 197
Day 190 to Day 204
Week 52
Day 365
Day 358 to Day 372
End of Week 28 (Week 28 or at 
early termination before Week 28)
Day 197
Day 2 to Day 204
End of treatment (Week 52 or at 
early termination)
Day 365
Day 2 to Day 372
*: Day 1 represents the first day of study treatment. The day before is expressed as Day −1.
(4)
Body weight
Time points defined in analysis
Reference date*
Acceptable time range
Screening
Day −28 to Day −1
Day −28 to Day −1
Week 12
Day 85
Day 78 to Day 92
Week 28
Day 197
Day 190 to Day 204
Week 40
Day 281
Day 274 to Day 288
Week 52
Day 365
Day 358 to Day 372
End of Week 12 (Week 12 or at 
early termination before Week 12)
Day 85
Day 2 to Day 92
End of Week 28 (Week 28 or at 
early termination before Week 28)
Day 197
Day 2 to Day 204
End of treatment (Week 52 or at 
early termination)
Day 365
Day 2 to Day 372
*: Day 1 represents the first day of study treatment. The day before is expressed as Day −1.
(5)
QT assessment
Time points defined in analysis
Reference date
Acceptable time range
Baseline
Day 1
Day 1
Before the initiation of treatment with the 
study drug
Week 4 or Week 8
(before study drug administration)
Day 29 or Day 57 
Before the initiation of treatment with the 
study drug on Reference date ± 7
Week 4 or Week 8
(after study drug administration)
Day 29 or Day 57
2 hours post-dose (reference time, but 
within the range of 1 hour to 4 hours 
post-dose is acceptable) on Reference 
date ± 7


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7.9.3
Handling of Schedule of Assessments of Pharmacodynamic Variables
(1)
Biomarkers and lymphocyte subsets
Time points defined in analysis
Reference date*
Acceptable time range
Baseline
Day 1
Before drug administration on Day 1
Week 4 to Week 28**
Day 7×x + 1
Day (7×x − 6) to Day (7×x + 8) and
before drug administration on the visit day
Week 52
Day 365
Day 358 to Day 372
End of Week 12 (Week 12 or at 
early termination before Week 12)
Day 85
Day 2 to Day 92
End of Week 28 (Week 28 or at 
early termination before Week 28)
Day 197
Day 2 to Day 204
End of treatment (Week 52 or at 
early termination)
Day 365
Day 2 to Day 372
*: Day 1 represents the first day of study treatment. The day before is expressed as Day −1.
**: Represents the reference date and acceptable time range for Week x.
7.9.4
Handling of Schedule of Assessments of Pharmacokinetic Variables
(1)
Trough concentration
Time points defined in analysis
Reference date*
Acceptable time range
Baseline
Day 1
Before drug administration on Day 1
Weeks 4, 8, 12, 20, 28, 40, and 
52**
Day 7×x + 1
Day (7×x − 6) to Day (7×x + 8) and 
within 19 to 29 hours between the time of 
treatment with the study drug before blood 
collection and the time of blood collection
*: Day 1 represents the first day of study treatment.
**: Represents the reference date and acceptable time range for Week x.
(2)
Post-dose concentration
Time points defined in analysis
Reference date*
Acceptable time range
Week 4 or Week 8**
Day 7×x + 1
Day (7×x − 6) to Day (7×x + 8) and 
within 1 to 4 hours between the time of 
treatment with the study drug before blood 
collection and the time of blood collection
*: Day 1 represents the first day of study treatment.
**: Represents the reference date and acceptable time range for Week x.


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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 
Electronic Data Capture (EDC) system. The investigator, sub-investigator, or collaborator 
will enter the data, in principle within 5 working days from the creation of the data (date of 
visit by the subject, date of obtaining information, etc.).
In principle, the name of AE must be entered within 5 working days of the date of confirming 
its occurrence. The name of concomitant drug/therapy must also be entered within 5 working 
days of the awareness of its use. Other information to be entered in the eCRF must be entered 
immediately on receipt.
The monitor should verify the data in the eCRFs with source documents and confirm that 
there are no inconsistencies between them.
For screening failures, the minimum demographic data (sex, birth date, and informed consent 
date) and, if reason for screening failure is to be obtained, the screening failure log (SFL) will 
be collected.
Measurements of laboratory tests, pharmacodynamic parameters, and plasma drug 
concentrations will be performed by 
. The Data Science 
Department of the sponsor will obtain the laboratory test results, pharmacodynamic 
measurements, and plasma drug concentration measurements in an electronic format from 
 at predefined intervals during the study.
The assessment of hand and foot radiography will be performed by 
. The Data 
Science Department of the sponsor will obtain the assessment results in an electronic format 
from 
, at predefined intervals during the study.
Analysis of Central ECG will be performed by 
. The Data Science 
Department of the sponsor will obtain the quality assured analysis data in an electronic 
format from 
 at predefined timing.
The central laboratory and 
will provide the sponsor with a copy of 
the complete and clean data, together with the quality control report.
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.


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The following information should be included in the source medical records:
●
Demographic data (birth date, 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
●
The results of the relevant examination (e.g., ECG charts, radiographic data, 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®, WPAI)
●
Subject questionnaire for 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 of use for previous and concomitant 
drugs
●
Type, treatment dates, and reason of 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
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 site must accept monitoring and auditing by the Sponsor or 
delegated CRO as well as inspections from the IRB/IEC and relevant regulatory authorities. 
In these instances, they must provide all study-related records, such as source documents 
(refer to 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 


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the subject's identities shall be well protected consistent with local and national 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 SOPs for data management. All study specific processes and definitions will 
be documented by Data Management. eCRF entry 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)
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 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.
Moreover, PGx research should be conducted consistent with “Ethical Guidelines for Human 
Genome/Gene Analysis Research” (Notification No. 1 issued by Ministry of Education, 
Culture, Sports, Science and Technology/Ministry of Health, Labour and Welfare 
[MHLW]/Ministry of Economy, Trade and Industry in 2004) and “Clinical Trials with 
Pharmacogenomics Analysis” (Notification from the Director of the Evaluation and 
Licensing Division, Pharmaceutical and Food Safety Bureau, MHLW, dated 30 September 
2008).
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 investigator should submit the written or revised 
informed consent form and any other written information to the sponsor to be subject to prior 
approval by IRB/IEC.
●
The investigator or other responsible personnel is responsible for explaining the nature 
and purpose of the study and 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, seal, and date the written information.


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●
Informed consent must be obtained by the time that the first observations/examinations 
before the pre-investigational period prior to the initial administration are performed.
●
The investigator or other responsible personnel must give a copy of the signed 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 the 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 investigator will retain the signed consent forms, which will be made available (for 
review only) to the study monitor and auditor on request.
8.2.3.2
Subject Information and Consent for PGx Research
The study centers with approval of the conduct of PGx research should obtain the consent to 
participate in PGx research in addition to the study entry. Prior to execution of the clinical 
study, the investigator should prepare the written informed consent form for PGx research in 
collaboration with the sponsor and revise the information whenever necessary. The written or 
revised written informed consent form and any other written information should be submitted 
to the sponsor and be subject to prior approval by the IRB.
Only subjects who have given consent for the study entry are subject to the consent for PGx 
research. Subjects can withdraw consent for PGx research only, separately from withdrawal 
of consent for the study entry. Procedures provided in Section 8.2.3.1 Subject Information 
and Consent should also be applied when obtaining consent for PGx research.
All of the remaining samples for PGx research obtained from the subject who has withdrawn 
consent for PGx research should be disposed of, except those anonymized.
The signed consent forms will be retained by the investigator and made available (for review 
only) to the study monitor and auditor upon request.
8.2.3.3
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 


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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.
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 
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
Medical information of individual subjects obtained as a result of this study is considered 
confidential, and disclosure to third parties is prohibited. Medical information of individual 
subjects 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 may use this information for the purpose 


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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 development of the 
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.
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 submitting all 
transcripts, texts of presentations, and abstracts related to the study to the sponsor at least 90 
days prior to the intended submission for publication or any other disclosure. Because such 
disclosure of study results is presupposed, it is important that the information concerning the 
invention is protected by a patent, through the preparation and submission of a patent 
application. Moreover, publication of facts and opinions summarized by the investigator is 
not restricted. 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(s) and sponsor, the manuscript can be submitted for publication.
8.3.2
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 Worksheet
●
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 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
●
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:
●
Other study documentation
●
Unused study drug(s)


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The investigator will archive all study data (e.g., subject identification code list, source 
documents, and investigator’s file) and relevant correspondence. These documents are to be 
kept on file for the appropriate term determined by local regulations (for study centers in the 
US, 2 years from the approval of NDA or termination of IND). The sponsor will archive and 
retain all documents pertaining to the study according to local regulations.
The records to be retained at the study sites are the ones listed as essential documents in 
GCP. These records shall be retained by the head of the study site 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 head of the study site will retain the essential documents that should be stored at the 
study site in an appropriate manner according to the rules of the study site concerned until the 
date defined in 1. or 2. below, whichever comes later.
1.
Approval date of marketing of the test drug (if development of the drug is stopped, until 
three years after the decision to discontinue development is notified)
2.
Until three years after discontinuation or termination of the study.
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, radiographic 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 [e.g., 
questionnaires at CPK monitoring, Herpes Zoster (singles) Worksheet] specified by the 
sponsor, 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 and collaborators, 
list of signatures and print of seals (copy), and electronic media storing the eCRF data, 
etc.
3.
Documents obtained related to the adequacy of conducting the clinical study by the head 
of the study centers and the protocol, documents obtained related to the adequacy of 
conducting the clinical study whose period exceeds one year or the adequacy of 
continuously conducting the clinical study from which information on adverse drug 


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reactions is obtained, and other documents obtained.
An agreed-upon protocol (including revisions), Investigator’s Brochure (including 
revisions), SOP for the investigator, materials and information supplied by the sponsor 
(e.g., AE report), matters reported by the investigator (revisions of the protocol, AE 
report, etc.), SOP for the IRB, the list of names of the IRB members, material or IRB 
review (including continuous deliberation), IRB review records (including continuous 
deliberation), and the review result report of the IRB (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
The documents of the Independent DSMB (minutes, SOPs, and others) shall be retained 
by the sponsor.
●
Records of PGx research samples
The study centers where the conduct of PGx research has been approved should retain the 
Subject Identification Code List and written informed consent form (including amendments) 
for PGx research for up to 15 years after the data lock point in order to comply with the 
subject's consent withdrawal of PGx research and storage of their samples.
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 
revision, either IRB/IEC/regulatory authorities’ approval or notification is required. The 
changes and revisions will become effective only after the approval of the sponsor, the 
investigator, and the IRB/IEC (if applicable), 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 site, the Sponsor will consult with the study site 
about handling the injury, based on the agreed study contract. Compensation for the 
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 site 
should provide medical treatment and other necessary measures. The Sponsor should be 
notified of the injury.
2.
When the subject claims compensation from the study site for the above study-related 
injury, or such compensation may be claimed, the study site should immediately 
communicate the fact to the Sponsor. Both parties should work together towards 
compensation settlement.


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3.
The Sponsor shall pay compensation or indemnification and bear expenses necessary for 
the settlement as provided in the clinical contract.
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 that forms part of a marketing authorization application be signed by a coordinating or 
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 sponsor prior to database lock.


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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, eCRF, and source documents. Direct access to these documents will be 
required by the auditors.


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10
STUDY ORGANIZATION
10.1 Independent Data and Safety Monitoring Board (DSMB)
An independent DSMB will be organized to review the unblinded safety data, to make a 
decision on whether to continue or stop the study, or modify the protocol with respect to the 
safety, and to provide the sponsor with recommendations. The DSMB should follow the 
procedures separately defined in details, including the frequency of meetings, blind-breaking 
and data review.
10.2 Other Evaluation Committee(s)
Not applicable.
10.3 Other Study Organization
See Attachment.


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10.4 Registration of Subjects
Investigator
or
sub-investigator
Subject registration center
Central laboratory 
assessments
Obtaining informed 
consent
Enter subject information
web
↓
Confirm inclusion/exclusion of the 
subject
Preregistration
web
Screening test
Sample submission
→
Laboratory test results 
on the day of screening 
visit
↓
Baseline:
Confirm the eligibility 
based on laboratory test 
results at screening and 
other demographics
Test results
←
↓
Enter subject information
web
Confirm inclusion/exclusion of the 
subject
Registration
Issue the drug number
(automatic allocation at Week 0)
Verify the registration 
confirmation form
Dispense the study drug
web
↓
Enter the visit status at 
Week 12 and Week 28
Register early termination
web
Automatically issue drug number at 
each scheduled visit
(Dose change of the placebo group 
only at Week 12* and Week 28**)
(Week 4 to Week 48)
Confirm drug number
Dispense the study drug
web
↓
Confirm the completion of 
Week 52
Confirm informed consent 
for extension study/register 
early termination (date of 
termination)
web
Confirmation/notification of 
eligibility to transfer to the 
extension study***
Confirm notification of 
eligibility to transfer to the 
extension study
web
*
At the Week 12 visit, TJC and SJC will be entered, and based on the results, some subjects in the placebo 
group will be switched to receiving ASP015K 100 mg or ASP015K 150 mg based on the allocation at 
baseline.
**
At the Week 28 visit, only the placebo group will be switched to receiving ASP015K 100 mg or ASP015K 
150 mg based on the allocation at baseline.
*** Only subjects who completed Week 52.


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<Subject registration center> 
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)
The investigator/sub-investigator is responsible for conducting a survey on demographics of 
the candidate subjects and obtaining their written consent. After obtaining written consent, 
the investigator/sub-investigator should make necessary entries in the case registration form 
on the web-based registration system. The subject registration center will notify the 
preregistration results to the study centers via the web-based registration system.
The investigator/sub-investigator will confirm the inclusion/exclusion criteria at baseline, and 
the investigator/sub-investigator will make the 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/sub-investigator will dispense the study drug to the subject who is 
considered “eligible” for the study registration.


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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.
Daniel A, Tuhina N, Alan J, et al. 2010 Rheumatoid arthritis classification: An American College of 
Rheumatology/European League against rhumatism collaborative initiative. Arthritis Rheum 
2010; 62:2569-2581.
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.
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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Silvia G. Priori, Arthur A.Wilde, et al. HRS/EHRA/APHRS Expert consensus statement on the
diagnosis and management of patients with inherited primary arrhythmia syndromes. Heart
Rhythm 2013: 10; 1932-1963
Reilly MC, Zbrozek AS, Dukes EM. The validity and reproducibility of a work productivity and 
activity impairment instrument. PharmacoEconomics 1993;4(5):353-65
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 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.
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.
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)
Cimzia Subcutaneous Injection 200 mg Syringe CTD, 2.7 Clinical Summary, 2.7.3 Summary of 
Clinical Efficacy, 2.7.3.2 Summary of Results of Individual Studies, 2.7.3.2.2 Comparison of 
Efficacy Results of All Studies, 2.7.3.2.2.1 Japanese Studies (1) Study CDP870-041, (2) Study 
RA0006 22-35 (2012)
Simponi®, Drug Interview Form (September 2013 Ver. 5)
Xeljanz®, Drug Interview Form (Revised July 2013 Ver. 3)
Xeljanz® Tablets, 5 mg CTD, 2.7 Clinical Summary, 2.7.3 Summary of Clinical Efficacy, 2.7.3.3 
Comparison of Results in Subpopulations, 2.7.3.3.1 Comparison of Japanese Population and 
Whole Population in Global Studies (Study No. A3921044) 123-139 (2013)
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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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2008;40:526-530. Japanese.


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12
APPENDICES
APPENDIX <1>: LIST OF PROHIBITED CONCOMITANT 
MEDICATION

Biologic DMARD (biological drugs for the treatment of RA)
Etanercept, adalimumab, golimumab, infliximab, tocilizumab, abatacept, certolizumab
pegol, rituximab, denosumab, sarilumab

Non-biologic DMARD*
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.
**: Administration of corticosteroids at doses exceeding 10 mg/day in prednisolone equivalent is prohibited. 
Intra-articular, intravenous, intramuscular, or endorectal administration is prohibited. However, suppositories for anal 
disease may be used concomitantly.

Oral morphine***
Morphine hydrochloride, morphine sulfate
***: Oral morphine in doses exceeding 30 mg/day (or equivalent amount of opioid analgesic)

CYP3A substrates with narrow therapeutic range
Dihydroergotamine, ergotamine, fentanyl, pimozide, quinidine, temsirolimus, 
disopyramide, etc.

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, 
pfreeze-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
Parameters to be 
analyzed
Hematology
Screening, Baseline, 
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 
52, at early termination, 
follow-up, unscheduled
2 mL vacutainer tube 
containing EDTA-2K
Hemoglobin, 
hematocrit, RBC, 
WBC, differential 
WBC, platelet count
Biochemistry
Screening, Baseline, 
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 
52, at early termination, 
follow-up, unscheduled
9mL vacutainer tube 
containing the 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, eGFR, 
β-D-glucan 
Biochemistry (at CPK 
monitoring)
At CPK monitoring
4 mL vacutainer tube 
containing the separating 
medium
CK-MB, troponin-T, 
aldolase
Fasting lipid profile test
Baseline, Week 12, Week 
20, Week 28, Week 40, 
Week 52, at early 
termination, follow-up, 
unscheduled
(Included among 
biochemistry tests)
Total cholesterol, LDL, 
HDL, triglycerides
Tuberculosis test
(When performed at the 
central laboratory)
Screening
10 mL vacutainer tube 
containing heparin Na
Interferon γ titer
Anti-CCP antibody, RF, 
hepatitis test
Screening
9 mL vacutainer tube 
containing the separating 
medium
Anti-CCP antibodies, 
RF, HBs antigens, HBs 
antibodies, HBc 
antibodies, and HCV 
antibodies
Hepatitis DNA test
Screening
If a subject is positive for 
HBc antibodies or HBs 
antibodies, tests should be 
performed at the 
following visits:
Baseline, 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 52, at early 
termination, follow-up, 
unscheduled
5 mL vacutainer tube 
containing the separating 
medium
HBV-DNA assay


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Urinalysis
Screening, Baseline, 
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 
52, at early termination, 
follow-up, unscheduled
For urinalysis: 10 mL 
light-blocking urine 
collection tubes
For urine microscopic 
examination: 10 mL urine 
collection tubes
pH, specific gravity, 
protein, glucose, keton 
bodies, bilirubin, occult 
blood, sediment
Pregnancy testing
Screening, Baseline, 
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 
52, at early termination, 
follow-up, unscheduled
Serum pregnancy test 
(Included among 
biochemistry tests)
Urine pregnancy test 
(In-hospital testing)
Human chorionic 
gonadotropin (hCG)
Acute phase reactants
Screening (CRP only), 
Baseline, 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 52, at early 
termination, follow-up, 
unscheduled
(Included among 
biochemistry tests)
CRP
In-hospital testing
ESR
PK
(Assessment of trough 
concentration)
Baseline, Week 4, Week 
8, Week 12, Week 20, 
Week 28, Week 40, Week 
52, at early termination
2 mL vacutainer tubes 
containing EDTA-3K
Concentration of 
ASP015K (and its 
metabolites H1, H2, 
and H4, if necessary)
Additional PK
(for post-dose 
concentration)
Week 4 or Week 8
2 mL vacutainer tubes 
containing EDTA-3K
Concentration of 
ASP015K (and its 
metabolites H1, H2, 
and H4, if necessary)
PD
Baseline, Week 4, Week 
8, Week 12, Week 28, 
Week 52, at early 
termination, follow-up, 
unscheduled
2 mL vacutainer tubes 
containing EDTA-2Na 
(MMP-3 is included 
among biochemistry 
tests.)
VEGF
MMP-3
Baseline, Week 4, Week 
8, Week 12, Week 28, 
Week 52, at early 
termination, follow-up, 
unscheduled
2 mL vacutainer tubes 
containing EDTA-2K
Lymphocyte subset
Pharmacogenomics
(Only at approved study 
centers)
After obtaining the 
subject’s consent for PGx
5 mL vacutainer tubes 
containing EDTA-2K
PGx analysis


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APPENDIX <3>: EVENTS ALWAYS CONSIDERED SERIOUS
If any of the following events occurs during the study, it should be regarded as an 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 should be regarded as SAE.
See Appendix 4 “Liver Safety Monitoring and Assessment.”


