A Multicenter, Randomized, Double-blind, PlacebO-controlled, Parallel-group Study to EValuate the Efficacy and Safety of JTE-051 Administered for 12 Weeks to Subjects With Active Rheumatoid Arthritis (MOVE-RA)
Phase: PHASE2
Conditions: Rheumatoid Arthritis
Sponsor: Akros Pharma Inc.

 
ClinicalTrials.gov Posted Document Cover Page 
Clinical Study Protocol 
 
PROTOCOL TITLE:  
A Multicenter, Randomized, Double-blind, PlacebO-controlled, 
Parallel-group Study to EValuate the Efficacy and Safety of 
JTE-051 Administered for 12 Weeks to Subjects with Active 
Rheumatoid Arthritis (MOVE-RA)  
PROTOCOL NUMBER: AE051-G-13-003  
PROTOCOL DATE:  
24 March 2016  
NCT NUMBER: 
NCT02919475 
 
 
 

JTE-051 
AKROS PHARMA INC. 
Clinical Study Protocol AE051-G-13-003 
Cover Page 
Akros Pharma Inc. 
Clinical Protocol 
PROTOCOL TITLE: 
A 
Multicenter, 
Randomized, 
Double-blind, 
PlacebO-controlled, Parallel-group Study to EValuate the 
Efficacy and Safety of JTE-051 Administered for 12 Weeks to 
Subjects with Active Rheumatoid Arthritis (MOVE-RA) 
PROTOCOL NUMBER: AE051-G-13-003 
DATE: 
24 March 2016  
IND NUMBER:  
 
EUDRACT NUMBER 
2015-003140-39 
SPONSOR: 
Akros Pharma Inc.  
302 Carnegie Center, Suite 300 
Princeton, NJ 08540 
SPONSOR CONTACT: 
Akros Pharma Inc.  
302 Carnegie Center, Suite 300 
Princeton, NJ 08540  
 
MEDICAL MONITOR: 
 
 
Confidentiality Statement 
The confidential information in this document is provided to you as an Investigator or consultant for review by you, your 
staff, and the applicable Institutional Review Board/Independent Ethics Committee (IRB/IEC). Your acceptance of this 
document constitutes agreement that you will not disclose the information contained herein to others or use the 
information for any purpose other than the performance of your obligations pursuant to your and/or your employer’s 
separate agreement with us, our affiliate or our contractor, as the case may be, without prior written authorization from 
Akros Pharma Inc. (Akros). 
 
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JTE-051 
AKROS PHARMA INC. 
Clinical Study Protocol AE051-G-13-003 
Signature Page 
 
Protocol Number:  AE051-G-13-003 
Protocol Number:  A Multicenter, Randomized, Double-blind, PlacebO-controlled, 
Parallel-group Study to EValuate the Efficacy and Safety of 
JTE-051 Administered for 12 Weeks to Subjects with Active 
Rheumatoid Arthritis (MOVE-RA) 
The signatures below indicate approval of the protocol. 
Sponsor 
Representative 
 
 
 
 
 
 
 
Date 
Sponsor 
Statistician 
 
 
 
 
 
Date 
 
 
 
Investigator's Statement of Agreement: 
 
I acknowledge possession of the JTE-051 Investigator’s Brochure (IB) and this protocol. 
Having fully reviewed all the information provided, I consider it ethically justifiable to 
give the study drug to subjects according to the agreed protocol. I will conduct the study 
in full accordance with this protocol and all applicable laws and regulations, including but 
not limited to current Good Clinical Practices. 
 
 
Investigator 
 
 
 
 
(Signature) 
 
 
 
 
Date 
 
(Printed Name) 
 
 
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JTE-051 
AKROS PHARMA INC. 
Clinical Study Protocol AE051-G-13-003 
Table of Contents 
Cover Page .......................................................................................................................... 1 
Signature Page ................................................................................................................... 2 
Table of Contents ............................................................................................................... 3 
List of Abbreviations and Definition of Terms ................................................................. 6 
Protocol Synopsis ............................................................................................................. 11 
1. 
Introduction .............................................................................................................. 17 
1.1. 
Background ..................................................................................................... 17 
1.1.1. 
Rheumatoid Arthritis ................................................................................ 17 
1.1.2. 
Treatment of Rheumatoid Arthritis ........................................................... 17 
1.1.3. 
Interleukin-2-inducible T-cell Kinase ....................................................... 18 
1.2. 
JTE-051 ............................................................................................................ 19 
1.2.1. 
Nonclinical Studies ................................................................................... 19 
 
2 
Study Objectives ....................................................................................................... 32 
3 
Investigational Plan ................................................................................................. 32 
3.1. 
Number of Sites and Subjects ........................................................................ 32 
3.2. 
Study Design .................................................................................................... 32 
3.3. 
Selection of Study Population ........................................................................ 33 
3.3.1. 
Inclusion Criteria....................................................................................... 33 
3.3.2. 
Exclusion Criteria ..................................................................................... 34 
3.4. 
Removal of Subjects from the Study ............................................................. 39 
3.5. 
Study Procedures ............................................................................................ 41 
3.5.1. 
Screening Period ....................................................................................... 44 
3.5.2. 
Double-blind Treatment Period ................................................................ 44 
3.5.3. 
Follow-up Period ...................................................................................... 45 
3.5.4. 
Study Restrictions ..................................................................................... 46 
 
3.5.6. 
Procedure Definitions ............................................................................... 52 
3.5.7. 
Clinical Institutions and Laboratories ....................................................... 60 
3.6. 
Adverse Events ................................................................................................ 61 
3.6.1. 
Safety Definitions ..................................................................................... 61 
3.6.2. 
Assessing Adverse Events ........................................................................ 62 
3.6.3. 
Reporting Adverse Events ........................................................................ 64 
3.7. 
Identification of Treatments .......................................................................... 66 
3.7.1. 
Method of Assigning Subjects to Treatment Groups ................................ 66 
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AKROS PHARMA INC. 
Clinical Study Protocol AE051-G-13-003 
3.7.2. 
Identity of Investigational Products .......................................................... 66 
3.7.3. 
Storage and Handling Procedures ............................................................. 66 
3.7.4. 
Clinical Supplies Packaging ..................................................................... 66 
3.7.5. 
Administration of Study Drug ................................................................... 67 
3.7.6. 
Management of Clinical Supplies ............................................................. 68 
3.7.7. 
Randomization .......................................................................................... 68 
3.7.8. 
Blinding ..................................................................................................... 68 
3.7.9. 
Breaking the Blind .................................................................................... 68 
3.8. 
Statistical Methods .......................................................................................... 69 
3.8.1. 
Subject Population for Analysis ................................................................ 69 
3.8.2. 
Interim Analysis ........................................................................................ 70 
3.8.3. 
Efficacy Analyses ...................................................................................... 70 
3.8.4. 
Safety Analyses ......................................................................................... 74 
3.8.5. 
Pharmacokinetic Analyses ........................................................................ 74 
3.9. 
Quality Control and Quality Assurance ....................................................... 75 
4 
Investigator Obligations ........................................................................................... 75 
4.1. 
Institutional Review/Independent Ethics Committee .................................. 75 
4.2. 
Subject Consent ............................................................................................... 76 
4.3. 
Data Collection ................................................................................................ 77 
4.3.1. 
Case Report Forms .................................................................................... 77 
4.3.2. 
Source Documents .................................................................................... 77 
4.4. 
Adherence to Protocol .................................................................................... 77 
4.5. 
Reporting Adverse Events .............................................................................. 77 
4.6. 
Investigator’s Final Report ............................................................................ 77 
4.7. 
Records Retention ........................................................................................... 77 
4.8. 
Confidentiality ................................................................................................. 78 
4.9. 
Publications ..................................................................................................... 78 
5 
Study Management .................................................................................................. 79 
5.1. 
Monitoring ....................................................................................................... 79 
5.2. 
Management of Protocol Amendments and Deviations .............................. 79 
5.3. 
Study Termination .......................................................................................... 80 
5.4. 
Sponsor’s Final Report ................................................................................... 80 
6 
References ................................................................................................................ 81 
7 
Appendices ................................................................................................................ 84 
Appendix 1. 
ACR/EULAR Classification Criteria for Rheumatoid Arthritis 85 
 
Appendix 3. 
Numeric Rating Scale Templates ................................................... 87 
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JTE-051 
AKROS PHARMA INC. 
Clinical Study Protocol AE051-G-13-003 
Appendix 4. 
Health Assessment Questionnaire ................................................. 88 
Appendix 5. 
Efficacy Endpoints Calculation ..................................................... 94 
Numeric ACR (ACR-N) Index ............................................................................... 94 
The ACR20/50/70 Response Rate .......................................................................... 94 
Simple Disease Activity Index ................................................................................ 95 
Clinical Disease Activity Index .............................................................................. 95 
Disease Activity Score (DAS) 2829 .......................................................................... 96 
Percentage of Subject achieving Boolean Remission ........................................... 96 
EULAR Response Criteria ..................................................................................... 96 
 
 
 
List of Figures 
 
Figure 1. 
Planned Study Schema .................................................................................... 41 
 
Figure 3. 
Tender and Swollen Joint Counts (68/66)...................................................... 52 
Figure 4. 
Tender and Swollen Joint Counts (28) ........................................................... 54 
 
 
List of Tables 
 
Table 1. 
Planned Schedule of Study Procedures.......................................................... 42 
Table 2. 
Companion Aids/Device Items for HAQ-DI Categories ............................... 93 
 
 
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AKROS PHARMA INC. 
Clinical Study Protocol AE051-G-13-003 
LIST OF ABBREVIATIONS AND DEFINITION OF TERMS 
Abbreviation 
Definition 
Ab 
Antibody 
ACPA 
Anti–citrullinated protein antibody 
ACR 
American College of Rheumatology 
ACR20  
Percentage of subjects achieving at least 20% improvement from baseline 
in tender and swollen joint counts and at least 20% improvement in 3 of 
the 5 remaining ACR core set measures 
ACR50  
Percentage of subjects achieving at least 50% improvement from baseline 
in tender and swollen joint counts and at least 50% improvement in 3 of 
the 5 remaining ACR core set measures 
ACR70  
Percentage of subjects achieving at least 70% improvement from baseline 
in tender and swollen joint counts and at least 70% improvement in 3 of 
the 5 remaining ACR core set measures 
ACR-N 
Numeric ACR: the lowest percentage improvement from baseline of 3 
measures: tender joint count, swollen joint count and median 
improvement of the remaining 5 core measures. 
ADL 
Activities of daily living 
ADP 
Action potential duration 
AEs 
Adverse events 
ALP 
Alkaline phosphatase 
ALT 
Alanine aminotransferase 
Anti-CCP 
Anti-cyclic Citrullinated Peptide 
aPTT 
Activated partial thromboplastin time  
AR 
Accumulation ratio 
AST 
Aspartate aminotransferase 
AUC 
Area under the concentration-time curve 
AUC0-24 
Area under the concentration-time curve from the time of dosing to 24 
hours 
AUC0-inf 
Area under the concentration-time curve from the time of dosing to 
infinity 
AUCtau 
Area under the concentration­time curve during the dosing interval 
BCG 
Bacille Calmette-Guérin 
BCRP 
Breast cancer resistance protein 
BMI 
Body mass index 
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JTE-051 
AKROS PHARMA INC. 
Clinical Study Protocol AE051-G-13-003 
Abbreviation 
Definition 
BUN 
Blood urea nitrogen 
CABG 
Coronary Artery Bypass Graft 
CAIA 
Collagen antibody-induced arthritis 
CDAI 
Clinical Disease Activity Index 
CFR 
Code of Federal Regulations 
CI 
Confidence interval 
CIA 
Collagen-induced arthritis 
CL_F 
Apparent oral clearance of drug following extravascular administration 
Cmax 
Maximum concentration 
COX 
Cyclooxygenase 
CRF 
Case report form 
CRP 
C-reactive protein  
CTCAE 
Common Terminology Criteria for Adverse Events 
Ctrough 
Trough concentration 
CV% 
Coefficient of variation 
CYP 
Cytochrome P450 
DAS 
Disease Activity Score 
DB 
Double-blind 
DDI 
Drug-drug interaction 
DIP 
Distal interphalangeal 
DMARDs 
Disease-modifying anti-rheumatic drugs 
ECG 
Electrocardiogram 
EGF 
Epidermal growth factor 
EOT 
End of treatment 
EULAR 
European League Against Rheumatism 
FGFR 
Fibroblast growth factor receptor 
Flt3 
Fms-like tyrosine kinase-3 
FSH 
Follicle-stimulating hormone 
GCP 
Good Clinical Practice 
GEE 
Generalized estimating equation 
eGFR 
Estimated glomerular filtration rate 
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JTE-051 
AKROS PHARMA INC. 
Clinical Study Protocol AE051-G-13-003 
Abbreviation 
Definition 
HAQ-DI 
Health Assessment Questionnaire Disability Index 
HBc 
Hepatitis B core 
HBsAg 
Hepatitis B virus surface antigen 
HCV 
Hepatitis C virus 
HDL-C 
High-density lipoprotein cholesterol 
HEENT 
Head, Ears, Eyes, Nose, Throat 
βhCG 
Human chorionic gonadotropin 
hERG 
Human ether-a-go-go related gene 
HIV 
Human immunodeficiency virus 
hs-CRP 
High-sensitivity C­reactive protein 
IB 
Investigator’s brochure 
ICH 
International Conference on Harmonisation 
IC50 
Half-maximal inhibitory concentration 
IEC 
Independent Ethics Committee 
IFNγ 
Interferon γ  
IL-2 
Interleukin-2 
IL-6 
Interleukin-6  
IL-17 
Interleukin-17 
IMP 
Investigational Medicinal Product 
IP 
Interphalangeal 
IRB 
Institutional Review Board 
ITK 
Interleukin-2-inducible T-cell kinase 
ITT 
Intent to treat 
IWRS 
Interactive web response system 
LDL-C 
Low-density lipoprotein cholesterol 
LOCF 
Last observation carried forward 
MBI 
Mechanism based inhibition 
MCMC 
Markov chain Monte Carlo 
MCP 
Metacarpophalangeal 
MDRD 
Modification of Diet in Renal Disease 
MedDRA 
Medical Dictionary for Regulatory Activities 
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AKROS PHARMA INC. 
Clinical Study Protocol AE051-G-13-003 
Abbreviation 
Definition 
MMF 
Mycophenolate mofeti 
MMP 
Matrix metalloproteinase  
MOA 
Mechanism of action 
MTP 
Metatarsophalangeal 
MTX 
Methotrexate 
N/A 
Not applicable 
 
NRS 
Numerical Rating Scale 
NSAIDs 
Non-steroidal anti-inflammatory drugs  
NYHA 
New York Heart Association  
PGA 
Physician’s Global Assessment 
P-gp 
P-glycoprotein 
PI 
Posterior interval 
PIP 
Proximal interphalangeal 
PK  
Pharmacokinetic(s)   
PP 
Per protocol 
PPD 
Purified Protein Derivative 
PR 
Interval from beginning of the P wave to the beginning of the QRS 
complex in the frontal plane 
PT 
Prothrombin Time 
PTCA 
Percutaneous Transluminal Coronary Angioplasty 
OAT 
Organic anion transporter 
OATP 
Organic anion transporting polypeptide 
OCT 
Organic cation transporter  
QD 
Once daily 
QOL 
Quality of life 
QRS  
Duration of QRS complex in the frontal plane  
QT  
Interval from beginning of the QRS complex to end of the T wave in the 
frontal plane  
QTcF  
Fridericia-corrected QT Interval  
RA 
Rheumatoid Arthritis 
RF 
Rheumatoid Factor 
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AKROS PHARMA INC. 
Clinical Study Protocol AE051-G-13-003 
Abbreviation 
Definition 
 
RR 
Interval from beginning of the QRS complex in the frontal plane to the 
next QRS complex  
SAA 
Serum amyloid 
SAE 
Serious adverse event  
SAP 
Statistical analysis plan  
SD 
Standard deviation 
SDAI 
Simplified Disease Activity Index   
SGA 
Subject’s Global Assessment 
SNRIs 
Serotonin-norepinephrine reuptake inhibitors  
SOC 
Standard of care 
SSRIs 
Selective serotonin reuptake inhibitors 
SUSAR 
Suspected Unexpected Serious Adverse Reaction 
t1/2 
Elimination half-life associated with the terminal slope (λz) of a 
semilogarithmic concentration-time curve  
TCR 
T cell receptor 
TDI 
Time-dependent inhibition  
TEAE 
Treatment-emergent adverse event 
TIA 
Transient ischemic attack 
tmax 
Time to reach peak or maximum concentration following drug 
administration  
TNF-α 
Tumor necrosis factor-α  
TNF-RI 
Tumor necrosis factor receptor I 
TSH 
Thyroid stimulating hormone 
ULN 
Upper limit of normal 
USP 
United States Pharmacopeia  
VCAM-1 
Vascular cell adhesion molecule-1  
VEGF-A 
Vascular endothelial growth factor A  
V_F 
Apparent volume of distribution following extravascular administration 
YKL-40 
Human cartilage glycoprotein 39 
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JTE-051 
AKROS PHARMA INC. 
Clinical Study Protocol AE051-G-13-003 
Protocol Synopsis 
 
STUDY TITLE 
A 
Multicenter, 
Randomized, 
Double-blind, 
PlacebO-controlled, Parallel-group Study to EValuate the 
Efficacy and Safety of JTE-051 Administered for 12 Weeks 
to Subjects with Active Rheumatoid Arthritis (MOVE-RA) 
PROTOCOL NUMBER AE051-G-13-003 
CLINICAL PHASE 
Phase 2a 
STUDY DURATION 
Approximately 20-week duration per subject: 
• 
Up to a 28-day Screening Period 
• 
A 12-week double-blind (DB) Treatment Period 
• 
Approximately a 4-week Follow-up Period  
STUDY OBJECTIVES 
• To evaluate the clinical efficacy of JTE-051 in subjects 
with active rheumatoid arthritis receiving background 
non-biologic disease-modifying anti-rheumatic drug 
therapy. 
• To evaluate the safety and tolerability of JTE-051 
administered for 12 weeks in subjects with active 
rheumatoid arthritis receiving background non-biologic 
disease-modifying anti-rheumatic drug therapy. 
• To evaluate the pharmacokinetics (PK) of JTE-051 in 
plasma of subjects with active rheumatoid arthritis.  
STUDY DESIGN 
 