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APPENDIX <4>: LIVER SAFETY MONITORING AND ASSESSMENT
If laboratory testing for a subject enrolled in the study and receiving the study drug reveals an 
increase in serum aminotransferase (ALT, AST) > 3 × ULN or TBL > 2 × ULN, the 
investigator/sub-investigator should repeat at least 4 parameters (ALT, AST, ALP, and TBL) 
of the usual hepatic function test parameters. Retesting should 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 
laboratory regarding moderate and marked liver abnormality to inform the investigator or 
other responsible personnel and the sponsor. Subjects should be asked if they have any 
symptoms suggestive of hepatobiliary dysfunction by the investigator/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
TBL
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/sub-investigator determines that abnormal liver function results, other than 
as described above, qualify as moderate or marked abnormalities, they should conduct 
additional monitoring and follow-up.
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/sub-investigator. The 
investigator should complete the liver abnormality case report form (LA-CRF) or an 
appropriate document. Subjects with confirmed abnormal liver function test results should be 
followed as described below by the investigator/sub-investigator.


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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 an 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/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/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, direct bilirubin
Consider gastroenterology or hepatology consultations
Enter the results for any additional testing and possible etiology into the LA-CRF or an 
appropriate document.
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:


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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 for 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 <5>: 1987 ACR CRITERIA FOR THE CLASSIFICATION
OF RA
For classification purposes, a patient shall be said to have RA if he/she has satisfied at least 4 
of these 7 criteria. Criteria [1] through [4] must have been present for at least 6 weeks.
Criterion
Definition
[1]Morning stiffness
Morning stiffness in and around the joints, lasting at least 1 hour 
before maximal improvement
[2]Arthritis of 3 or more joint 
areas
At least 3 joint areas simultaneously have had soft tissue swelling 
or fluid (not bony overgrowth alone) observed by a physician. The 
14 possible areas are right or left PIP, MCP, wrist, elbow, knee, 
ankle, and MTP joints.
[3]Arthritis of hand joints
At least 1 area swollen (as defined above) in a wrist, MCP, or PIP 
joint
[4]Symmetric arthritis
Simultaneous involvement of the same joint areas (as defined in 
[2]) on both sides of the body (bilateral involvement of PIPs, 
MCPs, or MTPs is acceptable without absolute symmetry)
[5]Rheumatoid nodules
Subcutaneous nodules, over bony prominences, or extensor 
surfaces, or in juxtaarticular regions, observed by a physician
[6]Serum rheumatoid factor
Demonstration of abnormal amounts of serum rheumatoid factor by 
any method for which the result has been positive in ≤5% of 
normal control subjects
[7]Radiographic changes
Radiographic changes typical of RA on posteroanterior hand and 
wrist radiographs, which must include erosions or unequivocal 
bony decalcification localized in or most marked adjacent to the 
involved joints (osteoarthritis changes alone do not qualify)
[Armett FC et al, 1988]


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APPENDIX <6>: 2010 ACR-EULAR CLASSIFICATION CRITERIA 
FOR RA
1. If a patient has at least 1 joint with synovitis not explained by another disease and scores 
≥6 in the scoring system of 4 categories, he/she is assessed as having “definite RA.”
Joint involvementa)
1 large jointb)
0
2–10 large joints
1
1–3 small jointsc)
2
4–10 small joints
3
≥11 joints (at least 1 small joint)
5
Serology
RF8 (−) and anti-CCP antibody (−)
0
Low positive RF or low positive anti-CCP 
antibody
2
High positive RF or high positive anti-CCP 
antibody
(High: > 3 × ULN)
3
Acute phase reactants
Normal CRP and normal ESR
0
Abnormal CRP or abnormal ESR
1
Duration of symptoms
< 6 weeks
0
≥6 weeks
1
a): The distal interphalangeal joints, first CMC joints, and first MTP joints are excluded from assessment.
b): Large joints: Shoulder, elbow, hip, knee, and ankle joints
c): Small joints: PIP joints, MCP joints, 2–5 MTP joints, first IP joints, and wrist joints
[Daniel A et al, 2010]


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APPENDIX <7>: 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 <8>: CLASSIFICATION OF DISEASE 
STAGE/PROGRESSION OF RA
Stage I: Early
1.
X-rays show no evidence of bone destruction.
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 surrounding 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: End Stage
1.
Fibrous or bony ankylosis is present.
2.
Other symptoms meet criteria for Stage III.
[Steinbrocker O. 1949]
(GPF 3.03)

SAP_001.pdf: 
Phase III Study of ASP015K
−A Randomized, Double-Blind, Placebo-Controlled 
Confirmatory Study of Efficacy and Safety of ASP015K in 
Patients with Rheumatoid Arthritis (RA) Who Had an 
Inadequate Response to MTX−
ISN/Protocol 015K-CL-RAJ4
ClinicalTrials.gov Identifier: NCT02305849
Date of Statistical Analysis Plan: Version 1.0, dated 18
January 2018
Sponsor: Astellas Pharma Inc. (API)
2-5-1 Nihonbashi-Honcho, Chuo-ku, Tokyo


Sponsor: Astellas Pharma Inc.
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Page 1 of 104
STATISTICAL ANALYSIS PLAN
Final Version, dated 18-Jan 2018
Phase III Study of ASP015K
A Randomized, Double-Blind, Placebo-Controlled Confirmatory Study of Efficacy and 
Safety of ASP015K in Patients with Rheumatoid Arthritis (RA) Who Had an Inadequate 
Response to MTX
ISN: 015K-CL-RAJ4
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
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18-Jan-2018
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Page 2 of 104
Table of Contents
I.
LIST OF ABBREVIATIONS AND KEY TERMS··········································· 5
1
INTRODUCTION·················································································· 9
2
FLOW CHART AND VISIT SCHEDULE···················································· 9
FLOW CHART ······························································································ 9
TABLE 1 SCHEDULE OF ASSESSMENTS··························································10
3
STUDY OBJECTIVE(S) AND DESIGN······················································13
3.1
Study Objective(s) ············································································13
3.2
Study Design···················································································13
3.3
Randomization·················································································14
4
SAMPLE SIZE ····················································································14
5
ANALYSIS SETS ·················································································15
5.1
Full Analysis Set (FAS) ······································································15
5.2
Per Protocol Set (PPS)········································································15
5.2.1
PPS for Assessing ACR and DAS at Week 12 (PPS-ACR)························15
5.2.2
PPS for the Assessment of the Inhibition of Joint Destruction at Week 28 
(PPS-MTSS) ·············································································16
5.3
Safety Analysis Set (SAF) ···································································16
5.4
Pharmacokinetic Analysis Set (PKAS)·····················································16
5.5
Pharmacodynamic Analysis Set (PDAS)···················································16
6
ANALYSIS VARIABLES ·······································································16
6.1
Efficacy Endpoints············································································16
6.1.1
Primary Efficacy Endpoints····························································16
6.1.2
Secondary Efficacy Variables··························································18
6.2
Safety Variables···············································································21
6.3
Pharmacokinetic Variables···································································22
6.4
Pharmacodynamic Variables ································································22
6.5
Other Variables················································································22
7
STATISTICAL METHODOLOGY ···························································24
7.1
General Considerations·······································································24
7.2
Study Population ··············································································27
7.2.1
Disposition of Subjects ·································································27


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7.2.2
Demographic and Other Baseline Characteristics ···································28
7.2.3
Previous and Concomitant Medications ··············································33
7.3
Study Drugs····················································································33
7.3.1
Exposure··················································································33
7.3.2
Treatment Compliance··································································34
7.4
Analysis of Efficacy ··········································································35
7.4.1
Analysis of Primary Endpoint(s) ······················································35
7.4.2
Analysis of Secondary Endpoints ·····················································38
7.5
Analysis of Safety·············································································40
7.5.1
Adverse Events ··········································································40
7.5.2
Clinical Laboratory Evaluation ························································44
7.5.3
Vital Signs················································································48
7.5.4
Electrocardiograms (ECGs)····························································48
7.5.5
Chest radiography ·······································································49
7.5.6
Pregnancies···············································································49
7.6
Analysis of PK·················································································49
7.7
Analysis of PD·················································································49
7.8
Subgroups of Interest ·········································································50
7.9
Other Analyses ················································································51
7.10
Interim Analysis (and Early Discontinuation of the Clinical Study)····················51
7.11
Handling of Missing Data, Outliers, Visit Windows, and Other Information ·········52
7.11.1
Missing Data ·············································································52
7.11.2
Outliers ···················································································57
7.11.3
Visit Windows ···········································································57
7.11.4
Handling of Schedule of Assessments of Efficacy Variables ······················57
7.11.5
Handling of Schedule of Assessments of Safety Variables ························60
7.11.6
Handling of Schedule of Assessments of Pharmacodynamic Variables ··········63
8
DOCUMENT REVISION HISTORY·························································64
9
REFERENCES ····················································································64
10
APPENDICES ·····················································································65
10.1
Appendix 1: Overview of ACR20 response at Week 12/ET, mTSS change from 
baseline at Week 28/ET analysis····························································65
10.2
Appendix 2: Overview of Secondary Endpoints ··········································68
10.3
Appendix 3: Overview of AE analysis ·····················································76


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10.4
Appendix 4: Overview of Clinical Laboratory Evaluation, Vital Singes, and 
Electrocardiograms (ECGs) analyses·······················································78
10.5
Appendix 5: Computation of HAQ-DI Score··············································83
10.6
Appendix 6: Computation of SF-36v2® Score·············································86
10.7
Appendix 7: Computation of WPAI Scale Score··········································98
10.8
Appendix 8: AE of Special Interest·························································99
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········································································· 100
10.10
Appendix 10: Key Contributors and Approvers········································· 103


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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 Transaminase
ANCOVA
Analysis of Covariance
ANOVA
Analysis of Variance
AST
Aspartate Transaminase
ASP015K
Astellas Pharmaceuticals compound 015K
BDRM
Blinded Data Review Meeting
BMI
Body Mass Index
BUN
Blood urea nitrogen
anti-CCP antibody 
anti-cyclic citrullinated peptide antibody
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
DBP
Diastolic Blood Pressure
DILI
Drug induced liver injury
DIP
Distal interpharangeal joint
DMARD
Disease-modifying antirheumatic drug
DSMB
Data and Safety Monitoring Board
ECG
Electrocardiogram
eCRF
electronic Case Report Form
EOS
End of Study
ESR
Erythrocyte sedimentation rate
ET
Early termination
EU
European Union
EULAR
European League Against Rheumatism
FAS
Full Analysis Set
FDA
Food and Drug Administration
GCP
Good Clinical Practice
GD
Global Development
GFR
Glomerular filtration rate
GMP
Good Manufacturing Practice
γ-GTP
γ-glutamyl transpeptidase (GGT)
H
High
HAQ-DI
Health Assessment Questionnaire – Disability Index
HBc antibody
Hepatitis B core antibody
HBs antigen/antibody
Hepatitis B surface antigen/antibody
hCG
Human chorionic gonadotropin
HBV
Hepatitis B virus


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Abbreviations
Description of abbreviations
HCV
Hepatitis C virus
HDL
High-density lipoprotein
hERG
Ether-a-go-go related gene
HIV
Human immunodeficiency virus
HSA
Human serum albumin
ICH
International Conference on Harmonization
INR
International normalized ratio
IP
Interphalangeal joint
IRB
Institutional review board
ISN
International study number
IV
Intravenous
JAK
Janus kinase
L
Low
LLN 
Lower Limit of Normal
LLOQ
Lower limit of quantification
LOCF
Last observation carried forward
MCP
Metacarpophalangeal joint
MCS
Mental component score of the SF-36v2®
MDRD
Modification of diet in renal disease
MedDRA
Medical Dictionary for Regulatory Activities
MMP-3
Matrix metalloproteinase 3
MTP
Metatarsophalangeal joint
mTSS
Modified Total Sharp Score
MTX
Methotrexate
N
Normal
NCI-CTCAE
National Cancer Institute Common Terminology Criteria for Adverse Events
NDA
New drug application
NK
Natural killer
NRI
Non-responder imputation
NSAID
Non-steroidal anti-inflammatory drugs
PCS
Phisical component score of the SF-36v2®
PD
Pharmacodynamic
PD1-x
Protocol Deviation 1-x
PDAS
Pharmacodynamic Analysis Set
PGA
Physician’s Global assessment of arthritis
PGx
Pharmacogenomics
PIP
Proximal interpharangeal joint
PK
Pharmacokinetic
PKAS
Pharmacokinetics Analysis Set
PPS
Per-Protocol Set
PT
Preferred Term
PY
Patient-years
QD
Once a day
RA
Rheumatoid arthritis
RCS
Role/social component score of the SF-36v2®
RF
Rheumatoid factor
SAE
Serious adverse event
SAF
Safety Analysis Set
SAP
Statistical Analysis Plan


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Abbreviations
Description of abbreviations
SAS 
Statistical Analysis Software
SBP
Systolic Blood Pressure
SDAI
Simplified disease activity index
SF-36v2®
Short form health survey – 36 questions, version 2
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
List of Key Terms
Terms
Definition of terms
Baseline
The last non-missing measurement prior to initial dosing of study 
drug(Screening or Day1)
Study period
Period of time from the time point when written informed consent is 
obtained from the subject and the end of the final assessment/observation 
specified in the protocol.
Treatment period
Period of time from the first study drug administration for the treatment 
period to the end of Week 52 visit or the end of the withdrawal visit in case 
of withdrawal.
Follow-up period
The follow-up period will be 4 weeks (on a per-protocol basis) starting after 
the early-termination visit for withdrawn subjects and after the Week 52 
visit for subjects who completed the study but are not willing to enroll into 
the extension study. For subjects who completed the study and wish to 
enroll into the extension study, the follow-up period will last for a maximum 
of 4 weeks starting after the Week 52 visit and ending at the initiation of the 
extension study treatment.
Subject
An individual who participates in a clinical trial as a recipient of the study 
drug.
Week 12/ET
Week 12 or early termination before Week 12
Week 28/ET
Week 28 or early termination before Week 28
EOT
Week 52 or early termination before Week 52


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Discontinuation
When a subject who was enrolled in the study discontinues his/her 
participation in the study before the completion of all the protocol-specified 
items of the study. 
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 unblinding. 
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).
2
FLOW CHART AND VISIT SCHEDULE
FLOW CHART
Obtain 
informed 
consent
Screening period 
(The screening test 
period must be 
within 28 days 
prior to the 
baseline visit.)
Confirmation of 
inclusion/exclusion 
criteria
Preliminary 
registration
Baseline
Confirmation of 
inclusion/exclusion 
criteria
Enrollment & 
randomization
Treatment period: 
maximum of 52 
weeks, ranging 
from the start of 
the study treatment 
to the completion 
of 
tests/assessments 
schedule at the end 
of treatment (Week 
52 or early 
termination)
See figure below.
Entry into the 
extension study
Subjects not 
enrolling into the 
extension study will 
undergo follow-up 
observation 4 weeks 
after the end of the 
study treatment.







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Table 1 Schedule of Assessments
Visit
Initiation 
of 
Screening1)
Screening
Test 
Period
0 
W
4 
W
8 
W
12 
W
16 
W
20 
W
24 
W
28 
W
32 
W
36 
W
40 
W
44 
W
48 
W
52 
W
Early 
Termination
Follow-up2)
Unscheduled 
Visit
Visit day
−1 at latest
−28 to −1
1
29
57
85
113
141
169
197
225
253
281
309
337
365
Within 2 
days of 
withdrawal
28 days after 
Week 52 or 
early 
termination 
visit
-
Allowable range from 
specified date
±7
±7
±7
±7
±7
±7
±7
±7
±7
±7
±7
±7
±7
+2
±7
-
Informed consent
○
Inclusion/exclusion 
criteria
○
○
○
Subject registration
○
○
○
○
○
○
○
Inadequate response to 
MTX
○
○
Demographics
○
○
○
Medical history
○
○
○
Height
○
TB
○
Anti-CCP antibody, RF
○
Safety
Physical examination
○
○
○
○
○
○
○
○
○
○
○
○
○
○
○
○
○
▲
Body weight
○
○
○
○
○
○
○
▲
Vital signs
○
○
○
○
○
○
○
○
○
○
○
○
○
○
○
○
○
▲
Hepatitis examination
○
▲
Hematology3)
○
○
○
○
○
○
○
○
○
○
○
○
○
○
○
○
○
▲
Serum biochemistry3)
○
○
○
○
○
○
○
○
○
○
○
○
○
○
○
○
○
▲
Urinalysis3)
○
○
○
○
○
○
○
○
○
○
○
○
○
○
○
○
○
▲
Fasting lipid profile test
○
○
○
○
○
○
○
○
▲
Chest radiography
○
○
○
▲
▲
12-lead ECG
○
○
○
○
▲
Central ECG6)
○
○


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Visit
Initiation 
of 
Screening1)
Screening
Test 
Period
0 
W
4 
W
8 
W
12 
W
16 
W
20 
W
24 
W
28 
W
32 
W
36 
W
40 
W
44 
W
48 
W
52 
W
Early 
Termination
Follow-up2)
Unscheduled 
Visit
Visit day
−1 at latest
−28 to −1
1
29
57
85
113
141
169
197
225
253
281
309
337
365
Within 2 
days of 
withdrawal
28 days after 
Week 52 or 
early 
termination 
visit
-
Allowable range from 
specified date
±7
±7
±7
±7
±7
±7
±7
±7
±7
±7
±7
±7
±7
+2
±7
-
Pregnancy test5)
○
○
○
○
○
○
○
○
○
○
○
○
○
○
○
○
○
▲
Adverse event
○
○
○
○
○
○
○
○
○
○
○
○
○
○
○
○
▲
Efficacy
Hand and foot 
radiography
○
○
○4)
○
○
○
CRP and ESR
○
(CRP
only)
○
○
○
○
○
○
○
○
○
○
○
○
○
○
○
○
▲
TJC/SJC (68/66 joints)
○
○
○
○
○
○
○
○
○
○
○
○
○
○
○
○
○
▲
PGA (VAS), SGA 
(VAS), and subject's 
assessment of pain 
(VAS)
○
○
○
○
○
○
○
○
○
○
○
○
○
○
○
○
▲
SF-36 v2®
○
○
○
○
○
○
○
○
▲
WPAI
○
○
○
○
○
○
○
○
▲
HAQ-DI
○
○
○
○
○
○
○
○
○
○
○
○
○
○
○
○
▲
PK/PD
▲
Blood sampling for 
trough concentration 
○
○
○
○
○
○
○
○
○
Blood sampling for 
post-dose drug 
concentration
○
Blood sampling for PD
(biomarkers)
○
○
○
○
○
○
○
○
▲
Blood sampling for PD
(lymphocyte subset)
○
○
○
○
○
○
○
○
▲
Informed consent for 
PGx research (relevant 
sites only)
○


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Visit
Initiation 
of 
Screening1)
Screening
Test 
Period
0 
W
4 
W
8 
W
12 
W
16 
W
20 
W
24 
W
28 
W
32 
W
36 
W
40 
W
44 
W
48 
W
52 
W
Early 
Termination
Follow-up2)
Unscheduled 
Visit
Visit day
−1 at latest
−28 to −1
1
29
57
85
113
141
169
197
225
253
281
309
337
365
Within 2 
days of 
withdrawal
28 days after 
Week 52 or 
early 
termination 
visit
-
Allowable range from 
specified date
±7
±7
±7
±7
±7
±7
±7
±7
±7
±7
±7
±7
±7
+2
±7
-
Blood sampling for 
PGx (relevant sites 
only)
○
Study drug
Confirmation of 
remaining unused drug
○
○
○
○
○
○
○
○
○
○
○
○
○
○
Prescription
○
○
○
○
○
○
○
○
○
○
○
○
○
The symbol "○” designates mandatory items, whereas the symbol "▲” denotes the optional items to be investigated on the basis of the clinical judgment of the 
investigator/sub-investigator.
For details, see the respective sections of the protocol.
1) Subjects who have signed the informed consent will undergo evaluation of MTX response at the screening visit.
2) Follow-up will not be performed for subjects starting the extension study immediately after the Week 52 visit. 
3) For details of the test parameters, refer to Section 5.4.4.
4) At Week 12, subjects with < 20% improvement from baseline in TJC and SJC will be required to undergo radiographic examination of their hands and feet.
5) For pregnancy tests, serum samples will be used at the screening visit, and urine samples will be used at and after the baseline visit.
6) Central ECG should be performed on the same day as blood sampling for post-dose drug concentration at Week 4 or Week 8 before and after study drug 
administration.