This 
is 
a 
multicenter, 
randomized, 
double-blind, 
placebo-controlled, parallel-group, 12-week study in biologic 
and kinase inhibitor treatment-naive rheumatoid arthritis 
(RA) subjects on stable disease-modifying anti-rheumatic 
drug (DMARD) therapy, including methotrexate (MTX). 
Eligible subjects will be randomized at Visit 2 to receive 
JTE-051 50 mg, 100 mg, 150 mg, 200 mg or placebo once 
daily (QD) for 12 weeks. Subjects will continue to receive up 
to two non-biologic DMARDs, including MTX, throughout 
the study (at a stable background dose and route of 
administration for at least 12 weeks prior to Visit 2 and 
throughout the study) and will return for a Follow-up Visit 
approximately four weeks after the last dose of study drug is 
administered. 
Randomization 
will 
be 
stratified 
by 
geographical region and by the screening high-sensitivity 
C-reactive protein (hs-CRP). 
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JTE-051 
AKROS PHARMA INC. 
Clinical Study Protocol AE051-G-13-003 
NUMBER OF 
SUBJECTS TO BE 
ENROLLED AND 
RANDOMIZED 
A sufficient number of subjects will be screened to ensure 
the randomization (in a 1:1:1:1:1 ratio) of approximately 
250 subjects (50 subjects per treatment group). 
KEY ELIGIBILITY 
CRITERIA 
• 
Males and females, 18 to 75 years of age (inclusive) at the 
time of the Screening Visit; 
• A diagnosis of RA prior to the Screening Visit, based on 
the American College of Rheumatology (ACR)/European 
League 
Against 
Rheumatism 
(EULAR) 
2010 
Classification Criteria; 
• Active disease despite ongoing therapy with up to two 
non-biologic DMARDs, including MTX at both the 
Screening and Baseline Visits (Visits 1 and 2), as defined 
by both: 
 ≥6 out of 68 tender joints AND 
 ≥6 out of 66 swollen joints; 
• Screening hs-CRP ≥1.2 x upper limit of normal (ULN), 
based on the central laboratory values;  
• Background treatment with up to two non-biologic 
DMARDs including MTX (mandatory) and one of the 
following medications (optional): sulfasalazine ≤3 g/day, 
hydroxychloroquine 
≤400 mg/day 
or 
chloroquine: 
≤250 mg/day at the time of the Screening Visit; 
 The MTX dosage must be 15-25 mg/week (or the 
maximum documented tolerated dose for the 
subject, not <10 mg/week) and all background 
therapy must be stable, defined as no change in 
dose or route of administration for ≥12 weeks 
prior to the Randomization Visit (Visit 2). 
• No prior/current exposure to biologic and/or kinase 
inhibitor therapy;  
 
 
 
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JTE-051 
AKROS PHARMA INC. 
Clinical Study Protocol AE051-G-13-003 
INVESTIGATIONAL 
PRODUCT         
(STUDY DRUG), 
FORMULATION, 
DOSAGE,  
ROUTE AND TIME OF 
ADMINISTRATION 
 
 
JTE-051  
50 mg tablets 
50 mg, 100 mg, 150 mg and 200 mg 
Oral administration for 12 weeks starting on the day of 
randomization at Visit 2, once daily in the morning, 
regardless of meals. On study visit days, subjects should 
take their scheduled study treatment at the site under the 
supervision of the investigator or designee after all 
study-related procedures have been completed (except for 
Visit 6, when no study drug will be administered).   
REFERENCE 
PRODUCT         
(STUDY DRUG), 
FORMULATION, 
DOSAGE, 
ROUTE AND TIME OF 
ADMINISTRATION 
 
Placebo  
Tablets (identical in appearance to the JTE-051 tablets)  
Not applicable (N/A)   
Oral administration for 12 weeks starting on the day of 
randomization at Visit 2, once daily in the morning, 
regardless of meals. On study visit days, subjects should 
take their scheduled study treatment at the site under the 
supervision of the investigator or designee after all 
study-related procedures have been completed (except for 
Visit 6, when no study drug will be administered).   
EVALUATION 
CRITERIA 
Primary Efficacy Parameters 
• Percentage 
of 
subjects 
achieving 
at 
least 
20% 
improvement from baseline in tender and swollen joint 
counts and at least 20% improvement from baseline in 3 
of the 5 remaining ACR core set measures (ACR20 
response rate) at end of treatment (EOT) 
Secondary Efficacy Parameters  
(will be evaluated at Weeks 2, 4, 8, 12 and 16 unless 
otherwise stated) 
• Percentage of subjects achieving at least 20, 50 and 70% 
improvement from baseline in tender and swollen joint 
counts and at least 20, 50 and 70% improvement from 
baseline in 3 of the 5 remaining ACR-core set measures, 
respectively (i.e., ACR20/50/70 response rate)  
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JTE-051 
AKROS PHARMA INC. 
Clinical Study Protocol AE051-G-13-003 
EVALUATION 
CRITERIA, Cont. 
Secondary Efficacy Parameters, Cont. 
• Change from baseline in Simplified Disease Activity 
Index (SDAI) 
• Percentage of subjects who achieved remission based on 
SDAI (≤3.3) 
• Percentage of subjects who achieved low disease activity 
based on SDAI (≤11) 
• Change from baseline in Clinical Disease Activity Index 
(CDAI) 
• Percentage of subjects who achieved remission based on 
CDAI (≤2.8) 
• Percentage of subjects who achieved low disease activity 
based on CDAI (≤10) 
• Percentage of subjects in Boolean Remission 
• Change from baseline in Disease Activity Score (DAS) 
based on hs-CRP (DAS28-CRP) 
• Percentage of subjects with DAS28-CRP of <2.6 
• Percentage of subjects with DAS28-CRP of <3.2 
• Percentage of subjects with good EULAR response at 
Week 12 
• Percentage of subjects with moderate EULAR response at 
Week 12 
• The lowest percentage change from baseline of 
3 measures: tender joint count, swollen joint count and 
median change of the remaining 5 core measures 
(numeric ACR [ACR-N] index)  
• Change from baseline in the Health Assessment 
Questionnaire Disability Index (HAQ-DI)  
• Change from baseline in the number of tender and 
swollen joint counts (68/66 joints will be counted)  
• Change from baseline in subject pain score by numeric 
rating scale (NRS) 
• Change from baseline in subject global assessment (SGA) 
of disease activity by NRS  
• Change from baseline in physician global assessment 
(PGA) of disease activity by NRS  
• Change from baseline in hs-CRP 
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JTE-051 
AKROS PHARMA INC. 
Clinical Study Protocol AE051-G-13-003 
EVALUATION 
CRITERIA, Cont. 
 
 
Safety Parameters 
• 
The number of subjects with adverse events (AEs), type 
and severity of AEs, change from baseline in the safety 
laboratory, vital sign and electrocardiogram (ECG) 
parameters 
Pharmacokinetic (PK) Parameters 
• Trough plasma levels of JTE-051  
• The relationship between the JTE-051 dose (exposure) 
and response may be assessed (exploratory) 
STATISTICAL 
METHODS 
For the primary efficacy parameter (ACR20 at EOT), the 
Fisher’s exact test will be used to compare each JTE-051 
dose 
group 
with 
placebo. 
Furthermore, 
the 
exact 
Cochran-Armitage trend test will be computed. 
For dichotomous secondary efficacy parameters, similar 
analyses as the primary efficacy parameter will be used by 
time point. 
 
 
 
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JTE-051 
AKROS PHARMA INC. 
Clinical Study Protocol AE051-G-13-003 
STATISTICAL 
METHODS, Cont. 
The model includes effects for treatment, time, treatment by 
time interaction, and the stratification factors and subject as 
the repeated factor. 
For continuous efficacy parameter analysis with multiple 
time points, a mixed effect model will be employed. It 
includes fixed effects for treatment, time, treatment by time 
interaction, the stratification factors and the appropriate 
baseline, and subject as the random effect. A linear trend test 
at each time point will be computed using appropriate linear 
contrast. 
All analyses will be performed at the two-sided α=5% 
significance 
level. 
No 
formal 
multiple 
comparison 
adjustment will be made. The estimated treatment effect 
(relative to placebo) from the model, along with a two-sided 
95% confidence interval (CI) and p-value, will be tabulated 
where appropriate. 
Descriptive statistics of efficacy parameters over time will be 
presented by treatment. They will include the number of 
subjects (N), arithmetic mean, standard deviation (SD), 
median, minimum and maximum for continuous parameters, 
and in frequency tabulation form for dichotomous 
parameters. 
The Newcombe’s CI of the rate difference between JTE-051 
dose and placebo will be computed when performing the 
Fisher’s exact test. Graphical presentations of the treatment 
profile may be depicted. Sensitivity analysis, model fit 
assessment may be conducted and data transformation may 
be employed if appropriate. 
Descriptive statistics of efficacy parameters over time will be 
presented by treatment.  
With respect to the safety data analysis, descriptive statistics 
of vital signs, ECG parameters, and clinical laboratory data 
will be presented by treatment. Potentially clinically 
significant values for vital signs, ECG, and laboratory data 
will be flagged in data listings and may be summarized as 
appropriate. 
For PK data, descriptive statistics of the trough plasma 
concentration of JTE-051 will be presented by treatment.  
 
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JTE-051 
AKROS PHARMA INC. 
Clinical Study Protocol AE051-G-13-003 
1. 
INTRODUCTION 
1.1. 
Background 
1.1.1. Rheumatoid Arthritis 
Rheumatoid arthritis (RA) is a systemic autoimmune disease of unknown cause 
characterized by chronic and persistent joint swelling, joint tenderness and synovial joint 
destruction that leads to pain and disability.1 Approximately 1% of the world’s population 
is considered to be suffering from the disease2 and the number of patients is estimated to 
be approximately 1.3 million in the US.3 Females are more likely to suffer from the 
disease, with a reported ratio of male to female patients of 1:2.5. The disease can occur at 
any age, but it is most common among those aged 40 to 70 years, its incidence increasing 
with age. 
In rheumatoid arthritis, abnormal activation of various inflammatory cells such as T cells 
and macrophages causes and exacerbates chronic synovitis. Patients mostly complain of 
morning stiffness as an initial symptom. The disease is characterized by inflammatory 
findings that involve multiple joints such as those in the fingers, hands and knees, leading 
to the development of pain, swelling associated with synovial fluid retention and local 
warmth. The inflammatory symptoms are mostly experienced in the early stage followed 
by repeated remissions and relapses, which lead to the destruction of cartilage and bone, 
with deformation of the joints over time, finally causing severe dysfunction. When the 
disease is highly active, various clinical symptoms such as general malaise, pyrexia, and 
anemia are observed as non­joint-related symptoms. It is known that these symptoms 
markedly impair the activities of daily life and finally worsen life prognosis. It has been 
reported that insufficient treatment shortens the life of patients with rheumatoid arthritis 
by 10 to 15 years compared with that of healthy individuals.4  
1.1.2. Treatment of Rheumatoid Arthritis 
The treatment of rheumatoid arthritis aims to maintain the physical functions of the 
patients and improve their quality of life (QOL) through control of symptoms and 
prevention of joint destruction.5 To achieve these aims, drug treatments from an early 
stage of the disease based on the background of appropriate nonmedical therapies is 
recommended in US and Europe.6,7 Currently, as therapeutic agents, disease-modifying 
anti-rheumatic drugs (DMARDs), non-steroidal anti-inflammatory drugs (NSAIDs), oral 
use and intraarticular injection of steroids, and biological agents are used. 
Disease-modifying anti-rheumatic drugs that can inhibit progression of the pathological 
conditions play a central role in the treatment. Methotrexate (MTX) is prescribed as the 
standard therapy and immunosuppressive drugs are prescribed as switch or combination 
therapy. Disease-modifying anti-rheumatic drugs alleviate pain and swelling by correcting 
the immune abnormality, but their efficacy is not sufficient, leaving some non-responders 
and those with a reduced response without relief. These drugs may also be able to inhibit 
the joint destruction, but their inhibitory effect on the progression of destruction of the 
cartilage and bone is not sufficient in the absence of remission. Since DMARDs are slow-
acting, it takes a long time to improve the QOL, and the pathological condition may be 
allowed to progress if judgment to change the drug for non-responders is delayed. Since 
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rheumatoid arthritis has a chronic course, long-term therapies are usually required, 
however, very often, it is difficult to continue sufficient treatment due to adverse events 
(AEs) such as disorders in gastrointestinal tract associated with NSAID use, blood and 
liver AEs caused by DMARDs, as well as osteoporosis associated with steroids. Recently, 
it has been demonstrated that biological agents can quickly alleviate arthritis symptoms 
and suppress progression of joint destruction by selectively inhibiting the action of 
cytokines such as tumor necrosis factor-α (TNF-α) and interleukin-6 (IL-6).8-11 However, 
long-term use of biological agents is also problematic, because they have the potential to 
increase the risk of infections and induce serious allergic reactions, are expensive and can 
be administered only by injection. Based on these considerations, new oral therapeutic 
drugs that can quickly alleviate pain and swelling, inhibit the progression of cartilage and 
bone destruction, and are superior to existing drugs in terms of safety, convenience, and 
cost efficiency are desired.  
1.1.3. Interleukin-2-inducible T-cell Kinase 
Interleukin-2-inducible T-cell kinase (ITK) is a non-receptor protein tyrosine kinase that 
is mainly expressed in T cells, mast cells, and natural killer cells. In the T cells, the 
molecule plays a role in transmitting stimulation triggered by the antigen via the T cell 
receptor (TCR) located on the cell membrane.12 When antigen is presented with the major 
histocompatibility complex on the antigen-presenting cells such as dendritic cells and 
macrophages, T cells are activated by recognizing the antigen via the TCR. As a result of 
activation, T cells produce cytokines such as interleukin-2 (IL-2), interleukin-17 (IL-17) 
and interferon γ (IFNγ) and accelerate their own proliferation. It is also considered that 
T cells are significantly involved in the development of tissue inflammation and damage 
by activation of other inflammatory cells by these cytokines. Findings that indicate a 
relationship between ITK and pathological changes have been reported. T cells obtained 
from ITK­knockout mice could not show IL-2 production in response to stimulation 
mimicking antigen presentation, which led to decreased cell proliferation. Cell 
proliferation is also less sensitive in the mixed lymphocyte reaction if obtained from mice 
of a different strain.13 Furthermore, it has been reported that ITK-knockout mice show 
impaired response in allergic airway inflammation induced by the antigen: the production 
of various cytokines in the T cells in lymphoid tissues, the infiltrative inflammatory cell 
counts in the airway, and the secretion of airway mucus.14 This information suggest that 
ITK may be involved in the development of pathological changes in autoimmune 
diseases, transplant rejection and allergic diseases of which the onset and exacerbation are 
caused by an excessive immune response to the antigen. 
 
 
 
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1.2. 
JTE-051 
A brief summary of the nonclinical findings to date is included below. Additional details 
are described in the JTE-051 Investigator’s Brochure (IB). 
1.2.1. Nonclinical Studies 
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1.3. 
Justification of Study Population and Dose Selection 
Justification for Study Population 
 
 
Patients with a diagnosis of RA, based on the American College of Rheumatology 
(ACR)/European League against Rheumatism (EULAR) 2010 Classification Criteria23 
(see Appendix 1), that are MTX-insufficient responders, i.e., have active RA (defined by 
the number of tender and swollen joints) despite stable dosing of at least 12 weeks with 
MTX (and up to one additional non-biologic DMARD) will be enrolled in this study (for 
the purpose of the study,  RA patients will be referred to as “subjects” throughout the 
protocol). The inclusion/exclusion criteria and the restrictions set in this study are based 
on its objectives, i.e., to demonstrate the clinical efficacy of the compound and to 
evaluate safety and tolerability of JTE-051 in patients with RA, the stage in development 
(i.e., early Phase 2 study, first to evaluate clinical efficacy in RA) and the 
nonclinical/clinical characteristics of JTE-051, based on the data available to date. Efforts 
have been made to take into account feasibility and enrollment-related considerations 
while maintaining the scientific integrity of the study and minimizing the risks for the 
study subjects. 
Briefly, from an efficacy perspective, study subjects must have not been exposed to 
biologic or kinase inhibitor therapy in order to minimize the variability in the efficacy 
response due to prior exposure to these immunosuppressive/immunomodulator agents in 
this “first-in patient” study. Additionally, in order to be eligible, subjects would have to 
have high-sensitivity C-reactive protein (hs-CRP) levels >1.2 x the upper limit of normal 
(ULN) at study entry, to confirm a sufficient level of disease activity and to allow for an 
adequate evaluation of the primary efficacy parameter (i.e., the ACR20 response rate at 
EOT). Considering other parameters of upmost significance for the evaluation of 
JTE-051’s efficacy, such as ACR50 and ACR70, an hs-CRP cut-off above 1.2 x ULN 
would be ideal from a scientific perspective, however, taking into account feasibility, the 
current value is considered appropriate with the appropriate stratification criteria set in 
place, to ensure a comparable distribution of high vs. lower hs-CRP subjects across 
treatment groups. Minimum of a 12-week stable dosing (with respect to dose and the 
route of administration) for the background MTX and for the other non-biologic 
DMARDs permitted by the protocol is mandatory and restrictions pertaining to the 
anti-inflammatory and anti-pain medications (including corticosteroids and NSAIDs), as 
well as other anti-RA medications administration have been set, in order to ensure that 
the maximum efficacy response to these medications has been attained and that the 
subject is stable by the time of baseline evaluations in this study, and to subsequently 
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minimize the placebo response, which is known to be significant in studies of similar 
indication. Also, in an attempt to minimize other confounding factors, subjects with 
inflammatory and rheumatic conditions other than RA are prohibited from being 
randomized in the study. 
From a safety perspective, study restrictions were implemented based on the 
 
o
 
i
 
nonclinical and clinical data available to date. These include restrictions aiming to 
minimize the risk to the participating subjects, to minimize the confounding factors in the 
assessment process and to monitor and adequately manage any safety-related findings, as 
they occur. Thus, subjects at high risk of developing immunosuppression-related AEs, 
such as infections or malignancies, including those with pre-existing conditions (e.g., 
clinically-manifest or latent tuberculosis, active infections with hepatitis B or C viruses or 
the human immunodeficiency virus [HIV] infection) or significant hematological 
abnormalities (see Exclusion Criterion # 3) are excluded from participating in the study. 
 