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3
STUDY OBJECTIVE(S) AND DESIGN
3.1
Study Objective(s)
The main objective of this study is to evaluate the efficacy of ASP015K (100 and 150 
mg/day) versus placebo administered in combination with MTX in RA patients who had an 
inadequate response to MTX. The primary efficacy variables are the ACR20 response rate at 
Week 12 and suppression of joint destruction (change from baseline in mTSS) at Week 28.
This study will also investigate pharmacokinetic, pharmacodynamic, and safety profiles.
Furthermore, this study will examine the long-term efficacy and safety (52 weeks).
3.2
Study Design
This study is a multi-center, randomized, placebo-controlled, double-blind, parallel-group,
confirmatory study to evaluate the efficacy and safety of ASP015K (100 and 150 mg/day) 
administered in combination with MTX in patients with RA who had an inadequate response 
to MTX. The geographical scope of this study will be confined to Japan. MTX response is 
evaluated at the initiation of screening and then after the screening period, subjects will be 
randomly assigned at a 1:1:1 ratio to receive ASP015K 100 mg, ASP015K 150 mg, or 
placebo QD in combination with MTX. Subjects will orally receive the study drug after 
breakfast for 52 weeks. The target number of subjects is 170 patients per group.
Re-screening is allowed only in situations in which a subject underwent the screening 
procedures (i.e., scans and laboratory work) and owing to logistical circumstances, the 
allocated time window for these tests has expired. Re-screening is not permitted in cases in 
which the initial test results do not support eligibility based on inclusion and exclusion 
criteria. The subject must be classified as a screening failure at that time point. 
Based on the consideration of the ethical issues related to long-term placebo use, inadequate 
responders in the placebo group, as determined by < 20% improvement from baseline in 
tender or painful joint count (TJC) and swollen joint count (SJC), will be switched at Week 
12 to either ASP015K 100 mg or ASP015K 150 mg, and the dosage will be maintained until 
the end of treatment. In addition, subjects receiving placebo at Week 28 will be switched to 
either ASP015K 100 mg or ASP015K 150 mg, and the dosage will be maintained until the 
end of treatment. The ASP015K dose that will be started for placebo group subjects at Week 
12 or Week 28 (100 or 150 mg) will be randomly chosen at baseline. The dose will be 
switched under the blinded condition.
Subjects who complete this study will be eligible for participation in the open-label extension 
study (015K-CL-RAJ2). Subjects will make a follow-up visit after the Week 52 visit if they 
do not enroll into the extension study on the day of the Week 52 visit.
Safety data obtained from this study will be reviewed by the Independent Data and Safety 
Monitoring Board (DSMB), which will make recommendations on study continuation, 
termination, or protocol revision from the safety perspective.


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3.3
Randomization
The person responsible for assigning study drugs will randomly assign the study drugs and 
retain the treatment code under secrecy until the breaking of the treatment code. 
The Case Registration Center will assign subjects who have been found to be eligible for 
enrollment in accordance with the case registration procedures to 1 of the following groups: 
ASP015K 100 mg, ASP015K 150 mg, or placebo groups at baseline in 1:1:1 ratio. At Week 
12, subjects in the placebo group whose tender and swollen joint counts have not improved 
by 20% from baseline will be assessed as having an inadequate response, and they will be 
switched to receive either ASP015K at a dose of 100 mg or ASP015K at a dose of 150 mg. 
Subjects who are continuing to receive placebo at Week 28 will be switched to receive either 
ASP015K at a dose of 100 mg or ASP015K at a dose of 150 mg.
The dose of ASP015K (100 mg or 150 mg) to be administered to the placebo group from 
Week 12 or Week 28 is decided randomly at baseline, and study drugs must always be 
switched under double-blind conditions.
All drug numbers are assigned randomly by the Case Registration Center under blind 
conditions.
4
SAMPLE SIZE
A total of 510 treated patients, with 170 in each treatment group
[Rationale for the sample size]
The sample size calculation was based on ASP015K Japanese Phase IIb study (015K-CL-
RAJ1) result and other Japanese studies for patients with RA [XELJANZ®, tablet, 5 mg,
CTD (2013)] [CIMZIA, sc, 200 mg, Syringe, CTD (2012)]. In the 015K-CL-RAJ1 study, the 
primary efficacy endpoint, which was Percentage of Subjects achieving ACR20 response at 
Week 12/ET, was 54.5% in the 100 mg, and 65.5% in the 150 mg. Therefore, in the 015K-
CL-RAJ4 study, it can be assumed to achieve same magnitude of ACR20 response at Week 
12/ET for both 100 mg and 150 mg. For ACR20 response at Week 12/ET in the placebo 
group, it was assumed 25% based on other Japanese drugs for RA.
Meanwhile, the change in mTSS at Week 28 was estimated to be 0.5 in ASP015K 150 mg 
group, considering the results of the Japanese subgroup analysis of the Oral Scan Study of 
Tofacitinib, a drug of same class and indication (5 mg group: −0.0, 10 mg group: 0.5), Study 
CDP870-041 of Cimzia (100 mg group: 1.05, 200 mg group: 0.21, 400 mg group: 0.65), and 
Study RA0006 (200 mg group: 0.44). Similarly, the change in mTSS at Week 28 was 
estimated to be 2.0 in the placebo group, considering the results of the Japanese subgroup 
analysis of the Oral Scan Study (placebo group: 1.4), Study CDP870-041 (placebo group: 
2.78), and Study RA0006 (placebo group: 2.49). The standard deviation of the change was 
also estimated and set to 4.0 based on the results reported from the same studies [Japanese 
subgroup analysis of the Oral Scan Study (placebo group: 3.15, 5 mg group: 1.09, 10 mg 


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group: 1.54), Study CDP870-041 (placebo group: 5.15, 100 mg group: 2.85, 200 mg group: 
2.01, 400 mg group: 2.95), and Study RA0006 (placebo group: 5.52, 200 mg group: 1.83)].
On this assumption, the necessary sample size was calculated to enable to analyze ACR20 
using the Fisher’s exact test and the change in mTSS at Week 28 using the t-test. When a 
closed testing procedure (in Section 7.4.1.1 Primary Analysis) considering multiplicity is 
used in the primary analysis, the sample size needed to verify the hypotheses Step 1 through 
Step 3 at a 2-sided 5% significance level with 90% power is 151 subjects per group. By 
considering about 10% drop-out, this study will enroll 170 patients in each treatment group. 
Moreover, from the long term safety point of view, this sample size is also needed to keep 
300 subjects for 6 month period, 100 subjects for 1 year period in both ASP015K 100 mg and 
150 mg among RAJ2/RAJ3/RAJ4 studies.
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. FAS will be 
the primary data set for efficacy analyses.
5.1
Full Analysis Set (FAS)
The FAS will consist of all subjects who are randomized and receive at least one dose of the 
study drug. This will be the primary data set for efficacy analyses.
5.2
Per Protocol Set (PPS)
5.2.1
PPS for Assessing ACR and DAS at Week 12 (PPS-ACR)
The PPS-ACR includes all subjects of the FAS who meet the following criteria. PPS-ACR is 
defined based on the data up to Week 12.
●
Have no violation of inclusion criteria;
●
Do not meet any exclusion criteria possibly interfering with the efficacy evaluation;
●
Period of study treatment between the initiation of administration and Week 12 is 8 
weeks (56 days) or longer (those who have discontinued study treatment due to the 
lack of efficacy will be included in PPS);
●
Have treatment compliance of 75% or higher during the 12 weeks of study 
administration (Week 12 or at early termination before Week 12);
●
Have evaluable ACR20 at the end of Week 12 (Week 12 or at early termination 
before Week 12);
●
Have no major protocol violations after registration.
Subjects who are considered to have no impact on the efficacy evaluation at the Case Review 
Meeting will also be included in the PPS-ACR, if they are not satisfying these criteria.


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5.2.2
PPS for the Assessment of the Inhibition of Joint Destruction at Week 28 (PPS-
MTSS)
The PPS-MTSS includes all subjects of the FAS who meet the following criteria. PPS-MTSS 
is defined based on the data up to Week 28.
●
Have no violation of inclusion criteria;
●
Do not meet any exclusion criteria possibly interfering with the efficacy evaluation;
●
Period of study treatment between the initiation of administration and Week 28 is 8 
weeks (56 days) or longer (those who have discontinued study treatment due to the 
lack of efficacy will be included in PPS);
●
Have treatment compliance of 75% or higher during the 28 weeks of study 
administration (Week 28 or at early termination before Week 28)
●
Have evaluable change in mTSS from baseline at the end of Week 28 (Week 28 or 
at early termination before Week 28)
●
Have at least 1 mTSS data at baseline and from Week 12
●
Have no major protocol violations after registration
Subjects who are considered to have no impact on the efficacy evaluation at the Case Review 
Meeting will also be included in the PPS-MTSS, if they are not satisfying these criteria.
5.3
Safety Analysis Set (SAF)
The SAF is defined as all subjects who received at least one dose of the study drug.
5.4
Pharmacokinetic Analysis Set (PKAS)
The PKAS will consist of all subjects who receive at least one dose of the study drug and 
who provide samples for drug concentrations for at least one time point.
5.5
Pharmacodynamic Analysis Set (PDAS)
All subjects who receive at least one dose of the study drug and who provide samples for the 
determination of pharmacodynamic parameters at least one time point will be included in the 
PDAS.
6
ANALYSIS VARIABLES
6.1
Efficacy Endpoints
6.1.1
Primary Efficacy Endpoints
There are two primary efficacy endpoints.
●
ACR20 response rate at Week 12 or early termination (Week 12/ET)


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●
Change from baseline in mTSS at Week 28 or early termination (Week 28/ET)
(suppression of joint destruction)
Definitions
ACR20 response rate at Week 12 or early termination (Week 12/ET)
It is defined as percentage of subjects achieving ACR 20 response at Week 12/ET, 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/ET) if the subject meet ALL the following American College of Rheumatology 
(ACR) response criteria:
●
At least 20% reduction from baseline at the time point (e.g. Week 12/ET) 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/ET) 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/ET) 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)
Baseline is defined in Section 7.11.3. 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 component is regarded as 
non-responder at that component and used for ACR calculation. The handling of missing data 
in ACR components is described at Section 7.11.1.


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Non-responder: A subject will be defined as an ACR20-CRP non-responder at the time point
(e.g. Week 12/ET), if the subject does not meet the ACR20-CRP responder criteria.
Change from baseline in mTSS at Week 28 or early termination (Week 28/ET)
(suppression of joint destruction)
The severity of joint destruction in hands and feet (bone erosion and joint fissure narrowing) 
will be assessed by the third party through the mTSS method by scoring the severity of bone 
erosion and joint fissure narrowing of the target joints and calculate the total score. The target 
joints and the scoring method are described in the SOP prepared by the third party institution.
The results of the assessment will be sent to the sponsor by the third party institution.
The higher scores in mTSS represent greater damage and the positive change from baseline 
in mTSS represents unfavorable values.
6.1.2
Secondary Efficacy Variables
6.1.2.1 Categorical Variables
●
Percentage of subjects achieving ACR 20/50/70-CRP response at each analysis visit 
(except ACR20 Week 12/ET)
●
Percentage of subjects achieving ACR 20/50/70-ESR response at Week 12/ET
Note: ACR 20-ESR response is similar to definition in 6.1.1 by replacing CRP with 
ESR.
●
Percentage of subjects achieving ACR20-CRP response at Week 4 and sustaining the 
response at Weeks 8 and 12
●
Percentage of subjects achieving ACR20-CRP response at Week 8 and sustaining the 
response at Week 12
●
Percentage of subjects achieving mTSS change from baseline <= 0.5 at each analysis 
visit
●
Percentage of subjects achieving mTSS change from baseline <= 0 at each analysis visit
●
Percentage of subjects showing Clinically Relevant Radiographic Progression: CRRP
(mTSS change from baseline >= 3) at each analysis visit
●
Percentage of subjects showing Rapid Radiographic Progression: RRP (Yearly 
progression of mTSS >= 5)
Calculation DAS-CRP/ESR response:
DAS-CRP/ESR response is consist of following parameters, and calculated according to 
below description.
o
TJC (28 joints)
o
SJC (28 joints)


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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 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
Definition EULAR:
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 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
●
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.
[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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●
Percentage of subjects with a 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
●
Percentage of subjects achieving SF-36v2 of difference >= 5 at each analysis visit
6.1.2.2 Continuous Variables
Continuous efficacy variables are: 
●
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®


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o SDAI score 
o CDAI score 
o WPAI score
o mTSS
o Joint Space Narrowing Score
o Erosion Score
o Yearly progression of mTSS
Note: yearly progression will be calculated as follows.
[the final value of mTSS up to Week 52] -  [the baseline value of mTSS]
----------------------------------------------------------------------------------------------------x 365.25
[date of the final value of mTSS up to Week 52] - [date of baseline value of mTSS]
Note: if subject switched from placebo then the final value of that subject is the final 
value before switching placebo.
6.1.2.3 Time to Event Variables
o Time to the first ACR20-CRP response up to Week 12
o Time to the first ACR50-CRP response up to Week 12
o Time to the first ACR70-CRP response up to Week 12
o Time to the first occurrence of DAS28-CRP <2.6 up to Week 12
o Time to the first occurrence of SDAI score <= 3.3 up to Week 12
o Time to the first occurrence of CDAI score <= 2.8 up to Week 12
o Time to the first occurrence of ACR/EULAR score for remission up to Week 12
6.2
Safety Variables
●
AEs
●
Vital signs (body temperature, pulse rate and blood pressure in sitting position)
●
Body weight
●
Central ECG
●
12-lead ECG
●
Central electrocardiogram
●
Chest radiography
●
Laboratory assessments
Treatment emergent adverse events (TEAEs) will be defined as any adverse event that 
started or worsened in severity after initial dose of study drug through Week52 or 
Withdrawal. 
AE for the subjects who switched ASP015K 100 mg or ASP150 mg from Placebo at Week 
12 or Week 28 will be handled as follows.


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●
AE onset before the first dose of week12 study drug will be considered to be occurred at 
Placebo.
●
AE onset after the first dose of week12 study drug before the first dose of week28 study 
drug will be considered to be occurred at Placebo if the subject did not switch Placebo at 
Week 12. Else, if the subject switched ASP015K 100 mg or 150 mg at Week12, then the 
AE onset after the first dose of week12 study drug before the first dose of week28 study 
drug will be considered to be occurred at ASP015K 100 mg or 150 mg.
●
AE onset after the first dose of week28 study drug will be considered to be occurred at 
ASP015K 100 mg or 150 mg, which is switched treatment from Placebo.
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).
6.3
Pharmacokinetic Variables
Refer to PK analysis plan.
6.4
Pharmacodynamic Variables
●
Change from baseline in MMP-3 level
●
Change from baseline in vascular endothelial growth factor (VEGF) level
●
Change from baseline for following variables in lymphocyte subset assays 
●
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)
6.5
Other Variables
●
Duration of RA (years), calculated as: (Date of Baseline mTSS taken – 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). 


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●
Age at onset of RA (years), calculated as: (date of onset of RA – date of birth +1) / 
365.25. Onset Date of RA will be handled in the same way as described above.
●
Duration of exposure (days) 
Duration of exposure will be calculated in days, using the following formula:
(‘Date of Last Dose of Study Drug’* - ‘Date of First Dose of Study Drug’**) + 1
* = Max(EX1ENDT, EX2ENDT, EX3ENDT) [Study Drug and Reference Drug
Dosing-page of the CRF]
** = EX1STDT [Study Drug Dosing -page of the CRF]
●
Overall treatment compliance (during overall treatment period)
In the study, the subjects will be instructed to take 2 tablets once per day, totaling a 
daily dose of study dose. Therefore, overall 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 = 2 × number 
of days the subject was in the treatment period (the previous date of Week 52 visit [for 
completed subjects] / date of withdrawal date [for discontinued subjects] – date of 
initial dose of study drug +1), 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). 
●
Treatment compliance during the 12 weeks of study (up to Weeks 12)
Treatment compliance (%) =
[Total number of tablets actually received up to Weeks 12] 
--------------------------------------------------------------------------------------------x 100
[Total number of tablets planned to receive up to Weeks 12]
where total number of tablets planned to receive up to Weeks 12 = 2 × number of 
days the subject was during 12 weeks (the previous date of Weeks 12 visit date [for 
completed Week 12 subjects] / date of withdrawal date [for discontinued before 
Week 12 subjects] – date of initial dose of study drug +1), and total number of 
tablets actually received up to Weeks 12 will be calculated as:
(total number of tablets dispensed up to Weeks 12) – (total number of tablets 
returned up to Weeks 12) – (total number of tablets lost up to Weeks12). 
●
Treatment compliance during the 28 weeks of study (up to Weeks 28)
Treatment compliance (%) =


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[Total number of tablets actually received up to Weeks 28] 
--------------------------------------------------------------------------------------------x 100
[Total number of tablets planned to receive up to Weeks 28]
where total number of tablets planned to receive up to Weeks 28 = 2 × number of 
days the subject was during 28 weeks (the previous date of Weeks 28 visit date [for 
completed Week 28 subjects] / date of withdrawal date [for discontinued before 
Week 28 subjects] – date of initial dose of study drug +1), and total number of 
tablets actually received up to Weeks 28 will be calculated as:
(total number of tablets dispensed up to Weeks 28) – (total number of tablets 
returned up to Weeks 28) – (total number of tablets lost up to Weeks28). 
*If Weeks 28 visit date is missing but not discontinue before Day 197, then the total 
number of tablets planned to receive up to Weeks 28 = 2 × 196 (i.e. days from the 
previous date of scheduled visit at Week 28 – the date of initial dose of study drug + 
1)
●
Number of prior DMARD biologics, calculated as number of unique kinds of DMARD 
biologics prior to initial dose from following CRF page. 
[Concomitant Medication 2B -page of the CRF]
[Biologic DMARD -page of the CRF]
●
Number of prior DMARDs (including biologics), calculated as number of unique kinds 
of DMARD prior to initial dose from following CRF page. 
[Concomitant Medication 2B -page of the CRF]
[Concomitant Medication(Non-Biologic DMARD) -page of the CRF]
[Non Biologic DMARD_MTX -page of the CRF]
[Non Biologic DMARD except for MTX -page of the CRF]
[Biologic DMARD -page of the CRF]
●
MTX Dose at Baseline (mg/week) is defined as the dose which is taken during 6 days 
before “date of initial dose of study drug” up to “the initial dose of study drug”. 
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.