 
 
 
 Other, general safety-related restrictions, such as cardiovascular-system-
related, hepatic and renal function-related restrictions have been implemented, taking into 
account the co-administration with MTX (a medication with known significant hepatic 
and renal-related toxicity), as well as the known safety signals associated with other 
comparable compounds on the market or in development (e.g., hepatic or lipid-related 
signals). The procedures set in place to ensure that the appropriate subjects are 
randomized in this “first-in patient” POC study in subjects with RA, as well as the safety 
management strategies implemented in the study are discussed in the following section: 
“Justification for Study Design”.   
Justification for Study Design 
A parallel group, placebo-controlled, add-on therapy design will be employed in this 
study, to assess the effect of JTE-051 on the efficacy parameters and to evaluate the safety 
of JTE-051, compared to placebo in subjects with active RA. Briefly, upon completion of 
all protocol-mandated screening procedures, the qualified subjects will be randomized at 
Visit 2 in a 1:1:1:1:1 ratio to one of the following five parallel dose groups: JTE-051 
50 mg QD, JTE-051 100 mg QD, JTE-051 150 mg QD, JTE-051 200 mg QD or placebo 
QD (50 subjects to be randomized per arm; see Section 3.8.1.6 for considerations related 
to sample size calculation), and will receive the double-blind (DB) treatment for 
12 weeks followed by a four-week Follow-up Period. The single-dose AE051-U-11-001 
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study data demonstrated no food effect on the PK of JTE-051; thus, study drug will be 
administered regardless of meals; nonetheless, the protocol requires that the once daily 
study drug administration to occur in the morning, to ensure an approximately 24-hour 
period between dosing, based on the PK characteristics of the compound (see 
Section 1.2.2). The duration of the DB Treatment Period is sufficient to allow for proof of 
efficacy in subjects with RA, as an initial step in development. Following attainment of 
this objective, longer-duration (≥6 months) studies, including open-label extensions, as 
appropriate, are planned. The duration of the Follow-up Period was set to approximately 
four weeks, standard duration for similar out-patient studies administered an 
investigational product. Considering the PK characteristics of JTE-051 (see Section 1.2.1), 
it was determined that this interval is conservative,
 
a
 
The efficacy parameters assessed in this study are consistent with the standards in the 
industry in similar RA trials 
 
 
 Appropriate efficacy analyses are 
planned, as detailed in Section 3.8.3.2. To minimize the chance for errors, all calculations 
of derived parameters will be done by the Sponsor based on the appropriate core data 
points collected and documented by the Investigators. Additionally, although all joint 
evaluators in the study are expected to be rheumatologists with experience in joint 
assessments, adequate training on these assessments is planned, to ensure consistency and 
to minimize intra- and inter-assessor variability. For this reason, the protocol also 
strongly recommends that the same assessor performs the joint counts for a subject 
throughout the study duration. 
With respect to safety, adequate procedures have been implemented to minimize the risks 
to the study subjects (based on the compound’s MOA and the nonclinical and clinical 
data available to date [see Sections 1.2.1 
 for summary information and the 
Investigator’s Brochure for detailed information]) and to facilitate further characterization 
of the safety profile of JTE-051.  
Specifically, 
 
 
 
 screening procedures were set in place to exclude 
subjects at high risk of infections (e.g., medical history, chest radiography and serologic 
screening for tuberculosis, screening for hepatitis B and C, as well as HIV infections) and 
adequate withdrawal criteria, based on the Common Terminology Criteria for Adverse 
Events (CTCAE), see Section 3.4, have been implemented. 
 
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With respect to the musculoskeletal AE, considering the underlying disease of subjects in 
this study (i.e., RA), it is expected that musculoskeletal-related signs and symptoms will 
be common; thus, differentiation by the Investigator of the etiology of these events, 
i.e., underlying disease vs. potential other causes will be required. 
 
 
 
 These type of events will be adequately managed through the 
standard AE collection, processing and reporting procedures, per Good Clinical Practice 
(GCP) and all actions to ensure the safety of the subjects will be taken by the study 
investigators. Additionally, the CTCAE withdrawal criteria will be applied to all AEs 
reported in the study. 
 
 
 
 
 
 The safety data obtained after the completion for the study will facilitate a better 
understanding of the compound’s safety profile as a stepping stone in the next stage of 
development.    
Justification for Dose Selection 
The selection of JTE-051 doses in this study is based on the collective data from 
nonclinical pharmacology/toxicology studies and Phase 1 clinical studies.  
 
 
 
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2 
STUDY OBJECTIVES 
• To evaluate the clinical efficacy of JTE-051 in subjects with active rheumatoid 
arthritis receiving background non-biologic disease-modifying anti-rheumatic drug 
therapy 
• To evaluate the safety and tolerability of JTE-051 administered for 12 weeks to 
subjects with active rheumatoid arthritis receiving background non-biologic 
disease-modifying anti-rheumatic drug therapy 
• To evaluate the pharmacokinetics of JTE-051 in plasma of subjects with active 
rheumatoid arthritis  
3 
INVESTIGATIONAL PLAN 
3.1. 
Number of Sites and Subjects 
Multiple sites will be employed to ensure screening of sufficient number of subjects to 
randomize (in a 1:1:1:1:1 ratio) approximately 250 subjects (50 subjects per treatment 
group). 
3.2. 
Study Design 
This is a multicenter, randomized, double-blind, placebo controlled, parallel-group, 
12-week study in biologic and kinase inhibitor treatment-naive RA subjects on stable 
background non-biologic DMARD therapy, including MTX. 
Eligible subjects will be randomized at Visit 2 to receive JTE-051 50 mg, 100 mg, 
150 mg, 200 mg or placebo once daily for 12 weeks. Subjects will continue to receive up 
to two non-biologic DMARDs, including MTX throughout the study (at a stable 
background dose and route of administration for at least 12 weeks prior to Visit 2 and 
throughout the study) and will return for a Follow-up Visit approximately four weeks 
after the last dose of study drug is administered. Randomization will be stratified by 
geographical region and by the screening hs-CRP. 
The study duration will be of approximately 20 weeks per subject: 
• Up to a 28-day Screening Period 
Note: Certain pre-defined exceptions that would allow for a longer duration of 
the Screening Period to ensure a 28-day pre-randomization stabilization of 
concomitant medications are permitted, as described in Section 3.5.4.1. 
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• A 12-week double-blind Treatment Period 
• Approximately a 4-week Follow-up Period 
3.3. 
Selection of Study Population 
Written informed consent must be obtained prior to performing any study-related 
procedures. A copy of the informed consent will be provided to the subject. 
3.3.1. Inclusion Criteria 
1. Males and females, 18 to 75 years of age (inclusive) at the Screening Visit (Visit 1); 
2. A diagnosis of RA prior to the Screening Visit, based on the ACR/EULAR 2010 
Classification Criteria23 (see Appendix 1); 
3. Active disease despite ongoing therapy with up to 2 non-biologic DMARDs, 
including MTX at both the Screening and Baseline Visits (Visit 1 and Visit 2), as 
defined by both: 
a. ≥6 out of 68 tender joints AND 
b. ≥6 out of 66 swollen joints;  
4. Screening hs-CRP ≥1.2 x ULN, based on the central laboratory values;  
5. Background treatment with up to 2 non-biologic DMARDs, including MTX 
(mandatory) and one of the following medications (optional): sulfasalazine ≤3 g/day, 
hydroxychloroquine ≤400 mg/day or chloroquine: ≤250 mg/day, at the time of the 
Screening Visit (Visit 1); 
• The MTX dose must be 15-25 mg/week (or the maximum documented tolerated 
dose for the subject, not <10 mg/week) and all background therapy must be stable, 
defined as no change in dose or route of administration for ≥12 weeks prior to the 
Randomization Visit (Day 1). See Section 3.5.4.1 for all concomitant 
medication-related restrictions. 
6. Body Mass Index (BMI): 18 to 40 kg/m2 (inclusive) at the Screening Visit (Visit 1); 
7. Females may participate if they meet one of the following criteria:  
• Surgically sterile (e.g., hysterectomy or bilateral oophorectomy), or 
• Post-menopausal (i.e., history compatible with menopause [i.e., reported lack of 
menses for ≥12 months prior to Visit 1] and no other biological/surgical cause 
AND a serum follicle-stimulating hormone (FSH) measurement of ≥40 mIU/mL 
at Visit 1), or 
• Of childbearing potential and are compliant with at least 2 acceptable forms of 
birth control (in conjunction with their partner) for the duration of the study and 
for at least 12 weeks after the last dose of study drug. Acceptable contraceptive 
methods include the following: intrauterine devices; partner sterilization (with the 
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appropriate post-vasectomy documentation of the absence of sperm in the 
ejaculate); condom with a spermicide; diaphragm, cervical cap, vaginal sponge, or 
“female condom”, all with spermicide; 
Notes:  
• Females with sterilization history limited to tubal ligation will be considered 
of childbearing potential and must comply with the contraception regimen as 
described above. 
• Females with a history compatible with menopause and have a serum 
FSH <40 mIU/mL at Visit 1 will be considered of childbearing potential and 
must agree to comply with a contraceptive regimen as described above. 
• Concomitant use of a female condom and a male condom is not considered an 
acceptable method of contraception for the study. 
8. Males with female partners of childbearing potential must agree to practice total 
abstinence or to utilize a barrier contraceptive method with spermicide for the 
duration of the study and for at least 12 weeks after the last dose of study drug; 
additionally, male subjects must not donate sperm for the duration of the study and 
within 12 weeks of the last dose of study drug; 
• Female partners of male subjects randomized in this study must be surgically 
sterile, postmenopausal, or use an acceptable form of birth control (see description 
listed in inclusion criterion # 7; additionally, oral and implantable hormonal 
contraceptives are considered acceptable in female partners of male subjects) for 
the duration of the study and for at least 12 weeks after completing the study; 
9. Able and willing to give written informed consent. 
3.3.2. Exclusion Criteria 
The following criteria will exclude a subject from participating in the study:  
1. Prior/current exposure to biologic and/or kinase inhibitor therapy;  
2. Does not meet all study restrictions, including previous/concomitant medication 
restriction criteria, as described in Section 3.5.4 of the protocol; 
3. White blood cell count of <3.0 x 109/L (<3000/mm3), absolute neutrophil count 
of <1.5 x 109/L (<1500/mm3) or absolute lymphocyte count <0.8 x 109/L (<800/mm3) 
at the Screening Visit (Visit 1); 
4. Hemoglobin <9 g/dL or platelet count <100,000/mm3 at the Screening Visit (Visit 1); 
5. Alanine aminotransferase (ALT) >1.2 x the ULN; aspartate aminotransferase 
(AST) >1.2 x the ULN or total bilirubin >1.5 x the ULN at the Screening Visit 
(Visit 1); 
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6. Clinical evidence of renal impairment or an estimated glomerular filtration rate 
(eGFR) ≤60 mL/min/1.73m2 at the Screening Visit (Visit 1), using the abbreviated 
Modification of Diet in Renal Disease (MDRD) equation; 
7. Serum triglycerides >400 mg/dL at the Screening Visit (Visit 1); 
8. Positive viral serology at the Screening Visit (Visit 1) for: 
• Human immunodeficiency virus: positive HIV antibodies (Ab)   
• Hepatitis B virus: positive total hepatitis B core (HBc) Ab or positive hepatitis B 
surface antigen (HBsAg) or  
• Hepatitis C virus (HCV): positive HCV Ab; 
9. Positive drug of abuse and alcohol test results at the Screening Visit (Visit 1); 
Note: Adequate (i.e., non-abusive) use of prescription drugs, according to the 
Investigator’s judgment is permitted, provided that the concomitant medications 
restrictions required by the protocol are met. Positive test results for cannabinoids will 
result in exclusion of subject from the study. 
10. History or presence of substance abuse, drug addiction or alcoholism within 1 year 
prior to the Screening Visit (Visit 1); 
11. Positive Purified Protein Derivative (PPD) or quantiFERON®-TB Gold-In-Tube test 
(Note: either test can be performed, according to the local guidelines), positive chest 
radiography findings for tuberculosis or any other evidence of tuberculosis; 
• For subjects with a history of Bacille Calmette-Guérin (BCG) vaccination the 
quantiFERON®-TB Gold-In-Tube test should be performed; 
• A PPD test is considered positive if, at 48 to 72 hours of administration, the 
induration (not erythema) obtained is ≥5 mm.  
• If the quantiFERON®-TB Gold-In-Tube test is performed and it is indeterminate, 
a retest is allowed if results can be obtained in time prior to Visit 2. If the retest 
results are also indeterminate, the PPD test may be performed (unless the subject 
has a history of BCG vaccination) and, if negative, the subject may be randomized 
into the study. 
• The quantiFERON®-TB Gold-In-Tube test should not be performed within 
≤4 weeks from the date of a live vaccination.  
• Subjects who have had contact with a person with active tuberculosis are excluded, 
unless documentation of appropriate completion (>12 weeks prior to the 
Screening Visit) of tuberculosis prophylaxis is provided to the investigator. 
12. History of live attenuated vaccination within 6 weeks prior to Day 1 (Visit 2), or have 
a live attenuated vaccination planned during the course of the study or within 6 weeks 
after the last dose of study drug; 
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13. Have donated or received any blood or blood products within 8 weeks prior to the 
Screening Visit (Visit 1); 
14. History of a clinically-significant infection (e.g., required oral antimicrobial or 
antiviral therapy) within 8 weeks prior to Day 1 (Visit 2), except for treated urinary 
tract infections, which will be permitted if resolved >1 week prior to Day 1 (Visit 2); 
Note: Subjects with confirmed Zika infection within 4 weeks prior to the 
Screening Visit (Visit 1) are prohibited to participate in the study, whether or not 
they have received antiviral therapy. 
15. History of opportunistic infections or infection requiring hospitalization or parenteral 
antibiotic, antiviral, antifungal, or antiparasitic therapy within 6 months prior to Day 1 
(Visit 2) or any history of recurrent infections or conditions predisposing to chronic 
infections (e.g., bronchiectasis, chronic osteomyelitis); 
16. History of shingles within 12 months prior to the Screening Visit or any known 
history of disseminated/complicated herpes zoster; 
17. History of acute inflammatory joint disease of an origin other than RA or subject has 
any other rheumatic disease other than RA (e.g., any arthritis with onset prior to age 
16 years, gout, mixed connective tissue disease, seronegative spondylarthropathy, 
psoriatic arthritis, reactive arthritis or systemic lupus erythematosus) or fibromyalgia;  
Note: Subjects with Sjögren's syndrome secondary to RA are permitted in the study 
provided that all other inclusion/exclusion criteria are met; 
18. History or presence of any lymphoproliferative disorder, such as Epstein Barr 
Virus-related lymphoproliferative disorder, lymphoma, leukemia, multiple myeloma, 
etc., or signs and symptoms suggestive of current lymphatic disease, such as 
Hodgkin's or Non-Hodgkin's lymphoma; 
19. History of or current malignancies with the exception of adequately treated or excised 
non-metastatic basal cell or squamous cell carcinoma of the skin or cervical 
carcinoma in situ >6 months prior to the Screening Visit (Visit 1); 
20. History of organ transplantation; 
21. Acute coronary syndrome (e.g., myocardial infarction or unstable angina), 
percutaneous 
coronary 
intervention 
(Percutaneous 
Transluminal 
Coronary 
Angioplasty [PTCA] or similar procedures), coronary artery bypass graft (CABG) 
surgery, cerebrovascular accident or transient ischemic attack (TIA) within 6 months 
prior to the Screening Visit (Visit 1); 
22. Any history or presence of Class III or IV heart failure, as defined by the New York 
Heart Association (NYHA)24 or known Rutherford category 4 or higher peripheral 
arterial disease; 
23. Any history or presence of clinically significant arrhythmias or other ECG 
abnormalities, according to the Investigator’s judgment; 
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24. Uncontrolled arterial hypertension defined as repeated (i.e., up to 3 repeat 
measurements are allowed) systolic blood pressure ≥160 mmHg or diastolic blood 
pressure ≥100 mmHg at the Screening Visit (Visit 1); 
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32. Pregnant or nursing females at Screening Visit or Day 1 (Visit 1 and Visit 2) or 
subjects who plan to become pregnant or initiate breastfeeding during the study and 
within 12 weeks after the last dose of study drug; 
33. Significant history of drug or other hypersensitivities (e.g., multiple drug allergies or 
severe allergic reactions, including angioedema); 
34. History or presence of any other clinically relevant medical condition or disease, or 
laboratory abnormality, including hepatic, renal, gastroenterologic, respiratory, 
cardiovascular, 
endocrinologic, 
 
psychiatric 
(e.g., schizophrenia, manic-depressive disorder, treatment-resistant major depression), 
immunologic (e.g., immunocompromised subjects or subjects with autoimmune 
conditions other than RA, such as type I diabetes) or hematologic (e.g., sickle cell) 
disease that, in the opinion of the Investigator, may place the subject at unacceptable 
risk for study participation and may prevent the subject from completing the study 
(e.g., low life expectancy, high risk of non-compliance) or would interfere with the 
study conduct or data interpretation, according to the Investigator’s judgment; 
35. Cannot communicate reliably with the Investigator (including inability to complete 
the self-assessment questionnaires) or are unlikely to cooperate with the requirements 
of the study.   
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3.4. 
Removal of Subjects from the Study 
A subject will not participate further in the study under the following conditions: 
1. 
Withdrawal by Subject: subjects have the right to withdraw from the study at any 
time. However, if a subject withdraws consent because of experiencing an adverse 
event, the reason for subject termination should be documented as the adverse event. 
2. 
Adverse Event: a clinical or biological adverse event or intercurrent condition(s), 
requiring study drug discontinuation, whether or not related to the study drug 
If grade 3 findings (defined as severe or medically significant but not immediately 
life-threatening; hospitalization or prolongation of hospitalization indicated; 
disabling; limiting self-care activities of daily living [ADL] such as bathing, dressing, 
undressing, feeding self, using the toilet, taking medication, but not bedridden), 
according to the CTCAE25, are noted in a subject, he/she must be promptly evaluated 
by the Investigator (including repeat tests, evaluation of the baseline parameters, 
concomitant medications, etc.) for potential withdrawal from the study. Every effort 
should be made to discuss with the study’s Medical Monitor prior to final decision, 
unless not feasible, based on safety considerations. Subjects who interrupted study 
drug administration due to a grade 3 CTCAE finding may be re-started on therapy if 
the event has resolved and it is considered appropriate by the Investigator and 
Sponsor or designee. 
Notes:  
• The investigator may decide to evaluate or withdraw the subject from the study 
based on findings of lesser than grade 3 severity, according to his/her judgment. 
 
3. 
Consistent* Non-compliance with Study Drug (i.e., <80% or >120% compliance; 
exceptions  on a case-by-case basis may be permitted if approved by Sponsor or 
designee) 
*Determined at >1 study visit during the Treatment Period. If compliance of 
<80% or >120% is identified at a study visit, the Investigator or designee is to 
counsel the subject and ensure steps are taken to improve compliance. 
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4. 
Inclusion/Exclusion Criteria Not Met: the subject was randomized in the study and 
did not meet all inclusion/exclusion criteria mandated by the protocol (exceptions  on 
a case-by-case basis may be permitted if approved by Sponsor or designee) 
5. 
Protocol Violation: the subject is non-compliant with regard to this protocol (other 
than the withdrawal criteria 3. and 4. listed above), as determined by Sponsor or the 
Investigator 
6. 
Lost to Follow-up 
7. 
Death 
8. 
Study Terminated by Sponsor: the sponsor may suspend or terminate the study or 
part of the study at any time for any reason 
9. 
Pregnancy 
10. Investigator Decision: the Investigator decides a subject should be discontinued for 
any reasons other than those already mentioned (actual reason must be documented 
by site) 
11. Other: actual reason must be documented by site 
Subjects who are removed from the study or withdraw consent to participate in the study 
after receiving the first dose of study drug on Day 1 will be requested to complete an 
Early Termination Visit at which time the subject will undergo all the procedures 
described for Visit 6 (EOT). Every effort should be made to perform the EOT 
assessments as soon as possible after the decision of discontinuation is made and prior to 
any changes made in the subject’s anti-RA therapy. Additionally, at approximately 
4 weeks after study drug discontinuation, subject should return for a Follow-up Visit, 
where all procedures as described at Visit 7 should be performed.   
 
 
 
 
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3.5. 
Study Procedures 
Figure 1. 
Planned Study Schema 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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Table 1. 
Planned Schedule of Study Procedures 
  
Screening
Period
Follow-up
Period
Duration/ Study Week (Day)a
 Up to 4 
weeks
Week 0
(Day 1)
Week 2
(Day 14±2)
Week 4
(Day 28±2)
Week 8
(Day 56±2)
Week 12
(Day 84±2)
Week 16
(Day 112±2)
Visit
1
2
3
4
5
6
7
Informed Consent
X
Inclusion/ Exclusion Criteria
X
X
Medical History
X
Demographic Information
X
Review Prior/ Concomitant Medications
X
X
X
X
X
X
X
Physical Exam
X
X
X
X
X
X
Vital Signs, including Weight
X
X
X
X
X
X
X
Height and Calculate BMI 
X
12-Lead ECG
X
X
X
X
Chest Radiographyc
X
TB test (PPD or quantiFERON gold)
X
Drugs of Abuse Screen 
X
Viral Serology 
X
FSH (post-menopausal females only)
X
Pregnancy Test (all females)d
X
X
X
X
X
X
X
Serum Biochemistry
X
X
X
X
X
X
X
Hematology
X
X
X
X
X
X
X
Urinalysis
X
X
X
X
X
X
X
Coagulation
X
X
X
X
X
Lipid Profile
X
X
X
X
X
25-hydroxyvitamin D
X
Serum IgG, IgM and IgA 
X
X
RFe and Anti-CCP antibodiesf 
X
Bone-specific ALP
X
X
X
hs-CRP
X
X
X
X
X
X
X
CRP
X
X
Tender Joint Count (68)
X
X
X
X
X
X
X
Swollen Joint Count (66)
X
X
X
X
X
X
X
Subject's Assessment of Arthritis Pain
X
X
X
X
X
X
X
Subject's Global Assessment of Arthritis
X
X
X
X
X
X
X
Physician's Global Assessment of Arthritis
X
X
X
X
X
X
X
HAQ-DI
X
X
X
X
X
X
X
Randomization using IWRS
X
Access IWRS and Dispense Study Drugg
X
X
X
X
Collect Study Drug and Check Complianceh
X
X
X
X
Study Drug Administrationi
X
X
X
X
JTE-051 Trough PK Blood Samples
X
X
X
X
Document Adverse Eventsj
X
X
X
X
X
X
X
Treatment  Period
 
a. The target day for each visit timepoint will be calculated relative to the date of 
Randomization Visit (Visit 2) and not relative to the date of the previous visit. All visits 
should be performed within the windows specified in the table. Every attempt should be 
made to have the subject attend each visit as scheduled. The investigational site is 
encouraged to a make a reminder phone call to the subject approximately a day or two before 
the scheduled visit. However, if a subject is unable to attend a visit within the specified 
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windows, the visit should be scheduled as closely as possible to these windows. A subject 
should not skip a protocol-specified visit due to scheduling difficulties. 
 
c. Unless a chest radiography had been performed within 3 months (12 weeks) of the 
Screening Visit, and documentation is available for review by the Investigator and inclusion 
in the subject’s file. 
d. At Visit 1 serum pregnancy test will be performed; at all other visits, urine pregnancy tests 
will be performed. Pregnancy tests may also be repeated as needed or per request from 
IRBs/IECs or if required by local regulations. 
e. Rheumatoid Factor 
f. Anti-cyclic citrullinated peptide antibodies 
g. At Visit 2, a back-up drug blister card will be dispensed to all subjects, in addition to the 
regular study drug blister cards. Subjects will be instructed not to use the back-up blister card 
unless all drug in the regular blister cards has been used and to bring all used and unused 
(including back-up) blister cards to each study visit for accountability purposes. At Visit 6, 
study drug will not be dispensed. If a study subject discontinues study drug prematurely, the 
appropriate systems will be accessed to record termination as soon as possible after the 
decision has been made. 
h. Study drug compliance will be calculated by the site at each visit during the Treatment 
Period starting at Visit 3, based on the number of tablets dispensed/returned by the subject. 
The subject is to maintain the back-up blister card for the duration of the Treatment Period. 
i. 
Oral administration for 12 weeks starting on the day of randomization at Visit 2, QD in the 
morning, regardless of meals. On study visit days, subjects should take their scheduled study 
treatment from their existing study drug supply (if available) at the site, under the 
supervision of the investigator or designee after all study-related procedures have been 
performed (except for Visit 6, when no study drug will be administered, as the last dose will 
be taken the day prior to the visit). If no tablets from the previously supplied non-back-up 
blister cards are available, then the subject should dose from the new blister card supplied at 
that visit. Following completion of accountability and compliance assessments, the back-up 
blister card will be re-dispensed at Visits 3 through 5 and will be collected at Visit 6 along 
with all non-back-up drug blister cards. The back-up blister card should only be utilized by 
subjects if all study drug from the regularly-supplied (i.e., non-back-up) blister cards has 
been used. 
j. 
Adverse event information will be collected at the specified time points as well as at any 
time when a clinical research unit staff member becomes aware of an AE after the subject 
signs the informed consent for the study. However, stable or improving pre-existing 
conditions that are detected through the screening procedures throughout the 
Screening Period (e.g., abnormalities in ECG, physical examination, 
 
 vital signs, and laboratory tests) are considered to be medical history and 
should be documented accordingly. 
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3.5.1. Screening Period 
Day -28 (Visit 1) to Day 1 (Visit 2) 
Following signature of the Informed Consent for the study, screening procedures to 
confirm eligibility may be performed across multiple days, as needed, during the 
Screening Period. If a subject arrives for a visit not having fasted (overnight fast, at least 
10 hours prior to blood and urine sample collection), all study procedures with the 
exception of the blood/urine collection activities may be performed; the subject’s 
remaining procedures will be rescheduled for blood/urine collection on a subsequent day 
within the visit window and he/she will be reminded to fast overnight.  
Please refer to Table 1 for the list of screening procedures to be performed in the study. A 
one-time repeat of the screening laboratory (except for drugs of abuse and alcohol, viral 
serology and pregnancy tests), vital sign and ECG assessments is permitted, if considered 
appropriate by the Investigator, except if stated otherwise (e.g., an up to a three-time 
repeat of blood pressure measurements at the Screening Visit is permitted). The repeat 
test(s) results are to be utilized for subject qualification purposes. If the repeat test results 
are outside the protocol-required range, the subject should be excluded from the study.  
Re-screening of subjects may be permitted on a case-by-case basis, pending discussion 
and approval by the medical monitor. 
3.5.2. Double-blind Treatment Period 
Day 1 (Visit 2) to Day 84 ±2 (Visit 6/Week 12) 
Please refer to Table 1 for the by-visit list of procedures to be performed in the study 
during this period.  
All visits during the Double-blind Treatment Period (i.e., including Visit 2 
[Randomization Visit]), should be performed under fasted conditions (overnight fast, at 
least 10 hours prior to blood and urine sample collection). If a subject arrives for a visit 
not fasted, then all study procedures with the exception of the blood/urine collection 
activities may be performed; the subject’s remaining procedures will be rescheduled for 
blood/urine collection on a subsequent day within the visit window and he/she will be 
reminded to fast overnight. Exception to this would be Visit 2 (Randomization Visit), at 
which all study procedures have to be completed within the same session, therefore, if the 
subject is not fasted, the full visit should be rescheduled. 
All visits should be performed within the windows specified in the table. Every attempt 
should be made to have the subject attend each visit as scheduled. The investigational site 
is encouraged to a make a reminder phone call to the subject approximately a day or two 
before the scheduled visit. However, if a subject is unable to attend a visit within the 
specified windows, the visit should be scheduled as closely as possible to these windows. 
A subject should not skip a protocol-specified visit due to scheduling difficulties. 
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Subjects will be administered the first dose of study drug in the clinical research center, 
upon completion of all pre-dosing procedures and randomization at Visit 2; subsequently, 
they will be instructed to self-administer study drug once daily, in the morning, regardless 
of food. However, subjects should not take study drug in the morning of the day of a 
study visit until after all study procedures have been completed. On those days study drug 
will be administered at the site by the study personnel from the subject’s previously 
supplied non-back-up study drug blister cards, if available, except for Visit 6, when no 
study drug will be administered, as the last dose will be taken the day prior to the visit. If 
no tablets from the previously supplied non-back-up blister cards are available, then the 
subject should dose from the new non-back-up blister card supplied at that visit. 
Following completion of accountability and compliance assessments, the back-up blister 
card will be re-dispensed at Visits 3 through 5 and will be collected at Visit 6 along with 
all non-back-up blister cards. The back-up blister card should only be utilized by subjects 
if all study drug from the regularly-supplied (i.e., non-back-up) blister cards has been 
used. If the subject inadvertently took study drug on the day of the study visit, prior to the 
visit, he/she may complete the visit and the actual date and time of the last dose prior to 
the PK blood samples collection will be accurately recorded. 
The exact date and time of last dose prior to the PK sample collection at each visit should 
be documented.  
Study drug will not be administered and all drug will be collected from the subjects at 
Visit 6.  
If a subject discontinues the study prematurely after receiving at least one dose of study 
drug, an Early Termination Visit should be completed at which all procedures listed for 
the EOT visit (Visit 6) should be performed, if possible, prior to initiation of any change 
in the anti-RA medication regimen of the subject. 
3.5.3. Follow-up Period 
Day 84 ±2 (Visit 6/Week 12) to Day 112 ±2 (Visit 7/Week 16)  
The Follow-up Visit will occur approximately four weeks after the last dose of study drug. 
Similar to all other study visits, subjects should arrive under fasted conditions 
(i.e., overnight fast, at least 10 hours prior to blood and urine sample collection). Please 
refer to Table 1 for the list of follow-up procedures to be performed in the study.  
For subjects who discontinue the study prematurely after receiving at least one dose of 
study drug, follow-up procedures, as described for Visit 7 should be performed 
approximately four weeks after the last dose of study drug. 
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3.5.4. Study Restrictions  
3.5.4.1. 
Previous and Concomitant Medication Restrictions 
Medications PROHIBITED any time prior or during the study (through the Follow-
up Visit [Visit 7]): 
• Biologics and kinase inhibitor agents; 
• Antipsychotic therapy; 
• Anti-retroviral therapy and alpha-interferon;  
• Anti-cancer chemotherapy; 
Note: Methotrexate, as background treatment for RA is permitted; 
• Tacrolimus and mycophenolic acid/mycophenolate mofeti (MMF)  
Medications PROHIBITED within 6 months (24 weeks) prior to Day 1 (Visit 2) 
through the Follow-up Visit (Visit 7): 
• Cyclophosphamide. 
Medications PROHIBITED within 3 months (12 weeks) prior to Day 1 (Visit 2) 
through the Follow-up Visit (Visit 7): 
• Oral or injectable gold, azathioprine, penicillamine and cyclosporine; 
• Leflunomide, unless the subject has undergone cholestyramine washout at least 
28 days prior to Visit 2;   
• Monoamine oxidase inhibitors; 
• Isoniazid. 
Medications PERMITTED AT STABLE DOSE for at least 3 months (12 weeks) 
prior to Day 1 (Visit 2) through the Follow-up Visit (Visit 7): 
• All subjects must receive background MTX at stable doses of 15-25 mg/week, or at the 
maximum documented tolerated dose for the subject, not <10 mg/week. For the 
purpose of the study “stable” is defined as no change in dose or route of MTX 
administration for ≥12 weeks prior to the Visit 2. Methotrexate dose and route of 
administration must not change throughout the study (i.e., until after the 
Follow-up Visit [Visit 7]); 
 Supplementation with folic acid or folinic acid (leucovorin), according to the local 
standard of care (SOC) (i.e., local MTX package insert) is required in all subjects 
as follows: subjects must receive folic acid between 1 and 5 mg per dose, 
inclusive, at least four days each week, and at least 7 mg total weekly dose, unless 
this regimen violates the local MTX label, case when the later should be followed. 
Alternatively, study subjects may receive folinic acid (leucovorin) up to 5 mg per 
dose administered 8 to 24 hours after the MTX weekly dose. Dosing regimen for 
folic acid/folinic acid must be stable for at least 4 weeks (28 days) prior to Visit 2. 
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Note: If the subject has not been receiving folic acid or folinic acid prior to signing 
the informed consent, then a prescription for dosing according to the local SOC 
and MTX package insert must be provided by the investigator at the Screening 
Visit and subject should initiate administration within two calendar days from 
signing the Informed Consent. In this case, the duration of Screening Period may 
be extended by two days, to allow for a 4-week (28-day) stabilization period for 
folic acid/folinic acid.  
• Sulfasalazine ≤3 
g/day, hydroxychloroquine ≤400 mg/day and chloroquine: 
≤250 mg/day; 
Note:  
 If a subject has not been on stable treatment with these drugs for at least 12 weeks 
prior to Visit 1, these must not be initiated until after the Follow-up Visit (Visit 7); 
 For candidates receiving chloroquine or hydroxychloroquine, fundoscopic and 
visual field examination results performed within the timeframe consistent with the 
local SOC, but not exceeding 12 months prior to the Screening Visit must be 
reviewed by the Investigator and filed in the subject’s source documents. If not 
available, such examinations should be performed (as part of SOC) and results 
should be reviewed/filed by the investigator prior to randomization; 
• Selective serotonin reuptake inhibitors (SSRIs), serotonin-norepinephrine reuptake 
inhibitors (SNRIs), bupropion (Wellbutrin) and tricyclic or tetracyclic antidepressants. 
Medications PROHIBITED within 4 weeks (28 days) prior to Day 1 (Visit 2) 
through the Follow-up Visit (Visit 7): 
• Parenteral or intra-articular corticosteroids, as well as oral prednisone/prednisolone or 
steroid equivalent at doses >10 mg/day; 
Note: Topical or inhaled corticosteroids for indications other than RA are permitted as 
needed throughout the study 
• Doxycycline and minocycline; 
• Pentoxifylline; 
• Sulfamethoxazole/Trimethoprim (Bactrim), sulfones (e.g., Dapsone), colchicine and 
systemic metronidazole; 
• Vitamin B6 at doses >100 mg/day; 
• Cannabinoids, including marijuana. 
Medications PROHIBITED within 4 weeks (28 days) PRIOR TO VISIT 1 
(SCREENING VISIT) through the Follow-up Visit (Visit 7): 
• Investigational drugs: prohibited within 4 weeks or 5 PK half-lives prior to the 
Screening Visit (Visit 1), whichever is longer;  
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 Subjects cannot participate in any other investigational or long-term observational 
studies related to an investigational medication after signing the AE051-G-13-003 
consent form through the Follow-up Visit (Visit 7); 
Note: Participation in registries and long-term population-based studies (e.g., nurse 
health studies) is permitted.  
 If the investigational drug was a biologic or a kinase inhibitor, the subject cannot 
be randomized in the study regardless of the timing of exposure. 
Medications PERMITTED AT STABLE DOSE for at least 4 weeks (28 days) prior 
to Day 1 (Visit 2) through the Follow-up Visit (Visit 7): 
• Oral prednisone/prednisolone or steroid equivalent at doses ≤10 mg/day; 
• Daily doses of oral NSAIDs, cyclooxygenase (COX)-2 inhibitors, opioids and 
acetaminophen/paracetamol; 
 Subjects with occasional use (i.e., not more than two consecutive days) of the 
above medications for indications other than RA (e.g., headache) may be permitted 
in the study pending discussion with the Medical Monitor, provided that the intake 
of such drugs did not occur within 1 week (i.e., 7 days) of Visit 2 and all other 
inclusion/exclusion criteria are met. 
• Hormone replacement, lipid-lowering, antihypertensive and anti-osteoporosis agents; 
 Following receipt of screening lipoprotein assessment results, the investigator may 
initiate lipid lowering drug therapy, as appropriate, according to the local SOC and 
his/her judgment; such action should be taken as soon as possible, but not 
>2 business days from the time of receipt of the results and in these cases the 
Screening Period may be extended with the number of days necessary to meet the 
4-week (28-day) prior to Visit 2 stability requirement. 
• Over-the-counter, herbal, traditional, ayurvedic therapy, including vitamins, minerals 
and supplements. 
• Vitamin D supplementation at doses according to the local standard of care is to be 
initiated in patients with Vitamin D concentrations below the lower limit of normal at 
the Screening Visit. Dosing must be initiated immediately after the deficiency is 
identified and should be stable for at least 4 weeks prior to JTE-051 dosing initiation 
and throughout the study (in this situation, the duration of Screening Period may be 
extended beyond 28 days to ensure a duration of Vitamin D stability of 28 days). 
• Generally, every effort should be made to ensure that all other permitted 
chronically-administered concomitant medications are taken by subjects at stable 
dose/route of administration for at least 4 weeks (28 days) prior to Day 1, unless a 
change in dose/route of administration is considered medically necessary.  
 