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●
For the definition of subgroups of interest can be referred to section 7.8.
●
Summaries based on FAS and PPS (e.g. disposition, baseline and efficacy data) will be 
presented by actual treatment groups, unless specifically stated otherwise. Safety 
analysis and other summaries based on SAF will also be presented by actual treatment 
groups.
●
Initial Randomization Set of efficacy analyses except for mTSS, erosion score, and joint 
space narrowing score are those of the efficacy data up to Week 12 and include the 
primary analysis (ACR20 at Week 12/ET) as described 7.4.1.1. This set will be analyzed 
by the initially treated groups (ASP015K 100 mg, ASP015K 150 mg, and Placebo) and 
statistical testing will be performed for ASP015K 100 mg, and 150 mg, compared with 
Placebo. In addition, statistical testing will also be conducted at Week 28/ET. 
Table 3   Initial Randomization Set 
Initial
Randomiz
ation
Arm Code
Initial
Randomization
Label
Analysis Scope 
PLACEBO
Placebo
Screening,
Week 0 to Week 12, 
Week 12/ET, Week 28/ET
100MG
100 mg
150MG
150 mg
●
Treatment Sequence Set of efficacy analyses except mTSS, erosion score, and joint 
space narrowing score are those of the efficacy data up to Week 52. Taking into 
consideration a switch from placebo to active treatment at Week 12 or Week 28, this set 
will be analyzed by following groups defined below. The four types of "Placebo to 
ASP015K xx mg at Week xx" groups are not for primary objective and are conducted 
optionally for efficacy and safety. 
Table 4   Treatment Sequence Set 
Treatment 
Sequence 
Code
Treatment 
Sequence Label
Week0- Week12
Week 12- Week 28
Week 28- Week 
52
Analysis 
Scope
SEQ1
100mg, 
ASP015K 100 mg
ASP015K 100 mg
ASP015K 100 mg
Screening, 
Week 0 to 
Week 52, EOT
SEQ2
150mg
ASP015K 150 mg
ASP015K 150 mg
ASP015K 150 mg
SEQ3
Placebo to 100mg 
at Week 12
Placebo
ASP015K 100 mg
ASP015K 100 mg
SEQ4
Placebo to 150mg 
at Week 12
Placebo
ASP015K 150 mg
ASP015K 150 mg
SEQ5
Placebo to 100mg 
at Week 28
Placebo
Placebo
ASP015K 100 mg
SEQ6
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


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○
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
●
The analyses for mTSS (Appendix1, Appendix 2), erosion score, and joint space 
narrowing score will be performed at Week 28/ET and Week 52/ET, and statistical 
testing will also be conducted at Week 28/ET, Week 52/ET , compared with Placebo.
These analyses include primary analysis (mTSS change from baseline at Week 28/ET).
●
MedDRA11.1 will be used as the coding dictionary for adverse event and medical 
history. 
●
Statistical hypothesis testing will be performed only if specified. All statistical 
comparisons of treatment groups will be versus placebo (i.e., each ASP015K treatment 
versus placebo) and will be made using two sided tests at the 0.05 significance level, 
unless stated otherwise. Multiplicity adjustment will be done in the primary analysis and 
other analysis if specified.
●
Statistical analysis including hypothesis testing for efficacy variables to compare 100 mg 
or 150 mg versus Placebo, only the data for the pairwise comparison will be used.
●
All statistical results will be presented, as appropriate, by treatment group, by treatment 
group and scheduled visit; the schedule of assessments is provided in 7.11.4. 
●
In addition, demographics and other baseline characteristics, and safety results will be 
provided for all ASP015K treatment groups combined ("ASP015K Total") and for all 
treatment groups, including placebo, combined ("Total"). Efficacy presentations will not 
contain combined treatment groups. 
●
Chi-square test is continuity corrected in all analysis.
●
Confidence interval for binary outcome is continuity corrected in all analysis.
●
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 
and displayed in the listings. As for β-D-glucan, it is used for shift-from baseline 
analysis.
●
If anti-CCP antibody (U/mL) is beyond measurement (i.e. >-500 U/ml) then Anti-CCP 
antibody is regarded as 500 U/ml, and categorized in >-500 U/ml. Also, if anti-CCP 
antibody (U/mL) is below measurement (i.e. <0.6 U/ml) then Anti-CCP antibody is 
regarded as 0.6 U/ml, and categorized in < 4.5 U/mL.


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●
CRP (mg/dL) is below measurement (i.e. <0.01 mg/dL) then CRP is regarded as 0.01 
U/ml, and used for the calculation of DAS28-CRP, etc. and categorized in <1.0 mg/dL.
●
If Rheumatoid Factor (IU/mL) is below measurement (i.e. <3 IU/mL), then Rheumatoid 
Factor is regarded as 3 IU/mL and categorized in <- 15 IU/ml.
●
Baseline for safety is defined as last non-missing value before the first dose of study 
drug for all subjects including placebo assigned subjects.
●
Baseline for efficacy is defined as value at Day1 before the first dose of study drug for 
all subjects including placebo assigned subjects.
●
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. 
●
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 imputed onset date of AE is earlier than the first date of study drug, then the onset 
date of AE is onset at the first date of study drug, because AE data in CRF is 
collected only after the first date of study drug.
7.2
Study Population
7.2.1
Disposition of Subjects
The following subject data will be summarized and presented with regard to All Subjects 
with Screening Failure Log and Case Report Form.
●
Screened
●
Screen failed
●
Randomized
The following subject data will be summarized and presented by Initial Randomization Set 
and Treatment Sequence Set:
●
Subjects randomized and dosed (same as the FAS)
●
Subjects who prematurely discontinued from the study period during overall period
●
Subjects who prematurely discontinued from the study period by 4 weeks
●
Subjects who included/excluded of FAS, PPS-ACR, PPS-MTSS, SAF, PKAS, and 
PDAS


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●
Subjects who were excluded from FAS, PPS, SAF, PKAS, and PDAS will be 
summarized by reason for exclusion.
The following analysis will be conducted for Initial Randomization Set.
●
For time-to-withdrawal from initial dose up to Day 92: Kaplan-Meier plot will be 
constructed.
Withdrawal Due to Lack of Efficacy: 
In addition to the disposition summaries, the percentage of subject withdrawal due to lack of 
efficacy as the primary reason for withdrawal will be compared (each ASP015K dose group 
versus placebo) using Fisher’s exact test, and the analysis will be based on SAF by Initial 
Randomization Set. Fisher’s exact p-values (No multiplicity adjustment) will be provided.
The following subject data will be summarized and presented by Initial Randomization Set 
and Treatment Sequence Set
●
Subjects who discontinued after starting the study period will be summarized for primary 
reason for withdrawal during overall period.
●
Subjects who discontinued after starting the study period will be summarized for primary 
reason for withdrawal by 4 weeks.
[Analysis population: FAS]
●
Subjects who applied to the improvement rate from baseline in tender/swollen joint 
count(68/66) less than 20% at Week12
7.2.2
Demographic and Other Baseline Characteristics
All demographic and other baseline characteristics (defined below) will be summarized by 
treatment group. To explore the imbalance among treatment groups, comparisons with 
respect to categorical variables (e.g., sex) will be based on chi-squared test (continuity 
corrected), and comparisons with respect to continuous variables (e.g., BMI) will be based on 
a one-way ANOVA model with fixed effect for treatment group. All analyses/summaries 
except for (7.2.2.4) will be based on the SAF, FAS, and PPS.
If the imbalance of the factors between treatment groups is found (at a two-sided 0.05
significance level) and considered to clinically affect the primary variable, an analysis 
adjusted for the factor will be performed to assess the effect of the primary variable on the 
primary analysis.
7.2.2.1 Demographics
The following demographic variables will be summarized and presented for each treatment 
group.


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Table 1. Demographic Variables and Analysis Methods
Item
Classification
Testing Method
Age (at the time of Informed 
Consent)
Measurement value
one-way ANOVA
<65, >= 65
-
Sex
Male, Female
chi-squared test
Height (cm)
Measurement value
one-way ANOVA
Body Weight[Screening] (kg)
Measurement value
one-way ANOVA
<- 40 kg,
40 kg <- 60 kg,
60 kg <- 80 kg,
> 80 kg
-
BMI [Screening]  (kg/m2)
Measurement value
one-way ANOVA
Complications
No, Yes
Previous Medications
No, Yes
Concomitant Medications
No, Yes
Concomitant DMARD except for 
MTX at Baseline
No, Yes
chi-squared test
Concomitant Steroid at Baseline*
No, Yes
chi-squared test
Prednisone dose at Baseline 
(mg/day) *
Measurement value
one-way ANOVA
None, 0 <- 5 mg/day, 
> 5 mg/day
*: Concomitant Steroid and Prednisone dose is applied for “Oral Use”.
7.2.2.2 Baseline Disease Activity
The following baseline disease activity variables will be summarized by descriptive statistics,
and imbalance between treatment groups will be considered based on a one-way ANOVA 
model with fixed effect for treatment group. 
○
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 
○
WPAI
○
SF-36V2®


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○
mTSS
○
Erosion Score
○
Joint Space Narrowing Score
○
Estimated mTSS yearly progression
Note: yearly progression from onset to baseline; baseline mTSS/ Duration of RA
(years)
In addition, following baseline efficacy categorical variables will be summarized as well.
○
Baseline mTSS (<=Median, > Median)
○
Baseline CRP ( < 1.0, >= 1.0)
○
Baseline DAS28-CRP (<= 3.2, 3.2 <- 5.1, > 5.1)
○
Baseline DAS28-ESR (<= 3.2, 3.2 <- 5.1, > 5.1)
All summaries will be provided separately for SAF, FAS and PPS.
7.2.2.3 RA History
The following RA history variables will be summarized and presented for each treatment 
group. All summaries will be provided separately for SAF, FAS and PPS.
Table 2. RA History and Analysis Methods
Item
Classification
Testing 
Method
ACR 1991 Revised Criteria for Global 
Functional Status in RA
Class I, Class II, Class 
III
chi-squared 
test
Steinbrocker Classification
Stage I, Stage II, Stage 
III, Stage IV
chi-squared 
test
Prior Surgical Procedure to Treat RA
No, Yes
chi-squared 
test
Duration of RA (years)
Measurement value
one-way 
ANOVA
<5 years, >= 5 years
-
< 1 year,
1 year -<5 years,
5 years -< 10 years,
>- 10 years
-
Onset Age of RA (years), calculated as: (onset 
date of RA – date of birth+1) / 365.25
-
one-way 
ANOVA
Anti-CCP Antibody (U/mL)
Measurement value
one-way 
ANOVA
Low-positive or 
negative (<- 3 x ULN),
High-positive (> 3 x 
-


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ULN)
< 4.5 U/mL,
4.5 -< 13.5 U/mL, 
13.5 -< 90 U/mL, 
90 -< 180 U/mL, 
180 -< 500 U/mL, 
>- 500 U/ml
-
Rheumatoid Factor (IU/ml)
Measurement value
one-way 
ANOVA
Low-positive or 
negative (<- 3 x ULN),
High-positive (> 3 x 
ULN)
-
<- 15 IU/ml, 
15 <- 45 IU/ml, 
45 <- 150 IU/ml, 
> 150 IU/ml
-
Prior MTX
Maximum Dose
Fixed Unit: mg/week
-
Reactivity
Response, Inadequate 
Response, Unknown
-
Tolerance
Intolerance, Tolerance, 
Unknown
-
MTX Dose at Baseline (mg/week)
Measurement value
one-way 
ANOVA
0 <- 8 mg/week, 
8 <- 12 mg/week, 
> 12 mg/week
0 <- 6 mg/week, 
6 <- 8 mg/week, 
8 <- 10 mg/week, 
10 <- 12 mg/week,
12 <- 16 mg/week, 
16 <- mg/week
Prior Non-Biologic 
DMARD Except for MTX
Use
Non-User, User
chi-squared 
test
Prior Anti-TNF DMARD 
Use
Use
Non-User, User
chi-squared 
test
Prior Biologic DMARD 
Use
Non-User, User
chi-squared 
test
Number of Prior DMARD Biologics
0, 1, 2, >= 3
chi-squared 
test
Number of Prior DMARDs (including biologics)
0, 1, 2, >= 3
chi-squared 
test
Prior Adalimumab
Use
Non-User, User
-
Reactivity
Response , Inadequate 
Response, Unknown
-


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Tolerance
Intolerance, Tolerance, 
Unknown
-
Prior Etanercept
Use
Non-User, User
-
Reactivity
Response, Inadequate 
Response, Unknown
-
Tolerance
Intolerance, Tolerance, 
Unknown
-
Prior Golimumab
Use
Non-User, User
-
Reactivity
Response, Inadequate 
Response, Unknown
-
Tolerance
Intolerance, Tolerance, 
Unknown
-
Prior Infliximab
Use
Non-User, User
-
Reactivity
Response, Inadequate 
Response, Unknown
-
Tolerance
Intolerance, Tolerance, 
Unknown
-
Prior Certolizumab Pegol
Use
Non-User, User
-
Reactivity
Response, Inadequate 
Response, Unknown
-
Tolerance
Intolerance, Tolerance, 
Unknown
-
Prior Abatacept
Use
Non-User, User
-
Reactivity
Response, Inadequate 
Response, Unknown
-
Tolerance
Intolerance, Tolerance, 
Unknown
-
Prior Tocilizumab
Use
Non-User, User
-
Reactivity
Response, Inadequate 
Response, Unknown
-
Tolerance
Intolerance, Tolerance, 
Unknown
-
Prior Rituximab
Use
Non-User, User
-
Reactivity
Response, Inadequate 
Response, Unknown
-
Tolerance
Intolerance, Tolerance, 
Unknown
-
Prior Denosumab
Use
Non-User, User
-
Reactivity
Response, Inadequate 
Response, Unknown
-
Tolerance
Intolerance, Tolerance, 
Unknown
-


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7.2.2.4 Medical History
Medical history will be coded using MedDRA/J (Version 11.1) and summarized. All
summaries will be provided for SAF.
7.2.3
Previous and Concomitant Medications
Previous DMARD medications will be summarized as described in 7.2.2.3.
In addition to this, previous and concomitant medications will be coded using 
WHODDE(B2) (V2011SEP) and summarized by "Non-Biologic DMARD" and "previous 
and concomitant medications except for Non-Biologic DMARD" with preferred WHO name, 
respectively from following CRF page. Concomitant medications are defined as any drug 
medications after the first dose of study drug up to the last dose date of study drug and before 
the last efficacy evaluation at Week52 or Withdrawal.
[Concomitant Medication 2B -page of the CRF]
[Concomitant Medication (Non-Biologic DMARD)]
Subjects taking the same medication multiple times will be counted once per medication.
All summaries will be provided for SAF.
7.3
Study Drugs
7.3.1
Exposure
The following information on drug exposure will be presented for each treatment group for 
the SAF and presented by overall period and treatment period up to Week 12, separetely. 
Duration of exposure will be summarized in two ways.
●
Descriptive statistics will be presented by treatment group.
●
Exposure time will be categorized according to the following categories by treatment 
group:
<Category for Treatment period up to Week 12>
○1 - < 29 days
○29 - < 57 days
○57 - < 85 days
○85 days -
< Category for  Overall Period>
○1 - < 85 days
○85 - < 197 days


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○197 - < 281 days
○281 - < 365 days
○365 days -
Counts and percentages of subjects in each of these categories will be summarized for each 
treatment group for the SAF.
7.3.2
Treatment Compliance
Overall treatment compliance, treatment compliance during the 12 weeks of study (up to 
Weeks 12), treatment compliance during the 28 weeks of study (up to Weeks 28) with the 
dosing schedule will be examined for subjects in the SAF whose total study drug count and 
first and last days of treatment are known. These analyses will be summarized in two ways 
for the SAF:
●
Descriptive statistics will be presented by Initial treatment set and 4 types of Placebo 
treated subjects.
●
Descriptive statistics up to Week 12 will be presented by Initial treatment set. Similarly, 
descriptive statistics up to Week 28 will be presented by Initial treatment set.
●
Percent compliance will be categorized according to the following categories by 
treatment group:
○<50%
○50% - <75% 
○75% - <90%
○90% - 100% or greater
●
Percent compliance up to Week 12 will be categorized according to the following 
categories by treatment group Similarly, Percent compliance up to Week 28 will be 
presented by Initial treatment set:
○<50%
○50% - <75% 
○75% - <90%
○90% - 100% or greater
For Drug Suspension and Interruption, following will be summarized.
○Experience for Drug Suspension
○Experience for Drug Interruption
○The Number of Experience for Drug Suspension per Subject
○The Number of Experience for Drug Suspension per Subject, Categorized
○
0
○
1
○
2
○
>= 3


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○The Number of Experience Drug Interruption Per Subject, Categorized
○
0
○
1
○
2
7.4
Analysis of Efficacy 
Efficacy analysis will be conducted on FAS and PPS. The interpretation of results from 
statistical tests will be based on the FAS. In the primary analysis, the purpose of using PPS is 
to assess the robustness of the results from the statistical tests based on FAS. Efficacy 
analysis up to Week 12 including primary analysis will be performed by Initial 
Randomization Set. Efficacy analysis up to Week 52 will be performed by Treatment 
Sequence Set for secondary purpose. Details for analysis groups will be described in 10.1 
Appendix1 and 10.2 Appendix2..
7.4.1
Analysis of Primary Endpoint(s)
Summary for analysis of primary endpoints are displayed at Section 10.1 Appendix 1.
7.4.1.1 Primary Analysis
Primary analysis will be conducted on FAS. However, the assessment of joint destruction 
will be performed in subjects with at least 1 data at baseline and after Week 12. Therefore, 
post-baseline values for mTSS, Erosion Score, Joint Space Narrowing Score before lower 
allowance limit of Week 12 (Day48) will not be used for the analysis (it will be displayed in 
the listing).
For ACR20-CRP response at Week 12/ET, pairwise comparisons to placebo will be 
performed at each ASP015K dose level using Fisher's exact test in the primary analysis. For 
mTSS change from baseline at Week 28/ET, pairwise comparisons to placebo will be 
performed at each ASP015K dose level using rank analysis of covariance (RANCOVA) with 
treatment group (Placebo, ASP015K 100 mg, ASP015K 150 mg) as factor and baseline rank 
mTSS as covariate in the primary analysis.
Closed testing procedure shown below will be used for multiplicity adjustment in the primary 
analysis.
Four null hypotheses will be constructed:
●
H01: ACR20-CRP response at Week 12/ET in ASP015K 150 mg is equal to that in 
placebo
●
H02: ACR20-CRP response at Week 12/ET in ASP015K 100 mg is equal to that in 
placebo
●
H03: mTSS change from baseline at Week 28/ET in ASP015K 150 mg is equal to that in 
placebo


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●
H04: mTSS change from baseline at Week 28/ET in ASP015K 100 mg is equal to that in 
placebo
The accompanying alternative hypotheses are:
●
H11: ACR20-CRP response at Week 12/ET in ASP015K 150 mg is not equal to that in 
placebo
●
H12: ACR20-CRP response at Week 12/ET in ASP015K 100 mg is not equal to that in 
placebo
●
H13: mTSS change from baseline at Week 28/ET in ASP015K 150 mg is not equal to 
that in placebo
●
H14: mTSS change from baseline at Week 28/ET in ASP015K 100 mg is not equal to 
that in placebo
Step 1. ACR20-CRP response at Week 12/ET: ASP015K 150 mg vs. Placebo
Step 2. ACR20-CRP response at Week 12/ET: ASP015K 100 mg vs. Placebo
Step 3. mTSS change from baseline at Week 28/ET: ASP015K 150 mg vs. Placebo
Step 4. mTSS change from baseline at Week 28/ET: ASP015K 100 mg vs. Placebo
The null hypothesis at Step 1 will be tested at a two-sided significance level of 0.05. 
If it is statistically significant, the next step will be initiated and implemented in the same 
manner. Otherwise, it is completion of the hypothesis test. These hypothesis tests continue up 
to Step 4 unless it is rejected.
For each comparison, only the data for two treatment groups to be compared will be used. 
For the missing imputation of ACR20-CRP at Week 12/ET, Last Observation Carried 
Forward (LOCF) methodology will be used.
For subjects who discontinued at or before Week 28 or switched to receive ASP015K instead 
of placebo at Week 12 due to the lack of efficacy, mTSS at Week 28 will be extrapolated 
using linear extrapolation method based on the mTSS at baseline and early termination or 
Week 12 (before switching).
Cumulative probability plot for the change from baseline in mTSS score at Week 28/ET will 
be created.
7.4.1.2 Sensitivity Analysis
Multiplicity adjustment is not executed for these analyses.
ACR20-CRP response at Week 12/ET
In order to assess the robustness of findings from the primary efficacy analysis, the following 
sensitivity analyses will be performed: 
●
LOCF for components and NRI for response (see Section 7.11.1. for details) 