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General Medication-related Protocol Instructions: 
 
• Generally, medication dose/route of administration changes or initiation of new 
medications during the conduct of the study is not recommended unless such actions 
are considered medically necessary, case when any appropriate action, according to 
the Investigator’s judgment should be taken; 
• All medications taken by the subject, including over-the-counter, herbal, traditional, 
ayurvedic compounds (whether permitted or excluded by the protocol) must be 
documented in the case report form (CRF); 
• Contact the Medical Monitor with questions regarding prior/concomitant therapy.  
3.5.4.2. 
General Restrictions 
• Joints that have been injected with corticosteroid medications within <6 weeks of the 
assessment, were replaced or are fused will not be included in the assessments. 
• Following enrollment in the study, subjects should continue all non-pharmacological 
therapies, such as physical therapy, as indicated and deemed appropriate for his/her 
physical condition. 
• Routine household contact with children or others vaccinated with live vaccine 
components (e.g., varicella, or attenuated typhoid fever, oral polio, attenuated 
rotavirus or inhaled flu vaccines) should be avoided during the study and for 6 weeks 
after the last dose of study drug. 
• Travel to countries with known high prevalence of tuberculosis should be avoided 
from the time of signing the Informed Consent through the Follow-up Visit. 
• Local standard recommendations (e.g., insect repellents) should be followed to 
minimize the risk of infection with the Zika virus in subjects enrolled in the study. 
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3.5.6. Procedure Definitions 
3.5.6.1. 
Efficacy Assessments 
3.5.6.1.1. 
Quantitative Joint Assessments (68/66) 
Standardized 68 and 66 joint counts will be performed for assessment of the number of 
tender and swollen joints, respectively, according to the schedule summarized in Table 1. 
See Figure 3 for a diagram of joints to be assessed as part of the 68/66 tender and swollen 
joint counts. Every effort should be made to ensure that the quantitative joint assessments 
is performed by an experienced, trained independent assessor, different from the Principal 
Investigator/Sub-investigator who is performing overall evaluation of the subject. The 
independent assessor must have medical training (e.g., he/she may be a medical doctor, 
physician assistant, nurse practitioner or registered nurse), must have performed RA joint 
assessments for clinical studies prior to the current study and must have undergone the 
joint count training provided by Akros or designee, as applicable. The same assessor 
should perform the counting for a specific subject throughout the study (scheduling of 
study subjects should take into account the assessor’s availability). In exceptional 
circumstances, if conditions do not permit the availability of the same assessor, an 
alternate assessor may perform the quantitative joint assessment provided that he/she 
meets that experience/training requirements as described above. These exceptions should 
be documented and communicated to the medical monitor. Additionally, every effort will 
be made to limit the number of assessors within a site (ideally, the same assessor will 
perform the quantitative joint assessments for all subjects at a site). See Section 3.5.4.2 
for the restrictions pertaining to the joints to be included in these assessments.  
Figure 3. 
Tender and Swollen Joint Counts (68/66) 
 
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3.6.6.1.1.1 
 Tender/Painful Joint Counts (68) 
Sixty-eight (68) joints will be assessed to determine the number of joints that are 
considered tender or painful. Artificial/missing/fused joints or joints that have received 
corticosteroid injection within 6 weeks of the assessment must not be included in the 
assessment.  
The 68 joints to be assessed are: 
• Upper Body: temporomandibular (2), sternoclavicular (2), acromioclavicular (2); 
• Upper Extremity: shoulder(2), elbow (2), wrist (2) (includes radiocarpal, carpal 
and carpometacarpal considered as one unit), metacarpophalangeals (MCP I[2], II[2], 
III[2], IV[2], V[2]), thumb interphalangeal (IP) (2), proximal interphalangeals (PIP 
II[2], III[2], IV[2], V[2]), distal interphalangeals (DIP II[2], III[2], IV[2], V[2]); 
• Lower Extremity: hip(2), knee(2), ankle(2), tarsus (includes subtalar, transverse 
tarsal and tarsometatarsal considered as one unit) (2), metatarsophalangeals (MTP 
I[2], II[2], III[2], IV[2], V[2]), great toe IP (2), proximal and distal interphalangeals 
combined (PIP II[2], III[2], IV[2], V[2]). 
3.6.6.1.1.2 
 Swollen Joint Counts (66) 
The joint assessor will also assess joints for swelling. Artificial/missing/fused joints or 
joints that have received corticosteroid injection within 6 weeks of the assessment must 
not be included in the assessment. 
The sixty-six (66) joints that will be assessed for swelling are the same as those listed 
above for tenderness/pain, except that the right and left hip joints are not included in the 
swollen joint count.  
3.5.6.1.2. 
Quantitative Joint Assessments (28) 
The 28 joints utilized for the calculation of certain efficacy parameters, such as Disease 
Activity Score (DAS)28, Clinical Disease Activity Index (CDAI) and Simplified Disease 
Activity Index (SDAI), see Appendix 5, are a sub-set of the 68/66 joints assessed per the 
instructions in Section 3.5.6.1.1 (see Figure 4); thus, the results of the above-described 
68/66 joint assessments applicable to the 28 joints should be utilized when reporting the 
28-joint assessment results (i.e., no re-assessment of the 28 joints will be done). 
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Figure 4. 
Tender and Swollen Joint Counts (28) 
 
3.5.6.1.2.1. Tender/Painful Joint Counts (28) 
The twenty-eight tender/painful joint count includes the following joints: shoulders (2), 
elbows (2), wrists (2), MCP joints (10), PIP joints (10) and knees (2).  
3.5.6.1.2.2. Swollen Joint Counts (28) 
The twenty-eight swollen joint count includes the same joints as those included in the 
tender joint counts. 
3.5.6.1.3. 
Subject’s Assessment of Arthritis Pain 
Subjects will assess the severity of their arthritis pain according to the schedule 
summarized in Table 1 using a numeric rating scale (NRS) with 0 representing “no pain” 
and 10 representing “pain as bad as it can be”. See Appendix 3 for a template in English 
of the NRS for subject pain assessment. Whenever available, the local language-validated 
tool will be utilized. 
3.5.6.1.4. 
Subject’s Global Assessment (SGA) of Disease Activity 
Using a 0 to 10 NRS format, subjects will assess their disease activity according to the 
schedule summarized in Table 1. See Appendix 3 for a template in English of the 
subject’s global assessment of disease activity scale. Whenever available, the local 
language-validated tool will be utilized. 
3.5.6.1.5. 
Physician’s Global Assessment (PGA) of Disease Activity 
The Investigator will assess the subject’s overall arthritis activity according to the 
schedule summarized in Table 1 using a 0 to 10 NRS format. This is an evaluation based 
on the subject’s disease signs, functional capacity and physical examination, and should 
be independent of the SGA of disease activity. See Appendix 3 for a template in English 
of the PGA of disease activity scale. Whenever available, the local language-validated 
tool will be utilized. 
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3.5.6.1.6. 
Health Assessment Questionnaire Disability Index (HAQ-DI) 
The HAQ-DI assesses the extent of the subject’s functional ability by assessing the degree 
of difficulty a subject has experienced during the past week in eight categories of daily 
living activities: dressing and grooming, arising, eating, walking, hygiene, reach, grip, 
and common daily activities. Each category has at least two sub-category questions. The 
subjects report the amount of difficulty they have in performing some of these activities. 
The HAQ-DI is designed to assess the subject’s usual ability during the past week, not a 
particularly good or bad day. This questionnaire should be completed by the subject prior 
to any procedures being performed at the visit, if possible. The form should then be 
checked by the site staff for completeness. See Appendix 4 for the Stanford University 
School of Medicine, Division of Immunology & Rheumatology Health Assessment 
Questionnaire Worksheet and for instructions on handling the responses by the 
Investigator, as well as the scoring process that will be performed by the Sponsor. 
3.5.6.1.7. 
High-sensitivity C-reactive Protein 
The blood samples for hs-CRP measurements will be collected according to the schedule 
summarized in Table 1 and will be analyzed by the central laboratory. 
3.5.6.1.8. 
C-reactive Protein 
The blood samples for CRP measurements utilizing the non-high sensitivity method will 
be collected at Visit 2 and Visit 6 and will be analyzed by the central laboratory. 
3.5.6.2. 
Medical History 
A complete medical history will be obtained at the Screening Visit (Visit 1) and will 
include evaluations for past or present conditions. 
 
 
 Stable or improving pre-existing conditions that are 
detected as part of the screening procedures (e.g., ECG, physical examination, 
, vital signs, and laboratory test abnormalities) are considered to 
be medical history. 
3.5.6.3. 
Prior/Concomitant Medications 
Information pertaining to all medication use (including prescription, over-the-counter, 
supplements, vitamins and minerals) will be collected for the period of at least 30 days 
prior to the Screening Visit (Visit 1) and throughout the study. For medications excluded 
for a longer than a 30-day period, as described in Section 3.5.4.1, the timeframe for 
collecting this information will be extended to cover at least the exclusion period. 
With respect to the use of corticosteroids, detailed information (including but not limited 
to dose, route, indication, duration of administration) will be obtained. Every effort 
should be made to document this information from the time of first use by the subject, 
with focus on chronic use of these agents (i.e., having a duration of ≥ 2 weeks); 
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nonetheless, for the period within 30 days prior to Visit 1, all corticosteroid use 
(including short-term) will be documented. 
3.5.6.4. 
Physical Examination 
Physical examinations will be performed by a physician or qualified designee according 
to the schedule summarized in Table 1 and will include examination of the following 
body systems: general appearance, skin (including hair and nails), HEENT (head, ears, 
eyes, 
nose, 
throat), 
neck/thyroid, 
chest/lungs, 
cardiovascular, 
gastrointestinal, 
, psychiatric/emotional, lymphatic, and musculoskeletal.  
3.5.6.6. 
Height and Weight Measurements, and BMI Calculation 
Height and weight measurements will be performed according to the schedule 
summarized in Table 1. Subjects will remove their shoes and wear light clothing in order 
to be consistent between measurements of height and weight. Body mass index will be 
calculated at the Screening Visit (Visit 1) using the following equation:  
(weight (kg) / height [m2]), where the weight in kilograms will be documented to one 
decimal place and the height in centimeters will be rounded to the nearest whole number.  
3.5.6.7. 
Vital Signs 
Vital sign assessments including blood pressure, pulse rate, respiratory rate and body 
temperature (°C) will be performed in a sitting position according to the schedule 
summarized in Table 1. Subjects must rest in a sitting position for at least 5 minutes in 
preparation for blood pressure and pulse rate assessments. 
3.5.6.8. 
12-Lead ECG  
Twelve-lead ECG recordings and conduction intervals including the interval from 
beginning of the QRS complex in the frontal plane to the next QRS complex (RR), the 
interval from beginning of the P wave to the beginning of the QRS complex in the frontal 
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plane (PR), duration of QRS complex in the frontal plane (QRS), interval from beginning 
of the QRS complex to end of the T wave in the frontal plane (QT), and 
Fridericia-corrected QT interval (QTcF) will be obtained according to the schedule 
summarized in Table 1. Subjects will lay supine for at least 5 minutes prior to the 12-lead 
ECG assessments. 
3.5.6.9. 
Hematology  
Blood samples to assess complete blood count including erythrocytes, hematocrit, 
hemoglobin, platelets, leucocytes and differential (percent and absolute [neutrophil, 
eosinophil, basophil, lymphocyte, monocyte]) will be obtained under fasted conditions 
according to the schedule summarized in Table 1. 
3.5.6.10. 
Serum Biochemistry  
Blood samples to assess serum ALT, albumin, alkaline phosphatase (ALP), AST, 
bilirubin, BUN, calcium, carbon dioxide, chloride, creatine kinase, creatinine, 
gamma-glutamyl transferase, globulin, glucose, lactate dehydrogenase, phosphate, 
potassium, protein, sodium and urate will be obtained according to the schedule 
summarized in Table 1. The eGFR will be calculated at each study visit by the central 
laboratory using the MDRD equation. 
3.5.6.11. 
Bone-specific Alkaline Phosphatase 
Blood samples to measure bone-specific alkaline phosphatase will be obtained according 
to the schedule summarized in Table 1. 
3.5.6.12. 
Lipid Panel  
Blood samples to measure cholesterol, low-density lipoprotein cholesterol (LDL-C), 
high-density lipoprotein cholesterol (HDL-C) and triglycerides will be obtained according 
to the schedule summarized in Table 1. 
3.5.6.13. 
25-hydroxyvitamin D 
Blood samples to measure 25-hydroxyvitamin D will be obtained at the Screening Visit. 
3.5.6.14. 
Rheumatoid Factor, Anti-cyclic citrullinated peptide antibodies, 
Serum Immunoglobulins G, M and A 
Blood samples to measure the rheumatoid factor (RF), anti-cyclic citrullinated peptide 
(anti-CCP) antibodies and serum immunoglobulins G, M and A (IgG, IgM and IgA) will 
be obtained at the Screening Visit. 
3.5.6.15. 
Coagulation 
Blood samples to assess prothrombin time (PT) and activated partial thromboplastin time 
(aPTT) will be obtained according to the schedule summarized in Table 1. International 
normalized ratio will also be calculated. 
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3.5.6.16. 
Viral Serology 
Blood samples to assess HBsAg, HBc antibodies, HCV antibodies, and HIV antibodies 
will be obtained at the Screening Visit (Visit 1). 
3.5.6.17. 
Pregnancy Test 
Pregnancy tests to assess βHCG levels will be performed for all female subjects. Blood 
samples will be collected at the Screening Visit (Visit 1) for a serum pregnancy test. At 
Visits 2 through 7, urine pregnancy tests will be performed at the site. Pregnancy tests 
may also be repeated as needed, per request from IRBs/IECs or if required by local 
regulations. 
3.5.6.18. 
Follicle-stimulating Hormone 
Blood samples to assess the menopausal status will be collected at the Screening Visit 
(Visit 1) from all female subjects who report a history compatible with menopause with 
no other identified biological/surgical cause.  
3.5.6.19. 
Drugs of Abuse and Alcohol Screen  
Urine samples to assess amphetamine, barbiturates, benzodiazepine, cannabinoids, 
cocaine, ethanol, opiates, oxycodone and methadone will be obtained at the 
Screening Visit (Visit 1).  
3.5.6.20. 
Tuberculosis Screening 
The Mantoux skin test (also known as the PPD test) or the Quantiferon®-TB 
Gold-In-Tube test (according to the local SOC) may be used as tuberculosis screening 
tools for the study during the Screening Period.  
If the Mantoux test is selected, the reaction must be read between 48 and 72 hours after 
administration (a subject that does not return after 72 hours must be rescheduled for a 
repeat Mantoux test). The reaction will be measured in millimeters of the induration 
(palpable, raised, hardened area or swelling). The reader will not measure erythema 
(redness). The diameter of the indurated area will be measured across the forearm 
(perpendicular to the long axis). An induration of 5 or more millimeters is considered 
positive. 
If the Quantiferon®-TB Gold-In-Tube test is performed, blood samples will be collected, 
processed and shipped during the Screening Period, according to the laboratory 
instructions. In the case of an indeterminate Quantiferon®-TB Gold-In-Tube test, the test 
may be repeated up to one time if results can be obtained in time prior to Visit 2. If the 
retest is also indeterminate, the PPD test may be performed and, if negative, the subject 
may be randomized into the study, however re-training of the applicable parties at the site 
and/or central laboratory level should be considered. 
Subjects who have had household contact with a person with active tuberculosis are 
excluded, unless appropriate/documented prophylaxis for tuberculosis was administered. 
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3.5.6.21. 
Chest Radiography 
Chest radiography to include two views (anterior-posterior and lateral) will be obtained 
during the Screening Period in all subjects. If an adequate chest radiography has been 
performed within 3 months (12 weeks) prior to the Screening Visit and documentation 
(including interpretation of TB status) is available and is provided to the Investigator to 
review and file in the subject’s file, that radiography may be utilized to determine 
eligibility of the subject. To be considered eligible for the study, the radiography must be 
negative for active tuberculosis infection; however the Investigator may decide to exclude 
the subjects based on clinically-significant chest radiography findings other than 
tuberculosis (e.g., due to an acute or chronic inflammatory process), according to his/her 
judgment.  
3.5.6.22. 
Urinalysis  
Urine samples to assess bilirubin, occult blood, color, glucose, ketones, leukocyte 
esterase, nitrite, pH, protein, specific gravity, turbidity, and urobilinogen, as well as for a 
microscopic exam (in case of positive macroscopic findings only) will be obtained under 
fasted conditions according to the schedule summarized in Table 1.  
 
3.5.6.24. 
Pharmacokinetic Procedures 
3.5.6.24.1. 
Blood Samples for Pharmacokinetic Assessments 
Blood samples for the quantification of plasma JTE-051 will be collected, according to 
the schedules summarized in Table 1. Trough PK blood samples will be collected in the 
fasted state at pre-specified study visits.  
The actual date and time of the last dose of study drug prior to the PK sample collection, 
as well as the sample collection date and time will be documented for PK data analysis. 
Refer to the laboratory manual for specific instructions for the collection, processing, 
storing and shipping of blood samples for PK assessments. 
3.5.6.24.2. 
Analysis of JTE-051 in Plasma 
JTE-051 in plasma will be analyzed using a validated LC-MS/MS method. 
The laboratory performing the JTE-051 plasma concentration assessments will be 
unblinded to facilitate analysis of only the samples from the JTE-051-treated subjects. 
Plasma samples from placebo subjects may be analyzed as needed. 
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3.5.7. Clinical Institutions and Laboratories 
This study will be conducted by: 
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3.6. 
Adverse Events 
3.6.1. Safety Definitions 
Akros complies with the following International Conference on Harmonisation (ICH) AE 
definitions: 
Adverse Event: An AE is any untoward medical occurrence in a patient or clinical 
investigation subject administered a pharmaceutical product and which does not 
necessarily have a causal relationship with this treatment. An AE can therefore be any 
unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or 
disease temporally associated with the use of a medical (investigational) product, whether 
or not related to the medical (investigational) product.  
Serious Adverse Event: As provided by the ICH criteria, an SAE is any adverse drug 
experience occurring at any dose that results in any of the following outcomes: 
• death 
• a life-threatening adverse drug experience 
• inpatient hospitalization or prolongation of existing hospitalization 
• a persistent or significant disability/incapacity 
• a congenital anomaly/birth defect 
• other important medical event 
Note: Important medical events that may not result in death, be life-threatening, or 
require hospitalization may be considered a serious adverse drug experience when, based 
upon appropriate medical judgment, they may jeopardize the patient or subject or may 
require medical or surgical intervention to prevent one of the outcomes listed in this 
definition. Examples of such medical events include allergic bronchospasm requiring 
intensive treatment in an emergency room or at home, blood dyscrasias or convulsions 
that do not result in hospitalization, or the development of drug dependency or drug 
abuse.  
Adverse Reaction: All noxious and unintended responses to an investigational medicinal 
product (IMP) related to any dose administered. 
Note: The phrase "responses to a medicinal product" means that a causal relationship 
between the medicinal product and an adverse event is at least a reasonable possibility, 
i.e., the relationship cannot be ruled out. 
Unexpected Adverse Drug Reaction: An adverse reaction, the nature (specificity) or 
severity of which is not consistent with the applicable product information 
(e.g., Investigator's Brochure). 
Death: Death represents an outcome and a SAE criterion, not an event term. The medical 
condition with the fatal outcome should be reported unless the cause of death is unknown, 
in which case the term “Death” is acceptable. 
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Inpatient Hospitalization/Prolongation of Hospitalization: Any admission (even if 
less than 24 hours) to a healthcare facility. Admission also includes transfer within the 
hospital to an acute/intensive care unit (e.g., medical floor to the coronary care unit). 
Initial and prolonged hospitalizations that do not meet this SAE criterion include those 
due to social and/or convenience reasons (e.g., lack of personal care at home, unable to 
transfer to non-acute facility), admission to rehabilitation/hospice/skilled nursing 
facilities, emergency room visits, same-day/outpatient/ambulatory procedures, and those 
for pre-planned, elective procedures for a pre-existing condition that did not worsen after 
the informed consent has been signed (no AE present). However, if the hospitalization 
was prolonged due to a complication of a pre-existing condition, the complication 
(diagnosis of same) would qualify as an SAE. 
Disability: A substantial disruption of a person’s ability to conduct normal life functions. 
Life-threatening: Any adverse drug experience that places the patient or subject, in the 
view of the Investigator, at immediate risk of death from the reaction as it occurred, i.e., it 
does not include a reaction that had it occurred in a more severe form, might have caused 
death. 
Physical Examination, 
 Vital Signs, Laboratory Test and 
ECG Abnormalities: Any abnormalities fulfilling the criteria for an SAE should be 
reported as such, in addition to being recorded as an AE in the CRF. Any abnormal vital 
sign, physical 
 finding or laboratory/ECG result which is 
clinically significant (i.e., meets one or more of the following conditions) should be 
recorded as a single diagnosis on the AE page in the CRF: 
• Accompanied by clinical symptoms 
• Leads to permanent discontinuation of study drug 
• Requires a change in concomitant therapy (e.g., addition of, interruption of, 
discontinuation of, or any other change in a concomitant medication, therapy or 
treatment). 
This does not apply to abnormal vital signs, physical finding or laboratory/ECG results 
that do not meet the clinical significance criteria or those which are a result of an AE 
which has already been reported. 
Pre-existing conditions that are detected at the Screening Visit (Visit 1), including 
abnormalities in ECG, physical examination, n
 vital signs, and 
laboratory tests, are considered to be medical history. 
3.6.2. Assessing Adverse Events 
When completing appropriate forms for reporting the AE, the Investigator will be asked 
to assess the AE as follows: 
Seriousness of Adverse Event: 
• Serious: The AE meets a criterion of the SAE definition. 
• Not Serious: The AE does not meet a criterion of the SAE definition. 
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Severity of Adverse Event:  
• Mild: No interference with functioning. 
• Moderate: No significant interference with functioning. 
• Severe: Significant interference with functioning. 
Relationship of Adverse Event (Causality):  
The Investigator’s causality assessment is the determination whether there is a reasonable 
possibility that the IMP caused or contributed to the adverse event. Generally, the facts 
(evidence) or arguments to suggest causal relationship should be documented. Factors to 
be taken into consideration when assessing causality include: subject’s underlying and 
pre-existing conditions, prior/concomitant medications, timing of onset relative to study 
drug administration, the known PK characteristics of JTE-051, the currently-known safety 
profile 
of 
JTE-051, 
known 
class 
effects 
of 
similar 
MOA 
drugs, 
the 
de-challenge/re-challenge response (if available) and any other information that is 
considered relevant by the Investigator. 
Akros Pharma Inc. evaluates the relationship of an AE to the study drug using the 
following three categories: 
• Not Related  
• Possibly Related 
• Related 
Action Taken with Regard to Study Drug: 
Akros Pharma Inc. evaluates the action taken with the treatment product and/or 
interacting product using the following four definitions: 
• Dose Not Changed: The subject was on treatment with the study drug when the 
AE occurred, and the study drug dosing was maintained at the same dose level 
• Drug Interrupted: The subject was on treatment with the study drug when the 
AE occurred, and the study drug dosing was temporarily discontinued and then 
re-started 
• Drug Withdrawn: The subject was on treatment with the study drug when the 
AE occurred, and the study drug dosing was permanently discontinued  
• Not Applicable: The subject was not receiving treatment with the study drug 
when the AE occurred (i.e., AE occurred before the first study drug 
administration or after the last study drug administration) 
Other Action Taken:  
• None 
• Additional Treatment Given for the AE 
• Therapeutic/ Diagnostic Procedure 
• Other (including discontinuation/reduction of a concomitant medication due to 
the AE)  
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Outcome to Date: 
• Not Recovered/Not Resolved: The subject has not yet recovered from the AE; 
the event has not improved (follow-up of all serious AEs will be continued 
until the overall clinical outcome has been ascertained). 
• Recovering/Resolving: The subject has not yet recovered from the AE, 
however, the event is improving (follow-up of all serious AEs will be 
continued until the overall clinical outcome has been ascertained).  
• Recovered/Resolved: The subject recovered from the AE with no sequelae. 
• Recovered/Resolved with Sequelae: The subject recovered from the AE with 
sequelae. 
• Fatal: The subject’s death was a result of the AE.  
3.6.3. Reporting Adverse Events  
Adverse Events Reporting  
Adverse events occurring (initial occurrence or a worsening of a pre-existing condition) 
after the informed consent has been signed and up to 4 weeks (28 days) after the last dose 
of study drug will be reported and included in the study database. However, pre-existing 
conditions detected as part of the screening procedures should be documented as medical 
history. Adverse events will be reported on the AE CRF page.  
Serious Adverse Event Reporting 
Reporting by Investigators 
Detailed instruction regarding SAE reporting will be provided in the appropriate 
documents outside of this protocol. A brief, non-all-inclusive summary is provided below. 
Any SAE experienced by a study subject after signing the informed consent to 28 days 
after the last dose of study drug will be reported to the Sponsor or designee. Additionally, 
SAEs that occur after this period will also be reported to the Sponsor or designee if the 
Investigator considers the SAE related to the study drug. 
Serious adverse events (both initial reports and follow-up information) must be reported 
to the Sponsor or designee within 24 hours of the Investigator’s (site’s) awareness or 
notification of the event. 
The Investigators should make every effort to provide complete information when 
reporting the SAE (both for initial reports, as well as for follow-ups).  
The Investigator must continue to follow the subject until the SAE has subsided, the 
condition becomes chronic in nature, stabilizes (in the case of persistent impairment), or 
the subject dies. Within 24 hours of receipt of follow-up information, the Investigator 
must submit it to the Sponsor or designee. 
The Investigator is also required to submit SAE reports to the IRB/IEC in accordance 
with local requirements. All investigators involved in studies using the same IMP will 
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receive any Suspected Unexpected Serious Adverse Reaction (SUSAR) reports for 
onward submission to their local IRB/IEC as required. All reports sent to investigators 
will be blinded. 
Reporting by the Sponsor 
Competent authorities and IRBs/IECs will be informed by the Sponsor or designee of 
SUSARs according to the local requirements. Additionally, all SUSARs will be reported 
by the Sponsor or designee into the EudraVigilance system, as appropriate. Cases will be 
unblinded by designated personnel for reporting purposes as required. 
Exposure in Utero Reporting: 
If a female subject becomes pregnant or the female partner of a male subject participating 
in the study becomes pregnant after the subject receives the first dose of study drug, or 
within 28 days of discontinuing study drug, the Investigator should report the pregnancy 
to the Sponsor or designee within 24 hours of being notified.  
The subject/partner should be followed by the Investigator until completion of the 
pregnancy. If the pregnancy ends for any reason before the anticipated date, the 
Investigator should notify the Sponsor or designee. At the completion of the pregnancy, 
the Investigator will document the outcome of the pregnancy. If the outcome of the 
pregnancy meets the criteria for immediate classification as an SAE (i.e., spontaneous 
abortion, stillbirth, neonatal death, or congenital anomaly), the Investigator should follow 
the procedures for reporting an SAE as described above. 
Overdose Reporting: 
An overdose is a significant variation from the recommended/scheduled dosage for a 
product. For the purposes of this study, overdose is defined by any confirmed use of 
blinded study medication of more than four tablets once a day. If such situations occur, 
the Investigator should provide additional training to the subject on study drug dosing 
instructions and emphasize the importance of compliance. Currently there is no known 
antidote to JTE-051, thus appropriate symptomatic and/or supportive care is to be 
provided at the Investigator’s discretion, as needed. The subject’s continued eligibility 
will be left to the judgment of the Investigator. 
Information on overdoses in subjects is collected by the Sponsor or designee. Should a 
subject experience an overdose during the course of the study, the investigator or 
qualified designee must report the overdose as soon as possible, but not later than the 
timeframe requested by the Sponsor or designee after the investigator or qualified 
designee first becomes aware of the overdose. Instructions will be provided on how to 
collect this information. 
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3.7. 
Identification of Treatments  
3.7.1. Method of Assigning Subjects to Treatment Groups 
At the Screening Visit (Visit 1), each site will assign potential study subjects an 
eight-character subject number. This number will consist of a four-digit site number (with 
the first two digits representing the country-specific number and the next two digits 
representing the site-specific number) and a three-digit subject number assigned in a 
sequential manner. The hyphen between the site and subject number will account for the 
eighth character. This number will represent the subject’s identifier throughout the study. 
Following confirmation of eligibility at Visit 2, the Interactive Web Response System 
(IWRS) will be contacted by the site and it will assign the subject a four-digit 
randomization number that will correspond to a randomly assigned treatment group. 
3.7.2. Identity of Investigational Products  
 
3.7.3. Storage and Handling Procedures 
The JTE-051 and placebo tablets should be stored at room temperature between 20 and 
25°C (United States Pharmacopeia [USP]) and in a secure location with restricted access.  
3.7.4. Clinical Supplies Packaging 
Each site will receive a supply of double-blind study drug packaged as blister cards 
corresponding to 8 days of QD dosing. Each blister card will contain a total of 
32 JTE-051 tablets.  
Study drug blister cards may be labeled with the following information, as appropriate: 
• Sponsor identity and protocol number 
• Card number 
• Dosing instructions 
• Spaces for site personnel to add subject number and subject initials 
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• Spaces for site personnel to add visit number, site number, and Investigator name 
• Spaces for site personnel to add the card identifier, as appropriate 
• Quantity and identity of contents 
• Lot number and storage conditions 
• Expiration date 
• For investigational use only statement 
The planned blister card allocation of tablets for each dose, broken down by treatment 
group, is provided below. 
Treatment 
Group 
Tablet 1 
Tablet 2 
Tablet 3 
Tablet 4 
JTE-051 50 mg 
JTE-051 50 mg 
JTE-051 Placebo 
JTE-051 Placebo 
JTE-051 Placebo 
JTE-051 100 mg 
JTE-051 50 mg 
JTE-051 50 mg 
JTE-051 Placebo 
JTE-051 Placebo 
JTE-051 150 mg 
JTE-051 50 mg 
JTE-051 50 mg 
JTE-051 50 mg 
JTE-051 Placebo 
JTE-051 200 mg 
JTE-051 50 mg 
JTE-051 50 mg 
JTE-051 50 mg 
JTE-051 50 mg 
Placebo 
JTE-051 Placebo 
JTE-051 Placebo 
JTE-051 Placebo 
JTE-051 Placebo 
3.7.5. Administration of Study Drug 
During the Treatment Period, beginning on the day of Visit 2, subjects will 
self-administer one dose of study drug (4 tablets) daily for 12 weeks. Study drug will be 
taken once daily in the morning, regardless of meals. On the day of scheduled study visits, 
subjects should not take study drug prior to arriving to the study site. At the site, study 
drug will be administered from the previously supplied non-back-up blister card, if 
available, after all study procedures have been completed. If no tablets from the 
previously supplied non-back-up blister cards are available, then the subject should dose 
from the new non-back-up blister card supplied at that visit. The back-up study drug 
blister card should only be utilized by subjects if all study drug from the 
regularly-supplied (non-back-up) blister cards has been used. 
Randomized subjects will receive two study drug blister cards at Visits 2 and 3, 
respectively. Subjects will receive four blister cards each on Visits 4 and 5. Additionally, 
at Visit 2, all subjects will receive a back-up blister card (identical in appearance with the 
other blister cards) for use as needed throughout the study. The back-up blister card may 
be identified at the site level and subjects will be instructed to utilize all tablets from the 
other (non-back-up) blister cards before initiating tablet use from the back-up blister card. 
The subjects will be instructed to return the clinical supplies (full, partially full, and 
empty blister cards, including the back-up blister card) at Visits 3, 4, 5 and 6 for 
accountability and compliance assessment. Following completion of accountability and 
compliance assessments, the back-up blister card will be re-dispensed at Visits 3 through 
5 and will be collected at Visit 6 along with all non-back-up blister cards. 
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In the event that the subject does not take the study drug on a given day during the 
Treatment Period, the subject should not take more than the daily dosage on the following 
treatment day. 
3.7.6. Management of Clinical Supplies 
The Investigator will have responsibility for the control and proper distribution of all 
study drug (including any investigational product or reference product) in accordance 
with this protocol. The Investigator is responsible for ensuring that all study drug will be 
stored at the site at recommended storage temperatures and conditions, in a secured area, 
free of environmental extremes, with restricted access. The Investigator also ensures that 
all study drug will be dispensed only to study subjects who have provided written 
informed consent and have met all entry criteria. 
Study drug accountability will be performed by the Investigator or designee at each study 
visit during the Treatment Period, according to the schedule of procedures presented in 
Table 1. Study drug compliance will be assessed and documented per GCP. 
3.7.7. Randomization 
Approximately 250 eligible subjects with active RA will be randomized into this study. 
Subjects will be randomized in a 1:1:1:1:1 ratio (50 subjects per treatment group) to 
receive JTE-051 50 mg, JTE-051 100 mg, JTE-051 150 mg, JTE-051 200 mg or placebo 
once daily. Randomization will be stratified by region and by the screening hs-CRP level 
(the qualifying hs-CRP value must be utilized). 
An IWRS will be employed for the randomization activities. It will use a stratified 
randomization algorithm that takes into account the strata specified above. 
The randomization code will be controlled by an unblinded member of the Sponsor or 
designee who will provide the randomization code to select laboratories, see 
Section 3.7.8.  
3.7.8. Blinding  
This study is double-blind (i.e., the treatment assigned to each subject will not be 
disclosed to the Sponsor members or designees involved in the study, study staff at the 
site or to the subject). The JTE-051 50 mg tablets, as well as the placebo tablets will be 
supplied as unbranded tablets which are identical in appearance.  
The laboratory performing the JTE-051 plasma concentration assessments will be 
unblinded to facilitate analysis of only the samples from the JTE-051-treated subjects. 
Plasma samples from placebo-treated subjects may be analyzed as needed (see 
Section 3.5.6.24). 
3.7.9. Breaking the Blind 
The study drug code may be broken by the Investigator for a particular subject only in the 
event of a serious adverse experience, which the Investigator feels cannot be adequately 
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treated without knowing the identity of the study drug by using the IWRS. Every effort 
must be made to contact the Sponsor’s Medical Monitor prior to breaking the code. If this 
is not possible and the situation is an emergency, the Investigator may break the blind to 
identify the treatment assignment for the specific subject only and must contact the 
Sponsor’s Medical Monitor as soon as possible thereafter. The Sponsor may also elect to 
break the blind for cause. If the blind is broken, appropriate documentation should be 
completed as soon as possible. 
Additionally, breaking of the blind may be performed by designated members of 
pharmacovigilance group not involved in the clinical conduct of the study for regulatory 
reporting purposes, as appropriate.  
3.8. 
Statistical Methods 
This section provides an abbreviated statistical analysis plan (SAP) for the efficacy and 
safety parameters. A formal SAP will be developed at a later time. Statistical issues not 
addressed in the present section may be developed in the formal SAP. The plans outlined 
in this section may be modified in the SAP; however, any major modifications of the 
primary endpoint definition and/or its analysis may also be reflected in a protocol 
amendment, as appropriate. Other deviations to the SAP will be discussed in the study 
report. 
3.8.1. Subject Population for Analysis 
3.8.1.1. 
Randomized Population 
The randomized population consists of all subjects who are randomized at Visit 2 to one 
of the five treatment groups: JTE-051 50 mg QD, 100 mg QD, 150 mg QD, 200 mg QD 
and matching placebo QD. 
3.8.1.2. 
Safety Population 
Safety population consists of the randomized subjects who receive at least one dose of the 
study drug (the actual received drug will be considered).   
3.8.1.3. 
Intent-To-Treat (ITT) Population 
The ITT population consists of the randomized subjects who receive at least one dose of 
the study drug per randomization. 
3.8.1.4. 
Per Protocol (PP) Population 
The PP population is a subset of the ITT population in which subjects do not have any 
major protocol deviations. A pre-analysis meeting will take place after all data have been 
entered into the database and cleaned, but before the release of the randomization code, to 
identify the PP population. The decisions made to select the PP population will be 
documented. 
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3.8.1.5. 
Pharmacokinetic Population 
The PK population consists of the randomized subjects who receive at least one dose of 
JTE-051 and have at least one usable JTE-051 plasma concentration measurement. 
3.8.1.6. 
Sample Size 
Approximately 250 eligible subjects (50 in each treatment group) will be randomized into 
the DB treatment period of this study.   
The primary efficacy evaluation will be to compare the ACR20 response rate between 
JTE-051 with placebo at EOT. From one study comparing marvilimumab with placebo in 
combination with stable methrotrexate26, the ACR20 of marvilimumab and placebo at 
Week 12 were 0.69 and 0.40, respectively. Assuming the ACR20 of at least one of the 
JTE-051 doses to be at least 0.30 above placebo, the following sample size per group will 
be needed to detect a statistical significant difference at the 5% level with about 80% 
power (using 2-sided Fisher’s exact test): 
 