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●
Analysis using the PPS-ACR as the analysis set with closed testing procedure
Note: The FAS will be replaced with the PPS as analysis set, to assess robustness results 
from FAS. 
●
Observed data (data as collected, no imputation)
●
Multiple Imputation, assuming Missing at Random Mechanism (see Section 7.11.1. for 
details)
●
Placebo Multiple Imputation (pMI) (see Section 7.11.1. for details)
mTSS change from baseline at Week 28/ET
In order to assess the robustness of findings from the primary efficacy analysis, the following 
sensitivity analyses will be performed: 
●
Rank Analysis of Covariance with LOCF (see Section 7.11.1. for details)
●
Rank Analysis of Covariance with Observed data (data as collected, no imputation)
●
Rank Analysis of Covariance (LEP) using the PPS-mTSS as the analysis set with closed 
testing procedure
●
Analysis of Covariance (ANCOVA) with treatment group (Placebo, ASP015K 100 mg, 
ASP015K 150 mg) and baseline mTSS as covariate. Imputation method is linear 
extrapolation. 95% confidence interval will be calculated.
●
Analysis of Covariance (ANCOVA) with treatment group (Placebo, ASP015K 100 mg, 
ASP015K 150 mg) and baseline mTSS as covariate. Imputation method is Multiple 
Imputation (see Section 7.11.1. for details).
7.4.1.3 Subgroup Analysis
In order to evaluate homogeneity of treatment effects across subjects with different 
demographic and baseline characteristics, subgroup analysis of the primary efficacy variables
will be performed, respectively. In addition, logistic regression model will be performed for 
each subgroup category and odds ratios, and 95% confidence intervals will be provided for
each subgroup. The subgroups in Section 7.8 will be analyzed. As for subgroup analysis, it is 
not executed any statistical testing. These subgroup analyses will be displayed graphically as 
Dot-and-Forest plot.
7.4.1.4 Adjustment for imbalances in demographics and other baseline characteristics
As for the variables in which imbalance is present in 7.2.2, adjusted analysis will be 
performed to evaluate the influence.
ACR20-CRP response at Week 12/ET
Logistic model with each treatment group as a factor and the variables in which imbalance is 
present as a covariate.
mTSS change from baseline at Week 28/ET


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Rank Analysis of Covariance (RANCOVA) with treatment group (Placebo, ASP015K 100 
mg, ASP015K 150 mg) and adjusted variable (if imbalance will be detected) as factor and 
baseline rank mTSS as covariate. 
7.4.1.5 Time to the first response analysis
Time to the first ACR20-CRP response analysis will be analyzed as following procedure.
This analysis will be applied during first 12 weeks of treatment period, because placebo 
treated subjects can be switched to ASP015K after Week 12.
●
Time to the first response analysis will be analyzed using KM profile plots for each 
treatment group, and log-rank test will be used for comparing each ASP015K dose group 
time-to-event profile versus placebo. This analysis will be applied up to Week 12.
●
For each subject, time to the first event (days) will be defined as the number of days 
from the date of initial dose of study drug to the date the first occurrence of the event, 
and calculated as: date of the first occurrence of the event (most recent assessment 
among each components if the assessment date is different among each components) –
date of initial dose of study drug +1. In addition to this, Cox proportional hazards model 
with a main effect for treatment group will be used comparing each ASP015K dose 
group versus placebo.
●
Subjects who complete the treatment period through Week 12 without having the event 
will be censored at one day before the dosing at Week 12 day up to Day 92, and the 
censored time will be calculated as: one day before the dosing at Week 12 up to Day 92
– date of initial dose of study drug +1.
●
In the time to response analysis, each subject will be classified as either a responder 
(event = 1 in time-to-event model) or a non-responder (event = 0 in time-to-event 
model), based on the definition in Section 6.1.1. The definition of event is the same as 
the definition of the binary response.
●
Subjects who prematurely discontinued the treatment period through Week 12 (i.e. 
before the dosing at Week 12) without having the event up to Day 92 will be censored at 
the date of early discontinuation, and the censored time will be calculated as: date of 
early discontinuation from the treatment period up to Day 92 – date of initial dose of 
study drug +1.
7.4.2
Analysis of Secondary Endpoints 
Refer to Section 10.2 Appendix 2. They include categorical, continuous, and time-to-event 
variables, with "X" indicating that the variable will be analyzed. As for secondary variables, 
no multiplicity adjustment will be done. Basically, analysis of secondary endpoints except for 
mTSS, erosion score, and joint space narrowing score will be performed by Initial 
Randomization Set and Treatment Sequence Set defined at Secrion7.1.
The secondary variables and analyses are as follows:


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<Initial Randomization Set>
●
Categorical variables at each visit (including Baseline, Weeks 4, 8, 12, 12/ET, Week 
28/ET) will be analyzed using Fisher’s exact test, as described for the primary efficacy 
variable, unless otherwise specified in Section10.2 Appendix 2. 
●
Raw value and change from baseline variables at each visit (Baseline, Weeks 4, 8, 12,
12/ET, Week 28/ET) will be analyzed using the ANCOVA model with fixed effects for 
treatment, and baseline value as a covariate. 
●
Time to the first response analysis will be analyzed similarly as described in 7.4.1.5.
o ACR50-CRP
o ACR70-CRP
o DAS28-CRP <2.6
o SDAI score <= 3.3
o CDAI score <= 2.8
o ACR/EULAR score for remission
As for DAS28-CRP < 2.6, CDAI score <= 2.8, SDAI score <= 3.3, ACR/EULAR score for 
remission, if the event is occurred at baseline, then that subject is excluded from this 
analysis.
●
Graphical analysis (including Baseline, Weeks 4, 8, 12, 12/ET, Week 28/ET).  
○ACR20/50/70-CRP will be plotted for over time. 
○The mean-standard deviation plot of actual values and changes from baseline will be 
presented for DAS28-CRP and DAS28-ESR.
○To visually explore possible relationships between ACR20-CRP and DAS28-CRP, 2-
panel line graphs of DAS28-CRP over time will be plotted for ACR20-CRP responders 
(in 1 panel) and non-responders (in another panel). Similar graphs will be provided for 
DAS28-ESR.
<Treatment Sequence Set>
●
Categorical variables at each visit (including Baseline, Weeks 4, 8, 12, 16, 20, 24, 28, 
32, 36, 40, 44, 48, 52, EOT) will be summarized as described in Section10.2 Appendix 
2. 
●
Raw value and change from baseline variables at each visit (including Baseline, Weeks 
4, 8, 12, 16, 20, 24, 28, 32, 36, 40, 44, 48, 52, EOT) will be summarized by descriptive 
statistics. 
●
Graphical analysis (including Baseline, Weeks 4, 8, 12, 16, 20, 24, 28, 32, 36, 40, 44, 48, 
52, EOT).  
○ACR20/50/70-CRP will be plotted for over time. 
○The mean-standard deviation plot of actual values and changes from baseline will be 
presented for DAS28-CRP and DAS28-ESR.
<mTSS, Erosion Score, and Joint Space Narrowing Score>


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In this analysis, mTSS, Erosion Score, and Joint Space Narrowing Score will be imputed 
using linear extrapolations as described in the primary analysis.
●
Categorical variables at each visit (including Week 28/ET, Week 52/ET) will be 
analyzed using Fisher’s exact test. 
○mTSS change from baseline >= 3
○mTSS change from baseline <= 0.5
○mTSS change from baseline <= 0
●
Yearly progression of mTSS will be analyzed
●
Percentage of subjects showing Rapid Radiographic Progression: RRP (Yearly 
progression of mTSS >= 5)
●
Raw value and change from baseline variables at each visit (including Week 28/ET, 
EOT) will be analyzed using the RANCOVA model with treatment group (Placebo, 
ASP015K 100 mg, ASP015K 150 mg) as factor and baseline rank mTSS as covariate. 
○mTSS (Week 52/ET)
○Erosion Score (Week 28/ET, Week 52/ET)
○Joint Space Narrowing Score (Week 28/ET, Week 52/ET)
●
Graphical analysis (including Week 28/ET, Week 52/ET).  
○Cumulative probability plot for the change from baseline in mTSS score, Erosion 
Score, Joint Space Narrowing Score will be presented at Week 28/ET, Week 52/ET.
○Scatter plot for mTSS score at baseline to mTSS at Week 28/ET, Week 52/ET will be 
presented.
○Scatter plot for mTSS score at baseline to mTSS change from baseline at Week 28/ET, 
Week 52/ET will be presented.
7.5
Analysis of Safety
In general, For AE Analysis up to Week 12 will be performed by Initial Randomization Set 
in SAF. AE Analysis from "Week 12 to the Last Evaluation" will be performed by Treatment 
Sequence Set in SAF. AE 100 Patient-Years analysis will be performed by Groups for 
Patient-Years. Details for analysis groups will be described in 10.3 Appendix3.
For other safety analysis except for AE up to Week 12 will be performed by Initial 
Randomization Set in SAF. For other safety analysis except for AE up to Week 52 will be 
performed by Treatment Sequence Set in SAF. Details for analysis groups will be described 
in 10.3 and 10.4.
7.5.1
Adverse Events
If an AE occurs on the same date as the initial dose date, the subject will be asked to select 
one of the following (see the eCRF page for AE): onset before initial dose of study drug, 


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onset after initial dose of study drug. Any AEs occurring after initial dose of study drug 
through the follow-up period will be considered treatment emergent.
Adverse events will be coded using the Medical Dictionary for Regulatory Activities 
(MedDRA). 
All adverse events reported during the study period will be presented in subject listings. 
Only TEAEs in the study period will be analyzed, and 2 types of analyses will be performed: 
TEAE occurrence analysis and TEAE per 100 patient-years analysis, as described below.
TEAE occurrence analysis will be displayed by whole treatment period and by the following 
period. Primarily, TEAE occurrence analysis for Week 0   to Week 12 will be conducted in 
the view of comparison with placebo.
TEAE occurrence analysis for overall treatment period will be conducted in focus for 
ASP015K dose groups.   
1. Week 0   to Week 12
2. Week 12 to Week 28
3. Week 28 to Week 52 or Later
TEAE per 100 patient-years analysis will be displayed above category, and by Week 0   to 
Week 12, and overall period.
7.5.1.1 Adverse events
The coding dictionary for this study will be MedDRA/J 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 ASP015K Total column, and PTs 
within SOC will be presented by decreasing frequency in the ASP015K Total. 
Number and percentage of subjects with TEAE in the following AE categories will be 
summarized by SOC and PT for each treatment group, ASP015K Total and Total: 
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 study drug discontinuation


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●
Number and percentage of subjects with drug related TEAE leading to study drug 
discontinuation
●
Number and percentage of subjects with serious TEAE leading to permanent 
discontinuation of study drug or reference drug
●
Number and percentage of subjects with drug related serious TEAE leading to 
permanent discontinuation of study drug or reference drug
The number and percentage of subjects with TEAEs, as classified by SOC and PT will be 
summarized for each treatment group. 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.
●
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
●
TEAEs excluding serious adverse events that equal to or Exceed a threshold of 5% in 
Any Treatment Group
●
Most common TEAEs (> 5% in any treatment group)
●
Most common serious TEAEs (> 5% in any treatment group)
●
The number and percentage of subjects with TEAEs by subgroups defined in section 7.8.


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●
The number and percentage of subjects with TEAEs of special interest. 
Following adverse events of special interest are defined in the Appendix 10.8:
○
Serious Infections
○
Malignancies
○
Herpes Zoster Related Disease (Herpes Zoster and Varicella)
○
Herpes Zoster
○
Varicella
○
Infections That Require Intravenous Anti-infectious Therapy
In addition, the subgroup analysis of Sex, Age Group, Concomitant Steroid at Baseline, and 
Predonisone Dose at Baseline 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 treatment groups, TEAEs per 100 patient-years (PYs)
will be calculated for each treatment group 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 in the treatment group / 
Total PYs in the treatment group).
For number of TEAEs for all subjects in the treatment group, 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 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. 
Patient-Year analysis will be calculated by Placebo, 100 mg, 150 mg, 100mg+150mg, 
ASP015K Total, Total.
The number of TEAEs and AEs per 100 PYs will be provided by Definition 2, for all TEAEs 
(if analyzable), by SOC and PT for each treatment group, ASP015K Total and Total. 


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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
Note: Definition will be provided in the Appendix 8.
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 

 + Z ∗


○
Lower limit of CI (TEAEs per 100 PYs) : 100 ∗exp 
log 

 −Z ∗

 
A: Number of subjects who had at least 1 incidence
T: Total PYs by 100 PYs as one unit
Z(alpha): alpha % point of standard normal distribution
alpha = 0.025
In addition, the subgroup analysis of Sex, Age Group, Concomitant Steroid at Baseline, and 
Predonisone Dose at Baseline 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
All Laboratory Tests
For clinical laboratory parameters (hematology, chemistry, urinalysis and fast lipid profile), 
raw values at each scheduled visit, change from baseline at each post-baseline visit, shift 
from baseline and shift from reference range will be summarized using descriptive statistics 
or frequency tabulation. No statistical hypothesis testing will be performed. For Fasting 
Lipids Profile, all analysis will be conducted using the measured values which are confirmed 
under fasting condition. In addition, all Lipid Profile values including non-fasting condition 
will also be summarized for descriptive statistics.


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●
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 baseline value will be 
summarized at each post-baseline visit using SI unit.
●
For categorical variables, frequencies and percentage will be displayed at each scheduled 
visit.
●
Shift-from-baseline table: Shift from baseline to highest value up to Week 12 or during 
entire period, and baseline to lowest value up to Week 12 or 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 baseline up to Week 12 or during entire 
period.
Laboratory Tests for NCI-CTC Toxicity Grading
Laboratory test results for the select laboratory tests will be graded programmatically using 
the standardized NCI-CTC toxicity grading criteria (Grade 0, 1, 2, 3, 4) specified in the 10.8
Appendix8 for this study. Shift-from-baseline to worst value up to Week 12 or during entire 
period will be provided. 
Note: AEs in this study are graded the investigator using NCI-CTAE Grade (1, 2, 3, 4, 5).
Laboratory Tests for Reference Range
Test results for the select laboratory tests in Table 3 will be summarized against the reference 
range indicated. Number and percentage for the Highest/Lowest values of each subjects 
included in pre-specified reference range for select laboratory up to Week 12 or during entire 
period, will be provided.


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Table 3. Select Laboratory Variables and Corresponding Reference Ranges
Select Laboratory 
Variable
Reference Range
Highest/Lowest
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)
< 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)
>= (Baseline-2) to <(Baseline-1) g/dL
<(Baseline-2) g/dL
Lowest
Hemoglobin (HGB)
∙
Mild to Moderate: decrease from 
baseline >=1 to <=2 g/dL,
∙
Severe: decrease from baseline >2 
to <3 g/dL or absolute value >7 
and <8 g/dL,
∙
Potentially Life Threatening: 
decrease from baseline >=3 or 
absolute value <=7 g/dL
Lowest
Creatine 
Phosphokinase 
(CPK)
> 500 to <= 2,000 U/L
> 2,000 U/L
Highest
Creatine 
Phosphokinase 
(CPK)
> 5 × Baseline
Highest
Creatine 
Phosphokinase 
(CPK)
> 2× ULN to <= 5 × ULN
> 5 × ULN to <= 10 × ULN
> 10 × ULN
Highest


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Select Laboratory 
Variable
Reference Range
Highest/Lowest
Creatinine
> 1.5 × Baseline to <= 3.0 × Baseline
> 3.0 × Baseline
Highest
Absolute Neutrophil 
Count (ANC)
>= 1,500 to < 2,000 / mm^3
>= 500 to < 1,500 / mm^3
< 500 / mm^3
Lowest
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
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.
7.5.2.1 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
            > 8xULN
Total Bilirubin
> 2xULN
ALP
> 1.5xULN


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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 by treatment group.
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.
Liver Functions Plots
A matrix scatter plot of liver function test will be plotted showing the maximum ALT, AST, 
ALP and total bilirubin during study period crossed against each other. Different dots will be 
used for randomization arm.
7.5.3
Vital Signs
Raw values and changes from baseline at each scheduled visit will be summarized using 
descriptive statistics.
7.5.4
Electrocardiograms (ECGs)
<12-lead ECG>
●
Raw values (categorical) and changes from baseline (shift from baseline) 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.
< Cetnral electrocardiogram >
QTc intervals should be calculated by followed procedure:
○
Bazett’s formula: QTc = QT/(RR/1000)1/2
○
Fridericia’s formula: QTc = QT/(RR/1000)1/3


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Change for ECG variables is defined in two ways.
○
baseline:  before the first dose of study drug
○
predose : before the Week 4 / Week 8 dose of study drug
●
Descriptive statistics of the central ECG variables (QTcF, QTcB, QT, PR, RR 
intervals,QRS and HR) and the corresponding changes from baseline by each visit and 
time of measurement will be calculated. In addition, the corresponding changes from 
pre-dose to post-dose at Week 4 / Week 8 will be calculated.
●
The QT, QTc interval variables will be summarized by the frequencies of subjects with 
following categories up to Week 12, and each time points.
○
< 300 msec
○
< 330 msec
○
< 360 msec
○
> 450 msec
○
> 480 msec
○
> 500 msec
●
The change from baseline of QT, QTc interval variables will be summarized by the 
frequencies of subjects with following categories up to Week 12, and each time points.
In addition, the corresponding changes from pre-dose to post-dose at Week 4 / Week 8 
will be calculated.
○
> 30 msec increase
○
> 60 msec increase
○
> 30 msec decrease
○
> 60 msec decrease
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
Following analysis is executed for PDAS.
Vascular Endothelial Growth Factor (VEGF), Matrix metalloproteinase 3 (MMP-3) , following 
Lymphocytes subset variables.


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○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)
●
Raw values and changes from baseline will be summarized using descriptive statistics.
7.8
Subgroups of Interest 
Primary efficacy endpoint and selected safety variables (treatment emergent adverse events) 
will be summarized by the treatment group for the subgroups defined on the basis of the 
categorized variables listed below:


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○
Sex (Male, Female)
○
Age Group (< 65 years, >= 65 years)
○
Prior Anti-TNF DMARD Use (User, Non-user)
○
Prior Biologic DMARD Use (User, Non-user)
○
Duration of RA (years) (< 5 years, >= 5 years)
○
Number of Prior DMARDs Used (0, 1, 2, >= 3)
○
Number of Prior Biologic DMARDs Used (0, 1, 2, >= 3)
○
MTX Dose (mg/week) at Baseline (0 <- 8 mg/week, 8 <- 12 mg/week, > 12
mg/week)
○
Concomitant Steroid at Baseline (No, Yes)
○
Prednisone Dose at Baseline (mg/day) (None, 0 <- 5 mg/day, > 5 mg/day)
○
Baseline DAS28-CRP (<= 3.2, 3.2 <- 5.1, > 5.1) *
○
Baseline DAS28-ESR (<= 3.2, 3.2 <- 5.1, > 5.1) *
○
Baseline mTSS (<= Median, > Median) *
○
Baseline CRP (< 1.0, >= 1.0) *
○
Baseline Anti-CCP Antibody (Low-positive or negative (<- 3 x ULN),
High-positive (> 3 x ULN)) *
○
Baseline Rheumatoid Factor (Low-positive or negative (<- 3 x ULN),
High-positive (> 3 x ULN)) *
○
mTSS at Week 28 Imputation Status (Yes, No)**
○
Body Weight (kg) at Screening (<- 40 kg, 40 kg <- 60 kg, 60 kg <- 80 kg, > 
80 kg)
*: Only applied to efficacy analysis.
**: Only applied to mTSS subgroup analysis. If mTSS at Week 28 does not exists and Week 
28/ET is linear extrapolated from previous data, or switched to receive ASP015K instead 
of placebo at Week 12 due to the lack of efficacy, those subjects are regarded as "Yes". 
If mTSS at Week 28 exists and Week 28/ET is not imputed by linear extrapolation, then 
those subjects are regarded as “No”.).
For more details refer to section 7.4.1.3, 7.5.1.3.
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 
completed by an independent DSMB during the study in accordance with separate SOP.