 
 
 
About 50 randomized subjects per group would therefore give at least an 80% power for a 
range of placebo responses. The sample size calculation was carried out using the 
software SiZ 6.2 (Cytel Inc., 2013). 
3.8.2. Interim Analysis 
No interim analysis is planned for the study. 
3.8.3. Efficacy Analyses 
The ITT population will be used for all efficacy data analysis. The analysis of the primary 
efficacy parameter will be repeated on the PP population if it excludes 20% or more of 
the subjects from the ITT population. Additional efficacy parameter analyses using the PP 
population and/or other sub-population may be performed if deemed appropriate.  
3.8.3.1. 
Efficacy Parameters 
The primary efficacy parameter is the ACR20 response rate at EOT. 
The secondary efficacy parameters are (evaluated at Weeks 2, 4, 8, 12 and 16 
respectively, unless otherwise stated): 
• Percentage of subjects achieving ACR20/50/70 response rate  
• Change from baseline in SDAI 
• Percentage of subjects who achieved remission based on SDAI (≤3.3) 
• Percentage of subjects who achieved low disease activity based on SDAI (≤11)  
• Change from baseline in CDAI 
• Percentage of subjects who achieved remission based on CDAI (≤2.8) 
• Percentage of subjects who achieved low disease activity based on CDAI (≤10)     
• Percentage of subjects achieving Boolean Remission 
• Change from baseline in DAS28-CRP 
Placebo ACR20 
0.25 
0.35 
0.45 
Sample size per group 
47 
48 
47 
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• Percentage of subjects with DAS28-CRP of <2.6  
• Percentage of subjects with DAS28-CRP of <3.2 
• Percentage of subjects with good EULAR response at Week 12 
• Percentage of subjects with moderate EULAR response at Week 12 
• The ACR-N index 
• Change from baseline in HAQ-DI 
• Change from baseline in the number of tender and swollen joint counts (68/66 
joints will be counted) 
• Change from baseline in subject pain score by NRS  
• Change from baseline in SGA of disease activity by NRS 
• Change from baseline in PGA of disease activity by NRS 
• Change from baseline in hs-CRP 
3.8.3.2. 
Efficacy Data Analysis 
For the purpose of efficacy analysis, the EOT value is defined as the last value taken 
during the DB treatment period after the first dose of study drug without any treatment 
intervention. For subjects who receive rescue treatment, the last value prior to the 
intervention will be defined as the EOT. 
For the primary efficacy parameter (ACR20 at EOT), the Fisher’s exact test will be used 
to compare each JTE-051 dose group with placebo. Furthermore, the exact 
Cochran-Armitage trend test27 will be computed, using the ordinal score for treatment, 
e.g., score 1 for placebo, score 2 for the lowest JTE-051 dose, etc. 
For dichotomous secondary efficacy parameters, similar analyses as the primary efficacy 
parameter will be used by time point, i.e., the Fisher’s exact test for pairwise comparisons 
with placebo and the Cochran-Armitage test for trend. 
 
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For continuous efficacy parameter analysis with multiple time points, a mixed effect 
model will be employed. It includes fixed effects for treatment, time, treatment by time 
interaction, the stratification factors and the appropriate baseline, and subject as the 
random effect. The appropriate baseline will be the parameter from which the efficacy 
parameter is derived, e.g., SDAI at Week 0 for the analysis of change from baseline in 
SDAI. The treatment effect of each JTE-051 dose group relative to placebo at the same 
time point will be estimated. A linear trend test at each time point will be computed using 
appropriate linear contrast. 
All analyses will be performed two-sided at the 5% significance level. No formal multiple 
comparison adjustment will be made, therefore results should be interpreted with the 
multiplicity in mind. The estimated treatment effect (relative to placebo) from the model, 
along with a two-sided 95% CI and p-value, will be tabulated where appropriate. The 
Newcombe’s CI of the rate difference28 between JTE-051 dose and placebo will be 
computed when performing the Fisher’s exact test. Graphical presentations of the 
treatment profile may be depicted. Sensitivity analysis, model fit assessment may be 
conducted and data transformation may be employed if appropriate. 
Descriptive statistics of efficacy parameters over time will be presented by treatment. 
They will include the number of subjects (N), arithmetic mean, standard deviation (SD), 
median, minimum and maximum for continuous parameters, and in frequency tabulation 
form for dichotomous parameters. 
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3.8.3.3. 
Treatment by Center Effect 
The randomization of this study is stratified by region and by the screening hs-CRP level. 
Center effect is not considered due to the expectation that many centers will be used and 
only a small number of subjects will be enrolled in most centers. The region effect will be 
included in the analysis model where appropriate. 
3.8.3.4. 
Treatment by Baseline Covariate Effect 
The treatment-by-baseline effect is not considered, however the baseline will be included 
in the respective parametric analysis model of the efficacy parameters where appropriate.  
3.8.3.5. 
Subgroup Analysis 
Subgroup analyses may be performed if appropriate. 
3.8.3.6. 
Handling of Dropouts or Missing Data 
Some efficacy parameters are a composite value derived from a complex instrument. The 
chance that one of its components is missing increases greatly due to various reasons. In 
order to minimize missing data, algorithms will be prepared to compute the derived value 
where reasonable in case some of the components are missing. These algorithms will be 
described in the SAP. 
There will be missing data however, either intermittent like a missing visit or due to 
subject dropout. For dichotomous efficacy parameters analysis by time point, subjects 
with missing data will not be included in the analysis. For analysis with multiple time 
points, any missing data will be imputed using the last observation carried forward 
(LOCF) method except for subjects who withdraw for reasons related to treatment. In the 
latter case, any value after withdrawal will be imputed as treatment failure. For 
parameters analyzed both by time point and with multiple time points, these two 
approaches would strengthen the findings when they are similar. 
For continuous efficacy parameters, no imputation will be employed. This is because the 
mixed effect model gives valid estimates if the missing data mechanism is “missing at 
random”, a common assumption made as the first approach for analysis. 
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Other missing data imputation methods may be employed for additional sensitivity 
analysis if deemed necessary. 
3.8.4. Safety Analyses 
The safety population will be used for the safety data analysis unless otherwise stated. 
3.8.4.1. 
Safety Parameters 
The safety parameters are: 
• 
Adverse events 
• 
Clinical laboratory safety tests  
• 
Vital signs, ECG parameters 
3.8.4.2. 
Safety Data Analysis 
Descriptive statistics of vital signs, ECG parameters, and clinical laboratory data will be 
presented by treatment in tabular form with N, arithmetic mean, SD, median, minimum 
and maximum, or in frequency tabulation form as appropriate. For continuous 
parameters, change from baseline will be summarized by treatment as appropriate. 
Potentially clinically significant values for vital signs, ECG, and laboratory data will be 
flagged in data listings and may be summarized as appropriate. 
All safety data will be presented in the data listings, and will be flagged for events of 
interest (e.g., out of range laboratory data) as appropriate. 
Adverse events will be coded using the Medical Dictionary for Regulatory Activities 
(MedDRA) and will be summarized by system organ class and preferred term. 
Other safety parameters will be summarized as appropriate. 
3.8.5. Pharmacokinetic Analyses 
The PK population will be used for the PK data analysis unless otherwise stated. 
3.8.5.1. 
Pharmacokinetic Parameters 
The PK measurements are: 
• 
Trough concentrations (Ctrough) of JTE-051 will be measured at each visit during 
the Treatment Period; 
• 
Population PK parameters for JTE-051 may be generated using population PK 
analysis.  
3.8.5.2. 
Pharmacokinetic Data Analysis 
If data allow, population PK analysis will be performed using plasma concentration data 
of JTE-051. Population estimates of PK parameters of JTE-051 such as the apparent oral 
clearance of drug following extravascular administration (CL_F) and apparent volume of 
distribution following extravascular administration (V_F) will be estimated, and intra- 
and inter-subject variability of these parameters will be characterized. The effect of 
demographics/covariates (e.g., age, body weight, gender, race, use of concomitant 
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medications) on the pharmacokinetics of JTE-051 will be evaluated. Other PK parameters 
will be determined and reported as deemed appropriate.  
The relationship between exposure of JTE-051 and response (e.g., efficacy) may also be 
explored. Descriptive statistics of plasma concentration data for JTE-051 will be 
presented by treatment with N, arithmetic mean, geometric mean, SD, coefficient of 
variation (CV%), median, minimum and maximum. 
The population PK analysis results may be reported in a separate report. 
3.9. 
Quality Control and Quality Assurance 
This study will be conducted in compliance with the protocol, GCP as defined by the US 
Code of Federal Regulations (CFR) 21 parts 50, 56 and 312, Sponsor/designee policies 
and procedures and all applicable local and national regulations. 
The following steps will be taken to ensure the accuracy, consistency, completeness, and 
reliability of the data: 
a) Routine site monitoring; 
b) CRF review against source documents; 
c) Data management quality control checks; 
d) Statistical quality control checks; 
e) Continuous data acquisition and cleaning; and 
f) Quality control of final report. 
A representative from the Sponsor and/or authorized representatives may conduct 
periodic audits of the clinical sites and study processes, including, but not limited to, the 
clinical database and the final report. The study may also be subject to inspection by 
regulatory authorities. The Investigator hereby agrees to allow access to required subject 
records and other documentation and facilities related to the review and conduct of the 
study. 
4 
INVESTIGATOR OBLIGATIONS 
4.1. 
Institutional Review/Independent Ethics Committee  
An Investigator shall ensure that an IRB/IEC that complies with the requirements set 
forth in the US CFR 21 Part 56 or in the applicable local regulations for countries outside 
US, as applicable, will be responsible for the initial and continuing review and approval 
of the proposed clinical study. The Investigator shall also assure that he or she will 
promptly report to the IRB/IEC all changes in the research activity and all unanticipated 
problems involving risk to human subjects or others, and that he or she will not make any 
changes in the research without IRB/IEC approval, except where necessary to eliminate 
apparent immediate hazards to human subjects. 
All advertisements used in conjunction with this study must be reviewed and approved by 
the Sponsor or designee prior to use and the IRB/IEC, if applicable. The IRB/IEC’s 
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approval will be documented in writing and sent to the Investigator. The Investigator will 
forward a copy of the IRB/IEC approval document to the Sponsor or designee.  
The Investigator will not begin the study until the Sponsor or designee has authorized 
release of investigational drug product. 
Any amendments to the protocol must be approved in writing by the IRB/IEC prior to 
implementation by the Investigator. However, any change to the protocol to eliminate an 
apparent immediate hazard to the subjects may be implemented immediately, provided 
that the IRB is subsequently notified in accordance with the US 21 CFR Part 56.104 (c) 
or the applicable regulations in countries outside US. 
The Investigator will also provide the IRB/IEC with a current copy of the IB at the start of 
the study, as well as an updated version of each if revised during the study. 
A progress report will be submitted by the Investigator to the IRB/IEC at intervals 
established by the IRB/IEC. The Investigator will retain a copy of this report in the 
Investigator’s Documentation File. After completion or termination of the study, the 
Investigator will submit a final documentation to the IRB/IEC. A copy of all reports will 
be sent to the Sponsor or designee. 
4.2. 
Subject Consent 
In obtaining and documenting informed consent, the Investigator should comply with the 
applicable regulatory requirement(s), i.e., US 21 CFR Part 50 in the US and any 
applicable regulations in countries outside the US, and should adhere to GCP. Prior to the 
beginning of the trial, the Investigator should have the IRB/IEC written approval of the 
written informed consent form and any other written information to be provided to 
subjects. 
The written informed consent form and any other written information to be provided to 
subjects must be revised whenever important new information becomes available that 
may be relevant to the subject’s consent. Any revised written informed consent form, and 
written information must receive the IRB/IEC approval in advance of use. The subject or 
the subject’s legally acceptable representative must be informed in a timely manner if 
new information becomes available that may be relevant to the subject’s willingness to 
continue participation in the trial. The communication of this information should be 
documented. 
The Investigator, or a person designated by the Investigator, should fully inform the 
subject or, if the subject is unable to provide informed consent, the subject’s legally 
acceptable representative, of all pertinent aspects of the trial including the written 
information and the approval by the IRB/IEC. A copy shall be given to the person signing 
the form. 
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4.3. 
Data Collection 
It is the Investigator’s responsibility to ensure that data are collected and reported 
according to the study protocol. The Investigator will ensure the accuracy, completeness, 
and timeliness of the data reported on the CRF and in all required reports.  
Additionally, laboratory data may be received by Clinical Data Management from the 
appropriate clinical laboratory in electronic format. These data files may be merged with 
the clinical database. 
4.3.1. Case Report Forms 
Electronic CRFs will be produced according to protocol requirements, and access/training 
will be provided to the site in order for the research staff to record the data obtained on 
each subject during the study.  
The CRFs must be completed for each subject randomized in the study and will be 
reviewed by the Clinical Monitor and verified against source documents. The CRFs must 
be kept up-to-date so that they always reflect the latest observations on the subjects 
enrolled in the study. All records should be kept in conformance to applicable national 
and local laws and regulations. 
4.3.2. Source Documents 
It is the responsibility of the Investigator to collect and record all study data on source 
documents. The Investigator must provide access to source data/documents for 
study-related monitoring, audits, IRB/IEC review, and regulatory inspection. 
4.4. 
Adherence to Protocol 
By signing the Signature Page of this protocol, the Investigator confirms in writing that 
he/she has read, understands and will strictly adhere to the study protocol. This study will 
be conducted in accordance with GCP regulations. Additional information regarding 
management of protocol amendments can be found in Section 5.2. 
4.5. 
Reporting Adverse Events 
For details regarding AE and SAE reporting, see Section 3.6.3. 
4.6. 
Investigator’s Final Report 
Upon completion of the study, the Investigator will provide the Sponsor or designee with 
a copy of the summary of the study’s outcome provided to the IRB/IEC. 
4.7. 
Records Retention 
An Investigator is required to maintain adequate records of the disposition of the drug, 
including dates, quantity, and use by subjects. When the investigation is terminated, 
suspended, discontinued, or completed, the Investigator shall return the unused supplies 
of the drug to the sponsor, or otherwise provide for disposition of the unused supplies of 
the drug under the US 21 CFR Part 312.59 and all applicable local regulations. 
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An Investigator shall retain records required to be maintained under this part for a period 
of two years following the date a marketing application is approved for the drug for the 
indication for which it is being investigated; or, if no application is to be filed or if the 
application is not approved for such indication, until two years after the investigation is 
discontinued and the FDA is notified. 
The Sponsor or designee should inform the Investigator(s)/institution(s) in writing of the 
need for record retention and should notify the Investigator(s)/institution(s) in writing 
when the trial related records are no longer needed. 
Custody of the records may be transferred to another responsible party, acceptable to the 
Sponsor, who agrees to abide by the retention policies. Written notice of transfer must be 
submitted to the Sponsor or designee. The Investigator must contact, and obtain the prior 
written permission of the Sponsor prior to disposing of or transferring any study records. 
4.8. 
Confidentiality 
The Investigator, Medical Monitor, the Sponsor, and its representatives, agree to protect 
the privacy and confidentiality of the protected health information in accordance with 
applicable laws and regulations.  
Subject medical information obtained by the study is confidential and disclosure to third 
parties other than those noted below is prohibited unless required by law. The Investigator 
shall retain all such information, and any other information designated by the Sponsor as 
confidential, or is otherwise of reasonably confidential nature, in confidence and shall not 
use such information for any purpose other than the performance of obligations pursuant 
to the agreement with the Sponsor and designated affiliates or contractors, as the case 
may be, without prior written authorization from the Sponsor. 
At the subject’s request, medical information may be given to his or her personal 
physician or other appropriate medical personnel responsible for his or her welfare. 
Data generated by this study must be available for inspection on request by 
representatives of regulatory authorities, the Sponsor or designee, and the IRB(s)/IEC(s) 
if appropriate. 
4.9. 
 Publications 
The Investigator agrees that all data, calculations, interpretations, opinions and 
recommendations regarding the study shall be the sole and exclusive property of the 
Sponsor, and that the Sponsor may make any use thereof at its discretion without 
obligation to Investigator. The Investigator agrees to consider the results as information 
subject to confidential and use restrictions. 
In the event that the study results are published in the scientific literature by the Sponsor, 
acknowledgment will be made to the Investigator(s) in the accepted style, as appropriate. 
The names of the Investigators or their representatives shall not be used by the Sponsor in 
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publications, for advertising, for other commercial purposes, or otherwise, without 
appropriate written permission, unless required by law or government regulation. 
Individual study center manuscript(s) for publication, text for talks, abstracts of papers, 
poster presentations, and similar material will be submitted to the Sponsor for review and 
comment prior to publication or disclosure. In order to ensure that the Sponsor will be 
able to make comments and suggestions where pertinent, material for public 
dissemination will be submitted to the Sponsor for review at least sixty (60) days prior to 
submission for publication, public dissemination, or review by a third party committee. 
The Sponsor will have sixty (60) days from receipt of such information to review and 
comment on and discuss the contents thereof with the Investigator. If the Sponsor 
requests, the Investigator will remove any and all confidential information (other than 
study results) prior to submitting or presenting the materials. Upon the Sponsor’s request, 
the Investigator will delay submitting or presenting the materials for a further sixty (60) 
days to permit the Sponsor to take necessary actions to protect its confidential 
information, including the filing of patent applications thereon. 
5 
STUDY MANAGEMENT  
5.1. 
Monitoring 
Monitoring visits will be conducted by the Sponsor or designee according to applicable 
regulations and guidelines for GCP. The Investigator will permit the Sponsor and/or 
designated representative(s) to make regular site visits during the study. The frequency of 
monitoring visits will be agreed upon by the Sponsor and/or designee. At each visit, the 
Investigator and staff will be expected to cooperate with the Sponsor or designee for the 
review and verification of protocol compliance, AE reporting, CRFs, source documents, 
clinical supplies and inventory records, and any additional records as may have been 
previously arranged between the Investigator and Akros or designated representative(s). 
The Investigator and/or other designated study personnel are expected to contact the 
monitor of the Sponsor or designee as needed regarding study concerns and/or questions. 
5.2. 
Management of Protocol Amendments and Deviations 
With the exception of emergency situations, implementation of any change in the 
protocol that affects the safety of the subjects, the scope of the investigation, or the 
scientific quality of the study will not be permitted until the Sponsor and the Investigator 
have approved the protocol amendment and the IRB/IEC responsible for review and 
approval of the study has reviewed and approved the protocol change. 
Implementation of changes that do not affect the safety of the subjects, the scope of the 
investigation, or the scientific quality of the study cannot be made until the protocol 
changes are reviewed and approved by Akros and the Investigator. The IRB/IEC must be 
notified of these protocol changes. 
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The Investigator will not deviate from the protocol without prior written approval from 
the Sponsor or designee. 
5.3. 
Study Termination 
The study may be terminated at any time at the request of the Sponsor or the Investigator 
with proper and timely notification of all parties concerned. The IRB/IEC will be 
informed promptly and reasons for the termination or suspension will be provided by the 
Investigator, as specified by the applicable regulatory requirements. The study can be 
considered complete and/or terminated after the Sponsor or designee has received the 
following data and materials: 
• Laboratory findings, clinical data, and all special test results from screening through 
the end of the follow-up 
• CRFs properly completed by appropriate study personnel (including correctly 
answered and closed system or manually-generated edit checks) and signed by the 
Investigator 
• Completed Drug Accountability Records 
• Statement of outcome for each SAE reported 
• Approval/notification of protocols and protocol amendments from IRB/IEC as well as 
relevant health authorities (if applicable) 
5.4. 
Sponsor’s Final Report 
A final report will be prepared by the Sponsor or a designee at the conclusion of this 
clinical study. 
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6 
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8. Maini R, St Clair EW, Breedveld F, Furst D, Kalden J, Weisman M, et al. Infliximab 
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rheumatoid arthritis patients receiving concomitant methotrexate: a randomised phase 
III trial. ATTRACT Study Group. Lancet. 1999 Dec 4;(354):1932-9. 
9. Klareskog L, van der Heijde D, de Jager JP, Gough A, Kalden J, Malaise M, et al. 
Therapeutic effect of the combination of etanercept and methotrexate compared with 
each treatment alone in patients with rheumatoid arthritis: double-blind randomised 
controlled trial. Lancet. 2004 Feb 28;(363):675-81. 
10. Weinblatt ME, Keystone EC, Furst DE, Moreland LW, Weisman MH, Birbara CA, 
et al. Adalimumab, a fully human anti-tumor necrosis factor alpha monoclonal 
antibody, for the treatment of rheumatoid arthritis in patients taking concomitant 
methotrexate: the ARMADA trial. Arthritis Rheum. 2003 Jan;(48):35-45. 
11. Maini RN, Taylor PC, Szechinski J, Pavelka K, Broll J, Balint G, et al. Double-blind 
randomized controlled clinical trial of the interleukin-6 receptor antagonist, 
tocilizumab, in European patients with rheumatoid arthritis who had an incomplete 
response to methotrexate. Arthritis Rheum. 2006 Sep;(54):2817-29. 
12. Sahu N, August A. ITK inhibitors in inflammation and immune-mediated disorders. 
Cur Top Med Chem. 2009;(9):690-703. 
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13. Liao XC, Littman DR. Altered T cell receptor signaling and disrupted T cell 
development in mice lacking Itk. Immunity. 1995 Dec;(3):757-69. 
14. Mueller C, August A. Attenuation of immunological symptoms of allergic asthma in 
mice lacking the tyrosine kinase ITK. J Immunol. 2003 May 15;170:5056-63. 
 