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7.11
Handling of Missing Data, Outliers, Visit Windows, and Other 
Information
7.11.1
Missing Data
PD variables
Values below the LLOQ will be set to 0 for calculation of descriptive statistics. As defined in 
7.11.6, Week 12/ET, Week 28/ET, EOT are analysis visit using LOCF method.
Missing Data in ACR20/50/70, DAS28
Table 4 addresses the handling of missing ACR components and ACR response in the 
inferential analyses of ACR20/50/70, DAS28, and DAS28-related variables at Week12/ET. 
Note that if subject does not have any post-baseline values, then that subject will be defined 
as an ACR20-CRP non-responder. Moreover, if subject does not have baseline values, then 
that subject will be defined as an ACR20-CRP non-responder.
For ACR20/50/70, if some of ACR components include missing, then the following handling 
will be done.
TJC-68
SJC-66
Remaining 5 
Components
ACR20/50/70
Pattern 1
Non-Responder
Any
Any
Non-Responder
Pattern 2
Any 
Non-Responder
Any
Non-Responder
Pattern 3
Any
Any
The Number of the 
Response is Less than 
3 Components.
Non-Responder
Pattern 4
Missing
Responder or Missing
The Number of the 
Response is at least 3 
Components, or 
the Number of the 
Missing is at least 3 
Components.
Missing
Pattern 5
Responder or Missing
Missing
The Number of the 
Response is at least 3 
Components, or 
the Number of the 
Missing is at least 3 
Components.
Missing
Pattern 6
Responder or Missing
Responder or Missing
The Number of the 
Missing is at least 3 
Components 
(Baseline=0 regarded 
as Non-Responder).
Missing
Pattern 7
Responder
Responder
The Number of the 
Response is at least 3 
Components.
Responder


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Table4. Imputation Methods for Missing ACR and DAS28 for Components and Response at 
Week 12/ET
Imputation 
Method
Explanation/Instruction
For use in all ACR20/50/70 analyses at Week 12/ET including primary analysis.
1
LOCF 
components
●
First LOCF all missing ACR component value(s) at Week 12 and 
then calculate ACR response as Week 12/ET. 
For use in sensitivity analysis of ACR20-CRP at Week 12/ET
2
LOCF 
components 
and NRI 
response
●
If all ACR component values are missing at Week 12 for any 
reason and therefore the ACR response is missing, the missing 
ACR response at Week 12/ET will be imputed using NRI (i.e., 
subject is a non-responder).
●
If NOT all ACR component values are missing at Week 12 for any 
reason, all missing ACR component value(s) at Week 12/ET will 
first be imputed using LOCF and then the ACR response will be 
calculated.
3
Observed
●
Data as observed (i.e., data as reported in the study database) will 
be analyzed. Missing ACR response components will remain 
missing if reported in the study database as missing. Missing ACR 
response will remain missing.
*: ACR20 at Week 12 is used for this sensitivity analysis


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Imputation 
Method
Explanation/Instruction
4
Multiple 
Imputation, 
assuming 
Missing at 
Random 
Mechanism
Multiple imputation (MI) will be conducted in the following 
procedure.
<Step1>Imputation Part
1)
Multiple Imputation for Non-Monotone Missing data
If non-monotone missing pattern exists, then those non-monotone 
missing data will be imputed by adapting Markov Chain Monte 
Carlo method, using each non-missing ACR components data up to 
Week 12. Imputation will be conducted by each ACR components 
(i.e. TJC-68, SJC-66, SGAP, SGA, PGA, HAQ-DI, CRP), and 
treatment groups, respectively. 
2)
Multiple Imputation for Monotone Missing data
Completing the imputation for non-monotone missing data, each 
ACR components (i.e. TJC-68, SJC-66, SGAP, SGA, PGA, HAQ-
DI, CRP) at Week 12 will be imputed, respectively, based on the 
regression model with treatment group (Placebo, ASP015K 100 
mg, ASP015K 150 mg) as factor and all values up to Week 12 as 
covariate. In this method, using seed as 12345, 1000 imputed 
datasets for each ACR components will be created based on SAS 
ver. 9.4 PROC MI procedure, monotone reg statement. Then, 
ACR20 response at Week 12 will be calculated with imputed 
datasets for each ACR components based on the same method 
described in Section 6.1.1.
<Step2>Analysis Part
Based on 1000 Imputed datasets created at Step1, ACR20 at Week 
12 in each treatment group will be summarized by Imputed 
datasets. Also, the difference in ACR20 at Week 12 between 
ASP015K 100 mg / 150 mg and placebo and their standard error 
will be calculated. Moreover, the log odds ratio to placebo in 
ACR20 at Week 12 and its standard error will be calculated by 
each Imputed datasets using logistic regression model with 
treatment group as factor. 
<Step3>Combine Part
In accordance with Rubin’s rule (Little and Rubin, 2002), the 1000 
estimated
ACR20 response rate in each treatment groups are combined. In 
addition, the difference between ASP015K 100 mg and placebo, 
the difference between ASP015K 150 mg and 95% confidence 
interval for the difference will be combined. Moreover, the Wald's
chi-squared test using logistic regression model with treatment 
group (Placebo, ASP015K 100 mg, ASP015K 150 mg) as factor 
will also be calculated. 


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Imputation 
Method
Explanation/Instruction
5
Placebo 
Multiple 
Imputation 
(pMI)
Placebo Multiple Imputation, assuming the statistical behavior of 
ASP015K 100 mg or 150 mg treated patients who discontinue 
becomes that of placebo-treated patients after the time of dropout will 
be conducted in the following procedure.
<Step1>Imputation Part
1)
Multiple Imputation for Non-Monotone Missing data
If non-monotone missing pattern exists, then those non-monotone 
missing data will be imputed by adapting Markov Chain Monte Carlo 
method, using each non-missing ACR components data up to Week 
12. Imputation will be conducted by each ACR components (i.e. TJC-
68, SJC-66, SGAP, SGA, PGA, HAQ-DI, CRP), and treatment 
groups, respectively. 
2)
Multiple Imputation for Monotone Missing data
Completing the imputation for non-monotone missing data, each 
ACR components (i.e. TJC-68, SJC-66, SGAP, SGA, PGA, HAQ-DI, 
CRP) at Week 12 will be imputed, respectively, based on the 
regression model using only data from the placebo group up to Week 
12. In this method, using seed as 12345, 1000 imputed datasets for 
each ACR components will be created based on SAS ver. 9.4 PROC 
MI procedure, monotone reg statement. 
Then, ACR20 response at Week 12 will be calculated with imputed 
datasets for each ACR components based on the same method 
described in Section 6.1.1.
<Step2>Analysis Part
For 1000 Imputed datasets created at Step1, ACR20 at Week 12 in 
each treatment group will be calculated. Also, the difference in 
ACR20 at Week 12 between ASP015K 100 mg / 150 mg and placebo 
and their standard error will be calculated. Moreover, the log odds 
ratio to placebo in ACR20 at Week 12 and its standard error will be 
calculated by each Imputed datasets using logistic regression model
with treatment group as factor. 
<Step3>Combine Part
In accordance with Rubin’s rule (Little and Rubin, 2002), the 1000 
estimated ACR20 response rate in each treatment groups are 
combined. In addition, the difference between ASP015K 100 mg and 
placebo, the difference between ASP015K 150 mg and 95% 
confidence interval for the difference will be combined. Moreover, 
the Wald's chi-squared test using logistic regression model with 
treatment group (Placebo, ASP015K 100 mg, ASP015K 150 mg) as 
factor will also be calculated.


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Imputation 
Method
Explanation/Instruction
For use in all DAS28 and DAS28-based analyses, unless otherwise specified in Section 10.2
Appendix 1
6
LOCF 
DAS28 
ACR 
components
●
LOCF all missing DAS28 ACR component value(s) and then 
calculate the DAS28 score.
Missing Data in mTSS
For mTSS, Erosion Score, Joint Space Narrowing Score, will be imputed by linear 
extrapolation at Week 28 evaluation (Day197) described as Week 28/ET. Namely, for 
subjects who discontinued at or before Week 28 (after Day48) or for initially placebo treated 
subjects who switched to receive ASP015K at Week 12 due to the lack of efficacy, mTSS at 
Week 28 (Day 197) will be extrapolated using linear extrapolation method based on the 
mTSS at baseline and early termination (after Day48) or Week 12 (Day85) (before 
switching). For subjects who initially treated placebo, if the subjects have the measurement 
data at Week 28 (from Day 160 to Day 234) and not switched to ASP015K yet, then that data 
will be used (No imputation will be done). For Week 52 (Day365) evaluation, described as 
Week 52/ET, the value will be extrapolated as well (at baseline and early termination (after 
Day48) or Week 12/Week 28 (before switching for placebo treated subjects). If the subjects 
have the measurement data at Week 52 (from Day 328 to Day 402) and not initially 
randomized to placebo, then that data will be used (No imputation will be done).
For use in sensitivity analysis, mTSS, Erosion Score, Joint Space Narrowing Score will be 
imputed using LOCF. Moreover, Observed analysis will also be conducted.
In addition, Multiple Imputation for sensitivity analysis will be conducted in the following 
procedure.
1) mTSS at Week 28 will be imputed based on the regression model treatment group as 
factor and all mTSS values up to Week 28 as covariate. For subjects who 
discontinued at or before Week 28 or switched to receive ASP015K instead of 
placebo at Week 12 due to the lack of efficacy, mTSS data will be applied before 
switching. In this method, using seed as 12345, 1000 Imputed datasets will be 
created based on SAS ver. 9.4 PROC MI procedure, monotone regression statement.
2) For 1000 Imputed datasets created at Step1, Analysis of Covariance (ANCOVA) 
with treatment group (Placebo, ASP015K 100 mg, ASP015K 150 mg) and as factor 
and baseline mTSS as covariate will be conducted by each Imputed datasets and the 
lsmeans difference between ASP015K each group and placebo will be put.
3) In accordance with Rubin’s rule (Little and Rubin, 2002), the 1000 estimated 
difference value and standard error are combined, and 95% confidence interval will 
be calculated. Moreover, statistical test will be conducted. 


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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 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, as defined in 7.11.5, Week 12/ET is analysis visit using LOCF method.
7.11.2
Outliers
All values will be included in the analyses.
7.11.3
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 date 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. Subjects who have no evaluable post-dose data on ACR20, ACR50, and 
ACR70 response rates will be counted as non-responders and included in the analysis at the 
end of Week 12 (Week 12 or at early termination before Week 12).
7.11.4
Handling of Schedule of Assessments of Efficacy Variables
For data after the end of study treatment, data obtained within +2 days after the last dose is 
taken will be included in analysis. Baseline for efficacy is defined as value at Day 1 before 
the first dose of study drug for all subjects including placebo assigned subjects. For Week 


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12/ET, or Week 28/ET, the values at closest date to reference date will be used. As for the
subjects who switched to receive ASP015K instead of placebo at Week 12, the last 
observation before first dose of ASP015K at Week 12 will be used for the analysis for visit 
Week 4, 8, 12, 12/ET. In addition, the subjects who switched to receive ASP015K instead of 
placebo at Week 28, the last observation before the first dose of ASP015K at Week 28 will 
be used for the analysis for visit Week 4, 8, 12, 12/ET, 28/ET. For EOT, the closest value to 
the reference date will be used regardless of the switching from placebo. 
(1)
TJC (68 joints)/SJC (66 joints), laboratory test (CRP)
Table5. Visit Window for TJC (68 joints)/SJC (66 joints), laboratory test (CRP)
Time points defined in analysis
Reference date*
Acceptable time range
Screening**
Day −28 to Day −1
Day −28 to Day −1
Baseline
Day 1
Day 1
Week 4 to Week 48***
Day 7×x + 1
Day (7×x − 6) to Day (7×x + 8) and
before drug administration on the visit day
Week 52
Day 365
Day 358 to Day 372
Week 12/ET (Week 12 or at early 
termination before Week 12)
Day 85
Day 2 to Day 92
Week 28/ET (Week 28 or at early 
termination before Week 28)
Day 197
Day 2 to Day 204
EOT (Week 52 or at early 
termination)
Day 365
Day 2 to Day 372
*: Day 1 represents the first day of study treatment. The day before is expressed as Day −1.
**: PGA, SGA, subject’s assessment of pain, and CRP are not applicable.
***: Represents the reference date and acceptable time range for Week x.
(2)
Hand and foot radiography
Table6. Visit Window for Hand and foot radiography
Time points defined in analysis
Reference date*
Acceptable time range
Baseline
Day 1
Day 1 to Day 30
Week 28
Day 197
Day 160 to Day 234
Week 52
Day 365
Day 328 to Day 402
Week 28/ET (Week 28 or at early 
termination before Week 28)
Day 197
Day 48 to Day 234
EOT (Week 52 or at early 
termination)
Day 365
Day 48 to Day 402
*: Day 1 represents the first day of study treatment. The day before is expressed as Day −1.


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(3)
PGA and SGA (VAS), subject’s assessment of pain (VAS), HAQ-DI, laboratory test 
(ESR)
Table7. Visit Window for PGA and SGA (VAS), subject’s assessment of pain (VAS), HAQ-DI, 
laboratory test (ESR)
Time points defined in analysis
Reference date*
Acceptable time range
Baseline
Day 1
Day 1
Week 4 to Week 48**
Day 7×x + 1
Day (7×x − 6) to Day (7×x + 8) and
before drug administration on the visit day
Week 52
Day 365
Day 358 to Day 372
Week 12/ET (Week 12 or at early 
termination before Week 12)
Day 85
Day 2 to Day 92
Week 28/ET (Week 28 or at early 
termination before Week 28)
Day 197
Day 2 to Day 204
EOT (Week 52 or at early 
termination) 
Day 365
Day 2 to Day 372
*: Day 1 represents the first day of study treatment. The day before is expressed as Day −1.
**: Represents the reference date and acceptable time range for Week x.
(4)
SF-36 v2®, WPAI
Table8. Visit Window for SF-36 v2®, WPAI
Time points defined in analysis
Reference date*
Acceptable time range
Baseline
Day 1
Day 1
Week 4 to Week 28**
Day 7×x + 1
Day (7×x − 6) to Day (7×x + 8) and
before drug administration on the visit day
Week 52
Day 365
Day 358 to Day 372
Week 12/ET (Week 12 or at early 
termination before Week 12)
Day 85
Day 2 to Day 92
Week 28/ET (Week 28 or at early 
termination before Week 28)
Day 197
Day 2 to Day 204
EOT (Week 52 or at early 
termination) 
Day 365
Day 2 to Day 372
*: Day 1 represents the first day of study treatment. The day before is expressed as Day −1.
**: Represents the reference date and acceptable time range for Week x.


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(5)
QT assessment
Table9. Visit Window for QT assessment
Time points defined in analysis
Reference date
Acceptable time range
Baseline
Day 1
Day 1
Before the initiation of treatment with the 
study drug
Week 4 or Week 8
(before study drug administration)
Day 29 or Day 57 
Before the initiation of treatment with the 
study drug on Reference date ± 7
Week 4 or Week 8
(after study drug administration)
Day 29 or Day 57
2 hours post-dose (reference time, but 
within the range of 1 hour to 4 hours post-
dose is acceptable) on Reference date ± 7
Minimum on Treatment up to 
Week 12
Minimum value at allowance Range (Day 
2 to Day 92) before first dose of Week 12 
study drug
Maximum on Treatment up to 
Week 12
Maximum value at allowance Range (Day 
2 to Day 92) before first dose of Week 12 
study drug
7.11.5
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 is taken will be included in analysis. Baseline for safety is defined as last non-
missing value before the first dose of study drug for all subjects including placebo assigned 
subjects. For Week 12/ET, or Week 28/ET, the values at closest date to reference date will be 
used. As for the subjects who switched to receive ASP015K instead of placebo at Week 12, 
the last observation before first dose of ASP015K at Week 12 will be used for the analysis 
for visit Week 4, 8, 12, 12/ET. In addition, the subjects who switched to receive ASP015K 
instead of placebo at Week 28, the last observation before the first dose of ASP015K at Week 
28 will be used for the analysis for visit Week 4, 8, 12, 12/ET, 28/ET. For EOT, the closest 
value to the reference date will be used regardless of the switching from placebo. 


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(1)
Vital signs, laboratory test (hematology, biochemistry, urinalysis)
Table10. Visit Window for Vital signs, laboratory test (hematology, biochemistry, urinalysis)
Time points defined in analysis
Reference date*
Acceptable time range
Screening
Day −28 to Day −1
Day −28 to Day −1
Baseline
Day 1
Day 1
Week 4 to Week 48**
Day 7×x + 1
Day (7×x − 6) to Day (7×x + 8) and
before drug administration on the visit day
Week 52
Day 365
Day 358 to Day 372
Minimum on Treatment up to 
Week 12***
Minimum value at allowance Range (Day 
2 to Day 92) before first dose of Week 12 
study drug
Maximum on Treatment up to 
Week 12***
Maximum value at allowance Range (Day 
2 to Day 92) before first dose of Week 12 
study drug
Minimum on Treatment***
Minimum value during Entire Period (No 
limitation for period)
Maximum on Treatment***
Maximum value during Entire Period (No 
limitation for period)
Week 12/ET (Week 12 or at early 
termination before Week 12)
Day 85
Day 2 to Day 92
Week 28/ET (Week 28 or at early 
termination before Week 28)
Day 197
Day 2 to Day 204
EOT (Week 52 or at early 
termination) 
Day 365
Day 2 to Day 372
*: Day 1 represents the first day of study treatment. The day before is expressed as Day −1.
**: Represents the reference date and acceptable time range for Week x.
***: Applied to laboratory test only.


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(2)
Laboratory test (fasting lipid profile test)
Table11. Visit Window for Laboratory test (fasting lipid profile test)
Time points defined in analysis
Reference date*
Acceptable time range
Baseline
Day 1
Before drug administration on Day 1 and 
8 hours after the last meal
If Baseline data is not measured at Day 1, 
then the closest day up to Day 1 after Day 
−28 will be used for Baseline.
Week 12
Day 85
Day 78 to Day 92
Week 20
Day 141
Day 134 to Day 148
Week 28
Day 197
Day 190 to Day 204
Week 40
Day 281
Day 274 to Day 288
Week 52
Day 365
Day 358 to Day 372
Minimum on Treatment up to 
Week 12
Minimum value at allowance Range (Day 
2 to Day 92) before first dose of Week 12 
study drug
Maximum on Treatment up to 
Week 12
Maximum value at allowance Range (Day 
2 to Day 92) before first dose of Week 12 
study drug
Minimum on Treatment
Minimum value during Entire Period (No 
limitation for period)
Maximum on Treatment
Maximum value during Entire Period (No 
limitation for period)
Week 12/ET (Week 12 or at early 
termination before Week 12)
Day 85
Day 2 to Day 92
Week 28/ET (Week 28 or at early 
termination before Week 28)
Day 197
Day 2 to Day 204
EOT (Week 52 or at early 
termination) 
Day 365
Day 2 to Day 372
*: Day 1 represents the first day of study treatment.
**: Represents the reference date and acceptable time range for Week x.
(3)
12-lead ECG,  Chest radiography
Table12. Visit Window for 12-lead ECG
Time points defined in analysis
Reference date*
Acceptable time range
Screening
Day −28 to Day −1
Day −28 to Day −1
Week 28
Day 197
Day 190 to Day 204
Week 52
Day 365
Day 358 to Day 372
Week 28/ET (Week 28 or at early 
termination before Week 28)
Day 197
Day 2 to Day 204
EOT (Week 52 or at early 
termination) 
Day 365
Day 2 to Day 372
*: Day 1 represents the first day of study treatment. The day before is expressed as Day −1.