 
23. Aletaha D, Neogi T, Silman AJ, Funovitis J, Felson DT, Bingham CO, et al. 2010 
Rheumatoid 
Arthritis 
Classification 
Criteria. 
An 
American 
College 
of 
Rheumatology/European League Against Rheumatism Collaborative Initiative. 
Arthritis Rheum. 2010 Sep;(62.9):2569-81. 
24. Yancy CW, Jessup M, Bozkurt B, Butler J, Casey DE Jr, Drazner MH, et al. 2013 
ACCF/AHA Guideline for the Management of Heart Failure: Executive Summary: A 
Report of the American College of Cardiology Foundation/American Heart 
Association 
Task 
Force 
on 
Practice 
Guidelines. 
J 
Am 
Coll 
Cardiol. 
2013; (62):1495-539. 
25. U.S. Department of Health and Human Services. National Institutes of Health. 
National Cancer Institute. Common Terminology Criteria for Adverse Events 
(CTCAE) Version 4.0. 2009 May 28 (v4.03: 2010 June 14). 
26. Burmester GR, Weinblatt ME, McInnes IB, Porter D, Barbarash O, Vatutin M, et al. 
Efficacy and safety of mavrilimumab in subjects with rheumatoid arthritis. 
Ann Rheum Dis. 2013;(72):1445-52. 
27. Agresti A, Categorical Data Analysis. Second Edition. 2012 Dec 03. 
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28. Newcombe RG, Interval Estimation for the Difference between Independent 
Proportions: 
Comparison 
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Eleven 
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Medicine. 
1998;(17):873-90. 
29. DAS-score.nl: Disease activity score in rheumatoid arthritis. Available online at: 
http://www.das28.nl/.  
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7 
APPENDICES 
 
Appendix 1.  ACR/EULAR 2010 Classification Criteria for Rheumatoid   
 
 
 
Arthritis 
Appendix 3.  Numeric Rating Scale Templates 
Appendix 4. 
The Stanford Health Assessment Questionnaire© 
Appendix 5.  Efficacy Endpoints Calculation 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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Appendix 1. ACR/EULAR Classification Criteria for Rheumatoid Arthritis 
JOINT DISTRIBUTION (0-5) 
1 large joint 
0 
2-10 large joints  
1 
1-3 small joints (large joints not counted) 
2 
4-10 small joints (large joints not counted) 
3 
>10 joints (at least one small joint) 
5 
SEROLOGY (0-3) 
Negative RF AND negative Anti–citrullinated protein (ACPA) 
0 
Low positive RF OR low positive ACPA 
2 
High positive RF OR high positive ACPA 
3 
SYMPTOMS DURATION (0-1) 
<6 weeks 
0 
≥6 weeks 
1 
ACUTE PHASE REACTANTS (0-1) 
Normal CRP AND normal Erythrocyte Sedimentation Rate 
0 
Abormal CRP AND abnormal Erythrocyte Sedimentation 
Rate 
1 
If the cumulative score is ≥6 = definite RA; when the score is <6 a patient might fulfill 
the criteria (a) prospectively over time (cumulatively) or (b) retrospectively is data on all 
four domains have been adequately recorder in the past. 
Notes:  
• These are “classification”, not “diagnostic” criteria; the diagnosis is made by the 
rheumatologist.  
• The target population for the criteria must meet the following two requirements: 
o Patient with at least one joint with definite clinical synovitis (swelling) 
o Synovitis is not better explained by another disease 
See reference 23 for additional details pertaining to these classification criteria.  
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Appendix 3. Numeric Rating Scale Templates 
SUBJECT PAIN ASSESSMENT NRS TEMPLATE 
 
 
 
SUBJECT GLOBAL ASSESSMENT OF DISEASE ACTIVITY NRS TEMPLATE 
 
 
 
PHYSICIAN’S GLOBAL ASSESSMENT OF DISEASE ACTIVITY NRS 
TEMPLATE 
 
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Appendix 4. Health Assessment Questionnaire 
  
 
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Handling Responses (by the Investigator) 
For each question in the questionnaire, the level of difficulty is scored from 0 to 3 with 0 
for “Without ANY difficulty,” 1 for “With SOME difficulty,” 2 for “With MUCH 
difficulty,” and 3 for “UNABLE to do”. 
• The HAQ-DI questionnaire should be completed by the study subject, following 
receipt of detailed instructions from the Investigator/study staff. After the subject 
completes the questionnaire and prior to the subject leaving the study site, the study 
staff should perform a detailed review of the answers, discuss why any questions 
were not answered, and what was intended when answers were marked outside the 
box or more than one box was marked for a question. 
• Each subject should answer the questions according to his/her personal situation. 
Thus, the ratings, “Without ANY difficulty”, “With SOME difficulty”, “With 
MUCH difficulty”, and “UNABLE to do”, are deliberately not defined for subjects. 
For example, if a subject asks what “SOME” means, an appropriate response would 
be “Whatever you think ‘SOME’ means to you”. 
• When a sub-category item does not apply, e.g., when a subject does not use shampoo 
(or perhaps has no hair), the subject should give the response that represents the 
ability the subject believes he/she would have had in attempting the activity. 
• When a subject uses aids or devices (e.g., crutches, jar openers), the subject should 
answer the question based on the usual equipment or way of performing the activity. 
If the subject has no difficulty doing an activity when using aids/devices, the subject 
should mark the “Without ANY difficulty” option. In scoring, the use of aids/devices 
results in an adjusted score for that item. 
• Notes about Aids/Devices: The assignment of devices to particular disability 
categories assumes that the devices are used only for their intended purposes as 
shown in Table 2 below. For example, when a subject indicates use of a cane, it is 
presumed that the cane is used as an aid in walking. 
  If the subject informs the Investigator/site personnel that a device listed is being 
used for a different activity other than those shown in Table 2, (e.g., a cane is 
used for getting up from bed but not walking), or if a different device, not listed 
on the HAQ-DI form is utilized by the subject, then the Investigator must 
confirm for which activity category the specific device is utilized and a device 
from the list that is specific for that same activity category should be checked. 
This may be a different device than the one actually used (e.g., “built up or 
special chair” should be checked instead of “cane” in this example). 
  If a device is used for any activity in the “ACTIVITIES” category, as listed on 
Page 4 of the HAQ-DI questionnaire, only the “Errands and chores” under 
“HELP FROM ANOTHER PERSON” should be checked (i.e., none of the AIDS 
and DEVICES listed on Page 4 should be checked). This will ensure the 
appropriate adjustment to the score for the "ACTIVITY" category (this is done 
programmatically). 
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• Items left blank or multiple answers: If all component questions are blank or if 
more than one answer is given, then follow-up with the subject at the time of the 
visit is required. 
• Improperly Marked Items: If the subject’s mark is outside the answer box, then 
move it to the closest one. If it’s directly between the two, move it to the answer with 
greater difficulty. However, follow-up with the subject and confirmation of intended 
answer should be done at the time of the visit, and all items should be marked 
appropriately before the subject leaves the study center. 
NOTE: A HAQ-DI score cannot be calculated validly when there are scores for 
less than six of the eight categories. 
Scoring (performed by the Sponsor) 
The HAQ-DI’s scoring conventions allow for the computation of two disability indices: 
1. The Standard HAQ-DI is the preferred and traditional scoring method which takes into 
account the use of aids/devices. 
2. The Alternative Disability Index does not take into account the use of aids/devices. 
A subject must have a score for at least six of the eight categories. Otherwise a HAQ-DI 
score cannot be validly computed. For the purpose of the current study, the standard 
computing method will be applied. 
Computing the Standard HAQ-DI Score (With Aids/Devices): There are three steps: 
1. Sum the 8 category scores by using the highest sub-category score from each 
category (for example, in the category “EATING” there are three sub-category 
items. If a subject responds with a 1, 2, and 0, respectively; the category score is 2). 
2. Adjust for use of aids/devices and/or help from another person when indicated. 
Table 2 identifies the Aid/Devices companion variable for each HAQ-DI category. 
Table 2. 
Companion Aids/Device Items for HAQ-DI Categories 
HAQ-DI Category 
 
Companion Item 
Dressing & Grooming 
Devices used for dressing  
Arising 
Built up or special chair 
Eating 
Built up or special utensils 
Walking 
Cane walker, crutches, wheelchair 
Hygiene 
Raised toilet seat, bathtub seat, bathtub bar 
Long handled appliances in bathroom 
Reach 
Long handled appliances for reach 
Grip 
Jar opener (for jars previously opened) 
• Adjust the score for a category by increasing a zero or a one to a two. 
• If a subject's highest score for that sub-category is a two it remains a two, 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 (3=worst functioning). 
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Appendix 5. Efficacy Endpoints Calculation 
Numeric ACR (ACR-N) Index 
The ACR-N will be derived by the Sponsor for Visits 3 through 7 based on the ACR core 
set measures collected by the Investigator. See Section 3.5.6.1 for the description of the 
ACR core set measures assessments by the Investigator. 
This is a continuous variable expressing the percentage improvement from baseline a 
subject has experienced, defined as the minimum of percent improvement in swollen 
joints, tender joints and the median percent change in the other five ACR core set 
measures: 
1. Subject’s Assessment of Arthritis Pain. 
2. Subject’s Global Assessment of Disease Activity. 
3. Physician’s Global Assessment of Disease Activity.  
4. Health Assessment Questionnaire Disability Index (HAQ-DI) 
5. Acute phase reactant (hs-CRP) 
Thus, and ACR-N of X means that the subject has achieved a change of at least X% in the 
tender and swollen joint counts and a change of at least X% in the median of the other 
five other parameters. ACR-N will take a negative value if a there is a worsening in either 
the swollen joint count, tender joint count and the median of the other five ACR core set 
measures (i.e., a subject can have a negative ACR-N despite improving in two of the 
three components). 
The ACR20/50/70 Response Rate 
The ACR20/50/70 response rate will be calculated by the Sponsor for Visits 3 through 7 
based on the ACR core set measures collected by the Investigator.  
This composite parameter measures improvement in tender (68) and swollen (66) joint 
counts and improvement in at least three of the following five ACR core set measures as 
listed above. 
The ACR20/50/70 response rate is a dichotomous variable with a positive (= responder) 
or negative (= non-responder) outcome.  
 
ACR20 is ≥20% improvement 
 
ACR50 is ≥50% improvement 
 
ACR70 is ≥70% improvement  
 
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Simple Disease Activity Index 
The SDAI will be calculated by the Sponsor for all study visits. See Section 3.5.6.1.2 for 
the list of 28 joints included in the SDAI scoring. 
The scoring of SDAI will be done as follows: 
 
 
 
 
 
  
 
Interpretation of scoring will be done as follows: 
 
Clinical Disease Activity Index 
The CDAI will be calculated by the Sponsor for all study visits. See Section 3.5.6.1.2 for 
the list of 28 joints included in the CDAI scoring. 
The scoring of CDAI will be done as follows: 
 
 
 
 
 
 
 
Interpretation of scoring will be done as follows: 
 
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Disease Activity Score (DAS) 2829 
The DAS assessment is a derived measurement with differential weighting given to each 
component. The DAS 28 (CRP) will be calculated by the Sponsor at all study visits. See 
Section 3.5.6.1.2 for the list of 28 joints included in the DAS calculation. 
The components of the DAS 28 arthritis assessment include: 
1. Tender/Painful Joint Count (28) 
2. Swollen Joint Count (28) 
3. CRP 
4. Subject’s Global Assessment of Disease Activity 
DAS28(CRP) = 0.56 X √(TJC28) + 0.28 X √(SJC28) + 0.36 X Ln(CRP+1) + 0.014 X 
SGA + 0.96 
Percentage of Subject achieving Boolean Remission 
This secondary efficacy parameter will be calculated by the Sponsor, based on the 
following definition: 
• 
Tender joint count (TJC) (28) ≤1 
• 
Swollen joint count (SJC) (28) ≤1 
• 
C-reactive protein ≤1 mg/dL  
• 
Subject’s global assessment (SGA) of disease activity ≤1 (on a 0 - 10 scale) 
EULAR Response Criteria 
The EULAR response criteria will be assessed by the Sponsor. 
This parameter takes into account both the change in DAS28 between two timepoints, as 
well as DAS28 value at a specific timepoint. 
DAS28-CRP will be utilized in calculating the EULAR response in the study subjects.  
DAS28 improvement →
>1.2 
>0.6 and ≤1.2 
≤0.6 
Present DAS28↓ 
≤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 
 
Note: High-sensitivity CRP (hs-CRP) will be utilized in all primary and secondary 
endpoints calculations 
   
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