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(4)
Body weight
Table13. Visit Window for Body weight
Time points defined in analysis
Reference date*
Acceptable time range
Screening
Day −28 to Day −1
Day −28 to Day −1
Week 12
Day 85
Day 78 to Day 92
Week 28
Day 197
Day 190 to Day 204
Week 40
Day 281
Day 274 to Day 288
Week 52
Day 365
Day 358 to Day 372
Week 12/ET (Week 12 or at early 
termination before Week 12)
Day 85
Day 2 to Day 92
Week 28/ET (Week 28 or at early 
termination before Week 28)
Day 197
Day 2 to Day 204
EOT (Week 52 or at early 
termination) 
Day 365
Day 2 to Day 372
*: Day 1 represents the first day of study treatment. The day before is expressed as Day −1.
7.11.6
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 is taken will be included in analysis. Baseline for safety is defined as last non-
missing value before the first dose of study drug for all subjects including placebo assigned 
subjects. For Week 12/ET, or Week 28/ET, the values at closest date to reference date will be 
used. As for the subjects who switched to receive ASP015K instead of placebo at Week 12, 
the last observation before first dose of ASP015K at Week 12 will be used for the analysis 
for visit Week 4, 8, 12, 12/ET. In addition, the subjects who switched to receive ASP015K
instead of placebo at Week 28, the last observation before the first dose of ASP015K at Week 
28 will be used for the analysis for visit Week 4, 8, 12, 12/ET, 28/ET. For EOT, the closest 
value to the reference date will be used regardless of the switching from placebo. 
Table14. Visit Window for Pharmacodynamic Variables
Time points defined in analysis
Reference date*
Acceptable time range
Baseline
Day 1
Before drug administration on Day 1
Week 4 to Week 28**
Day 7×x + 1
Within ± 7 days of the reference date and
before drug administration on the visit day
Week 52
Day 365
Day 358 to Day 372
Week 12/ET (Week 12 or at early 
termination before Week 12)
Day 85
Day 2 to Day 92
Week 28/ET (Week 28 or at early 
termination before Week 28)
Day 197
Day 2 to Day 204
EOT (Week 52 or at early 
termination) 
Day 365
Day 2 to Day 372
*: Day 1 represents the first day of study treatment. The day before is expressed as Day −1.
**: Represents the reference date and acceptable time range for Week x.


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8
DOCUMENT REVISION HISTORY 
Version
Date
Changes
Comment/rationale for change
1.00
18-Jan-2018
Final Version
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)
Xeljanz® Tablets, 5 mg CTD, 2.7 Clinical Summary, 2.7.3 Summary of Clinical Efficacy, 2.7.3.3 
Comparison of Results in Subpopulations, 2.7.3.3.1 Comparison of Japanese Population and 
Whole Population in Global Studies (Study No. A3921044) 123-139 (2013)
Cimzia Subcutaneous Injectin 200 mg Syringe CTD, 2.7 Clinical Summary, 2.7.3 Summary of 
Clinical Efficacy, 2.7.3.2 Summary of Results of Individual Studies, 2.7.3.2.2 Comparison of 
Efficacy Results of All Studies, 2.7.3.2.2.1 Japanese Studies (1) Study CDP870-041, (2) Study 
RA0006 22-35 (2012)
Reilly MC, Zbrozek AS, Dukes EM. The validity and reproducibility of a work productivity and 
activity impairment instrument. PharmacoEconomics 1993; 4(5):353-65.
Reilly Associates Health Outcomes Research, http://www.reillyassociates.net.


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10
APPENDICES
10.1
Appendix 1: Overview of ACR20 response at Week 12/ET, mTSS 
change from baseline at Week 28/ET analysis
Table 14 summarizes the analyses of the ACR20 response at Week 12/ET and mTSS change 
from baseline at Week 28/ET, with "X" indicating that the variable will be analyzed. All 
analyses will be based on the FAS, unless otherwise specified. 
Table 15. Overview of ACR20 response at Week 12/ET, mTSS change from baseline at Week 
28/ET analysis
Analysis Type
Analysis Variable
Analysis Method
Primary / Sensitivity / Subgroup  
Primary:
Pimary
ACR20-CRP
response at 
Week 12/ET
mTSS change 
from baseline 
at Week 28/ET
Primary 
X1
X2
ACR20: Fisher's exact test.
mTSS: RANCOVA, 
Cumulative probability plot
Sensitivity3 (see Sections 7.4.1.2 and 7.11.1 for further explanation)
LOCF
X2
mTSS: RANCOVA
LOCF and NRI
X
ACR20: Fisher's exact test.
Observed data
X
X2
ACR20: Fisher's exact test.
mTSS: RANCOVA
PPS as analysis set
X
X2
ACR20: Fisher's exact test
(LOCF)
mTSS: RANCOVA
Analysis of Covariance
X
mTSS: ANCOVA (LEP)
Multiple Imputation Assuming 
Missing at Random
X
X
ACR20: Fisher's exact test.
mTSS: ANCOVA
Placebo Multiple Imputation 
(pMI)
X
ACR20: Fisher's exact test.
Subgroup 4
Sex
X
X
Age Group 
X
X
ACR20: LOCF
mTSS : LEP
Prior Anti-TNF DMARD Use 
X
X
Prior Biologic DMARD Use 
X
X
Baseline mTSS (<= Median
, > Median)
X
X
Baseline DAS28-CRP (<= 3.2, 
3.2 <- 5.1, > 5.1)
X
X


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Baseline DAS28-ESR (<= 3.2, 
3.2 <- 5.1, > 5.1)
X
X
Duration of RA (years)
X
X
Number of Prior DMARDs 
Used 
X
X
Number of Prior Biologic 
DMARDs Used
X
X
MTX Dose (mg/week) at 
Baseline (0 <- 8  mg/week, 8 <-
12 mg/week, > 12 mg/week)
X
X
Concomitant Steroid at 
Baseline (No, Yes)
X
X
Prednisone Dose at Baseline 
(mg/day) (None, 0 <- 5 
mg/day, > 5 mg/day)
X
X
Baseline CRP (< 1.0, >= 1.0)
X
X
Baseline Anti-CCP Antibody 
(Low-positive or negative (<- 3 
x ULN),High-positive (> 3 x 
ULN))
X
X
Baseline Rheumatoid Factor  
(Low-positive or negative (<- 3 
x ULN),High-positive (> 3 x 
ULN))
X
X
Imputation Status at Week 28 
(Yes, No)
X
Body Weight (kg) at Screening 
(<- 40 kg, 40 kg <- 60 kg, 60 
kg <- 80 kg, > 80 kg)
X
X
Adjusted analysis
X5
X6
Only in the case of 
imbalance presented. 
Logistic regression5
RANCOVA6
Abbreviations are defined in Section I, and subgroup categories in Section 7.8
1 Based on FAS as analysis set, Fisher's exact test as statistical test, 7.11.1 Table4. 1. LOCF components will be 
used.
2 Based on FAS as analysis set, Rank Analysis of Covariance (RANCOVA) with treatment group (Placebo, 
ASP015K 100 mg, ASP015K 150 mg) as factor and baseline rank mTSS as covariate as statistical test. The value 
will be imputed using linear extrapolation method described at 7.11.1
3 For the sensitivity analysis, Multiplicity adjustment is not executed.
4 Subgroup categories are provided in Section 7.8


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5 Logistic regression model with effect for treatment group and adjusted variable (if imbalance will be detected).
6 Rank Analysis of Covariance (RANCOVA)  with treatment group (Placebo, ASP015K 100 mg, ASP015K 150 
mg) and adjusted variable (if imbalance will be detected) as factor and baseline rank mTSS as covariate 


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10.2
Appendix 2: Overview of Secondary Endpoints
Table 15 summarizes the analyses of the primary and secondary efficacy variables, with "X" indicating that the variable will be 
analyzed. All analyses will be based on the FAS, unless otherwise specified. 
Table15. Overview of Secondary Endpoints analysis
Analysis Type/Analysis Variable 1
CRP
ESR
None
Treatment Group
Analysis Method 2
Categorical Variables
1.1.1
Percentage of subjects achieving ACR20/50/70 
at each visit (Weeks 4, 8, 12, 12/ET,28/ET)
X
X
Placebo, 100mg, 150mg
●
Fisher's exact test.
●
ACR20-CRP at Week 
12/ET is not displayed in 
this analysis.
1.1.2
Percentage of subjects achieving ACR20/50/70 
at each visit (Weeks 4, 8, 12, 16, 20, 24, 28, 32, 
36, 40, 44, 48, 52, EOT)
X
100mg, 150mg, 
Placebo to 100mg at Week 12, 
Placebo to 150mg at Week 12, 
Placebo to 100mg at Week 28, 
Placebo to 150mg at Week 28
No statistical test
1.2.1
Line graph of 1.1.1
X
X
Placebo, 100mg, 150mg
No statistical test
1.2.2
Line graph of 1.1.2
X
100mg, 150mg, 
Placebo to 100mg at Week 12, 
Placebo to 150mg at Week 12, 
Placebo to 100mg at Week 28, 
Placebo to 150mg at Week 28
No statistical test.
2.1
Percentage of subjects achieving ACR20 
response at Week 4 and sustaining response at 
each visit (Week 8, 12)
X
Placebo, 100mg, 150mg
Fisher's exact test.
2.2
Percentage of subjects achieving ACR20 
response at Week 8 and sustaining response at 
Week 12
X
Placebo, 100mg, 150mg
Fisher's exact test.
3.1
Percentage of subjects achieving DAS28 score <
2.6 at each visit (Baseline, Week 4, 8, 12, 12/ET, 
28/ET)
X
X
Placebo, 100mg, 150mg
Fisher's exact test.
3.2
Percentage of subjects achieving DAS28 score < 
2.6 at each visit (Baseline, Weeks 4, 8, 12, 16, 
20, 24, 28, 32, 36, 40, 44, 48, 52, EOT)
X
X
100mg, 150mg, 
Placebo to 100mg at Week 12, 
Placebo to 150mg at Week 12, 
Placebo to 100mg at Week 28, 
Placebo to 150mg at Week 28
No statistical test.
3.3
Percentage of subjects achieving DAS28 score 
X
X
Placebo, 100mg, 150mg
Fisher's exact test.


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<=3.2 at each analysis visit
3.4
Percentage of subjects achieving DAS28 score 
<=3.2 at each analysis visit
X
X
100mg, 150mg
No statistical test.
4.1
Percentage of subjects achieving "Good 
Response" using DAS28 EULAR response 
criterion at each visit (Baseline, Week 4, 8, 12, 
12/ET,28/ET)
X
X
Placebo, 100mg, 150mg
Fisher's exact test.
4.2
Percentage of subjects achieving "Good 
Response" using DAS28 EULAR response 
criterion at each visit (Baseline, Weeks 4, 8, 12, 
16, 20, 24, 28, 32, 36, 40, 44, 48, 52, EOT)
X
X
100mg, 150mg
No statistical test.
5.1
Percentage of subjects achieving "Good 
Response" or "Moderate Response" using 
DAS28 EULAR response criterion at each visit 
(Baseline, Week 4, 8, 12, 12/ET,28/ET)
X
X
Placebo, 100mg, 150mg
Fisher's exact test.
5.2
Percentage of subjects achieving "Good 
Response" or "Moderate Response" using 
DAS28 EULAR response criterion at each visit 
(Baseline, Weeks 4, 8, 12, 16, 20, 24, 28, 32, 36, 
40, 44, 48, 52, EOT)
X
X
100mg, 150mg
No statistical test.
6.1
Percentage of subjects in ACR/EULAR 
remission at each visit (Baseline, Week 4, 8, 12, 
12/ET,28/ET)
X
Placebo, 100mg, 150mg
Fisher's exact test.
6.2
Percentage of subjects in ACR/EULAR 
remission at each visit (Baseline, Weeks 4, 8, 12, 
16, 20, 24, 28, 32, 36, 40, 44, 48, 52, EOT)
X
100mg, 150mg
No statistical test.
7.1
Percentage of subjects in SDAI <= 3.3 at each 
visit (Baseline, Week 4, 8, 12, 12/ET,28/ET)
X
Placebo, 100mg, 150mg
Fisher's exact test.
7.2
Percentage of subjects in SDAI <= 3.3 at each 
visit (Baseline, Weeks 4, 8, 12, 16, 20, 24, 28, 
32, 36, 40, 44, 48, 52, EOT)
X
100mg, 150mg
No statistical test.


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8.1
Percentage of subjects in CDAI <= 2.8 at each 
visit (Baseline, Week 4, 8, 12, 12/ET,28/ET)
X
Placebo, 100mg, 150mg
Fisher's exact test.
8.2
Percentage of subjects in CDAI <= 2.8 at each 
visit (Baseline, Weeks 4, 8, 12, 16, 20, 24, 28, 
32, 36, 40, 44, 48, 52, EOT)
X
100mg, 150mg
No statistical test.
9.1
Percentage of subjects achieving HAQ-DI (<=
0.5) at each visit  (Baseline, Week 4, 8, 12, 
12/ET,28/ET)
X
Placebo, 100mg, 150mg
Fisher's exact test.
9.2
Percentage of subjects achieving HAQ-DI (<=
0.5) at each visit  (Baseline, Weeks 4, 8, 12, 16, 
20, 24, 28, 32, 36, 40, 44, 48, 52, EOT)
X
100mg, 150mg
No statistical test.
9.3
Percentage of subjects achieving decrease of 
baseline HAQ-DI of at least 0.22 at each visit  
(Baseline, Week 4, 8, 12, 12/ET,28/ET)
X
Placebo, 100mg, 150mg
Fisher's exact test.
9.4
Percentage of subjects achieving decrease of 
baseline HAQ-DI of at least 0.22 at each visit 
(Baseline, Weeks 4, 8, 12, 16, 20, 24, 28, 32, 36, 
40, 44, 48, 52, EOT)
X
100mg, 150mg
No statistical test.
10.1
Percentage of subjects showing no progression 
of joint damage (mTSS change from baseline <=
0.5) at each visit (Baseline, Week 28/ET, EOT)
X
Placebo, 100mg, 150mg
Fisher's exact test.
10.2
Percentage of subjects showing no progression 
of joint damage (mTSS change from baseline <=
0) at each visit (Baseline, Week 28/ET, EOT)
X
Placebo, 100mg, 150mg
Fisher's exact test.
10.3
Percentage of subjects showing Clinically
Relevant Radiographic Progression: CRRP
(mTSS change from baseline >= 3) at each 
analysis visit
X
Placebo, 100mg, 150mg
Fisher's exact test.
10.4
Percentage of subjects showing Rapid 
Radiographic Progression: RRP (Yearly 
progression of mTSS >= 5)
X
Placebo, 100mg, 150mg
Fisher's exact test.


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11.1
Percentage of subjects achieving SF-36v2 of
difference >= 5 at each visit (Weeks 4, 8, 12, 
12/ET, 28/ET)
X
Placebo, 100mg, 150mg
Fisher's exact test.
11.2
Percentage of subjects achieving SF-36v2 of
difference >= 5 at each visit (Weeks 4, 8, 12, 28, 
52, EOT)
X
100mg, 150mg
No statistical test.
Continuous Variables 
12.1.1
Raw value and change from baseline in mTSS 
score at each visit (Baseline, Week 52/ET) 
X
Placebo, 100mg, 150mg
Descriptive Statistics
RANCOVA3 analysis with Week 
52/ET.
No multiplicity adjustment.
12.1.2
Raw value and change from baseline in Erosion 
Score at each visit (Baseline, Week 28/ET, Week 
52/ET) 
X
Placebo, 100mg, 150mg
Descriptive Statistics;
RANCOVA3 analysis with each 
visit.
No multiplicity adjustment.
12.1.3
Raw value and change from baseline in Joint 
Space Narrowing Score at each visit (Baseline, 
Week 28/ET, Week 52/ET) 
X
Placebo, 100mg, 150mg
Descriptive Statistics;
RANCOVA3 analysis with each 
visit.
No multiplicity adjustment.
12.2.1
Cumulative probability plot for the change from 
baseline in mTSS score at Week 52/ET
X
Placebo, 100mg, 150mg
12.2.2
Cumulative probability plot for the change from 
baseline in Erosion Score at Week 28/ET, Week 
52/ET
X
Placebo, 100mg, 150mg
12.2.3
Cumulative probability plot for the change from 
baseline in Joint Space Narrowing Score at 
Week 28/ET, Week 52/ET
X
Placebo, 100mg, 150mg
12.3.1
Scatter plot for mTSS score at baseline to Week 
28/ET, Week 52/ET
X
Placebo, 100mg, 150mg
12.3.2
Scatter plot for mTSS score at baseline to mTSS 
change from baseline at Week 28/ET, Week 
52/ET
X
Placebo, 100mg, 150mg
12.4.1
Yearly Progression of mTSS
X
Placebo, 100mg, 150mg
Descriptive Statistics;
13 1 1
Raw value and change from baseline in DAS28
X
X
Placebo, 100mg, 150mg
Descriptive Statistics;


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score at each visit (Baseline, Week 4, 8, 12, 
12/ET,28/ET) 
ANCOVA3 analysis with each 
visit.
No multiplicity adjustment.
13.1.2
Raw value and change from baseline in DAS28 
score at each visit (Baseline, Weeks 4, 8, 12, 16, 
20, 24, 28, 32, 36, 40, 44, 48, 52, EOT) 
X
X
100mg, 150mg, 
Placebo to 100mg at Week 12, 
Placebo to 150mg at Week 12, 
Placebo to 100mg at Week 28, 
Placebo to 150mg at Week 28
Descriptive Statistics
13.2.1
Mean-standard deviation plot of 13.1.1
X
X
Placebo, 100mg, 150mg
Descriptive Statistics
ANCOVA3 analysis with each 
visit.
No multiplicity adjustment.
13.2.2
Mean-standard deviation plot of 13.1.2
X
X
100mg, 150mg, 
Placebo to 100mg at Week 12, 
Placebo to 150mg at Week 12, 
Placebo to 100mg at Week 28, 
Placebo to 150mg at Week 28
Descriptive Statistics
14.1
Raw values and change from baseline in SDAI 
score at each visit (Baseline, Week 4, 8, 12, 
12/ET,28/ET)
X
Placebo, 100mg, 150mg
ANCOVA3 analysis with each 
visit.
14.2
Raw values and change from baseline in SDAI 
score at each visit (Baseline, Weeks 4, 8, 12, 16, 
20, 24, 28, 32, 36, 40, 44, 48, 52, EOT)
X
100 mg, 150 mg
Descriptive Statistics
15.1
Raw values and change from baseline in CDAI 
score at each visit (Baseline, Week 4, 8, 12, 
12/ET,28/ET)
X
Placebo, 100mg, 150mg
ANCOVA3 analysis with each 
visit.
15.2
Raw values and change from baseline in CDAI 
score at each visit (Baseline, Weeks 4, 8, 12, 16, 
20, 24, 28, 32, 36, 40, 44, 48, 52, EOT)
X
100 mg, 150 mg
Descriptive Statistics
16.1
Raw values and change from baseline in SF-
36v2 at  each visit (Baseline, Week 4, 8, 12, 
12/ET,28/ET)
X
Placebo, 100mg, 150mg
ANCOVA3 analysis with each 
visit.
16.2
Raw values and change from baseline in SF-
36v2 at  each visit (Baseline, Weeks 4, 8, 12, 28, 
52, EOT)
X
100 mg, 150 mg
Descriptive Statistics
17.1
Raw values and change from baseline in WPAI 
at  each visit (Baseline, Week 4, 8, 12, 
X
Placebo, 100mg, 150mg
ANCOVA3 analysis with each 
visit.


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12/ET,28/ET)
17.2
Raw values and change from baseline in WPAI 
at  each visit (Baseline, Weeks 4, 8, 12, 28, 52, 
EOT)
X
100 mg, 150 mg
Descriptive Statistics
18.1
Raw value and change from baseline in TJC68 at 
each visit (Baseline, Week 4, 8, 12, 
12/ET,28/ET) 
X
Placebo, 100mg, 150mg
ANCOVA3 analysis with each 
visit.
18.2
Raw value and change from baseline in TJC68 at 
each visit (Baseline, Weeks 4, 8, 12, 16, 20, 24, 
28, 32, 36, 40, 44, 48, 52, EOT) 
X
100 mg, 150 mg
Descriptive Statistics
19.1
Raw value and change from baseline in TJC28 at 
each visit (Baseline, Week 4, 8, 12, 12/ET, 
28/ET) 
X
Placebo, 100mg, 150mg
ANCOVA3 analysis with each 
visit.
19.2
Raw value and change from baseline in TJC28 at 
each visit (Baseline, Weeks 4, 8, 12, 16, 20, 24, 
28, 32, 36, 40, 44, 48, 52, EOT) 
X
100 mg, 150 mg
Descriptive Statistics
20.1
Raw value and change from baseline in SJC66 at 
each visit (Baseline, Week 4, 8, 12, 12/ET, 
28/ET) 
X
Placebo, 100mg, 150mg
ANCOVA3 analysis with each 
visit.
20.2
Raw value and change from baseline in SJC66 at 
each visit (Baseline, Weeks 4, 8, 12, 16, 20, 24, 
28, 32, 36, 40, 44, 48, 52, EOT) 
X
100 mg, 150 mg
Descriptive Statistics
21.1
Raw value and change from baseline in SJC28 at 
each visit (Baseline, Week 4, 8, 12, 12/ET, 
28/ET) 
X
Placebo, 100mg, 150mg
ANCOVA3 analysis with each 
visit.
21.2
Raw value and change from baseline in SJC28 at 
each visit (Baseline, Weeks 4, 8, 12, 16, 20, 24, 
28, 32, 36, 40, 44, 48, 52, EOT) 
X
100 mg, 150 mg
Descriptive Statistics
22.1
Raw value and change from baseline in CRP at 
each visit (Baseline, Week 4, 8, 12, 12/ET, 
28/ET) 
X
Placebo, 100mg, 150mg
ANCOVA3 analysis with each 
visit.


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22.2
Raw value and change from baseline in CRP at 
each visit (Screening, Baseline, Weeks 4, 8, 12, 
16, 20, 24, 28, 32, 36, 40, 44, 48, 52, EOT) 
X
100 mg, 150 mg
Descriptive Statistics
23.1
Raw value and change from baseline in ESR at 
each visit (Baseline, Weeks 4, 8, 12, 12/ET, 
28/ET) 
X
Placebo, 100mg, 150mg
ANCOVA3 analysis with each 
visit.
23.2
Raw value and change from baseline in ESR at 
each visit (Baseline, Weeks 4, 8, 12, 16, 20, 24, 
28, 32, 36, 40, 44, 48, 52, EOT) 
X
100 mg, 150 mg
Descriptive Statistics
24.1
Raw value and change from baseline in SGAP 
(100 mm VAS) at each visit (Baseline, Week 4, 
8, 12, 12/ET, 28/ET) 
X
Placebo, 100mg, 150mg
ANCOVA3 analysis with each 
visit.
24.2
Raw value and change from baseline in SGAP 
(100 mm VAS) at each visit (Baseline, Weeks 4, 
8, 12, 16, 20, 24, 28, 32, 36, 40, 44, 48, 52, EOT) 
X
100 mg, 150 mg
Descriptive Statistics
25.1
Raw value and change from baseline in SGA 
(100 mm VAS) at each visit (Baseline, Week 4, 
8, 12, 12/ET, 28/ET) 
X
Placebo, 100mg, 150mg
ANCOVA3 analysis with each 
visit.
25.2
Raw value and change from baseline in SGA 
(100 mm VAS) at each visit (Baseline, Weeks 4, 
8, 12, 16, 20, 24, 28, 32, 36, 40, 44, 48, 52, EOT) 
X
100 mg, 150 mg
Descriptive Statistics
26.1
Raw value and change from baseline in PGA 
(100 mm VAS) at each visit (Baseline, Week 4, 
8, 12, 12/ET, 28/ET) 
X
Placebo, 100mg, 150mg
ANCOVA3 analysis with each 
visit.
26.2
Raw value and change from baseline in PGA 
(100 mm VAS) at each visit (Baseline, Weeks 4, 
8, 12, 16, 20, 24, 28, 32, 36, 40, 44, 48, 52, EOT) 
X
100 mg, 150 mg
Descriptive Statistics
27.1
Raw value and change from baseline in HAQ-DI 
at each visit (Baseline, Week 4, 8, 12, 12/ET, 
28/ET) 
X
Placebo, 100mg, 150mg
ANCOVA3 analysis with each 
visit.
27.2
Raw value and change from baseline in HAQ-DI 
X
100 mg, 150 mg
Descriptive Statistics


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at each visit (Baseline, Weeks 4, 8, 12, 16, 20, 
24, 28, 32, 36, 40, 44, 48, 52, EOT) 
Time-to-event Variable
28
Time to the first occurrence of ACR20/50/70-
CRP up to Week 12
X
Placebo, 100mg, 150mg
Cox, Kaplan-Meier, Log-rank
No multiplicity adjustment.
29
Time to the first occurrence of DAS28-CRP < 
2.6 up to Week 12
X
Placebo, 100mg, 150mg
Cox, Kaplan-Meier, Log-rank
No multiplicity adjustment.
30
Time to the first occurrence of SDAI score <=
3.3 up to Week 12
X
Placebo, 100mg, 150mg
Cox, Log-rank
No multiplicity adjustment.
31
Time to the first occurrence of ACR/EULAR 
score for remission up to Week 12
X
Placebo, 100mg, 150mg
Cox, Log-rank
No multiplicity adjustment.
32
Time to the first occurrence of CDAI score <=
2.8 up to Week 12
X
Placebo, 100mg, 150mg
Cox, Log-rank
No multiplicity adjustment.
Additional (Graphical Analysis)
33
Two-panel line graphs of DAS28 over time up to 
Week 12 for ACR20 responders and non-
responders at Week 12/ET (responders in 1 
panel, non-responders in other panel)
X
X
Placebo, 100mg, 150mg
Descriptive Statistics
1 Abbreviations are defined in Section I. All analyses will be based on the FAS. 
2 See Sections 7.4.2 for modeling details on ANCOVA, Kaplan-Meier, Cox proportional hazards, and Log-rank test. 
3 ANCOVA for change only. For raw value, only descriptive statistics will be presented. 


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10.3
Appendix 3: Overview of AE analysis
Table16, Table17 summarizes the analyses of AE occurrence, the analysis of SOC, PT 
analysis, with "X1", "X2", "X3", and "X4" indicating that the variable will be analyzed by 
each defined groups defined footnote. All analyses will be based on the SAF.
Table16. The overview of AE occurrence analysis
Overall
Week 0 
to Week 
12
Week 12 
to Week 
28
Week 28 
to Week 
52
Number and percentage of subjects with TEAE 
X4
X1
X2
X3
Number and percentage of subjects with drug 
related TEAE
X4
X1
X2
X3
Number and percentage of subjects with death 
X4
X1
X2
X3
Number and percentage of subjects with serious 
TEAE
X4
X1
X2
X3
Number and percentage of subjects with drug 
related serious TEAE
X4
X1
X2
X3
Number and percentage of subjects with TEAE 
Grade 3 or Higher in Severity
X4
X1
X2
X3
Number and percentage of subjects with TEAE 
leading to study drug discontinuation
X4
X1
X2
X3
Number and percentage of subjects with drug 
related TEAE leading to study drug 
discontinuation
X4
X1
X2
X3
Number and percentage of subjects with
Serious TEAE Leading to Permanent 
Discontinuation of Study Drug
X4
X1
X2
X3
Number and percentage of subjects with Drug-
Related Serious TEAE Leading to Permanent 
Discontinuation of Study Drug
X4
X1
X2
X3
X1: Placebo, 100mg, 150mg
X2: Placebo, 100mg, 150mg, Placebo to 100 mg at Week 12, Placebo to 150 mg at Week12
X3: 100mg, 150mg, Placebo to 100 mg at Week 12, Placebo to 150 mg at Week 12, Placebo to 100 mg at Week 
28, Placebo to 150 mg at Week 28
X4: 100mg, 150mg
Table17. The overview of the number of SOC/PT analysis
Overall
Week 0 
to Week 
12
Week 12 
to Week 
28
Week 28 
to Week 
52
TEAEs
X4
X1
X2
X3


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Drug related TEAEs, defined as any TEAE 
with possible, probable or missing relationship 
to study drug as assessed by the investigator. 
X4
X1
X2
X3
Serious TEAEs 
X4
X1
X2
X3
Drug related serious TEAEs
X1
TEAEs by severity based on NCI-CTCAE
X4
X1
X2
X3
Drug related TEAEs by severity
X1
Grade 3 or higher TEAEs by severity
X4
X1
TEAEs by relationship to study drug 
X1
TEAEs leading to death 
X4
X1
X2
X3
TEAEs leading to permanent discontinuation 
of study drug
X4
X1
X2
X3
Drug related TEAEs leading to permanent 
discontinuation of study drug
X1
Serious TEAEs leading to permanent 
discontinuation of study drug
X1
Drug related serious TEAEs leading to 
permanent discontinuation of study drug
X1
TEAEs excluding serious adverse events that 
equal to or Exceed a threshold of 5% in Any 
Treatment Group
X4
Most common TEAEs (> 5% in any treatment 
group) 
X4
X1
X2
X3
Most common serious TEAEs (> 5% in any 
treatment group) 
X4
X1
X2
X3
TEAEs by subgroups defined in section 7.8.
X1
The number and percentage of subjects with 
TEAEs of special interest
X4
X1
Serious Infections
X4
X1
Malignancies
X4
X1
Herpes Zoster Related Disease (Herpes Zoster 
and Varicella)
X4
X1
Herpes Zoster
X4
X1
Varicella
X4
X1
Infections That Require Intravenous Anti-
infectious Therapy
X4
X1
Subgroup 
Sex
X1
Age Group 
X1
Prior Anti-TNF DMARD Use 
X1
Prior Biologic DMARD Use 
X1
Duration of RA (years)
X1


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Number of Prior DMARDs Used 
X1
Number of Prior Biologic DMARDs Used
X1
MTX Dose (mg/week) at Baseline (0 <- 8  
mg/week, 8 <- 12 mg/week, >12 mg/week)
X1
Concomitant Steroid at Baseline (No, Yes)
X1
Prednisone Dose at Baseline (mg/day) 
(None, 0 <- 5 mg/day, > 5 mg/day)
X1
Body Weight (kg) at Screening
X1
X1: Placebo, 100mg, 150mg
X2: Placebo, 100mg, 150mg, Placebo to 100 mg at Week 12, Placebo to 150 mg at Week12
X3: 100mg, 150mg, Placebo to 100 mg at Week 12, Placebo to 150 mg at Week 12, Placebo to 100 mg at Week 
28, Placebo to 150 mg at Week 28
X4: 100mg, 150mg
Patient-year analysis
Week 0 to Week 
12
Overall Period
TEAEs
X1
X4
TEAEs of special interest
X1
X4
Serious Infections
X1
X4
Malignancies
X1
X4
Herpes Zoster Related Disease (Herpes Zoster and 
Varicella)
X1
X4
Herpes Zoster
X1
X4
Varicella
X1
X4
Infections That Require Intravenous Anti-infectious 
Therapy*
X1
X4
Subgroup 
Sex
X4
Age Group 
X4
Concomitant Steroid at Baseline (No, Yes)
X4
Prednisone Dose at Baseline (mg/day) (None, 0 <- 5 
mg/day, > 5 mg/day)
X4
X1: Placebo, 100mg 150mg
X4: 100mg 150mg
*: subgroup analysis will not be conducted.
10.4
Appendix 4: Overview of Clinical Laboratory Evaluation, Vital 
Singes, and Electrocardiograms (ECGs) analyses
Table18 summarizes the analyses of AE occurrence, the analysis of SOC, PT, with "X1" , 
"X2", "X3" indicating that the variable will be analyzed by each defined groups defined 
footnote. All analyses will be based on the SAF.


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Table18. The overview of Clinical Laboratory Evaluation, Vital Singes, and 
Electrocardiograms (ECGs) analyses
Screening, 
Baseline, 
Weeks 4, 8, 
12, 12/ET, 
28/ET
Screening, 
Baseline, Weeks 
4, 8, 12, 16, 20, 
24, 28, 32, 36, 40, 
44, 48, 52, EOT
Quantitative Laboratory Test Results in SI Units, 
Hematology
X1
X2
Actual and Change from Baseline
Quantitative Laboratory Test Results in SI Units, 
Biochemistry 
X1
X2
Actual and Change from Baseline 
Quantitative Laboratory Test Results in SI Units, 
Urinalysis
X1
X2
Actual and Change from Baseline 
Qualitative Laboratory Test Results, Urinalysis 1
X1
X2
Qualitative Laboratory Test Results, Urinalysis 2
X1
X2
Qualitative Laboratory Test Results, Urinalysis 3
X1
X2
Qualitative Laboratory Test Results, Urinalysis 4
X1
X2
Qualitative Laboratory Test Results, Urinalysis 5
X1
X2
Quantitative Laboratory Test Results in SI Units, 
Fasting Lipids Profile
X1
X2
Actual and Change from Baseline
Quantitative Laboratory Test Results in SI Units, 
Lipids Profile Including Values Under Non-fasting 
Condition at Baseline, Weeks 12, 12/ET, 28/ET
Actual and Change from Baseline
X1
X2
Quantitative Laboratory Test Results in SI Units, 
T-Chol/HDL, LDL/HDL Ratio
Actual and Change from Baseline
X1
X2
Quantitative Laboratory Test Results in SI Units, 
Erythrocyte Sedimentation Rate (ESR)
X1
X2
Actual and Change from Baseline
Shift-from-Baseline Table for Laboratory Test Results, 
Hematology
X1
X3
Baseline to Week 12/ET


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Shift-from-Baseline Table for Laboratory Test Results, 
Hematology
X1
X3
Baseline to Lowest Value  up to Week 12
Shift-from-Baseline Table for Laboratory Test Results, 
Hematology
X1
X3
Baseline to Highest Value  up to Week 12
Shift-from-Baseline Table for Laboratory Test Results, 
Biochemistry
X1
X3
Baseline to Week 12/ET
Shift-from-Baseline Table for Laboratory Test Results, 
Biochemistry
X1
X3
Baseline to Lowest Value up to Week 12
Shift-from-Baseline Table for Laboratory Test Results, 
Biochemistry
X1
X3
Baseline to Highest Value up to Week 12
Shift-from-Baseline Table for Laboratory Test Results, 
Urinalysis
X1
X3
Baseline to Week 12/ET
Shift-from-Baseline Table for Laboratory Test Results, 
Urinalysis
X1
X3
Baseline to Lowest Value up to Week 12
Shift-from-Baseline Table for Laboratory Test Results, 
Urinalysis
X1
X3
Baseline to Highest Value up to Week 12
Shift-from-Baseline Table for Laboratory Test Results, 
Fasting Lipid Profile
X1
X3
Baseline to Week 12/ET
Shift-from-Baseline Table for Laboratory Test Results, 
Fasting Lipid Profile
X1
X3
Baseline to Lowest Value  up to Week 12
Shift-from-Baseline Table for Laboratory Test Results, 
Fasting Lipid Profile
X1
X3
Baseline to Week 12/ET
Shift-from-Baseline Table in Pre-Specified Reference 
Range Laboratory test Results by Visit, Selected 
Laboratory Variables
  Aspartate Aminotransferase (AST)
X1
X2
  Alanine Aminotransferase (ALT)
X1
X2
  Alkaline Phosphatase (ALP)
X1
X2
  Total Bilirubin Category 1
X1
X2
  Total Bilirubin Category 2
X1
X2
  Low-Density Lipoprotein (LDL)
X1
X2
  Hemoglobin (HGB) Category 1
X1
X2


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  Hemoglobin (HGB) Category 2
X1
X2
  Hemoglobin (HGB) Category 3
X1
X2
  Creatine Phosphokinase (CPK) Category 1
X1
X2
  Creatine Phosphokinase (CPK) Category 2
X1
X2
  Creatine Phosphokinase (CPK) Category 3
X1
X2
  Creatinine
X1
X2
  Absolute Neutrophil Count (ANC)
X1
X2
  Lymphocytes Category 1
X1
X2
  Lymphocytes Category 2
X1
X2
  Platelets Cagetory1
X1
X2
  Platelets Cagetory2
X1
X2
Shift-from-Baseline Table for Selected Laboratory 
Variables using NCI-CTCAE Toxicity Grade (version 
4.0) 
Baseline to Week 12/ET
X1
X3
Liver Function Analysis 
Clinically Significant Values in Liver Function Tests
X1
X2
Summary of Moderate and Marked Liver 
Abnormalities by Visit
X1
X2
Liver Functions Plots
X1
X2
Vital Signs
Vital Signs
X1
X2
Actual and Change from Baseline
ECG Results by Local Investigator
Interpretation of 12- Lead ECG Results, Assessment by 
Investigator
X1
X2
Shift-from-Screening Table for 12-Lead ECG 
Central ECG Results
Summary of Central ECG Results
Actual and Change From Baseline
X1
Summary of Central ECG Results
Change From Predose to Postdose at Week 4/ Week 8
X1
Number and Percentage of Subjects with Categorized 
Central ECG Parameter Low Extreme Values
X1
Number and Percentage of Subjects with Categorized 
Central ECG Parameter High Extreme Values
X1
Number and Percentage of Subjects with Categorized 
Central ECG Parameter Low Extreme Values
Change From Baseline
X1
Number and Percentage of Subjects with Categorized 
Central ECG Parameter High Extreme Change Values
Change From Baseline
X1
Number and Percentage of Subjects with Categorized 
X1


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Central ECG Parameter Low Extreme Change Values
Change From Predose to Postdose at Week 4/ Week 8
Number and Percentage of Subjects with Categorized 
Central ECG Parameter High Extreme Change Values
Change From Predose to Postdose at Week 4/ Week 8
X1
X1: Placebo, 100mg, 150mg
X2: 100mg, 150mg, Placebo to 100 mg at Week 12, Placebo to 150 mg at Week 12, Placebo to 100 mg at Week 
28, Placebo to 150 mg at Week 28
X3: 100mg, 150mg


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10.5
Appendix 5: 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. 
Table 19. 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


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Category
Question
Checkbox
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
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.


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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. 
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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10.6
Appendix 6: 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), 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. 
Table 20.1 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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Table 20.2. 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
Table 20.3. 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
Table 20.4. 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
Table 20.5. 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
Table 20.6. 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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Table 20.7. 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
Table 20.8. 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
Table 20.9. 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 20 to compute simple algebraic sums of the presented final item scores. 


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Table 21. Formulas for Scoring and Transforming Scales
SF-36v2 Scale
Sum Final Item Values 
(after recoding items as 
in Tables 7.1-7.9)
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.


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Table22. 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
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 Table 20.
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:


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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 Table 22.
Table 23. 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)


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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 
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 


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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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10.7
Appendix 7: Computation of WPAI Scale Score
Work Productivity and Activity Impairment Questionnaire: WPAI
In this study, the following scoring method are applied. These scoring method 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
Table 24. 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×UL
N
>3.0×U
LN -
≤5.0×U
LN
>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×bas
eline
>1.5×U
LN - ≤
3.0×UL
N
or
>1.5×U
LN -
≤3.0×b
aseline
>3.0×U
LN -
≤6.0×U
LN
or
>3.0×b
aseline
>6.0×
ULN
4.0
109
n/a
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


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Gamma 
Glutamyl 
Transferase 
(GGT)
GGT
n/a
Increase/
GGT increased
WNL
>ULN -
≤2.5×UL
N
>2.5×U
LN -
≤5.0×U
LN
>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 
baseline 
if 
baseline 
is above 
ULN
Increas
e in >2 
- 4 g/dL 
above 
ULN or 
above 
baselin
e if 
baselin
e is 
above 
ULN
Increas
e in >4 
g/dL 
above 
ULN or 
above 
baselin
e if 
baselin
e 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
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


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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×UL
N
>1.5×U
LN -
≤3.0×U
LN
>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 
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 Advisor
, Statistical Advisor
 
 
 
 
 


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